Accd e Book

Contraception and
Fertility Control in
Dogs and Cats
A Report of the Alliance for
Contraception in Cats & Dogs (ACC&D)
February 2013
© 2013. All rights

Contraception reserved.
and Fertility Control in Dogs and Cats 1
Table Of Contents
Dedication.......................................................................................................................................... 8
Preface................................................................................................................................................ 9
1.0 Introduction............................................................................................................................ 11
1.1 Scope of the Report...................................................................................................................... 11
1.2 Brief Review of the Historical Context of Contraception and
Fertility Control Research in Animals............................................................................................ 11
1.3 Targets and Historical Approaches to Non-Surgical Sterilization in Dogs and Cats..................... 12
1.4 Considerations for Commercializable Approaches to Non-Surgical Contraceptive Methods....... 16
2.0 The Physiology of Reproductive Control in Mammals –

Overview of the Major Systems that Control Reproduction.............................................. 17
2.1 Brain.............................................................................................................................................. 17
2.2 Pituitary........................................................................................................................................ 17
2.3 Gonads (Ovaries and Testes)......................................................................................................... 17
2.4 Unique Aspects of Canine and Feline Reproductive Biology.......................................................... 17
3.0 Overview of Technological Approaches and Their Applications in Dogs and Cats.......... 19
3.1 Surgical Approaches...................................................................................................................... 19
3.1.1 Overview................................................................................................................................................. 19
3.1.2 Surgical Methodologies........................................................................................................................... 22
3.1.2.1 Females.......................................................................................................................................... 22
3.1.2.2 Males............................................................................................................................................. 22
3.2 Gonadotropin-Releasing Hormone (GnRH)..................................................................................... 23

3.2.1 Overview of GnRH Agonists........................................................................................................................ 23
3.2.1.1 Deslorelin.............................................................................................................................................. 24
3.2.1.1.1 Deslorelin in Dogs – Males................................................................................................................ 24
3.2.1.1.2 Deslorelin in Dogs – Females........................................................................................................... 25
3.2.1.1.3 Deslorelin in Cats – Toms................................................................................................................ 26
3.2.1.1.4 Deslorelin in Cats – Queens............................................................................................................. 27
3.2.1.1.5 Recently Reported Research Involving the Use of Deslorelin for Contraception.................................. 28
3.2.1.2 Nafarelin............................................................................................................................................... 29
3.2.1.2.1 Nafarelin in Dogs............................................................................................................................ 29
3.2.1.2.2 Nafarelin in Cats............................................................................................................................. 30
3.2.1.3 Other GnRH Agonists............................................................................................................................. 30
3.2.1.4 GnRH Agonists: Summary of Advantages and Disadvantages................................................................... 30
3.2.2 Overview of GnRH Antagonists................................................................................................................... 31
3.2.2.1 GnRH Antagonist Peptides...................................................................................................................... 31
3.2.2.2 Non-Peptide GnRH Antagonists.............................................................................................................. 32
3.2.2.3 GnRH Antagonist in Dogs....................................................................................................................... 32
3.2.2.3.1 Males............................................................................................................................................... 32
3.2.2.3.2 Females............................................................................................................................................ 33
Contraception and Fertility Control in Dogs and Cats 2
3.2.2.4 GnRH Antagonists in Cats............................................................................................................... 33
3.2.2.5 GnRH Antagonists: Summary of Advantages and Disadvantages....................................................... 34
3.2.3 Overview of GnRH-Toxin Conjugates........................................................................................................ 35
3.2.3.1 GnRH-Protein Synthesis Inhibitor Conjugate.................................................................................... 35
3.2.4 Overview of GnRH Vaccines..................................................................................................................... 36
3.2.4.1 GnRH Vaccines in Dogs.................................................................................................................. 38
3.2.4.2 GnRH Vaccines in Cats.................................................................................................................... 40
3.2.4.3 GnRH Vaccines: Summary of Advantages and Disadvantages............................................................ 42
3.3 Other Vaccine Approaches................................................................................................................. 43

3.3.1 Zona Pellucida (ZP) and Egg and Sperm Vaccines...................................................................................... 43
3.3.1.1 Overview........................................................................................................................................ 43
3.3.1.2 ZP Vaccines..................................................................................................................................... 43
3.3.1.2.1 ZP in Dogs................................................................................................................................. 44
3.3.1.2.2 ZP in Cats.................................................................................................................................. 45
3.3.1.2.3 ZP Vaccines: Summary of Advantages and Disadvantages............................................................ 47
3.3.1.3 Vaccination against Egg and Sperm Proteins......................................................................................... 47
3.3.1.3.1 Vaccination against Egg Proteins................................................................................................ 47
3.3.1.3.2 Vaccination against Sperm Proteins............................................................................................ 48
3.3.1.3.3 Egg and Sperm Proteins: Summary of Advantages and Disadvantages......................................... 49
3.3.2 Luteinizing Hormone (LH) Receptor Vaccines............................................................................................ 49
3.3.2.1 LH Receptor Vaccines: Summary of Advantages and Disadvantages.................................................. 49
3.4 Chemical Sterilants............................................................................................................................ 50
3.4.1 Zinc Gluconate............................................................................................................................................ 50
3.4.1.1 Zinc Gluconate in Dogs................................................................................................................... 51
3.4.1.2 Zinc Gluconate in Cats.................................................................................................................... 52
3.4.2 Calcium Chloride..................................................................................................................................... 52
3.4.2.1 Calcium Chloride in Dogs................................................................................................................ 52
3.4.2.2 Calcium Chloride in Cats................................................................................................................. 53
3.4.3 Chlorhexidine Digluconate.......................................................................................................................... 53
3.4.4 Vinylcyclohexene Diepoxide..................................................................................................................... 54
3.4.5 Hypertonic Saline..................................................................................................................................... 54
3.4.6 Chemical Sterilants: Summary of Advantages and Disadvantages.............................................................. 55
3.5 Sex Steroids.................................................................................................................................. 55

3.5.1 Progestins............................................................................................................................................... 55
3.5.1.1 Bitches and Queens........................................................................................................................ 56
3.5.1.2 Male Dogs and Cats........................................................................................................................ 57
3.5.2 Androgens.............................................................................................................................................. 57
3.5.3 Anti-Androgens, Anti-Estrogens and Aromatase Inhibitors........................................................................ 58
3.5.4 Progestational and Androgenic Drugs: Summary of Advantages and Disadvantages.................................. 58

3.6 Miscellaneous Research of Interest.............................................................................................. 58
3.6.1 Gene Silencing........................................................................................................................................ 58
3.6.2 Kisspeptin and Gonadotropin-Inhibitory Hormone (GnIH)......................................................................... 59
3.6.3 Egg Proteins and Peptides....................................................................................................................... 59
3.6.4 Targeted Delivery of Cytotoxins................................................................................................................ 61
3.6.4.1 Single-Dose Non-Hormonal Male and Female Sterilant..................................................................... 61
3.6.4.2 FSH Receptor Ligand-Cytotoxin Conjugates..................................................................................... 61
3.6.4.3 Reversible Inhibition of Sperm under Guidance (RISUG)................................................................... 61
3.6.5 Retinoic Acid Receptor Antagonists.......................................................................................................... 62
3.6.6 Sperm Protein Reactive with Antisperm Antibodies (SPRASA).................................................................... 62
4.0 Overview of Companies, Organizations, Institutions, and Agencies Involved

in Researching or Developing Approaches to Non-Surgical Contraception
in Dogs and Cats...................................................................................................... 63
4.1 Setting the Framework: Overview of Existing Non-Surgical Products......................................... 63
4.2 Companies.................................................................................................................................... 64
4.2.1 Major Animal Health Companies.............................................................................................................. 64
4.2.1.1 Historical Involvement..................................................................................................................... 65
4.2.1.2 Virbac Acquisition of Peptech Animal Health (Suprelorin).................................................................. 66
4.2.2 Smaller Companies.................................................................................................................................. 66
4.2.3 Update on Entities Profiled in the 2002 Report......................................................................................... 66
4.2.4 Companies Currently or Recently Involved in Non-Surgical Contraception and Fertility
Control for Dogs and/or Cats................................................................................................................... 69
4.2.4.1 Amplicon Vaccine, LLC, Pullman, WA................................................................................................ 69
4.2.4.2 Ark Sciences, Inc., New York, NY...................................................................................................... 69
4.2.4.3 Crinetics Pharmaceuticals, Inc., San Diego, CA................................................................................. 69
4.2.4.4 FeralStat, Old Lyme, CT.................................................................................................................... 69
4.2.4.5 Rhobifarma Industria Farmaceutica Ltda, Brazil................................................................................ 70
4.2.4.6 SenesTech, Inc., Flagstaff, AZ........................................................................................................... 70
4.2.4.7 Vaxin, Inc., Birmingham, AL............................................................................................................. 71
4.3 Research: Organizations and Foundations, Government Agencies, and Academic and
Research Institutions.................................................................................................................... 71
4.3.1 Update on Research Described in the 2002 Report................................................................................... 72
4.3.2 Universities Working on Non-Surgical Approaches.................................................................................... 75
4.3.3 Organizations and Foundations................................................................................................................ 77
4.3.3.1 Alliance for Contraception in Cats & Dogs, Portland, OR................................................................... 78
4.3.3.1.1 ACC&D Symposia....................................................................................................................... 78
4.3.3.1.2 ACC&D Think Tanks.................................................................................................................... 78
4.3.3.1.3 ACC&D-Sponsored Studies......................................................................................................... 79
4.3.3.2 Found Animals Foundation/Michelson Prize & Grants in Reproductive Biology, Los Angeles, CA......... 79
4.3.3.3 Morris Animal Foundation, Denver, CO............................................................................................. 82
4.3.3.4 Parsemus Foundation, San Francisco, CA.......................................................................................... 83
4.3.3.5 600 Million Stray Dogs Need You, Pompano Beach, FL..................................................................... 83

4.3.4 Government............................................................................................................................................ 84
4.3.4.1 United States Department of Agriculture National Wildlife Research Center, Fort Collins, CO............. 84
4.3.4.2 United States Centers for Disease Control and Prevention, Atlanta, GA............................................. 84
4.3.4.3 Cooperative Research Centres, Australia.......................................................................................... 85
4.3.4.4 AFSSA Nancy, Wildlife Health and Management Unit, Malzéville, France........................................... 85
4.3.4.5 Food and Environment Research Agency, United Kingdom................................................................ 85
4.3.4.6 The AZA Wildlife Contraception Center, St. Louis, MO....................................................................... 86
5.0 Marketing Overview and Issues.................................................................................. 87

5.1 Overview............................................................................................................................................ 87
5.2 “Owned” Dogs and Cats..................................................................................................................... 89
5.2.1 Population and Spending Estimates......................................................................................................... 90
5.2.1.1 North America................................................................................................................................ 90
5.2.1.1.1 United States............................................................................................................................. 90
5.2.1.1.2 Canada..................................................................................................................................... 94
5.2.1.2 Outside of North America............................................................................................................... 94
5.2.1.2.1 Europe....................................................................................................................................... 94
5.2.1.2.1.1 United Kingdom.................................................................................................................... 95
5.2.1.2.1.2 France................................................................................................................................... 95
5.2.1.2.1.3 Germany............................................................................................................................... 95
5.2.1.3 Cat and Dog Populations vis-a-vis Human Populations: Europe and US............................................ 96
5.2.1.4 Other Areas................................................................................................................................... 97
5.2.1.4.1 Australia.................................................................................................................................... 97
5.2.1.4.2 Asia (Japan and China).............................................................................................................. 97
5.2.1.4.2.1 Japan.................................................................................................................................... 97
5.2.1.4.2.2 China.................................................................................................................................... 98
5.2.1.4.3 Latin America............................................................................................................................. 98
5.2.2 Dynamics of the Spay/Neuter Decision......................................................................................................... 99
5.2.2.1 Summary of Pros and Cons of Spay or Castration in Dogs and Cats.................................................. 99
5.2.2.2 What Drives Owners’ Decisions and What Are Some Statistics?...................................................... 100
5.2.2.2.1 In the United States................................................................................................................. 100
5.2.2.2.1.1 Legislation.......................................................................................................................... 104
Sidebar: Estimated Size of the US Market for Sterilization of Dogs and Cats............................................ 104
5.2.2.2.1.2 Economic/Price Sensitivity.................................................................................................... 105
5.2.2.2.2 Outside the United States......................................................................................................... 105
5.2.2.3 A Sample of Spay/Neuter Costs..................................................................................................... 108
5.3 Show Animal Owners and Dog and Cat Breeders............................................................................. 112
5.4 “Unowned” Dogs and Cats............................................................................................................... 112
5.4.1 Dealing with “Free-Roaming” Animals....................................................................................................... 116
5.4.1.1 A Look at Methods of Dealing with Free-Roaming Dogs...................................................................... 116
5.4.1.2 A Look at Methods of Dealing with Free-Roaming Cats....................................................................... 117

5.4.1.3 Advocacy and Population Management Projects Utilizing Non-Surgical Methodology: Lessons Learned.119
5.5 “Shelters”......................................................................................................................................... 121

5.6 How Do Practicing and Shelter Veterinarians Feel about Pet Sterilization and Potential
Non-Surgical Approaches?................................................................................................................ 123
5.6.1 Private Practice Veterinarians................................................................................................................. 123
5.6.2 Shelter Veterinarians.............................................................................................................................. 124
5.6.3 Key Messages from the Surveys............................................................................................................. 124
5.6.4 Other Issues Veterinarians Can Be Expected to Consider......................................................................... 125
5.7 Owner Willingness to Pay for a Non-Surgical Alternative.......................................................... 125

5.8 The “Ideal” Product................................................................................................................... 126
5.8.1 An Initiative to Develop a Single, Permanent, Non-Surgical Sterilant for Male and Female Dogs and Cats.... 127
5.9 Commercializing, Manufacturing, and Marketing Products Profitably............................................ 128
5.10 Marketing Issues in Cats and Dogs: the Bottom Line.................................................................... 128
5.10.1 Issues that Affect Marketing of Contraception and Fertility Control for Dogs and Cats............................... 129
6.0 Regulatory Issues: Some Considerations for Evaluating Contraceptives

for Dogs and Cats....................................................................................................... 130
6.1 United States Regulatory Agencies............................................................................................................... 130
6.2 European Regulatory Agency........................................................................................................................ 131
6.3 Rest of World............................................................................................................................................... 132
6.4 General Considerations and Harmonization Efforts....................................................................................... 132
6.5 Time Frame for Regulatory Approval.............................................................................................................. 132
6.6 Effectiveness................................................................................................................................................ 133
6.7 Target Animal Safety.................................................................................................................................... 134
6.8 Human Safety.............................................................................................................................................. 134
6.9 Environmental Assessment........................................................................................................................... 135
6.10 Manufacturing........................................................................................................................................... 135
6.11 Conclusions............................................................................................................................................... 136
Glossary............................................................................................................................. 137
Guide to Acronyms........................................................................................................... 139
Bibliography...................................................................................................................... 141
Websites............................................................................................................................ 152
Trademarks and Registered Trademarks......................................................................... 154

Tables
Table 1-1: Summary of Characteristics Required for Commercialization.................................................................. 16
Table 3-1: Pros and Cons of Gonadectomy in Dogs and Cats................................................................................. 20
Table 3-2: Use of Deslorelin for Contraception in Cats and/or Dogs....................................................................... 28
Table 4-1: Entities Profiled in the 2002 Report...................................................................................................... 66
Table 4-2: Research Profiled in the 2002 Report................................................................................................... 72
Table 4-3: Universities Involved in Researching Non-Surgical Approaches to Dog and Cat
Contraception/Sterilization................................................................................................................... 75
Table 4-4: Michelson Grants in Reproductive Biology............................................................................................ 81
Table 4-5: Animal Foundation Dog and Cat Over population Projects..................................................................... 82
Table 5-1: Overview of US Pet Dog Population...................................................................................................... 90
Table 5-2: Overview of US Pet Cat Population....................................................................................................... 90
Table 5-3: Miscellaneous Statistics........................................................................................................................ 91
Table 5-4: Sources of Pet Dogs and Cats............................................................................................................... 92
Table 5-5: Pet Owner Expenditures....................................................................................................................... 93
Table 5-6: Overview of Dog and Cat Ownership in Canada................................................................................... 94
Table 5-7: Age Breakdown of Canadian Dogs....................................................................................................... 94
Table 5-8: Annual Estimated Cost of Care (CA$)................................................................................................... 94
Table 5-9: Top 10 European Countries: Dog and Cat Populations 2010.................................................................. 95
Table 5-10: Dogs/Person and People/Dog and Cats/Person and People/Cat in the Top 10
European Countries and the US.......................................................................................................... 96
Table 5-11. Overview of Consumer Expenditure on Pets in Australia in 2009......................................................... 97
Table 5-12: Reasons Japanese Dog Owners Have Dogs (2004).............................................................................. 97
Table 5-13: Summary of Reasons Pet Owners Have Not Spayed or Neutered Their Dogs and Cats
in the US (2000 Ralston Purina Study).............................................................................................. 101
Table 5-14: Potential Acceptance of a Non-Surgical Alternative to Spay/Neuter.................................................... 102
Table 5-15: Reasons Pet Owners Have Had Their Dogs or Cats Spayed or Neutered in the US............................... 103
Table 5-16: Dog Populations in European Countries and Rates of Spay/Neuter.................................................... 107
Table 5-17: Examples of Spay/Neuter Costs (Non-Subsidized).............................................................................. 108
Table 5-18: Examples of Subsidized or Low-Cost Spay/Neuter Services in the US................................................. 109
Table 5-19: Spay/Neuter Costs in Non-US Markets (US$)..................................................................................... 111
Table 5-20: Spay/Neuter Costs in the Philippines................................................................................................. 111
Table 5-21: Spay/Neuter Costs in Thailand.......................................................................................................... 112
Table 5-22: Classification of Dogs and Cats by Their Dependence on Humans...................................................... 114
Table 5-23: ACC&D Summary of “Key Learnings”................................................................................................ 120
Table 5-24: Issues Affecting Marketing of Contraception and Fertility Control for Dogs and Cats.......................... 129
Table 6-1: Contraceptive Products Approved by Regulatory Authorities in the US and EU..................................... 132
Figures
Figure 5-1: Sources of Pet Dogs and Cats in the US by Percentage........................................................................ 93
Figure 5-2: Summary of Reasons Pet Owners Have Not Spayed or Neutered Their Dogs and Cats in the US (%).... 101

Dedication
This publication is dedicated to the animals that have inspired us to care so deeply
about this topic, and to a future with new tools to improve the welfare of animals,
especially those animals beyond our grasp today.
Joyce Briggs
President
Alliance for Contraception in Cats & Dogs

Preface
In 2002, Katherine Moldave, MBA and Linda been updated by its original author, Linda Rhodes.
Rhodes, VMD, PhD compiled and published Con- ACC&D commissioned this update with the support
traception and Fertility Control in Animals, believed to of a generous grant from PetSmart Charities®. Happi-
be the first effort to summarize the technologies and ly, this has been a more significant undertaking than
issues related to this topic in a comprehensive format originally anticipated since so much has occurred in
that would be useful to scientists, academicians, the the intervening years. ACC&D thanks Ms. Moldave
animal health and welfare industries, and interested for her many hours of work beyond what was con-
laypeople alike. The authors subsequently donated tracted to update and expand the original text; her
the copyright to the Alliance for Contraception in commitment to the project has truly gone above and
Cats & Dogs (ACC&D). beyond.
In the past decade, several contraceptive products Contraception and Fertility Control in Dogs and Cats is
for use in dogs have been approved in various mar- not a scholarly work or exhaustive review article. It is
kets, research in relevant traditional and emerging intended to provide a single source of information and
technologies has expanded greatly, interest in this foster collaboration among interested parties. We are
area of animal health has increased, and, as a key counting on readers to help us identify information
component of our mission, ACC&D has worked to that may not have been included in this compilation
focus stakeholder attention on the opportunities and but should be covered in future updates. We have tried
issues involved in non-surgical approaches to contra- to be as geographically inclusive as possible but ac-
ception and fertility control in “owned” and “un- knowledge that some aspects of the compilation have
owned” cats and dogs. At the end of 2011, ACC&D a United States orientation. Therefore, we are particu-
decided that the time had come to update the por- larly interested in updates, additional information, and
tions of the report related to cats and dogs. perspectives from areas outside the US.
The lead author for Contraception and Fertility Con- The following ACC&D scientific advisors, mem-
trol in Cats and Dogs is one of the original authors of bers of the board of directors, and field experts have

Contraception and Fertility Control in Animals (2002), provided information and/or review and ACC&D is
Katherine Moldave. The regulatory chapter has grateful to them for their invaluable contributions:
� Cheryl Asa, PhD, Director, AZA Wildlife Contraception Center at the Saint Louis Zoo, St. Louis, MO
� Joyce Briggs, MS, President, Alliance for Contraception in Cats & Dogs, Portland, OR
� Scott Coonrod, PhD, Associate Professor, Cornell University College of Veterinary Medicine, Baker Institute,
Laboratory of Epigenetics and Reproductive Biology, Ithaca, NY
� Karen Green, Senior Director, Alliance for Contraception in Cats & Dogs, Portland, OR
� Wayne A. Jensen, PhD, MBA, Chief Scientific Officer, Morris Animal Foundation, Denver, CO
� Wolfgang Jöchle, DVM, DrMedVet, Diplomate ACT, Consultant, semi-retired, Manahawkin, NJ
� Shirley D. Johnston, DVM, PhD, Director of Scientific Research, Found Animals® Foundation,
Los Angeles, CA
� Michelle Kutzler, DVM, PhD, DACT, Banfield Professor of Companion Animal Industries,
®
College of Agricultural Sciences, Department of Animal Sciences, Oregon State University, Corvallis, OR
� Julie Levy, DVM, PhD, DACVIM, Director, Maddie’s® Shelter Medicine Program, College of Veterinary Medicine,
University of Florida, Gainesville, FL
� Elaine Lissner, Medical Director, Parsemus Foundation, San Francisco, CA

� Patricia N. Olson, Chief Medical Advisor, American Humane Association™, Washington, DC

� Linda Rhodes, VMD, PhD, Chief Scientific Officer, Aratana Therapeutics, Kansas City, KS
� Margaret Root Kustritz, DVM, PhD, Professor of Small Animal Reproduction, College of
Veterinary Medicine, University of Minnesota, St. Paul, MN
� Andrew Rowan, PhD, President and CEO, Humane Society International™ and Chief International Officer and Chief
Scientific Officer, The Humane Society of the United States™, Washington, DC
� Stephen Zawistowski, PhD, CAAB Science Advisor, The American Society for the
Prevention of Cruelty to Animals®, New York, NY
Thanks are also due to our proofreader, Julie Snyder.
This project was supported by a generous grant from
Design donated by MoldaveDesigns LLC. www.moldavedesigns.com.
Disclaimer
This compilation is intended to provide helpful and informative material based upon publicly available information. It is
provided with the understanding that the contributors and ACC&D are not engaged in rendering professional services in
this publication. No liability of any kind is assumed by ACC&D or the contributors with respect to the use of information
contained herein. Although every precaution has been taken in preparation of this publication, ACC&D and the contribu-
tors assume no responsibility for errors or omissions. Neither is any liability assumed for damages resulting from the use
of information contained herein. The publication is not intended as a substitute for the professional advice of a veterinar-
ian in matters relating to animal health and particularly in respect of any products which may require a prescription,
nor is it intended to give specific regulatory advice. All rights are reserved; however, material in this publication may be
reproduced or transmitted provided that ACC&D is notified and credit is given to the Alliance for Contraception in Cats
& Dogs © 2013.

1.0 Introduction landscape in the area of contraception and fertility in cats
and dogs will be able to gain a working knowledge, while
readers interested in a bit more information on the scientific
1.1 Scope of the Report
aspects will be able to review what research approaches
This report is an update of the canine- and feline-related have emerged and why. We hope interested lay people,
sections of the 2002 report Contraception and Fertility Control veterinarians, researchers, animal welfare organizations,
in Animals and is a compilation of publicly available business people, potential investors in emerging relevant
material on the subjects of contraception and fertility technologies, and animal health professionals will all find
control in dogs and cats, and dog and cat population the report useful.
statistics and issues. Sources include the published
scientific literature, government publications, company
1.2 Brief Review of the Historical Context
websites and other Internet pages, and discussions with
of Contraception and Fertility Control
leaders in the field. We have included references, not as a
comprehensive review of the literature, but to serve as a
Research in Animals
beginning for those interested in delving further into the “The Pill,” approved in the United States (US) in 1960,
subject. was considered a breakthrough in contraception for
women. Daily oral treatment with low dose estrogen or
Although we have tried to be thorough in researching
estrogen/progesterone combinations became a widely
and updating publicly available material describing
adopted method for human reproductive control.
methods of, and issues related to, contraception and
fertility control in dogs and cats, it is quite possible that Research has been published for more than 40 years
we have overlooked some fact our readers feel should indicating that non-surgical contraception for animals is
have been included, or included a statistic that’s become possible. Since daily treatment with steroids is impractical
outdated – for these oversights we offer our apologies for most species, other methods have been explored. A
in advance. We invite you to notify the Alliance for variety of approaches have been used in many species
Contraception in Cats & Dogs (ACC&D) (acc-d.org) of of animals, including early laboratory work in rodents
suggested additions for the next update. We trust readers and studies on dogs, cats, cows, and monkeys. Much of
will find that the important sources, topics, and opinions this work was directed towards exploring contraceptive
are well covered in this report. approaches for humans, but some of it was clearly geared
towards creating alternatives to surgery for animals.
We have included an overview of the basics of control of
reproduction and a review of the types of treatments that
have either been available commercially over the years or
have been investigated by experts.
To complement the scientific and technical material,
there is a review of various companies that have done
research and development in this field, including a
snapshot of the history of product development by animal
health companies over the years. Some of the important
characteristics of the market that will be helpful to consider
for a company interested in developing, commercializing,
and/or marketing a contraceptive product are reviewed,
and we also include an overview of the particular
regulatory considerations that we think apply to these
types of products.
Given that the research was so promising, why have so
We feel strongly that to make the decades of research in few of these approaches made it to the marketplace?
this field continue to come to fruition with products that
Demonstrating effectiveness (i.e., that a particular
can be used commercially, the science and the business
treatment can cause suppression of fertility for a period
must come together. This report is written for people who
of time) is not enough. To move an idea from the lab into
are interested in contraception and fertility control in cats
the marketplace, the technology must be efficacious and
and dogs. Some sections are more technical than others, but
safe, and a number of other requirements must also be
lay readers who wish to have an overview of the overall

met. For a company to decide to take a product forward, a in non-surgical contraception. A common opinion was
technically feasible, stable formulation must be developed that spaying and neutering were the drivers that brought
and large-scale manufacturing must be possible. The clients to the veterinary practice. Providing an alternative,
regulatory path must be clear, risks well defined, and they worried, could have a negative impact on the number
the cost of development reasonable. The market must be of new clients coming in the doors of the veterinary
clearly defined and the cost of the final product must be practice and thereby diminish the customer base. Non-
low enough to make the investment attractive (i.e., generate surgical contraception also suffered from the fact that when
sufficient profit margins). Money must be available to each company looked at what the other industry leaders
complete the project and support an initial marketing were doing, nobody seemed to be working in this area,
campaign. Finally, a company or a group of investors which also reinforced the negative perception – if this is
must be willing to take the risk of a long and expensive such a good idea, why aren’t our competitors doing it?
development project. Over the years, some of the animal health companies have
Other means of developing a contraceptive for cats supported research on various approaches, but only fairly
and dogs can be imagined. For example, a humanitarian, recently have commercial products emerged for non-
nonprofit organization could subsidize the development surgical contraception for dogs and cats.
and registration costs for a product that may not be
commercially feasible, and such a product could be 1.3 Targets and Historical Approaches to
provided at cost to spay/neuter clinics and shelters. Early- Non-Surgical Sterilization in Dogs and
stage companies and humanitarian organizations could Cats
collaborate to bring a product through the riskier stages of
Note: The majority of the information in this section is
development, and then partner with a larger company for
contained in a paper entitled Historical Approaches to Non-
distribution and sales, with the profits of such a venture
surgical Contraception in Dogs and Cats by Beverly J.
subsidizing the contraception of needy animals.
Purswell and Wolfgang Jöchle and submitted as an abstract in
the Proceedings of the 4th International Symposium on Non-
Surgical Contraceptive Methods of Pet Population Control
in 2010. It has been edited slightly and updated in places.
Proceedings from all previous symposia are available at acc-d.org.
For millennia, surgical castration – defined here as
removal of the testes or ovaries – has been the only reliable
and permanent method of contraception in domestic
animals. The oldest evidence of surgical castration of
domestic male animals can be traced back to the late
neolithicum (7000-6000 BC). Documentation for surgical
castration in male dogs goes back to ancient China, Siberia,
Over the years, technical issues and pitfalls have stood
and Greek and Roman antiquity. In literature throughout
between various approaches and the marketplace. In
the ages, many authors discuss dog breeding, management,
addition, there are sociopolitical factors (see Chapter 5)
and health care. Contraception is not a part of this body
that have likely slowed the advance of contraception and
of literature. This is in sharp contrast to the amount of
fertility control in animals.
literature on male and female castration of horses and
In the early 1980s, when some methods were being mules. One English book on the art of hunting, dating back
tested in research laboratories, the large pharmaceutical to 1575, mentions castration of male and female dogs, but
companies were dismantling their reproductive biology does not give any technical details.
research groups. Controversy over the side effects of
From the 15th to the 19th centuries, evidence of European
intrauterine devices and controversy over abortion and
professionals with a special license for castrating male
contraception in general led companies to shy away from
and female farm animals can be found. The professionals
the entire field. Animal health R&D groups working
were organized into guilds, and had lists of fees that
on reproduction were also downsized, a process that
were approved by local authorities or the ruling princes.
does not appear to have been reversed. In animal health
Modern veterinary medicine in the late 18th century and
companies, many decision makers were also not interested

19th century slowly took over the castration business, veterinarians and pet owners. Medroxyprogesterone
at least in pets and horses, and brought a level of acetate (MPA) in tablet form was the “Pill” that was
humaneness to the process. In 1975, in a British Small marketed first in Europe in 1963. In the US, MPA was
Animal Veterinary Society publication, it was mentioned marketed as an injectable product and was used in dogs
that anyone older than 18 years of age was legally entitled with disastrous results. Introduced in 1964, MPA was
to perform castration of a cat or a dog at any time until it produced as a long-acting crystalline suspension (4-5
is 6 months of age, provided that adequate anesthetic was months duration, Promone-E® or Depo-Provera®). This
administered. By 2007, the law had changed and castration product was very effective in estrous suppression but
of dogs and cats could only be provided by veterinarians. caused pronounced cystic endometrial hyperplasia in the
The 20th century saw modern animal welfare legislation uterus, resulting in an epidemic of pyometra. This problem
in a few Scandinavian countries that forbade any surgery resulted in a withdrawal of the product from the market 2
in healthy pets. Once data on the health benefits of years later, never to appear again for this use. As a further
gonadectomy (e.g., lessening of mammary tumors in consequence, veterinarians in the US lost confidence in
bitches1 (female dogs) and benign prostatic hyperplasia any hormone-based contraception and the veterinary
(BPH) in male dogs) were provided, neutering and spaying profession in North America thus went to a strictly surgical
of pets became legal again (with at least one exception).2 means of estrous control.
Contraceptive medications in dogs and cats have only

had more recent attention in the latter half of the 20th
century. Around 1960, due to the availability of orally
active and increasingly more effective progestins (“The
Pill”), efforts began on a larger scale to control reproduction
in dogs and cats. As oral contraception products became
widely available for women, the desire to use these
products in pets became more mainstream. The status
of dogs and cats also changed during this time to true
companions, family members, and even child substitutes.
It was at this time that animal welfare advocates began to
be concerned about the fate of unwanted and unplanned
offspring and the horror of increasing numbers of dogs
and cats euthanized each year, and launched educational Because of the veterinary and animal welfare
campaigns to inform the public about preventing environment in Europe, veterinarians worked with the
unwanted litters. Progestin-based “Pills for pets” were available pharmaceuticals to develop safe protocols for
developed in Europe, coming to the market in 1963. progestins. During the 1960s and 1970s, other progestins
Large-scale population control for dogs and cats in the US were introduced, such as chlormadinone acetate (CAP),
began in the early 1970s. delmadinone acetate (DMA), and proligestone (PRO).
Use of the progestins was refined by lowering the dose
Progestins (progesterone-like compounds) have been and adjusting the timing of administration. Emerging
the most common compounds used to address estrous insights into the canine reproductive cycle began to allow
control in the dog. These progestins, administered orally for strategies uniquely suited for the species. In the bitch,
or by injection, have had varying results and acceptance by pregnancy and pseudopregnancy are endocrinologically
and morphologically very similar. Use of these compounds
1
While the term “bitch” is not used commonly in the US to refer for treatment for estrous prevention and an interruption of
to female dogs, it is used in the rest of the world and we hope its cyclicity was found to be safe when begun 4 months after
use in this document does not offend any of our readers.
an estrus, and at least 1 month prior to the next anticipated
2
According to a December 2011 article on the Science Nordic estrus. The treatment could be repeated every 4-5 months
website, “The Norwegian Animal Welfare Act makes it clear for years of safe estrous prevention.
that surgical procedures are not to be used to adapt animals to
the needs of humans, unless strictly necessary.” The article also Megestrol acetate (MGA) was another early progestin
stated that the Norwegian Food Safety Authority (NFSA) was
working on a revision that would permit neutering of dogs that was marketed for use in dogs in Europe, the US, and
“when mandated by utility, or if it helps give the dog a justifi- Canada, beginning in the early 1970s. This product is an
able quality of life, including social contact with other dogs.”
See sciencenordic.com/should-dogs-be-neutered.

oral tablet that has been the only product approved for insensitive to GnRH. This process is called receptor down-
use in the breeding bitch in the US. Marketed as Ovaban®, regulation. As down-regulation occurs, production of
there were two protocols approved for use in the dog. One gonadotrophins by the pituitary (luteinizing hormone (LH)
was at a higher dose and short duration to stop a cycle once and follicle-stimulating hormone (FSH)) ceases, effectively
begun. The other protocol was at a lower dose and longer shutting down spermatogenesis and androgen production
duration to prevent the cycle from occurring. Although in the male and cyclic ovarian function in the female.
the marketing of MGA as a specific veterinary product This effect is well known and as early as 1989 had been
has been discontinued, MGA is available as a generic for suggested as a potential estrous suppression hormone for
human use but used only on a limited basis in the US. the bitch. Three factors have prevented rapid development
In cats, progestins have proven to be problematic. of a GnRH product for use in estrous suppression in small
Progestins have never been as popular as they were in animals:
dogs. Their use has been restricted to oral MGA or MPA, 1. High cost of these analogs
once or twice weekly for estrous suppression or prevention.
2. Initial induction of a (sometimes) fertile estrus
Cats have problems with progestins causing an adverse prior to down regulation
effect to the adrenals, resulting in diabetes which can be
3. Strong variations in the duration of contraception
irreversible. Because of this significant, life-altering side
among individual animals
effect and other health risks, progestins are not typically
used in the cat. Use of progestins in cats is especially rare in The GnRH agonist leuprolide (Lupron®) came onto the
the US, while in Europe it is somewhat more common. market for human use in the 1990s, but its substantial cost
prevented its veterinary use.
In addition to progestins, androgens have been used
for estrous control in the dog. Testosterone, either oral Peptech Animal Health in Australia developed two
or injectable, is used routinely in racing greyhound much less expensive implants for either a 6- or 12-month
bitches while training and competing. The side effect of suppression of fertility in male dogs using the GnRH
masculinization, while desirable in the racing athlete, limits analog deslorelin. Research showed that treatments with
the use of testosterone in the wider pet population. Another these implants, containing down-regulating doses of
compound with androgenic activity, mibolerone (MIB), deslorelin, resulted in cycle control in the bitch and queen
was marketed in North America. Introduced in 1978, MIB (female cat), and in suppression of spermatogenesis and
(Cheque®) was discontinued in 1990. Some veterinarians libido in male dogs. Its use has been studied in male cats
continue to use MIB for estrous control in the bitch by but the product is not approved for this use. Approval
accessing it from compounding pharmacies. MIB requires for the sale of the deslorelin implant for use in male dogs
daily oral use, begun at least 30 days from the onset of under the trade name Suprelorin® was obtained in New
an estrus, to successfully prevent cycling. Use of MIB, Zealand and Australia in 2003 and in the European Union
aside from the show-dog world, has been limited in the (EU) in 2007. Another GnRH analog, an azagly-nafarelin
pet population due to its androgenic side effects (clitoral implant, was approved in Europe in 2006 under the trade
enlargement, musky body odor, and behavioral changes). name Gonazon® for use in female dogs; its use has also
been studied in cats. Suprelorin and Gonazon are examples
The next hormonal approach to contraception in small
of a novel approach to defining duration of drug effect:
animals to be developed was gonadotropin- releasing
that is, not based on the median duration of relevant drug
hormone (GnRH) analogs. The advantage to using GnRH
effect, but on the minimal duration of such effects
or its analogs is that these compounds are effective in males
in a large population with varying duration
and females, since GnRH is the master control hormone for
of effectiveness.
reproduction. Also, the GnRH decapeptide has the same
amino-acid sequence in all mammals, making any product
potentially useful in a variety of species. The development
of long-acting preparation of the GnRH agonists has long
been sought. Compounds began to emerge as promising
candidates. Long-acting powerful analogs have been
shown to occupy GnRH receptors at the pituitary and after
a short period of stimulation cause the cells to reduce or
stop the synthesis of the receptor protein, making the cells

Note that Gonazon, although approved by European conjugated to large proteins and potent but safe adjuvants
regulators, was not introduced to the market, quite are needed. Adjuvants must render the vaccine effective
likely because of a business decision. The safety of these with a practical number of booster injections, and must
analogs allows for repeated treatments even if the effect also cause minimal site reactions. These vaccines would be
of a prior treatment has not expired. Induction of estrus effective in multiple species and in males and females, due
and ovulation as an initial treatment response can be to the fact that they antagonize the effects of GnRH.
avoided by either implanting bitches during their luteal In 2004, Pfizer Animal Health acquired the Australian
(progesterone) phase, 60 days post-estrus, or after a short- animal health company CSL and its US subsidiary Biocor,
term pretreatment with exogenous progestins, such as which had a gonadotropin-releasing factor (GnRF, another
MGA. term for GnRH) vaccine for use in male dogs for the
Male dogs have been subject to contraceptive treatments treatment of benign prostatic hyperplasia. Although Pfizer
only in the last decade. Surgical castration of male dogs obtained a conditional license for this product for treatment
continues to be taboo among many cultures. Beginning of canine BPH from the United States Department of
several decades ago, efforts were undertaken to find a Agriculture (USDA) in 2004, no further licensure occurred
safe single intratesticular treatment causing the testes to in the US and the product is no longer available. This
atrophy. A variety of compounds have been tested. The first vaccine required two injections, 4-6 weeks apart, to be
approved product (Neutersol®, zinc gluconate/arginine) repeated every 6 months, and did result in contraception in
to fulfill both the safety and effectiveness criteria required the course of treating BPH. Similar vaccines are currently
by the FDA became commercially available in the US in available in swine (Improvac™) and in horses (Equity™).
2003. Distribution was halted in 2005 when the patent- The availability and success of these GnRH(F) vaccines
holder and marketing company severed ties. Neutersol may hold promise for their use in cats and dogs.
is no longer available in the U.S; however the product Other avenues to non-surgical pet contraception are
has been brought back to certain markets re-named as being explored. They include the use of GnRH peptide and
Esterilsol®, sponsored by a company named Ark Sciences, non-peptide antagonists. To make these compounds useful
Inc. The product is approved in several Latin American as dog and cat contraceptives, depot preparations will need
countries. Ark Sciences plans to bring the product back to to be developed. Cost, again, will need to be addressed to
the US in 2013 under the new name, ZeuterinTM. Unlike gain widespread acceptance for use in companion animals.
the GnRH treatment, which in most animals is reversible, Depending on the objective (i.e., whether or not permanent
intratesticular treatments result in irreversible destruction sterility is desired), the advantages of these approaches
of germ cells and hormone-producing tissues. Another may be quick action, reversibility of effects, and safety.
zinc gluconate-based sterilant for male dogs, Infertile®, Research is also underway on approaches for providing
was introduced in Brazil in 2009. Work continues on other permanent sterilization.
formulations administered similarly and targeted to males.
As discussed in Chapter 5 of this update, there are
Another avenue for contraception is several general stakeholder groups whose visions of
immunocontraceptive vaccines. Porcine zona pellucida contraception and fertility control in dogs and cats differ.
(PZP) vaccines derived from porcine oocytes have been For some, reversibility is important; for others, permanence
used in a variety of species. These vaccines have been is essential; for still others, having several options is
shown to cause reversible infertility in ruminants, horses, desirable. This creates challenges as well as opportunities.
seals, and elephants. In bitches, an irreversible infertility
was induced by destroying the entire ovarian follicle but
treatment with a PZP vaccine was ineffective in the queen.
These results have led to efforts to identify canine-specific
and feline-specific antigens in canine and feline zonae
pellucidae and to use suitable candidates for attempting
to develop zona pellucida (ZP) immunocontraceptive
vaccines for bitches and queens.
Hormonal antigens are another avenue to
immunocontraceptive vaccines. The antigenicity of
GnRH complexes has been confirmed since the 1970s.
Because small peptides make weak antigens, they must be

1.4 Considerations for Commercializable Approaches to Non-Surgical
Contraceptive Methods
What does it take for a contraceptive or sterilant to be “commercializable?” The table below, based on A Summary of
ACC&D’s Priorities for Non-surgical Sterilization and Key Challenges in Their Development (Briggs and Rhodes, ACC&D 4th
International Symposium on Non-Surgical Contraceptive Methods of Pet Populations Control 2010), provides a summary:
Table 1-1: Summary of Characteristics Required for Commercialization
Parameter Comments
Approvable The ability of a given product to be approved by relevant regulatory agencies is a key
practical consideration. The question of potential for regulatory approval needs to be
asked repeatedly at different stages of research and development to encourage focus on
advances that have potential for commercialization.
Financially feasible Financing, whether the potential product is corporate- or organization (e.g., nonprofit)-
based, is critical. The Michelson Prize & Grants program (see Chapter 4, section 4.3.3.2) is
a significant new resource, and various types of public-private partnerships and emerg-
ing options such as L3C corporations (Limited Liability Corporations created to support
philanthropic investment) are examples of approaches that may be applicable to certain
stakeholder groups.
Deliverable The method of administration needs to fit a given application. For example, a product
requiring two or more treatments may have promise for some market segments such as
veterinary clinics, but there is likely only one opportunity to treat populations such as fe-
ral cats, community/street dogs, and certain pets that are difficult to treat more than once
(e.g., hard to handle, or owner who may not to return for follow-up treatment).
Documentable Traditionally, US-based veterinary practitioners and animal welfare agencies have had a
positive opinion of the value of perceived non-reproductive effects of sterilization surgery
on dog and cat health and behavior. Currently, there is a “reframing” occurring related to
the “gold standard” status of surgical contraception. This “reframing” strives for a more
objective comparison between spay/neuter and current or future non-surgical alterna-
tives. In addition, different cultures value these effects (e.g., the effects of castration on
some male dogs) differently.
Affordable While there will always be pet owners to whom cost is not a consideration in the health
of their companion animals, affordability is key for many individuals and stakeholder
groups, particularly those involved with shelter animals and animals that are feral or
free-roaming. Pet owners who are not price sensitive can also benefit from approaches that
may happen to be relatively inexpensive.
Able to be manufactured in Unfortunately, in the drug-development world there are many instances in which safe,
amounts that meet demand effective products able to be produced in a laboratory setting have been unable to be ap-
proved and commercialized because they were not able to be manufactured on a large
scale, either due to inherent product characteristics, manufacturing challenges that could
not be addressed successfully, or manufacturing cost.
Acceptable Stakeholder groups for which a given product is intended must find that product accept-
able. This includes veterinary practitioners who may be hesitant to embrace new alterna-
tives. As with any innovation, thought and opinion leaders representing relevant stake-
holder groups will be needed to explore how to integrate new methods.

2.0 The Physiology of Reproductive 2.3 Gonads (Ovaries and Testes)
Control in Mammals – Overview Once the pituitary secretes LH and FSH, they travel in
the blood to the gonads – ovaries in females and testicles
of the Major Systems that in males. These two hormones bind to receptors on the
Control Reproduction gonads. They coordinate the estrous cycle (heat) or the
menstrual cycle of the female and are important in the
The purpose of this brief overview is to give readers the production of estrogen and progesterone. In the male,
background necessary to understand how the potential LH and FSH are important for sperm maturation and
products for contraception and fertility control work. This stimulation of the production of testosterone.
is an oversimplification of a wonderfully complex system,
but the material should serve to orient non-biologists When the steroid hormones (estrogen, progesterone
reading this report. and testosterone) are secreted from the female or male
gonads, these hormones travel in the blood to the brain,
where they turn off the secretion of GnRH. This is called
2.1 Brain
negative feedback. For example, GnRH causes the pituitary
The major control center for reproduction is the brain, to make more LH, which stimulates the testes to make
where specific neurons synthesize gonadotropin-releasing more testosterone, which goes to the brain and causes the
hormone (GnRH) under a number of influences, such as brain to make less GnRH. Levels of LH go down, because
light levels, body condition, age, and the blood levels of the pituitary doesn’t get the GnRH signal. When the LH in
various hormones. One of the most interesting things about the blood falls, no testosterone is made. As blood levels of
brain secretion of GnRH is that it is secreted in pulses and testosterone decrease, the brakes are off the GnRH in the
not continuously. The pulses are important – if GnRH is not brain, and the system kicks in to make more GnRH, and so
delivered in pulses, it does not have the normal effect on on. This is how the system is regulated.
the reproductive system. This small fact becomes important
The system is more complex in the female, but
in understanding one of the leading approaches to animal
the essential message is the same. The estrogen and
contraception, the GnRH agonist compounds.
progesterone produced in the ovary are the negative
GnRH is a decapeptide (small protein made up of 10 feedback signals for GnRH. It is not important for this
amino acids) that acts directly on the pituitary. GnRH is report to detail the complex regulation of the estrous and
considered the master hormone that controls the release of menstrual cycles. However, this negative feedback concept
the major reproductive hormones. Interfere with GnRH, and is important in understanding contraceptive technology.
you interrupt all of reproduction in both males and females. Giving progesterone, for example, will shut down
In fact, not only is reproduction interrupted, but the species- production of GnRH, interrupting fertility.
specific reproductive behaviors are disrupted as well.
In the ovary, where the eggs are produced, each egg
is surrounded by a protective coating called the zona
2.2 Pituitary pellucida (ZP). The ZP is made up of several glycoproteins,
The pituitary gland has specific cells – the i.e., complex proteins with various sugar molecules
gonadotrophs – that have receptors for GnRH attached. From recent work in molecular biology, we
that bind to the peptide. The regulatory system is know that in each species there are different – but
highly complex, and at the risk of oversimplifying, similar – ZP proteins around the egg. For example,
we can say that once the GnRH binds to its the ZP proteins from a pig (porcine) are similar to –
receptor on specific pituitary cells, it causes the but not exactly the same as – the ZP proteins of a cat.
release of two larger protein hormones called A great deal of work in animal contraception has
gonadotropins – luteinizing hormone (LH) and been undertaken with vaccines using the porcine ZP
follicle-stimulating hormone (FSH) – which are proteins, including exploration of the potential of
secreted into the blood. As the brain gives off use in multiple species.
pulses of GnRH, these pulses reach the pituitary
and cause the pituitary to give off pulses of LH 2.4 Unique Aspects of Canine and
and FSH. Feline Reproductive Biology
During the 2009 Alliance for Contraception
in Cats & Dogs (ACC&D) Think Tank on

Immunocontraceptive Approaches for Sterilization of and canine follicles undergo pre-ovulatory luteinization.
Dogs and Cats, Dr. Beverly Purswell briefly described Dogs are monestrus, meaning they have one estrous cycle
canine- and feline-specific reproductive characteristics, as per season, which averages one to three cycles per year for
summarized below (acc-d.org/ThinkTanks). domesticated dogs.
Unique aspects of dog reproduction include the fact In contrast, domestic cats are induced ovulators,
that diestrus (progesterone phase) occurs after every stimulated to ovulate in response to mating, though
estrus; if not impregnated, bitches will experience a spontaneous ovulation events have been observed. Cats are
pseudo-pregnancy lasting the same length of time as an prolific breeders, able to become pregnant within days after
actual pregnancy, unlike most animals which experience delivering a litter, and have been demonstrated capable of
a decrease in progesterone as soon as it is determined that producing five litters in one year. Additionally, a cat can
the animal is not pregnant. Note that only one-quarter to become sexually mature as early as 4 to 5 months of age.
one-third of these pseudo-pregnancies are evident (Jöchle, Cats are also seasonal breeders, induced to reproduce by
personal communication 2012). Dogs also ovulate primary long daylight hours, such that equatorial populations breed
oocytes requiring two meiotic divisions before fertilization, year-round.

3.0 Overview of Technological � Ovariectomy refers to surgical removal of the ovaries
Approaches and Their (more common in Europe than in the US)
Applications in Dogs and Cats � The term “spay” is used commonly to refer to
ovariohysterectomy and ovariectomy
Chapter 3 summarizes technologies that: � Orchiectomy (male castration) refers to surgical removal
of the testicles and spermatic cords
� Have been the basis of the non-surgical products that � The term “neutering” is used commonly to refer to male
have been approved in various markets or surgical castration, although it is used to refer to surgical
� Are being investigated for their potential utility as non- sterilization of female animals as well.
surgical approaches to contraception or sterilization of
dogs and cats
� The term “castration” may refer to sterilization of males
or sterilization of males and females, and this is defined
Chapter 4 provides information on specific products as for a given example
well as companies, institutions, and organizations active in There is discussion and even controversy in the
the area. literature regarding how old dogs and cats should be when
Please see Chapter 5, section 5.8, for descriptions of gonadectomy is performed, as well as the benefits and
“ideal products” based on the different segments in the risks associated with the procedures. Because companion
market. animals are living longer, unanticipated effects related to
gonadectomy are becoming “more visible” (Reichler 2009).
In fact, veterinary practitioners vary regarding their
advice about when the surgery should be performed.
Generally, American veterinarians encourage their clients
to have elective gonadectomy performed in dogs and
cats when the animals are between 6 and 9 months old,
but “there does not appear to be any scientific evidence
to document that this is the optimal age, [and] the age at
which pets have traditionally been spayed and neutered
has varied through the years and with geographic location”
(Root Kustriz 2007).
“It is important to note that pediatric neutering has been
campaigned for and popularized by the animal welfare
field. By sterilizing puppies and kittens aged over 6 weeks
3.1 Surgical Approaches and weighing more than 2 pounds … shelters and breeders
can ensure the inability of those animals to be accidentally
3.1.1 Overview
or intentionally bred by new owners. Because this is
Gonadectomy refers to surgical removal of ovaries considered extremely important for population control,
or testes performed to eliminate reproductive function animal welfare and veterinary organizations (including
irreversibly. Reichler (2008) notes that the first written the American Veterinary Medical Association (AVMA))
documentation referring to neutering companion animals support pediatric sterilization. Shelters have found that
can be found in the Mosaic laws of approximately 600 there is poor follow-through by adopters on spaying/
BC. Eighteenth- and nineteenth-century writings refer to neutering, even when a contract with a deposit for the
employing gonadectomy not only to stop reproduction surgery is in place … there is accordingly great interest
in dogs and cats, but also to suppress sexually-related in non-surgical procedures that can treat juvenile cats and
behaviors. dogs” (Briggs, personal communication 2012).
Terms used in this overview: The Association of Shelter Veterinarians (ASV) medical
� Gonadectomy refers to the surgical removal of the male care guidelines for spay/neuter programs note that
or female gonads (testes or ovaries) “Owned pets may best be served by scheduling surgery at
� Ovariohysterectomy refers to the surgical removal of 4 months of age or older to allow time for the development
the ovaries and the uterus (more common in the United of immunity through vaccination. Neutering prior to sexual
States (US) than in Europe) maturity is strongly recommended to prevent the birth of
unintended litters, which commonly occurs when surgery
is delayed. In situations involving animals that will be Theoretically, the general health- and behavior-related
placed for adoption, neutering is best performed prior to advantages and disadvantages of surgical approaches
adoption (as early as 6 weeks of age) to ensure compliance” apply to both dogs and cats, though the relative weights of
(Looney et al. 2008). advantages and disadvantages may vary.
Further discussion of all the factors that may be The following table and related notes summarize the
involved in making this decision is beyond the scope of current thinking regarding pros and cons of gonadectomy,
this document. Readers may consult sources such as Root in general, in dogs and cats, and is derived from Root
Kustritz (2007), Reichler (2009), and other publicly available Kustritz (2007, personal communication 2012), Reichler
literature. (2009), and Rhodes (personal communication 2012).
Table 3-1: Pros and Cons of Gonadectomy in Dogs and Cats

Pros Cons
Female Completely effective sterilant Surgical complications
Dog
Decreased incidence of mammary neo- Increased incidence of urinary incontinence (e)
plasia (depending on timing of gonadec- Increased incidence of hematologic, bone, and blad-
tomy) (a) der tumors (f)
Decreased incidence of reproductive Increased disposition to knee injury (g)
tract (ovarian/uterine) disease (b)
Obesity (h)
Decreased incidence of reproductive
behaviors (c) Possible breed-related decreased lifespan (d)
Eliminates the risk of difficult birth
(dystocia)
Male Completely effective sterilant Surgical complications
Dog
Decreased incidence of reproductive Increased incidence of hematologic, bone, and pros-
tract (testicular and prostatic) disease tate tumors (f)
(except prostate tumors) (b) Increased predisposition to knee injury (g)
Decreased incidence of reproductive Obesity (h)
behaviors (c)
Possible increased lifespan (d)
Cat
Decreased incidence of mammary neo- Obesity (h)
plasia (depending on timing of gonadec- Possible increase in diabetes mellitus (i)
tomy) (a)
tract (ovarian/uterine) disease (b)
behaviors (c)
Eliminates the risk of difficult birth
(dystocia)
Male Cat Completely effective sterilant Obesity (h)
Decreased incidence of reproductive Possible increase in diabetes mellitus (i)
behaviors (c)

(a) Mammary neoplasia. In dogs, mammary neoplasia represents “significant association between gonadal hormone exposure and
the most common tumor type. Although the incidence is less risk of bone sarcoma … in [male dogs] castrated before 1 year
in cats, mammary tumors make up 17% of the neoplasms that of age (lowest gonadal exposure), the risk for bone sarcoma was
occur in female cats; 85% of those are cancerous. The risk for almost 4 times greater than in sexually intact males. In females
development of benign mammary tumors in cats and dogs may spayed before 1 year of age, bone sarcoma incidence was more
be reduced depending on the timing of gonadectomy (Reichler than 3 times greater than the rate in sexually intact females. The
2009). risk factor of early [gonadectomy] was found to be independent
of adult height or body weight” (Reichler 2009). The nature of a
(b) Reproductive tract disease. Ovarian tumors and cysts cannot cause-and-effect relationship has not been defined (Root Kustritz
occur after spaying; disease mediated by ovarian hormones (e.g., 2007).
vaginal hyperplasia) is “virtually nonexistent” after spaying
in dogs and cats (Reichler 2009). Owners can be expected to be In dogs, incidence of transitional cell carcinoma (TCC) of the
concerned about pyometra as well, which can be prevented by bladder is no more than 1% and certain breeds are more at risk
spaying. than others; however, gonadectomized animals have a 2 to 4
times greater risk of developing TCC than intact animals (Root
In male dogs, “Bilateral orchiectomy has a prophylactic and Kustritz 2007). Reichler (2009) notes “the increased risk for devel-
therapeutic effect on androgen-dependent diseases such as oping TCC in neutered dogs of both sexes is not explained at this
benign prostatic hyperplasia (BPH), chronic prostatitis, and peri- time.”
neal hernia … Castration also prevents testicular and epididymal
disorders, such as neoplasia, torsion of the spermatic cord, orchi- The relative risk for cardiac and splenic hemangiosarcoma
tis, and epididymitis … these diseases are very rare in tomcats” (reported incidence of 0.2%) in animals that have been spayed or
(Reichler 2009). neutered is increased. Spayed females appear to be at 2.2 and 5
times the risk of splenic and cardiac hemangiosarcoma, respec-
(c) Behavior. Typically male dogs are neutered to ameliorate tively, than intact females, while castrated males have 2.4 times
behavioral problems, while female cats [and female dogs] are the risk versus intact males (Root Kustritz 2007).
neutered to prevent reproduction, and tomcats are neutered to
limit particular sexually related behaviors such as urine spraying (g) Cruciate ligament. A study of records of animals treated at
(Reichler 2008). Note that behavioral effects of gonadectomy are an orthopedic veterinary practice over 2 years indicated that the
poorly defined (Levy, personal communication 2012). It can be prevalence of anterior cruciate ligament rupture (reported preva-
assumed that one of the reasons owners choose to have bitches lence in the subject population was 3.48%) in neutered male and
spayed is to eliminate the bleeding that accompanies estrus female dogs was significantly greater than that of intact dogs
(Rhodes, personal communication 2012). For more discussion on (Slauterbeck et al. 2004).
perception vs. data on behavior change in surgically sterilized
dogs and cats, see Chapter 5, section 5.2.2. (h) Obesity. Obesity is a multifactorial issue in dogs and cats.
Veterinarians report spayed or castrated dogs and cats as obese
(d) Lifespan. The literature refers to increased lifespan in gonad- compared to intact dogs and cats but gonadectomy is “the most
ectomized dogs (e.g., Reichler 2009), though Waters et al. (2009) commonly reported risk factor.” Cats have an increased tendency
determined that in a group of long-lived Rottweilers “removal of to become obese after surgical sterilization, with no correlation
ovaries during the first 4 years of life erased the female survival between age at gonadectomy, and weight or body fat. In dogs,
advantage.” age at gonadectomy does appear to be a factor, with an increase
in obesity incidence in dogs that underwent gonadectomy at
(e) Urinary incontinence. In 3%-21% of spayed bitches, urinary greater than 5 months of age than those gonadectomized at less
incontinence may occur right after surgery or as long as 10 years than 5 months of age. In any case, “in both dogs and cats, obesity
later. Approximately 75% of the dogs that do develop urinary in- is not a mandatory consequence of gonadectomy; instead, it is
continence do so within about 3 years of spaying. Factors includ- controllable with an appropriate diet, feeding regimen, and exer-
ing weight, breed, and timing of spaying can influence whether cise regimen” (Root Kustritz 2007).
or not a given bitch develops incontinence (Reichler 2009).
(i) Diabetes. Gonadectomized cats have a greater risk of devel-
(f) Cancer. Castrated dogs are at a 2.4 to 4.3 times increased risk oping diabetes mellitus than intact cats. Root Kustritz (2007)
of prostatic tumors – most of which are malignant – compared notes an 8.7 times greater risk versus intact cats; Reichler (2009)
to intact dogs. The nature of a cause-and-effect relationship is cites a 2- to 9-fold increased risk. Diabetes risk may be related to
unclear (Root Kustritz 2007). (preventable) increased obesity rates in gonadectomized cats and
dogs.
Castrated dogs are at a two-fold greater risk of developing osteo-
sarcoma (reported incidence of 0.2%) than intact dogs. There is a

3.1.2 Surgical Methodologies increased discomfort) compared with ovariectomy.” It is
clear that ovariohysterectomy is a bigger surgery (Jöchle,
personal communication 2012).
Studies of laparoscopic ovariohysterectomy have been
reported by European and US investigators. Laparoscopic
ovariohysterectomy and ovariectomy procedures provide
advantages of improved visualization of the genitourinary
tract, less tissue trauma, and reduced postoperative pain,
recovery time, and risk of infection and other complications
compared to traditional ovariohysterectomy. Possible
disadvantages include equipment cost, potential morbidity
related to bleeding and injury to the viscera (which can also
be seen in the open surgical technique), the need for specific
training and anesthetic protocols, equipment limitations
usually preventing large-scale use in neutering programs,
3.1.2.1 Females and difficulty taking laparoscopic techniques into remote
For owners of female cats and dogs who do not want or mobile applications (Dupré and Fiorbianco 2008, Levy,
their pets to reproduce or who don’t want to tolerate personal communication 2012). High Quality High Volume
estrous behavior, the current method of choice in the US is Spay Neuter (HQHVSN) veterinarians reportedly perform
ovariohysterectomy, although as noted above, ovariectomy much more efficient and less traumatic procedures than
is becoming increasingly accepted. less experienced veterinarians; these surgical procedures
may compare differently to laparoscopic procedures (Levy,
Ovariohysterectomy involves putting the animal under
general anesthesia, shaving the abdomen, making an
incision in the midline of the abdomen or the flank, and
3.1.2.2 Males
removing the entire uterus and both ovaries. Ligatures are
placed to tie off the major blood vessels, ligate the uterine Male dogs and cats are castrated under general
stump, and close the incision. Ovariectomy involves anesthesia. Incisions or an incision is made in the scrotum
removal only of the ovaries though still under general (pre-scrotal incisions are most common in the US in
anesthesia. Some veterinarians may administer fluids and dogs) and each testicle is exteriorized, the blood supply
post-operative pain management drugs. and spermatic cord are ligated, and the incision is closed
in dogs or (commonly) left open in cats. Typically the
Reichler (2008) notes that “preference [for
procedure is completed quickly and risk of infection is low.
ovariohysterectomy versus ovariectomy] was most likely
based on the presumption that future uterine pathology Some veterinarians recommend this surgery for dogs that
is prevented by removing the uterus. However, historical have not yet reached sexual maturity to prevent them from
reviews of the short-term and long-term complications developing aggressive behavior, in the belief that castration
after ovariohysterectomy and ovariectomy leads [sic] to the eliminates testosterone, and reduction in testosterone will
conclusion that there is no benefit and thus no indication result in a reduction in aggression, but there is controversy
for removing the uterus during routine neutering in on the relationship of aggressive behavior to sex steroids.
healthy bitches.” Castration may not result in decreased aggression.
Van Goethem et al. (2006) conducted a literature review Although there has been concern that the urethral
to assess whether or not ovariectomy can be considered a diameter is decreased in male cats following prepubertal
safe alternative to ovariohysterectomy in dogs. Researchers castration, numerous studies have found no correlation
concluded that the procedures were equivalent in terms between castration and urethral diameter or lower urinary
of long-term urogenital issues that include endometritis, tract disease (Root Kustritz 2010). In general, there seems
pyometra, and urinary incontinence, and pointed out that to be neither an increase nor a decrease in health issues in
ovariohysterectomy “is technically more complicated, castrated male cats versus non-neutered males; however,
time consuming, and is probably associated with greater there is a higher risk of diseases such as FIV and FeLV
morbidity (larger incision, more interoperative trauma, transmitted by fighting among non-neutered males.

One alternative to surgical castration in males is complete suppression of GnRH effect, since to be effective,
a vasectomy; however, this procedure is not widely GnRH must be “seen” through the receptors in the
performed in part because it does not affect undesirable pituitary cells.
aggressive behavior (University of California, Davis GnRH agonists have been developed for use in human
(UCD) 2012). However, behavior changes expected post- medicine and are available as generic peptide drugs such
castration may not be realized; the overwhelming issue as leuprolide, nafarelin, triptorelin, and histerelin. These
related to undesirable aggressive behavior is lack of owner peptides have to be given by injection or subcutaneous
satisfaction. Owners who spend money on contraception implantation, because if given orally, they are digested and
want the unwelcome behaviors to be rectified (Jöchle, not biologically active. Effective slow-release implants have
personal communication 2012). been developed for humans that are used for 3-12 months
to suppress testosterone in the treatment of prostate cancer
and to suppress estrogen in the treatment of endometriosis.
They have other uses such as treatment of precocious
puberty and have also been developed as inhalant
formulations. Further discussion of GnRH agonists for use
in humans is beyond the scope of this report.
Another GnRH agonist – deslorelin – was developed in
an implant formulation for use in dogs and has been used
in both domestic animals and wildlife (see section 3.2.1.1.
below).
3.2 Gonadotropin-Releasing Hormone A disadvantage of the GnRH agonist approach to

(GnRH) suppress reproductive activity is that initial administration
in males and females typically causes an initial temporary
There are three major considerations governing
increase in follicle-stimulating hormone (FSH) and
interventions to create fertility suppression at the level of
luteinizing hormone (LH). In females, this increase may
GnRH:
result in inducing estrous. In males, the increase in LH
� Potentially effective in males and females causes an increase in testosterone that does not express
� Potentially effective in canine and feline species, because itself clinically. (When GnRH agonist implants are used
GnRH is highly conserved (i.e., the gene coding for GnRH for treatment of human prostate cancer, the stimulation of
results in the translation of the same decapeptide with the testosterone aggravates the condition, causing increased
same sequence of amino-acids among mammals) bone pain from metastatic tumors and a stimulation of
� Suppression of GnRH will result in suppression of tumor growth. This initial stimulation is called a “flare.”)
the secretion of the reproductive steroid hormones It is important to understand that the mechanism of action
and therefore suppress sexual behavior and hormone- of GnRH agonists is characterized by flares of varying
mediated diseases as well as fertility duration and that GnRH agonists are therefore not effective
Concern has been expressed that since GnRH receptors in situations in which an immediate suppression of fertility
exist outside the pituitary gland and reproductive tract, is desired. Once the agonist is discontinued, either by
approaches targeting GnRH may have effects on non-target removing an implant, or depletion of the active drug or
tissues. However, no such effects have been identified stopping daily administration of the injectable form of the
despite more than a decade of treatment with these drug, the return-to-fertility timeframe is unpredictable.
approaches (Asa, personal communication 2012). So, although a minimum duration of effectiveness can be
determined, it is difficult to predict when the effects will
3.2.1 Overview of GnRH Agonists wear off in a treated individual.
Studies in dogs using these compounds date back to 1984
Effective GnRH agonists, which mimic the effect of (Vickery et al. 1984) and have continued to the present day.
native GnRH but have a longer half-life in the blood, A number of compounds have been shown to be effective
work by binding to and causing down-regulation of the for use in dogs, and many types of formulations have been
GnRH receptors in the pituitary gland. The continuous studied (Gobello 2007).
administration of agonists (as opposed to the normal
pulsatile release of endogenous GnRH) results in a While delivery systems for animals were one of the

early limiting factors for development of commercial condition of older intact male dogs. Dogs with clinical
formulations of GnRH agonists, biocompatible signs of prostate disease are typically castrated to shrink
formulations have been developed that are cost effective the prostate, so treatment with a GnRH agonist could be of
and convenient to use, and provide long-term release of benefit for dogs suffering from this condition.
adequate levels of GnRH agonist (Herbert and Trigg 2005).
In fact, in the last decade, two GnRH agonists have been
approved for use in contraception in dogs in markets
outside the US.
In a relatively recent review article, the authors explain
that “All the studies [of GnRH agonists reviewed for
this paper] reported a simultaneous decrease in testes
volume and consistency. In general testicular volume was
decreased 2- to 5-fold in the 4-5 weeks following treatment 3.2.1.1 Deslorelin
start, and this regardless of the GnRH agonist used. …
Although the original stimulating effect causes serum 3.2.1.1.1 Deslorelin in Dogs – Males
FSH and LH concentrations to rise from 20 m[inutes]
As noted above, there has been a great deal of research
after treatment start, with a peak after 40 m[inutes], these
into the use of GnRH agonists in dogs. This section
values return to normal in the next 5 h[ours] then collapse
provides some examples of studies on the use of deslorelin
on average 2-9 days later … The same is observed for
in male dogs:
testosterone blood levels. … However, the response was
very variable from one individual to another” (references A review article (Kutzler and Wood 2006) describes
cited in Fontaine and Fontbonne 2011). several studies that have examined the use of deslorelin as
a contraceptive in male dogs. Subcutaneous administration
One product, Suprelorin® (deslorelin implant), is
of a 6 mg, slow-release deslorelin implant reduced plasma
available as a 6-month (4.7 mg) or 12-month (9.4 mg)
concentrations of LH and testosterone to undetectable
implant for use in male dogs. Suprelorin was developed,
values within 4 weeks and caused infertility within 6
approved by regulatory bodies and launched in Australia
weeks. Testosterone and LH concentration and semen
and New Zealand by Peptech Animal Health. Peptech
quality returned to normal by 60 weeks after implant
also obtained regulatory approval for use in male dogs in
administration. Histological analysis at the end of the
the EU and the product was commercialized in Europe
treatment period indicated that the testes and prostate
by Virbac. (Virbac ultimately acquired Peptech Animal
gland of treated dogs were not different from those of
Health in 2011.) Research has shown that Suprelorin is
untreated controls. Researchers concluded that the implant
also effective in fertility suppression in bitches and in
would be effective for long-term, reversible fertility control
male and female cats. Suprelorin has been used off-label to
in male dogs (Junaidi et al. 2003). Other researchers also
contracept several canid and felid species in US zoos and
concluded that deslorelin-treatment-induced effects on
wildlife in South Africa.
fertility were completely reversible (Trigg et al. 2001, Dubé
The other GnRH agonist approved in the EU is et al. 1987).
Gonazon™ (azagly-naraferlin), a controlled-release device
Subsequent work by Junaidi et al. further described
developed by Intervet prior to the consolidation of Intervet
deslorelin research in dogs: A study published in 2007
and Schering-Plough Animal Health (now MSD or Merck
indicated that treatment with a 6 mg deslorelin implant
Animal Health). Gonazon was approved in the European
“desensitized the pituitary gonadotrophs to GnRH and
Union (EU) in 2006 for use in female dogs. Research has
also led to a desensitization of the Leydig cells to LH. This
shown that it is also effective in female cats, although it was
explains, at least in part, the profound reduction in the
never approved for cats. Unfortunately, Gonazon was not
production of androgen and spermatozoa in deslorelin-
commercialized and is therefore unavailable.
treated male dogs.”
Note that in addition to contraception, GnRH agonists
In 2009, Junaidi et al. reported on a dose-response
also cause significant shrinkage of the prostate gland
study in which the effects of 3-, 6-, or 12-mg deslorelin
(Limmanont et al. 2011), which is a clinical advantage
implants on pituitary and testicular function were
for dogs with benign prostatic hyperplasia, a common
assessed. The researchers concluded that the degree of

suppression of reproduction was not subject to a dose- 3.2.1.1.2 Deslorelin in Dogs – Females
response relationship; however, the maximum duration Suprelorin (deslorelin) has been shown to provide
of suppression, and therefore the time to resumption of effective long-term contraception in bitches (Kutzler and
fertility, was dose dependent, with dogs treated with the Wood 2006, Gobello 2007). For example, subcutaneous
12 mg implant taking the longest time to restoration of full administration of a deslorelin slow-release implant (3, 6,
ejaculates (Junaidi et al. 2009). or 12 mg) to bitches “increased the duration of the mean
Other work indicated that 8 weeks after treatment with a interoestrous interval … at all doses” and suppressed
deslorelin 12-month (9.4 mg) implant, plasma testosterone estrus for up to 27 months independent of the stage of the
could not be detected in 23 out of 25 dogs treated. In one estrous cycle at implantation. When serum progesterone
dog, plasma testosterone reached zero (below the level of (P4) was greater than 5ng/mL, the initial stimulatory effect
detection of the testosterone assay) at Week 12 and in a caused estrous cycle induction 4-8 days after implantation.
second dog, plasma testosterone rose after treatment and Six out of nine bitches that were mated after recovery from
subsequently fell to zero at Week 16. Plasma testosterone treatment became pregnant (Trigg et al. 2001). (See also
was reduced for at least 12 months in all but two treated Kaya et al., Chapter 3, section 3.2.1.1.5.)
dogs, one of whom was lost to the study on Day 68; in the To suppress the possibility of inducing an estrus when
other dog, suppression was rapid and complete between initiating treatment, the AZA Wildlife Contraception
Week 2 and Week 20 but subsequent surgery suggested Center (WCC) at the Saint Louis Zoo (US) recommends
that the implant had been “lost.” Researchers reported “supplemental progestin treatment for 2 weeks (7 days
a mean duration of efficacy of 89 weeks, with a range of prior to and 7 days after implant insertion),” suggesting
56-132 weeks (Trigg and Yeates 2008). It has also been that megestrol acetate (MGA) (a progestin) is the simplest
demonstrated that multiple serial implantation in males approach, and cautioning that Depo-Provera® should
did not cause adverse effects of diminished efficacy. Dogs not be used (stlzoo.org/animals/scienceresearch/
that have been re-implanted for four consecutive doses contraceptioncenter/contraceptionrecommendatio/
at 6-month intervals with 4.7 mg deslorelin returned to contraceptionmethods/suprelorin-deslorelin/).
normal steroidogenesis after cessation of treatment (Trigg
GnRH agonists also were at one time used as pro-
et al. 2006).
fertility agents in female dogs due to their characteristic
In a discussion of the clinical use of Suprelorin to control “flare” (Gobello 2007); however, for induction of estrus,
fertility in male dogs (von Heimendahl 2010) the author the agents had to be administered by constant infusion
points out that in Europe: or by injection several times a day for up to 14 days.
“Suprelorin is used for different purposes in Therefore, that approach was deemed clinically ineffective
different countries. This seems to depend on for estrous induction. Fontaine and Fontbonne (2011) point
attitudes to surgery for neutering in general out that while the “two-step mechanism” of deslorelin
and the number of un-neutered pets in the dog implants (Suprelorin 4.7 mg) “may allow activation and
population as well as the use in stud dogs. In inhibition of the oestrous cycle, which both find clinical
countries like the UK, where neuter- applications in our everyday activity
ing of male puppies at 6 months of age [as veterinarians], from oestrous [sic]
is routine, the implant is used mostly induction to chemical sterilization,”
in older non-neutered males where data regarding use in bitches were
the owner wants to avoid surgery or primarily derived from animals
by breeders with several stud dogs to in an experimental rather than a
avoid aggression between males … In clinical setting. In this study of use
Scandinavian countries where neuter- of deslorelin to control fertility in
ing of males is not performed routinely the bitch, researchers investigated
as it is against animal welfare legisla- responses to a 4.7 mg deslorelin
tion, Suprelorin is used more often implant administered at various stages
to pharmacologically castrate males. of the estrous cycle since responses to
The implant can be given routinely implantation vary depending on the
every six months or when the increase stage of the estrous cycle in a given
in testicular size indicates that it has animal. Forty-six out of 47 bitches
stopped working.” (97.8%) experienced induced estrus

during the week after implantation, and this response response relationship where a particular dose may be
was not related to the stage of estrus in any particular sub-threshold for some individual animals. An alternative
animal. By 30 days post-implantation, 43 of the 47 dogs hypothesis is that there may be some variability in the
(91.5%) were not exhibiting signs of estrus (Gobello 2007). implant manufacture process. There also appears to be a
Discussion of the use of the deslorelin implant to induce proportion of animals that continue to cycle during GnRH
estrus is included in the Gobello article but is beyond the agonist treatment, i.e. ‘non-responders.’ … The basis of this
scope of this report; readers wishing to learn more about variability is probably genetic … “
the findings related to estrous induction can access a Note that the use of GnRH agonists to treat urinary
summary at zoovet.ee/product/docs/2050981722.pdf. incontinence in ovariohysterectomized dogs has also been
Results reported in 2010 by Fontaine et al. at the 4th described (e.g., Reichler et al. 2003) but discussion of this
International Symposium on Non-Surgical Contraceptive application is beyond the scope of this document.
Methods of Pet Population Control involved documenting
the influence of the stage of the estrous cycle on the use of 3.2.1.1.3 Deslorelin in Cats – Toms
the 4.7 mg deslorelin implant for contraception in bitches. Work reported in 2010 (Goericke-Pesch et al.)
Researchers implanted 60 healthy bitches. Implants were demonstrated that male cats implanted with the 4.7 mg
placed in the umbilical region. The stage of the estrous Suprelorin implant displayed significantly reduced mean
cycle was determined based on history, vaginal smear, testosterone concentrations within 28 days. Researchers
progesterone assay, and ovarian ultrasound at study found that mean T concentrations were below the limit
start and on Day 15 and Day 30. Researchers found the of detection on Day 20. Time to complete suppression
following estrous cycle distribution in study animals: 41 of fertility, as measured by T values under the limit of
were in anestrus when implanted; 14 were in diestrus; 5 detection of the assay, was 20 days to 11 weeks post-
were in estrus. The following results were obtained:3 implantation.
� 40 of 41 bitches implanted in anestrous exhibited
induced estrus. Thirty days post-implantation, 38
animals no longer exhibited signs of estrus.
� 5 of the 14 bitches implanted in diestrus exhibited
estrous induction and researchers removed the implants.
� In 40 bitches exhibiting induced estrus, estrus was
observed 4.2 +/- 1.4 days after implantation, and
ovulation occurred 12 +/- 2 days later.
� 13 bitches were anovulatory, 11 of which were implanted
in early anestrus and 2 were implanted in estrus.
� Ovarian cysts were reported in 2 animals; persistent
estrus was reported in 2 animals. These animals were An approximately 21% decrease in mean testicular size
neutered via surgery. was observed at Week 4 in treated toms; beginning at
Researchers documented down-regulation in 31 of the Week 12, mean testicular size decreased by greater than
41 animals implanted in anestrus and concluded that 50% and this decrease was maintained as long as fertility
“deslorelin implants appear to be a quick and safe way to was suppressed. Researchers noted that “… penile spines
neuter bitches. Diestrus seems to represent the best period disappeared, as in surgically castrated cats. All castration-
to avoid estrous induction. It is advisable to monitor the related side effects [were] observed following successful
implanted bitches in the 30 days following implantation in down-regulation and ceased T production, [including]
order to confirm down-regulation.” a significant increase of food intake … urine marking
stopped or at least significantly decreased [and] following
Herbert and Trigg (2005) note the wide variability among
an initial increase, sexual behavior, mounting, libido, and
GnRH-agonist-treated bitches in terms of resumption
mating were significantly reduced in treated toms after 11-16
of estrous cycles: “This variability may be the result of
weeks; however, mounting could be observed after excessive
genetic variations in the sensitivity of individual animals
animation by a teaser queen. Toms become temporarily
to GnRH–induced down-regulation. As the variability
infertile after treatment; however, infertility may be delayed
is often greatest at lower doses it may represent a dose-
by about 6 weeks after successful down-regulation … all
3
Please note that the terms anestrus and diestrus seem to be
used interchangeably.

effects [were] fully reversible. Duration of efficacy – as As of the date of this 2010 Goericke-Pesch et al.
observed from clinical experiences – varied between six publication, no data regarding reversibility had been
and 24 months. Return of spermatogenesis to pre-treatment published; however, the authors note that “it can be
semen quality may take up to five - six months; initial return demonstrated that at the end of the efficacious period,
can be expected in five to nine weeks.” ovarian weight and uterine diameter are similar to
Histological examination of testes has confirmed untreated controls … observations restricted to clinical
induction of infertility, with a return to normal parameters cases [indicate] that queens mated following treatment in
after removal of the implants (Novotny et al. 2012). naturally occurring estrus conceived and delivered healthy
kitten[s].”
A study published in 2012 was designed to ascertain
the safety and efficacy of 4.7 mg deslorelin implants in
postponing puberty in 15 domestic queens. Researchers
diagnosed puberty by “the presence of the typical oestrous
behavior and vaginal cytology finding.” An estrous
response was seen in one treated queen; in another, clinical
signs of pyometra were seen. Upon ovariectomy at puberty,
ovaries “appeared small” in treated queens compared to
3.2.1.1.4 Deslorelin in Cats – Queens
control queens. Researchers concluded that “long-term-
Suprelorin (deslorelin) has been shown to effectively release deslorelin, administered at approximately 50%
suppress ovarian activity in cats, but the duration of adult body weight, postponed feline puberty without
suppression reported was variable. The drug was given at altering [growth] rate” (Risso et al. 2012).
6 mg via a long-acting subcutaneous implant to 10 mature
Another recently published study assessed the
female cats and compared with 10 untreated controls,
effectiveness and safety of deslorelin implants for
and animals were observed for 14 months. Treatment
suppression of estrous behavior and mating activity in
with deslorelin, as expected, initially stimulated estradiol
queens “in a controlled ambient environment in feline
release, followed by its decrease. Return to estrus was
queens in the presence of a tomcat.” Cats in treatment
variable, and ranged from 7.5 to up to 14 months or greater
Group 1 received a deslorelin implant (9.5 mg), cats
(six animals had not yet returned to estrus at the end of
in Group 2 received a 5 mg MGA tablet and 9.5 mg
the study). Some cats that demonstrated slightly elevated
deslorelin implant, and cats in Group 3 received a placebo
estrogen levels were given a second implant (Munson et al.
implant. At 18.5 months into the study the queens were
2001).
ovariohysterectomized. Researchers weighed the ovaries
Goericke-Pesch et al. 2010 reported that queens can and uteri and performed histological examination.
be implanted during seasonal anestrus, in estrus or in Estradiol levels in Groups 1 and 2 were significantly below
interestrus. Researchers noted that induction of estrus those in Group 3, and ovarian and uterine weights differed
in queens implanted during seasonal anestrus can be significantly among the groups, and were the lowest in
expected to occur. In the study, “following the initial Groups 1 and 2. Groups 1 and 2 had significantly higher
increase of [estradiol] (E2) and also of progesterone numbers of primordial and primary follicles than in Group
(P4) concentrations, hormone concentrations started to 3 (placebo group). Endometrial gland, antral follicle, and
decrease 2-4 weeks after implantation in treated queens. A corpora lutea numbers were highest in the placebo group
temporary increase of E2 with or without estrus signs may (Group 3). Researchers concluded “Deslorelin implants
be observed during the effective treatment and is followed successfully suppressed estrous behavior and E(2) secretion
by phases without sexual activity, indicating that treatment in queens for 18.5 mo[nths] of the study period. Further
is still effective.” In this study, suppression of estrus varied investigations are needed to demonstrate the effects of
between 6 and 24 months, and researchers noted that GnRH agonists on ovarian interstitial tissue” (Toydemir
“Interestingly, injection of a second 4.7 mg implant during and Kiliçarslan 2012).
effective estrous suppression (a temporary increase of E2
At this juncture “there is inadequate understanding of
was observed in 1/10 cats, therefore 5/10 were implanted
the incidence of induced estrus, ability to conceive during
again) did not influence the duration of efficacy (one
estrus, and – if pregnancy occurs – impact on parturition
implant: 11.1 ± 2.9 months versus two implants: 11.0 ± 2.3
and lactation” in female cats treated with deslorelin
months).”
(Briggs, personal communication 2012).

3.2.1.1.5 Recently Reported Research Involving the Use
of Deslorelin for Contraception
Research involving the use of deslorelin implants for The following studies or reviews related to contraception
contraception and other indications in dogs and/or cats and reported at the 7th International Symposium on Canine
is ongoing, with more than 50 studies believed to be and Feline Reproduction in July 2012 are summarized
underway at the time of this update (Briggs, personal below. Proceedings of this symposium are available at ivis.
communication 2012). org/proceedings.
Table 3-2: Use of Deslorelin for Contraception in Cats and/or Dogs4

Deslorelin acetate (Suprelorin) effects in semen quality of domestic cats
(Ackermann et al.)
Investigators found that the use of deslorelin acetate in domestic cats decreased semen quality but did not suppress production of
sperm completely, possibly due to inter-animal variation; “the return of spermatic production was not observed in semen collection.”
Effect of deslorelin acetate (Suprelorin) in domestic cat testicular morphology

(Ackermann et al.)
Investigators found that “deslorelin acetate causes atrophy in seminiferous tubules, lineage sperm depletion and decrease of epi-
didymal content, indicating partial suppression of spermatogenesis. After termination of treatment the recovery of spermatogenesis
was observed through the recovery of spermatozoa lineage in the seminiferous tubules and increase of sperm content in epididymal
lumen.”
Delay of puberty and reproductive performance in male dogs following the implantation of 4.7- and 9.4-mg GNRH-agonist deslo-
relin at early prepubertal age
(Sirivaidyapong et al.)
Investigators assessing the length of effectiveness (i.e., suppression of reproduction) of deslorelin implants in male dogs implanted at
4 months old found that the 4.7 mg implant was effective for less than 2 years in three of four treated dogs. The 9.4 mg implant was
effective for 2.5 years in Beagles (n=2) and 3.2 years in mixed breed dogs (n=2). Reproductive characteristics in control dogs devel-
oped normally.
Postponement of puberty using GnRH agonists implants in bitches of different breeds

(Fontaine et al.)
Researchers investigated the use of 4.7- or 9.4-mg deslorelin implants for puberty postponement in client-owned bitches younger
than 6 months old. One bitch implanted with a 4.7 mg implant “was re-implanted with a similar implant 6 months after the first
implantation at the request of the owner.” Bitches implanted with the 4.7 mg implant showed signs of estrus at 13-24 months post-
implantation; six did not display signs of estrus at study end (16-25 months post-implantation). None of the bitches treated with the
9.4 mg implant showed signs of estrus by the end of the study period (8-15 months post-implantation). Researchers concluded that
“Although further fertility could not be studied, [the] data seems [sic] to indicate that implantation of bitches of various breeds less
than 6 months of age is a valuable and safe way to postpone puberty, without noticeable side effects.”
Onset of sterility following administration of a 4.7 mg deslorelin implant in adult male dogs
(Romagnoli et al.)
Investigators administered deslorelin implants to six client-owned dogs referred to the University of Padova (Italy) Veterinary
Teaching Hospital “with the request to control aggressiveness and/or fertility.” All dogs presented with normal clinical and repro-
ductive parameters. The characteristic post-treatment “flare” occurred initially “during the first month … followed by a progressive
decline in most of the seminal parameters considered … during the subsequent 3 months.” Sterility characterized as “complete” was
achieved at 54 +/- 21 days.
Behaviour and the pituitary-testicular axis in dogs before and after surgical or chemical castration with the GnRH
agonist deslorelin
(de Gier et al.)
Investigators compared specific effects of surgical castration and use of a GnRH implant in owned dogs. Eighteen dogs underwent
surgical castration and 24 received a Suprelorin 4.7 mg implant. Endocrinological parameters and aggression, fear/insecurity, play
behavior and sexual behavior were assessed and questionnaires were completed prior to and 4-5 months post-procedure. No signifi-
cant difference was found between the two approaches in terms of plasma testosterone concentration and behavioral parameters. The
perceived effect of surgical castration on male sexual behavior in the presence of bitches in estrus was greater than that of the implant
and “despite the similarly low basal plasma testosterone concentrations in both groups … [in all implanted dogs] the pituitary tes-
ticular axis was not completely down-regulated.”

Pharmacodynamics and pharmacokinetics of a sustained-release implant of deslorelin in companion animals
(Navarro and Schober)
Investigators confirmed the characteristic “dual mode of action of sustained-release forms of GnRH agonists” and noted that “the individu-
al variations of the duration of action may be explained by the mode of action involving gene regulation.”
Clinical use of deslorelin implants for long-term contraception in prepubertal bitches
(Kaya et al.)
Investigators assessed the use of 4.7 mg (n=5) and 9.4 mg (n=5) deslorelin implants in prepubertal (4-month-old) bitches in terms of
duration of effectiveness, safety, and reversibility “with special regard to the time of epiphyseal closure.” The study indicated that
both formulations provide effective and safe long-term prevention of estrus in prepubertal bitches implanted at 4 months of age;
while height at withers was not affected significantly, delay in epiphyseal closure was seen. As of the reporting, none of the bitches
showed any sign of estrus throughout the study (15-17 months after the experiment had started).
GnRH agonist implants result in estrous induction and estrous suppression
(Fontbonne et al.)
GnRH agonists are used to induce estrus; however review of this specific use is beyond the scope of this document. The authors cite a
relative lack of information regarding estrous prevention and suppression in prepubertal bitches and queens, although some studies
have been undertaken (e.g., Trigg et al. 2006, Goericke-Pesch 2011 EVSSAR Congress). References cited in this abstract can be found at
ivis.org/proceedings/iscfr/2012/195.pdf?LA=1.
3.2.1.2 Nafarelin “Control dogs received a placebo implant and

treated dogs received Gonazon containing 18.5
3.2.1.2.1 Nafarelin in Dogs mg azagly-nafarelin. Throughout the 1-year
The GnRH agonist azagly-nafarelin is used in fish to treatment estrous behavior was monitored weekly
induce and synchronize egg production. In Europe, it and plasma progesterone concentration, body
was also approved as Gonazon, an 18.5 mg subcutaneous weight, and height were measured monthly.
controlled-release implant intended for use as a long- Following implant removal, estrous detection
term blockade of gonadotropin function in female dogs to and progesterone measurement were continued
prevent puberty. As noted earlier in this chapter, Gonazon until occurrence of puberty in all bitches. None of
was not commercialized by its developer Intervet or its the Gonazon-treated bitches displayed puberty
successor companies, Intervet/Schering-Plough Animal during the period in which Gonazon was present.
Health and MSD/Merck Animal Health. Following removal of Gonazon, resumption of
estrus and ovulation occurred naturally or was
The GnRH agonist nafarelin given daily at 2 µg/kg/day
induced approximately 8.5 months later. No
decreased testosterone levels within 3 weeks after initiation
clinically detectable side effects were noted in
of treatment, and normal fertility was restored within 8
Gonazon-treated bitches. Height at withers and
weeks following cessation of treatment (Vickery 1985).
body weight with time were also unaffected.
In one study of young Beagles approximately 5 months The implants were well tolerated and generally
of age, puberty was delayed for 8 to 16 months (Rubion et easy to remove. Researchers concluded that
al. 2006). In that study: Gonazon safely, efficiently, and reversibly prevents
4
As reported at the 7th International Symposium on Canine and
Feline Reproduction (Whistler, BC, Canada 2012).

reproductive function for 1 year in prepubertal queens had high progesterone levels, suggesting that
bitches. In older bitches (12 months or more), they had ovulated before treatment. During the week
Gonazon implants blocked reproductive function following treatment, two other queens displayed
for approximately 11 months.” a rise in progesterone concentrations. Later on, all
treated queens continuously displayed low progester-
3.2.1.2.2 Nafarelin in Cats one concentrations until 2.5 years post implant inser-
In a study described at the 6th International Symposium tion. At this stage, two queens had an isolated episode
on Canine and Feline Reproduction in Vienna and of follicular luteinization, but all queens in the treated
published in 2009, researchers inserted one azagly-nafarelin group again became anovulatory. This research indi-
(Gonazon) implant, containing 20 mg azagly-nafarelin, cated that Gonazon efficiently prevented ovulation in
subcutaneously in the necks of six treated queens. Ovarian queens for 3 years and was well tolerated. Return to
activity of treated queens and six control queens was estrus was not observed towards the end of treatment
monitored for 3 years. despite low azagly-nafarelin concentrations in some
queens.” (Prohaczik et al. 2008; Rubion and Drian-
“The contraceptive efficacy of Gonazon was assessed
court 2009).
by the proportion of queens in which a progesterone
rise indicating ovulation was demonstrated follow- 3.2.1.3 Other GnRH Agonists
ing continuous housing with a vasectomized tomcat,
which was rotated each week between treated and The GnRH agonist leuprolide acetate, given to dogs as
control queens. The marker of ovulation used was a single injected dose at 1 mg/kg, causes spermatozoa
progesterone concentrations exceeding 10 ng/mL abnormalities and significantly decreases ejaculate volume
for at least 2 weeks. General safety was assessed by and testosterone and LH concentrations for 6 weeks. In one
veterinary examinations including weight measure- study, normal spermatogenesis resumed 20 weeks after
ments, performed at study initiation, after one year, treatment (Lacoste et al. 1989). Buserelin implants (6.6 mg)
and then every 6 months. All six control queens decreased testosterone concentrations in male dogs and
ovulated regularly throughout the 3-year treatment produced infertility within 3 weeks; the effect persisted for
period. At treatment initiation three Gonazon-treated an average of 233 days (Kutzler and Wood 2006).
3.2.1.4 GnRH Agonists: Summary of Advantages and Disadvantages
Advantages Disadvantages
Proven to suppress fertility in both males and females Initially may induce estrus in females
Suppress sexual behavior – females will not come into Need to be given repeatedly to maintain effects
estrus during treatment, males will behave as castrates
Active compounds available as generics (manufac- No patent protection for common active drugs
tured under current good manufacturing practice
(cGMP))
Demonstrated to be effective in a variety of formula- A commercially viable product may need to have at least 6-12
tions, including depot injections, microspheres, and months of efficacy for convenience (longer duration will be
implants desired for many pets and unowned animals)
Reversible – when the drug is discontinued, reproduc- If lifetime contraception is desired, repeated treatments will be
tion should resume within a reasonable period of time necessary lifelong
(could be used in animals intended for breeding)
Slow onset of activity (generally a few weeks) and variable

duration of treatment effects

3.2.2 Overview of GnRH Antagonists least the 1990s. Danforth et al. (1991) characterized antide
as a promising compound and reported that in primates,
GnRH antagonists block GnRH receptors, and suppress antide manifested prolonged (several weeks) and reversible
fertility by blocking the GnRH receptors on the pituitary inhibition of pituitary gonadotropin secretion after a single
cells. Why were GnRH antagonists developed when high-dose injection. No agonistic actions of antide were
available GnRH agonists work so well? The answer is that seen in vitro. Antide was reported to have no apparent
the initial stimulation side effect caused by agonists can be noxious or toxic effect on pituitary cells in culture; the
avoided by using antagonists instead. An antagonist would actions of antide are immediately reversible upon removal
not cause the initial stimulation of sexual behavior. Unlike of antide from pituitary gonadotropes. Researchers
the GnRH agonists, which can take several weeks to have a concluded that the long-term inhibition of gonadotropin
suppressive effect, the antagonists have an immediate effect secretion by antide in vivo is not due to deleterious effects
of suppressing the reproductive hormones. of this compound at the level of the pituitary gonadotrope.
Gobello (2012) contends that while “GnRH antagonists
appear to have a promising future in domestic carnivore
reproduction there is still scarce information about them
and further work is needed before they could be widely
recommended.”
Another limiting factor at this juncture is the cost
of the peptide GnRH antagonists (Jöchle, personal
communication 2012).
3.2.2.1 GnRH Antagonist Peptides

The first GnRH antagonists were peptides with a
structure similar to GnRH. Most of the small peptides work
in all species, due to the highly conserved structure of the
GnRH receptor.
Serono was developing antide (Iturelix) for endometriosis
“The peptides involved are typically more expensive
and prostate cancer in humans in the early 2000s but
to manufacture [and] are often only effective at much
development was suspended in 2005. Serono become
higher doses [than GnRH agonists] … The high dose
Merck KGaA Serono in 2007 and there is no reference to
requirement in turn limits the potential for combination
antide on the Merck Serono website as of the date of this
of the antagonists into … long-term release technologies
update.
without involving overly large implants or injection depots.
First-generation GnRH antagonists [such as] detirelix had Merrion Pharmaceuticals, LLC has been developing
the problem of histamine release activity, most of which MER-104, an enteric-coated oral formulation of the GnRH
has been overcome in many [later-generation] antagonists antagonist acyline. The injectable form of acyline has been
[such as] azaline, acyline, degarelix, abarelix, cetrorelix, shown to have “potential as a contraceptive regimen in
and ganirelix [although unpleasant side effects were man.” A dose-ranging study with MER-104 demonstrated
reported in conjunction with use] in some human patients” “measurable serum levels of drug at all doses and dose-
(Concannon 2006). related suppression of serum LH and serum testosterone.
Liver function and creatinine were unaffected by treatment.
Examples of small peptide compounds that have been
The data indicate that MER-104 tablets may have
studied are antide (Iturelix), cetrorelix (Cetrotide™, Astra
potential in the treatment of prostate and breast cancer,
Medica), ganirelix (Antagon™, Organon (now Merck)), and
endometriosis, prostate hyperplasia, and as part of a male
acyline. Cetrorelix has activity in monkeys, dogs, rats, and
contraceptive” (Amory et al. 2007).
humans (for a review, see Reissman et al. 2000). In humans,
Cetrotide and Antagon, for example, are used for short- “Newer third- and fourth-generation decapeptide
term treatment to suppress GnRH to prevent premature antagonists have been reported to have increased potency
ovulation in women undergoing controlled ovarian and durations of action and are likely to further R&D at
stimulation for fertility treatments. least for human applications. However, durations are
Work on the GnRH antagonist antide dates back to at reported in days rather than weeks and even micro-particle

preparations have effective durations reported in weeks with Abbott Laboratories related to developing and
rather than months … [such] short-term GnRH antagonists commercializing elagolix and all the company’s next-
regimens might be useful to prevent the undesired effect generation GnRH antagonists specifically for men’s and
of estrous induction in agonist-treated anestrous animals” women’s health applications. Under the terms of the
(Concannon 2006). agreement, Neurocrine and Abbott are working together
towards regulatory approval and commercialization of
3.2.2.2 Non-Peptide GnRH Antagonists the GnRH antagonist compounds. The Phase III trial
Non-peptide (small molecule) GnRH antagonists of elagolix for endometriosis began in mid-2012, and
have the potential to be developed as oral, mucosal, approval is expected in the US in 2016 (Neurocrine Sciences
and/or dermal formulations delivered via drug-release website 2012). Abbott is bearing all costs of development,
technologies that differ from typical peptide-release marketing, and commercialization and in return will
implants (Concannon 2006). These small molecule receive a percentage of the global sales of GnRH antagonist
GnRH antagonists show species differences: They were compounds (Neurocrine Science Press Release, June 16,
designed to bind the human GnRH receptor and block 2010). Abbott has an animal health organization but to our
activity. They are significantly smaller than the peptide knowledge, this compound is not under development for
antagonists; the larger GnRH peptide antagonists will bind animals.
the GnRH receptors in rats, humans, dogs and likely most
all mammalian species, showing cross-species activity. 3.2.2.3 GnRH Antagonist in Dogs
However, it has been demonstrated that the small molecule As noted in the section above, one method of blocking
drugs do not work in all species. Although they bind and the action of GnRH is to make a small peptide or molecule
antagonize the GnRH receptor in some species, minor that is similar in structure to GnRH, and binds with the
differences in the receptor structure between species can GnRH receptor without activating it, e.g., an antagonist.
result in a particular compound being effective in rats Although several peptide GnRH antagonists are approved
and humans, for example, but not in dogs. Therefore it for various uses in humans, none is approved for use in
cannot be assumed that small molecule GnRH compounds dogs or cats as of mid-2012.
developed for use in human health will necessarily work A 2007 review article notes that although the effect of GnRH
in dogs and cats. Each compound will require testing in the antagonists in female and male dogs was described in the 1980s
target species (Cui, 2000). and third-generation GnRH antagonists have been studied in
Several biotechnology companies have worked on or dogs more recently, the data are limited. As noted previously,
are working on non-peptide GnRH antagonists. Note that first-generation GnRH antagonists were characterized by
these examples are not necessarily all inclusive. limited duration of activity and had a tendency to produce
For example: allergic reactions and other systemic adverse reactions (Gobello
2007). There are no publications describing research on non-
Research at Merck Laboratories advanced the peptide GnRH antagonists in dogs.
development of non-peptide orally active molecules
(DeVita 1999). As of 2006, Merck, Bayer, Takeda, and Abbott 3.2.2.3.1 Males
Laboratories were all engaged in investigating non-peptide
In a dog study, a single subcutaneous
GnRH antagonists (Concannon 2006).
injection of the GnRH antagonist acyline
In 2007 researchers, including Dr. R. Scott Struthers, then at 330 µg/kg suppressed semen quality in
of Neurocrine Biosciences, reported on pharmacological six dogs for 2 months. Libido and erection
characterization of a novel non-peptide GnRH antagonist; were unaffected throughout the 2-month
researchers also noted that as of that date “only three period in three of the dogs, while three
small-molecule GnRH antagonist compounds [had] other dogs did not display these actions for
been reported at scientific meetings as having 1 or 2 weeks following treatment (Gobello
been evaluated in humans” (Struthers et al. 2007). Another study in dogs demonstrated
2007). Neurocrine BioSciences is developing that 330 µg/kg given at 2-week intervals was
its lead compound, elagolix, an orally active effective for decreasing semen quality; there were
nonpeptide GnRH antagonist. In June no hematological, biochemical, local, or systemic
2010, the company entered into an side effects noted (Valiente et al. 2007). The
exclusive worldwide collaboration requirement for such frequent treatments

could be solved by availability of a sustained-release difference related to the timing of pregnancy interruption.
formulation. Researchers concluded that acyline prevents normal
In a 2009 study of acyline in domestic dogs (Garcia estrus and ovulation in female dogs when administered
Romero et al. 2009), researchers assessed how a single during proestrus, and that pregnancy will be terminated
dose affected serum concentrations of FSH, LH, and approximately 1 week after administration at 30 to 35 days
testosterone. Researchers took blood samples before of gestation (Valiente et al. 2009). Researchers have also
treatment with acyline and throughout a 29-day post- investigated the use of acyline to prevent the characteristics
treatment period. As described in the study abstract post-treatment “flare-up” related to the use of a GnRH
“Serum concentrations of FSH, LH, and [testosterone] agonist. Hermo et al. (2006) reported that a single acyline
varied throughout the study period … Gonadotrophins injection “failed to prevent post GnRH agonist stimulation
decreased below pretreatment concentrations 60 minutes in anestrous bitches.” See also a second Valiente et al. 2009
after injection, whereas [testosterone] took 90 minutes publication, Effect of a GnRH antagonist on GnRH agonist-
to decrease below baseline … FSH, LH, and testosterone implanted anestrous bitches, listed in the bibliography.
decreased until Day 9, when they reached their nadir …
3.2.2.4 GnRH Antagonists in Cats
Both gonadotrophins and testosterone began increasing
on Day 14 after treatment, although FSH and T serum In a 2010 paper (Risso et al.), researchers reported on the
concentrations still remained below baseline on that day … use of acyline in queens relative to ovulation, development
FSH and testosterone rebounded above baseline on Day 29, of ovarian follicles, and maintenance of pregnancy.
whereas LH concentrations were similar to baseline at this One experiment involved seven queens representing 24
time … No local or systemic side effects were detected in “proestrous periods.” Queens “were randomly assigned to
any dog following acyline treatment. In conclusion, a single treatment with either acyline (n=17) or a placebo (n=7). All
acyline treatment safely and reversibly decreased serum queens were mated with a fertile tomcat. In the [acyline-
gonadotrophin and [testosterone] concentrations in dogs treated] and [placebo] groups, cessation of estrus occurred
for 9 d[ays].” 7.0+/-1.3 d[ays] and 7.0+/-1.7 d[ays] after treatment
[respectively], ovulation occurred in 2 of 17 and all seven
In another study (Garcia Romero et al. 2012), researchers
estrous periods [respectively], and pregnancy rates were
investigated the response of testosterone to GnRH
1 of 16 and 7 of 7, respectively … intervals from treatment
challenge over a 30-day period in male dogs treated with
to the onset of the ensuing proestrus were 18.4+/-1.7 and
acyline versus male dogs treated with a placebo. Dogs in
120+/-17.2 d[ays], [respectively].”
both groups were serially challenged with buserelin, a
GnRH agonist, and blood samples were taken before and
after injection of the agonist. There were no differences
in basal testosterone serum concentrations between the
treated and placebo dogs prior to treatment. Post-treatment
assessment indicated a “significant interaction between
treatment and day” and independent analysis of each group
indicated that “basal testosterone varied in the acyline but
not in the placebo group.” The researchers reported that “on
Days 1, 3, 7, 10 and 14, the response to the agonist differed
between groups, becoming similar on Days 21 and 30. It was
concluded that, in dogs, a single administration of the GnRH In a second experiment, “14 pregnant queens were
antagonist kept the canine gonadal axis from physiologically randomly allocated, according to their mating date,
responding to agonistic challenge during 14 days.” to treatment with acyline in early pregnancy … mid
pregnancy … late pregnancy … or injection of a placebo
3.2.2.3.2 Females in early … mid … or late pregnancy … No pregnancies
Acyline has been studied for pregnancy termination were prematurely terminated and post-treatment [serum
in female dogs. Animals received either acyline or a progesterone] concentrations did not differ among
placebo mid-pregnancy. Treated dogs received a single treatment groups.” Investigators concluded that in queens,
dose of either 110 µg/kg or 330 µg/kg. Pregnancy was “GnRH withdrawal by acyline prevented ovulation when
terminated successfully in acyline-treated animals but given in early follicular phase (proestrus) but did not
not in placebo-treated animals. There appeared to be no significantly affect luteal function during pregnancy.”

A paper on the use of acyline (Garcia Romero et al. 2011) Significant differences … were found between days for
describes a study on the effects of the GnRH antagonist epididymal sperm motility, vigor, abnormal morphology,
acyline on the testis of the domestic cat. As described in germinal epithelium height, spermatocytes, spermatids,
the study abstract “… mature cats were orchidectomised spermatozoa, lumen, and cellular debris. Conversely, no
unilaterally (right testis) on Day 7 … or Day 15. On Day significant differences were found for gross testicular and
0, 330 µg/kg acyline was administered subcutaneously tubular characteristics, spermatogonia, Sertoli and Leydig
to all the animals. Left orchidectomy was carried out on cells, and intertubular compartments. It was concluded that
Day 15 … Day 30 … and Day 60 … Sperm were recovered a single dose of acyline reversibly impaired spermiogenesis
from the epididymis and the testes were evaluated grossly, and sperm motility for 2 weeks.”
histologically, and immunohistochemically. There are no publications on the use of non-peptide
GnRH antagonists in cats.
3.2.2.5 GnRH Antagonists: Summary of Advantages and Disadvantages

Proven to suppress fertility in males and females for Need to be given frequently to achieve effects
short periods
Suppress sexual behavior – females will not come No depot or long-acting formulations have been developed for
into estrus during treatment; males will behave as use in animals
castrates
Reversible – when the drug is discontinued, repro- Reversible – when the drug is discontinued, reproduction
duction should resume within a reasonable period should resume within a reasonable period of time. Note that
of time (could be used in animals intended for irreversibility is preferred for many pets by their owners and for
breeding) unowned and “community” dogs and cats.
May be less expensive to manufacture (non-peptide Some of the first-generation peptide antagonists may cause
antagonists) histamine release in dogs
May be given orally (non-peptide antagonists)
Effective within a short period after treatment initia-
tion (hours)

3.2.3 Overview of GnRH-Toxin Conjugates be delivered specifically to gonadotroph cells when the
GnRH binds to the GnRH receptor in the pituitary and
Another approach is internalized as part of normal cellular processes. The
to suppressing GnRH target gonadotroph cells in the anterior pituitary gland
involves ablation of the synthesize and secrete LH and FSH. Once destroyed,
gonadotrophs, which are the gonadotrophs are unable to produce LH or FSH and
cells in the pituitary that therefore the treated animal is rendered infertile, i.e.,
have GnRH receptors cannot produce viable sperm or eggs.
and secrete LH and
Sabeur et al. (2003) reported on a study to evaluate the
FSH. Coupling GnRH
effect of a GnRH analogue conjugated to the cytotoxin PAP
to a toxin or protein-
obtained as a plant extract, on reproductive function in 12
synthesis inhibitor is
adult male dogs. Four received GnRH–PAP every hour for
a way of delivering
36 hours via IV catheter; four dogs received GnRH–PAP
the toxin or inhibitor
as a bolus injection daily for three consecutive days; one
directly to only one type of cell – those that have GnRH
dog received a single bolus; and three served as controls,
receptors.
receiving GnRH without the PAP. Twenty-five weeks after
The concept is that the GnRH conjugate (GnRH plus a the initial treatment, all treated dogs received a single
toxin) will bind to the GnRH receptors in the target cells of administration; dogs in the control group received GnRH
the pituitary (gonadotrophs). This GnRH receptor/GnRH- analogue. Testosterone and LH serum concentrations were
toxin conjugate complex will then be internalized, and the monitored and testis size was measured for 9 months after
toxin will be released from the complex only in those specific treatment. Researchers found that serum testosterone
cells, causing them to die. (Nett and Jarosz 2002, Ball et al. concentrations were significantly lower after treatment
2002). Then, theoretically, permanent sterility would result, in the bolus and hourly groups than in the control group,
and little or no “off-target” toxicity would be seen. and that administration once a day for 3 days “appeared to
The specificity of the toxin delivery is a potential issue result in a greater suppression of pituitary LH release than
related to this approach. The pituitary gland is full of did hourly administration for 36 hours of an equivalent
other important cell types, such as cells that make growth dosage.” Pituitary function returned approximately 5
hormone and hormones that stimulate the thyroid and months after the first and second administrations, as
adrenal glands, among others. Showing that the GnRH- measured by increases in LH and testosterone. Researchers
toxin conjugate is safe to other pituitary cells will be concluded that “administration of the conjugate GnRH–
important. GnRH receptors are also found in nontarget PAP at a 25-week interval resulted in a major disruption
tissues (e.g., the heart and colon); therefore theoretically of reproductive parameters in male dogs; this effect was
these receptors could also internalize toxin and be killed, maintained for 11–12 weeks after a second injection of
thus having unintended toxicity. Also, assuring that GnRH–PAP” and noted that “further studies are required
conjugation of the toxin to the GnRH molecule is consistent to determine whether this approach may be useful to
and complete, both in the bottle and in the body, is disrupt reproductive function in this species permanently
important so animals don’t get exposed to free toxin. and should include a more thorough dose-ranging study”
(Sabeur et al. 2003).
See Chapter 4, section 4.2.3 for an update on Gonex, Inc.,
which became Cedus, Inc., a company that began working A 2006 publication described a study in which the
on a GnRH-toxin conjugate in the early 2000s. objective was to examine the ability of the conjugate
to disrupt reproductive function in two groups of
3.2.3.1 GnRH-Protein Synthesis Inhibitor Conjugate peripubertal male dogs (16-32 weeks old). The 7 dogs in
In the 2002 Contraception and Fertility Control in Animals Group I received a second treatment 20 weeks after the
report, it was noted that an approach to control of GnRH initial treatment; the 3 Group II dogs were treated in the
involving the use of GnRH conjugated to a protein same time frame but using a different dosage pattern.
synthesis inhibitor – in this case pokeweed antiviral There were 5 control dogs. Group I dogs not responding
protein (PAP) – was under investigation by Dr. Terry to the two initial treatments were treated a third time, at
Nett of Colorado State University. Linking GnRH to PAP 12 months following initial treatment. The initial GnRH-
was reported to allow the protein synthesis inhibitor to PAP treatment did not affect testis growth, LH release or

serum testosterone concentrations in the target animals, but synthetic GnRH vaccine with T-helper epitopes (Sad 1993),
administering “a higher dose of GnRH-PAP after puberty the use of a recombinant GnRH immunogen (Robbins
resulted in a marked and rapid decline in testis size, serum 2002), or estrus shock protein fusion (Wang et al. 2010)
testosterone concentration and LH responsiveness in 9 but these approaches were considered impractical for
of 10 dogs. Suppression of reproductive function was long-term contraception because multiple injections were
maintained in treated dogs for 18-50 weeks; four dogs had needed to cause the response, the response was short lived,
suppression of reproductive activity through the end of the not all animals responded, or the technology was early
study.” Researchers concluded that although “GnRH-PAP stage.
given after puberty markedly suppressed reproductive After approximately 40 years, why is there no
activity, [the] variability in the response and duration of commercialized vaccine available for use as a contraceptive in
suppression after treatment, additional research would be companion animals? The main technical hurdles have been:
required to determine efficacy for nonsurgical sterilization
of the male dog” (Ball et al. 2006). � Inconsistency of the immune response
At the time of this update, it appears that this particular
� Need for multiple injections to maintain results
conjugate is no longer being studied.
� Injection site reactions due to the use of adjuvants
� Difficulties in formulating the antigen and consistent
conjugation of GnRH
3.2.4 Overview of GnRH Vaccines
� Inconsistency in the duration of effect among treated
animals
About 40 years ago, it was hypothesized that if an animal
could be treated in such a way as to stimulate an immune � Difficulty and expense of doing large-scale, multiyear
studies
response to GnRH, the GnRH antibodies would interfere
with the action of GnRH and this could result in infertility. Nonetheless, since GnRH vaccines can be effective in
But since GnRH is a small decapeptide that is normally both genders and most mammals, work has continued on
present in all mammals, it is not recognized as “foreign” by GnRH vaccines for animals. For example:
the immune system. The challenge to immune suppression
of GnRH was to develop a suitable vaccine.
� In the early 2000s, MetaMorphix, Inc., a Maryland-
based biotechnology company, was working on a
Research has been conducted on GnRH vaccines for number of animal health projects, one of which was an
a number of years. In order for GnRH vaccines to be immunocontraceptive vaccine. Work on the use of the
effective, the treated animal (or human) must develop an vaccine in dogs and cats was published (e.g., Baker et al.
immune response significant enough to neutralize GnRH 2004, Robbins 2002 and 2004, Robbins et al. 2004). As of
for a period of time. Since it is difficult to raise an effective 2011, MetaMorphix was disposing of its assets during
immune response to a small self peptide, the general bankruptcy proceedings and there was no indication
approach to constructing GnRH vaccines is to couple the that the immunocontraceptive work had progressed.
small GnRH peptide to a large foreign protein (a hapten). A � In 2004, Pfizer Animal Health obtained a GnRH vaccine
number of conjugates have been used to enable or attempt for treatment of benign prostatic hyperplasia (BPH) in
to enable the animal’s immune system to recognize the dogs as part of its acquisition of the Australian company
coupled protein as foreign and make antibodies against CSL and its US subsidiary Biocor. The product received
the complex, some of which will bind to and inactivate a conditional license from United States Department
GnRH. In addition to the GnRH-hapten conjugate, various of Agriculture (USDA) for the BPH indication but the
adjuvants are used to further stimulate the immune product was never developed for contraception and is
response. Historically, developing such an immunity to no longer available for treating BPH.
many different experimental GnRH-hapten conjugates � GonaCon™, a GnRH vaccine, has been developed by the
has been variable and it can take several months before National Wildlife Research Center (NWRC) of the USDA
immunity, and therefore infertility, develops fully. APHIS Wildlife Services (WS). After beginning initial
research in 1991, NWRC began developing the single-
In general, formulations of these GnRH vaccine
shot, multiyear contraceptive for white-tailed deer in
preparations, when tested in laboratory animals, dogs,
2005. The vaccine received USDA licensure for use in
and other species, have required multiple injections and
white-tailed deer in 2010. The GonaCon vaccine induces
generated a weak, short-lived antibody response. Examples
a long-lasting contraceptive response with a single
of novel approaches that have been tried include a

injection; a single shot can successfully keep female team members as inventors provides the following
mammals infertile for 1 to 4 years without boosting, description:
and infertility is reversible over time as antibody levels “Disclosed are recombinant bacteriophage
decline. GonaCon has been shown to produce high constructs and related heterologous peptide
GnRH antibodies and prevent pregnancy in several sequences for contraception in animals. The
species – deer, wild rats, squirrels, cats, dogs, domestic disclosed recombinant phage constructs bind
and feral pigs, rabbits, coyotes, wild horses, and bison – to antibodies against gonadotropin-releasing
following a single dose. (Fagerstone 2006). hormone (GnRH) and can be administered to
“To make the GonaCon vaccine, multimers of a an animal to generate an immune response
synthetic GnRH are coupled to a limpet hemocya- against GnRH, including generating anti-
nin. This is combined with an adjuvant devel- GnRH antibodies. The disclosed recombinant
oped at the NWRC (AdjuVac™) that enhances phage may comprise an amino acid sequence
immunogenicity. The AdjuVac is a modification of of gonadotropin-releasing hormone (GnRH),
the USDA-licensed Johne’s disease vaccine Myco- epitopic fragments, variants, or functional
par™ that contains small amounts of killed Myco- mimics thereof. Also disclosed are methods
bacterium avium. As noted, GnRH is a decapeptide for making and selecting such recombinant
produced in the hypothalamus and carried to phage constructs and compositions that com-
the anterior pituitary gland, where it results in prise such constructs (e.g., compositions for
release of FSH and LH. In males, LH and FSH are inducing an immune response against GnRH
required for testosterone production by the testes including pharmaceutical or veterinary com-
and for spermatogenesis. In females, LH and positions used as vaccines). Also disclosed
FSH are required for estrogen production, follicle are recombinant polynucleotides compris-
formation, and ovulation. When linked to the ing genomic nucleic acid of the recombinant
large, foreign limpet protein, the resulting GnRH phage constructs disclosed herein” (faqs.org/
molecule “looks like” a giant new protein that patents/app/20120156215).
the animal’s immune system has never encoun- A study in mice to evaluate the formation and specificity
tered. As a result, when GonaCon is injected into of phage-GnRH conjugates indicated that such synthetic
an animal, the animal’s immune response makes phage-peptide constructs “are stable and stimulate anti-
antibodies to both the limpet protein and to the GnRH immune responses.” This study did not involve any
animal’s own hypothalamic GnRH. The antibod- fertility-related assessments (Samoylov et al. 2012). Note
ies inhibit GnRH interaction with receptors on that Drs. A. Samoylov and T. Samoylova are two
pituitary gonadotrope cells, and prevent the of the authors of this 2012 study abstract.
normal cascade of hormone secretion
Note that Dr. Samoylova, along with
that is required for gamete produc-
Auburn University colleagues Henry J. Baker,
tion” (Fagerstone 2006).
Nancy Cox, and Stephen Ditchkoff, are listed
The GonaCon vaccine has been tested as the inventors of a patent involving “a
in dogs and cats (see sections 3.2.4.1 and method for identifying a peptide that binds
3.2.4.2). specifically to oocytes of a target species
of animal in a species-specific manner,”
� Dr. Tatiana Samoylova, of Auburn number US 8,158,366 B2, issued April
University’s Scott-Ritchey Research
Center, received a Michelson Grant 17, 2012.
in Reproductive Biology in December Dr. Samoylova has also worked on
2011 (see Chapter 4, section 4.3.3.2) to zona pellucida (ZP) phage construct
fund work on a single-dose phage-GnRH vaccines (see section 3.3.1.2).
construct vaccine for long-term contraception
in male and female cats and dogs. The
abstract submitted in a patent application
naming Dr. Samoylova and two of her

3.2.4.1 GnRH Vaccines in Dogs GnRH(F) every 4 weeks for 20 weeks. Blood samples were
GnRH vaccines have been tested extensively for their taken at the time of the initial vaccination and again at
contraceptive effects in dogs (early citations include Weeks 4, 8, 12, 16, and 20. Researchers measured serum
Faulkner 1975 and Gonzalez 1989). Dogs have been GnRH antibody titers and serum testosterone. Titers were
immunized with various GnRH peptides coupled to such detectable in all dogs by Week 8 and decreased after Week
large proteins as ovalbumin, thyroglobulin, keyhole limpet 12. There was little to no change in behavior. At Week 8 and
hemocyanin, and tetanus toxoid. In addition, various Week 12, mean testosterone concentrations were consistent
adjuvants have been used, including Freund’s complete with those of castrated dogs, but as GnRH antibody titers
adjuvant, water and oil adjuvants, aluminum hydroxide decreased, testosterone concentrations began to increase.
gel, and CpG (Schanbacher 1983, Singh 1985, Vickery 1989, Researchers concluded that “this vaccination protocol
Ladd 1994, Baker 2002). resulted in a short period of immunocastration in male
dogs, with inconsistent effects on sexual behavior” (Peed
Baker et al. (2004) reported on the effectiveness of a
and Kutzler 2010). In another study a B-cell adjuvant was
leukotoxin-GnRH antigen administered with the molecular
added to the Pfizer BPH vaccine and administered to 20
immunostimulatory adjuvant CpG oligonucleotide. The
male dogs in four different treatment groups to investigate
formulation was tested in 8-month-old dogs, prepubescent
serum GnRH antibody titers, serum testosterone levels
and adult female cats, and prepubescent male kittens
and semen qualities during a 6-week post-vaccination
(see GnRH Vaccines in Cats, below). None of the dogs
period. Researchers found that adding B-cell adjuvants
(n=3 females and n=5 males) developed antibodies
did not result in improved short-term immune response
against GnRH following primary vaccination and booster
or decreased fertility compared to the GnRH vaccine with
vaccination 7 months later.
booster protocol (Brennecke et al. 2009).
As noted previously, Pfizer Animal Health obtained
As noted above, USDA has developed a GnRH
a conditional license from USDA for a product called
immunocontraceptive vaccine called GonaCon for use in
Canine Gonadotropin Releasing Factor® (GnRH(F))
female white-tailed deer. The vaccine has been studied in a
Immunotherapeutic, a vaccine indicated for benign
number of species including dogs (and cats).
prostatic hyperplasia in male dogs. The label indicated
that an initial injection should be followed by a booster 1 In a study, researchers immunized three healthy male
month later and then every 6 months to maintain effect. Beagle dogs with a single, intramuscular injection of 0.6mL
The product was not indicated for use as a contraceptive. GnRH-KLH with AdjuVac (i.e., GonaCon), and monitored
A study presented at the 4th International Symposium on their breeding soundness and fertility biweekly for 1
Non-Surgical Contraceptive Methods of Pet Population year. Serum anti-GnRH antibody concentrations, serum
Control was conducted to determine if this vaccine testosterone concentrations, testicular size, prostate size,
would also be effective for immunocastration of male and semen analysis were assessed. Two dogs became
dogs. Researchers hypothesized that in addition to infertile within 3-4 weeks of immunization; infertility was
stimulating anti-GnRH antibody formation and decreasing maintained for about 14 weeks. A second 14-week period
testosterone concentration, vaccination would decrease of infertility occurred in one of the dogs 8 weeks after the
male reproductive behavior. Six intact postpubertal male animal’s recovery from the initial period of infertility. All
dogs were injected with two subcutaneous injections of three dogs maintained “excellent libido throughout the

study period” and all three “experienced severe injection A study undertaken by the Mexican Ministry of Health
site reactions within days following administration of the and USDA APHIS WS, supported by the Rabies Program of
vaccine” which “persisted throughout the duration of the the CDC:
study.” Researchers concluded that “a single injection of this “tested an improved formulation of GonaCon™
vaccine formulation is neither safe (due to … severe local in Hidalgo State with the participation of the State
reaction), nor effective at inducing long-term suppression of Health Services as well as the local institutions and
reproductive function in dogs” (Griffin et al. 2004). organizations during 2011. Three groups of 6 fe-
In an 82-day study published in 2009 (Bender et male dogs were used in this study. The first group
al.), USDA and US Centers for Disease Control and received rabies vaccine, the second GonaCon™
Prevention (CDC) researchers investigated the feasibility and the last group received GonaCon™ and rabies
of simultaneous vaccination with GonaCon and a vaccine. Vaccines were delivered by IM injec-
commercially available rabies vaccine (Defensor® 3, tion. All animals were placed under observation
Pfizer) in female dogs of mixed breed. The rationale for and evaluated clinically during a 61-day period.
the study is based on the belief that to maximize the Results of the medical and clinical evolution of
effectiveness of “herd immunity” resulting from rabies the animals, as well as the blood serum results for
vaccination, “immunocontraception provided at the CBC, BCP, VNA, THR and GNRH measurements
time of rabies vaccination should reduce fecundity and and comparisons on D0, D31 and D61 will be
dog abundance.” Three groups of animals were divided presented. The preliminary conclusions show that
as follows: Group 1 (six animals) received a single adverse effects of GonaCon™ were less frequent
injection of GonaCon and was intended as an internal and in lower intensity than reported in the previ-
control for the rabies vaccinations in dogs in Groups 2 ous dog study [Bender et al. 2009, see above]. The
and 3; Group 2 (six animals) received a single injection immune responses to the rabies and GonaCon™
of rabies vaccine; and Group 3 (six animals) received vaccines were not limited by the simultaneous
a single injection of GonaCon plus a single injection administration of these products. Also, observa-
of rabies vaccine. Researchers determined anti-GnRH tions of the macro and microscopic lesions will be
antibody and rabies VNA on Days 0, 13, 27, 61, and 82 presented that are consistent with findings of the
(study end). The study “demonstrated the potential to previous GonaCon™ study” (Lecuona et al. 2012).
use this immunocontraceptive in breeding-age female In 2009, researchers at the CDC Rabies Program reported
dogs without affecting parenteral rabies immunization on efforts to develop a recombinant combined vaccine
in 100% of vaccinated animals.” Researchers further for rabies prevention and immunocontraception, noting
noted that this study may represent “the first use of that “an effective sterilant based on rabies vaccines has
the immunocontraceptive GonaCon in female dogs … the potential to create a supportive measure of public
future research should determine the potential effects of acceptability and to reduce associated clinic visit costs.”
immunocontraception upon duration or immunity and
efficacy against relevant challenge viruses.” The team:
In a 2010 Stakeholders Announcement from USDA, “inserted the coding sequence of gonadotropin-
the agency stated that the findings described in the releasing hormone (GnRH) into different locations
study “could aid in the development of new vaccination within the rabies virus ERA glycoprotein (G) gene,
programs, as well as a combined rabies-contraceptive and demonstrated that the amino terminus (N),
antigenic site IIa, and the junction between the
vaccine, for use with free-ranging and feral dog
ecto- and cytoplasmic domains (C) of the G were
populations. USDA hopes to pursue partnerships with
suitable sites for GnRH insertion. The rescued
industry and others for future development and potential
recombinant rabies viruses ERA-N-GnRH and
registration” (APHIS WS, April 8, 2010).
ERA-C-GnRH grew as well as the parental ERA

virus, reaching 1x10(9)ffu/ml in cell culture. Inser- 12 weeks of the study. The study was carried out only until
tion and expression of the GnRH were stable in the Week 20, so long-term effects were not observed. In the
viruses after multiple passages in vitro. To increase high-dose group, good suppression of serum testosterone
immunogenicity of the GnRH peptide, two copies and sperm production was seen.
of GnRH, aligned in tandem, were fused to the N
terminus of the G. The recombinant rabies virus
ERA-N-2GnRH was recovered and grown to high
titers in cell culture. All GnRH-carrying rabies
viruses induced antibodies against GnRH
in immunized mice and protected 100% of the
animals after rabies virus challenge. The recombi-
nant viruses reacted strongly with the serum from
a GonaCon-immunized animal” (Wu et al. 2009).
Jung et al. (2005) reported on the administration of
fusion proteins produced in E. coli and made up of canine
GnRH and T helper cell epitope p35 “originated from
canine distemper virus F protein and goat rotavirus VP6
protein.” In male dogs previously immunized with CDV
vaccine, injection of the fusion proteins induced antibody A study described at the 2nd International Symposium
higher than that of GnRH-rotavirus VP6 protein or GnRH on Non-Surgical Methods for Pet Population Control
alone. Spermatogenesis degeneration was present in the involved immunizing cats via primary vaccination and
male dogs immunized with the fusion protein. Researchers a booster 4.5 months afterward. At 2-4 week intervals
concluded that the vaccine “acted as a strong immunogen researchers assessed serum testosterone and testicular size
and the antibody to GnRH specifically neutralized GnRH in males, serum progesterone in females, and antibody
in the testes … and implies a potential application of titers in all animals. Fecal estradiol was assayed every other
GnRH-based vaccines for immunocastration of male pets.” day for females, while estrous behavior in queens was
A company called Amplicon Vaccine, LLC describes recorded each day. Data were gathered for 9-1/2 months
the composition of a vaccine called Repro-Bloc™ as “a after initial immunization (Baker et al. 2004).
series of GnRH genes [which] are cloned onto Ovalbumin
carrier gene which is held in an E. coli based expression
� In six out of six treated adult female cats, contraception
was maintained throughout the 38-week study
vector … the purified protein is added to an emulsifying
period and no estrous behavior was recorded.
agent, oil, dead [M]ycobacterium butyricum and a urea +
Ovariohysterectomy performed on treated and untreated
phosphate buffer.” The website refers to studies in mouse,
cats revealed that ovaries and uteri of treated cats were
swine, dogs, cats, lamb, caribou and several cattle. A
dramatically smaller, while the ovaries and uteri of
2010 PowerPoint® presentation on the company website
control cats were well developed; control cats cycled
describes several studies on heifers in the US and bulls in
normally during the study.
Brazil and notes that results of studies on other species
such as cats and dogs are available under confidentiality
� Five female 3-month-old kittens were given the
vaccine with CpG; one received the vaccine with no
agreements (amplicon-vaccine.com).
CpG; and two kittens served as controls. Failure to
attain normal reproductive cycling occurred in four
3.2.4.2 GnRH Vaccines in Cats
kittens in the vaccine plus CpG group and in the kitten
In a small study involving six male cats immunized with receiving vaccine alone. After administration of the
GnRH antigen (GnRH conjugated to tetanus toxoid) in an booster, the fifth kitten in the vaccine plus CpG group
adjuvanted formulation, five of the six had GnRH antibodies, was contracepted. The GnRH antibody response rose
but there was little or no effect on serum testosterone levels, sharply over 6 weeks and then reached a plateau.
even after multiple injections (Ladd 1994). Ovariohysterectomy of all cats at the end of the study
In a study using GnRH conjugated to ovalbumin in 30 showed that as with adult females, these organs were
male cats (Enright 1995), cats were immunized at 0, 4, 8 and dramatically smaller than those of controls.

the females, and none became pregnant. Three of the four
� Five male 3-month old kittens were given the vaccine males had serum testosterone concentration below the
with CpG; four received the vaccine with no CpG;
level of detection following the second immunization.
and four kittens served as controls. Control kittens
Serum chemistry was normal. Histology performed on
progressed to normal pubescence (i.e., developed
the testes and ovaries of two male and two female cats
measurable serum testosterone) during the study period,
was consistent with LH and FSH suppression. As noted,
while serum testosterone was undetectable in all five
multiple injections were required to stimulate and maintain
immunized cats at study end. The vaccinated kittens
“biologically relevant titers” for more than 20 months
did not develop secondary sex characteristics, and
(Robbins et al. 2004). Unfortunately MetaMorphix is no
“fighting behavior was noted to be absent in vaccinated
longer in business (see Chapter 4, section 4.2.3).
cats.” Control cats developed normal secondary sex
characteristics, testicular size, and typical “intermale In a short-term study of USDA-developed deer
aggression.” Surgical castration at study end showed product GonaCon in cats, a single administration blocked
severely atrophic testicles in all treated cats. One testosterone production and spermatogenesis in male
treated cat had one identifiable testicle, which was not cats for at least 6 months. Twelve male cats were divided
identifiable 1 year later. into groups of three. One group served as controls; the
remaining groups received a single immunization of
As noted previously, a GnRH vaccine was being
GonaCon at 50, 200, or 400 mg. Researchers monitored
developed by MetaMorphix, a company founded in
GnRH antibody titer, serum testosterone concentration,
Baltimore, Maryland. The vaccine was constructed as a
and scrotal size monthly; semen was collected at 6 months
recombinant protein, which would have made the eventual
post-injection. In all immunized cats, GnRH antibodies
manufacturing process more amenable to scale-up and
were detected by 1 month post-treatment and were
commercialization.
persistent during the course of the study. There was no
One study using the MetaMorphix GnRH Vaccine dose dependency related to titers. Six of the nine treated
presented data in 15 male or female prepubertal cats given cats “were classified as responders based on high GnRH
the GnRH antigen subcutaneously at 8 and 12 weeks antibody titers (greater than 32,000). By 3 months post-
of age and again at approximately 2 years of age. All treatment, responder cats had undetectable testosterone
immunized cats developed anti-GnRH antibodies by Day concentrations and testicular atrophy. Nonresponder
28 post-injection. After the second immunization at Day cats had GnRH titers of 4,000–32,000 and testosterone
28, titers increased and peaked at ~Day 84. Titers were concentrations intermediate between responder and sham-
maintained for at least 606 days, with a significant booster treated cats.” At 6 months post-treatment, control cats and
effect seen at 2 years. No reproductive activity was seen nonresponder cats had similar sperm counts. One of the
in immunized females, testosterone was suppressed in six responder cats produced non-motile sperm. Interstitial
males, and testicular and ovarian function was suppressed cells that were present in responder cats “were pale and
for the duration of the study (Robbins 2002). There was no shrunken” compared to those of control cats. There was
mention of any breeding studies done. marked tubular atrophy with vacuolated Sertoli cells
In a 2004 study, the MetaMorphix recombinant GnRH and a lack of germ cells in responder cats. Researchers
vaccine was tested in intact domestic male (n=4) and
female (n=10) cats at two different dose levels. One male
cat served as a control. Animals were 8-9 weeks old at
study start. The vaccine consisted of the antigen IPS-21,
a commercially available adjuvant, and the immune-
stimulant dimethyl dioctadecyl ammonium bromide.
Doses were administered at several time points (Days 0,
28, and 643) during the study. All 15 animals experienced
injection site reactions that resolved within 28 days post-
vaccination in the majority of animals. The 14 treated
animals all developed titers to GnRH, which peaked at
Day 45; 13 of 14 cats maintained these titers for more than
20 months. Estrous behavior was not observed in any of

concluded that “single-dose GnRH treatment resulted in of GonaCon. Nine responded to vaccination with “high
testosterone concentrations and semen quality consistent antibody titers;” the “median onset of testosterone
with immunocastration in a majority of cats treated” (Levy becoming undetectable was 2 months (range 1–12 months)
et al. 2004). and the median duration of effect was 14 months (range
A subsequent study of long-term fertility control in 5–33 months). One cat still had undetectable testosterone
female cats with GonaCon tested the efficacy and duration at the end of the observation period 34 months after
of activity of a single-dose on the fertility of adult female treatment. Loss of detectable testosterone was generally
cats in a laboratory setting. Fifteen cats received a single followed in 1–2 months by azoospermia, and restoration
dose; five cats served as controls. On Day 120, a breeding of normal sperm counts lagged behind recovery of
trial commenced. Control (sham-treated) cats had a median testosterone by 2 months.” In the nine responding cats,
time of 4.4 months to conception compared to the median semen characteristics prior to treatment and after the
time of 39.7 months in immunized cats. Fertility was recovery of fertility were similar. The three cats that
suppressed for 1 year in 93% of the cats, 2 years in 73%, 3 did not respond with high antibody titers experienced
years in 53%, and 4 years in 40% of the treated cats. At the minimal to no suppression of testosterone. In this study,
end of the study, 5 years post-immunization, four cats were “the average time from introduction of the female cats to
still infertile. Infertility was accompanied by a cessation successful breeding was 12 months (range 3–12 months) for
in estrous cyclicity and with weight gain. Approximately the responding cats, 5 months (range 5–6 months) for the
2 years after vaccination, five of the 15 vaccinated cats poorly responding cats, and 3 months (range 0– 9 months)
(27%) developed late-onset, persistent, non-painful for the sham-treated cats. In one extreme case, GnRH
granulomatous injection site masses. The researchers antibody titer did not begin to increase until 6 months
concluded that “GnRH immunocontraception is an ideal post-vaccination, testosterone was not suppressed until 12
candidate for further development,” particularly for feral months, and azoospermia did not occur until 14 months.
cat control (Levy et al. 2011). In this cat, the contraceptive effect lasted 14 months, after
which GnRH antibody titer waned, normal testosterone
In a review article, Levy (2011) describes the use of GnRH concentration and semen characteristics recovered, and the
vaccination to achieve long-term contraception in male cat sired a litter.” The reason for this delay in response is
cats. A breeding trial reported in 2004 assessed the fertility not known.
of 12 male cats vaccinated with a single administration
3.2.4.3 GnRH Vaccines: Summary of Advantages and Disadvantages

Proven to suppress fertility in both males and Immune response may be inconsistent in individual animals
females
Suppress sexual behavior – females will not Depending on the formulation, might cause injection site reactions
come into estrus during treatment, males will
behave as castrates
Reversible – when the vaccination boosters Reversible – when the vaccination boosters are discontinued, repro-
are discontinued, reproduction should resume duction should resume (irreversibility is preferred by many pet own-
(could be used in pets intended for breeding) ers and for unowned and “community” dogs and cats)
Under certain circumstances, may be possible Difficult to predict when reproduction would resume after cessation
to achieve longer duration of effect desired by of treatment, as this would depend on the gradual decrease in circu-
many pet owners and for unowned and “com- lating antibodies to GnRH
munity” dogs and cats May be need for multiple boosters to develop and maintain effect
Slow onset of activity (may be more than 2 to 3 months) as animal
mounts immune response

3.3 Other Vaccine Approaches molecules attached in specific ways. In each species, the ZP
proteins are similar but not exactly the same (for a review,
3.3.1 Zona Pellucida (ZP) and Egg and Sperm see Prasad 2000). In some species, the DNA that codes for
Vaccines the zona proteins has been isolated and sequenced, so the
amino acid sequence of the proteins is known.
3.3.1.1 Overview Much research related to veterinary applications has
Creating an immune response to some component of been done using PZP (porcine ZP), purified from pig
the egg or sperm could theoretically cause infertility by ovaries obtained from slaughterhouses. The PZP can then
interfering with the fertilization of the egg, sperm transport, be formulated in a variety of ways and used as a vaccine
and/or binding of sperm to the egg. This approach to antigen, which can be injected into female animals to raise
fertility control works in either the ovary or the reproductive an immune response. Various injection schedules have
tract, and in all cases is effective only in females. been used in various species. Fertility is blocked for some
period of time, and booster vaccinations are generally
Since the effect is dependent on the animal mounting required to maintain the infertility. Unlike GnRH vaccines
an immune response, the suppression of fertility will be which are used in both sexes, ZP vaccines are only useful in
gradual, likely over several months. Similarly, the effect female animals.
can be expected to wear off slowly, resulting in a gradual
resumption of fertility over several months or even years, ZP vaccines have, in some cases, caused a side effect of
depending on the formulation. This waning effect, or inflammation of the ovary, which might be due to raising
“reversibility,” is likely to be variable among individual an immune response to the zona on the eggs in the ovary.
animals. If the ZP preparations were not sufficiently purified, they
might have contained other components of ovarian tissue
Sexual behavior should not be affected by this approach, that could account for this effect, which has not been seen
as the whole cascade of hormones, which controls sexual in all studies. Different ovarian pathology was seen in a
behavior, will be normal in vaccinated animals, as there study using a subcomponent of the ZP (Paterson et al.
should be no disruption in the pituitary-gonadal axis 2002), in which a disruption of the follicles and depletion
(GnRH, LH and FSH and sex steroids). In other words, of the primordial follicles was seen, either of which could
female animals should still come into estrus, and show result in irreversible sterility.
normal mating behavior, but not become pregnant.
In situations in which mating behavior is unwanted Using PZP obtained from slaughterhouse material
(commonly for both pet and free-roaming cats and dogs) presents some challenges: Collection is labor intensive
this approach would not be desirable. and supplies may be limited. Using ovaries obtained at
slaughter is also a disadvantage because it is difficult
(and may be impossible) to manufacture this material
under good manufacturing practice (GMP) guidelines,
a requirement for regulatory approval by the Food and
Drug Administration (FDA) and European Medicines
Agency (EMA) (but not for the wildlife products approved
by the US Environmental Protection Agency (EPA)). (See
Chapter 6 for an overview of regulatory considerations
related to non-surgical approaches, including a discussion
of the differences in the US regulatory landscape between
products used in wildlife population control, regulated
under the aegis of the EPA, versus products used in
companion animal population control, regulated under
3.3.1.2 ZP Vaccines the aegis of the FDA Center for Veterinary Medicine
(CVM).) It is likely that in order to achieve regulatory
Many years of research have been devoted to exploring
approval and commercialization of a ZP product for use
the use of vaccination with components of the layer of
in owned dog and cats, a manufacturing method that
proteins that surrounds the mammalian egg – the zona
does not involve isolation of PZP from slaughterhouse
pellucida (ZP). The zona looks transparent and is made up
material may be required. Second-generation ZP vaccines
of several glycoproteins, that is, proteins with various sugar

using recombinant or synthetic ZP antigens have been In April 2011, the US Bureau of Land Management (BLM)
investigated (Dunbar 2002, Srivastava et al. 2002) and the and US Geological Survey (USGS) announced a 5-year
cDNAs for ZP proteins from several species have been wild horse contraceptive study at the BLM’s short term
cloned (Harris 1994, Yonezawa 2001). holding facility in Pauls Valley, Oklahoma. The pasture
ZP vaccines that incorporate recombinant proteins might breeding study is said to be testing the effectiveness of
be less expensive and easier to produce than those based two formulations of SpayVac to determine if treatment can
on slaughterhouse material. ZP is highly glycosylated, and reduce foaling rates in wild horse mares (BLM press release
the fact that recombinant proteins expressed in bacteria April 26, 2011).
will be missing this post-translational modification can In February of 2012, The Humane Society of the United
be expected to be associated with reduced antigenicity; States™ (HSUS) announced EPA approval of ZonaStat-H,
however, yeast can be engineered to produce glycosylated the first contraceptive vaccine for use in mares for
recombinant proteins, though this glycosylation may not controlling populations of wild horses. ZonaStat-H has
be identical to that which occurs in dogs and cats (ACC&D been “used to treat more than 1,600 wild, sanctuary and
Think Tank, Immunocontraceptive Approaches for tribal horses annually at dozens of trial sites across the US”
Sterilization in Cats in Dogs, 2009). and is produced by the Science and Conservation Center
Vaccination with ZP does not affect sexual behavior of Billings, Montana (HSUS press release February 17,
in the females of the species in which it is useful 2012). Further discussion of uses in wildlife and livestock is
as a contraceptive (e.g., horses). Females will still beyond the scope of this update. Please see Chapter 6 for a
come into estrus, because there is no effect of this description of regulatory considerations related to approval
immunocontraception of GnRH or sex steroid levels. and use of non-surgical contraceptives for animals.
Although there are many papers published on the use of 3.3.1.2.1 ZP in Dogs
ZP vaccines, there is no commercial product available for
Dog ZP proteins are ZP1, ZP2,
use in companion animals. The most extensive use of these
and ZP3, and the sequences of
vaccines is in wildlife, where they have been successfully
these proteins have been reported
used for many years to reduce fertility and overpopulation.
(Harris 1994). Using porcine ZP
First-generation (i.e., PZP-based) research in cats and
to immunize dogs has yielded
dogs was deemed largely unsuccessful (Briggs, personal
inconsistent results. In some
communication 2012). Cats did show a robust immune
studies, bitches vaccinated with
response to PZP vaccination, with measurable anti-PZP
PZP showed marked ovarian
antibodies in their serum, but had normal post-vaccination
pathology, but the mechanism was undefined. Some
fertility. It was concluded that the cat ZP proteins were
dogs have shown inhibition of fertility (Gwatkin 1980). In
different enough from the pig PZ proteins that the anti-pig
work published in 2002, although a significant anti-PZP
antibodies would not bind the cat ZP, and therefore normal
antibody response was detected, moderate and inconsistent
fertility was maintained. When cat ZP antigens were used
inhibition of pregnancy was seen in mated bitches (Liu
as antigens, there was some evidence of reduced fertility
and Ball 2002). The ovaries of bitches immunized with PZP
in treated cats, although numbers were small (Jewgenow
appeared normal. It may be that when the dog generates
2000, Eade 2009).
antibody to the PZP, the antibodies have inconsistent
A porcine ZP vaccine (SpayVac™) for use in seals was binding to the dog ZP, and therefore do not block
developed by the Canadian company Immunovaccine, conception in all cases.
Inc. (formerly Immunovaccine Technologies) and tested
Others are approaching this problem using molecular
in a few other species. The product is not commercially
biological techniques. By defining the genes that code for
available at this juncture (Root Kustritz 2009) and
dog ZP glycoproteins, and then creating recombinant dog-
the company’s primary focus is not on animal health
specific ZP (dZP) proteins, researchers hypothesize that it
applications. However, Pfizer Animal Health licensed the
may be possible to create a more species-specific antigen
platform technology for livestock vaccines in development
that might prove more effective. For example, researchers
in 2009 and in May of 2012, Immunovaccine announced
immunized three groups of female dogs (n=3 per group)
a collaboration with “one of the world’s leading animal
with recombinant dZP2 conjugated to diphtheria toxoid,
health companies” for developing companion animal
recombinant dZP3 conjugated to diphtheria toxoid,
vaccines (imvaccine.com/releases.php?releases_id=274).
or diphtheria toxoid alone. (Note: diphtheria toxoid
The specific indications were not disclosed.

was used as a hapten – a large protein to augment the
immune response.) Dogs immunized with dZP2 and
� Inconsistent immune response and efficacy with the
porcine ZP antigen
dZP3 generated antibodies against the diphtheria toxoid
and the respective dZP. When dogs were mated, the dogs
� Ovarian pathology seen in some studies but not others
previously immunized with the dZP2 conjugate all became

� Need for multiple injections to maintain results
pregnant while three of four animals receiving the dZP3

� Injection site reactions due to the choice of adjuvants
conjugate did not conceive. The researchers noted that “the

� Inconsistency in the duration of effect among treated
dogs
block in fertility was associated with anti-dSP3 antibody
titers. Ovarian histopathology revealed that the block in
� Difficulty and expense of doing large-scale, multiyear
studies in dogs
fertility … is probably manifested by inhibition [in the]
development of follicles and is due to atretic changes in the
� Difficulty in scaling up purification of PZP under GMP
zona pellucida.” The results, considered preliminary by the

� Difficulty developing recombinant antigens for use in
dogs (although there appears to be progress in this area).
team, indicated that using dZP3 immunization might be
useful in dog population control “providing that adequate 3.3.1.2.2 ZP in Cats
antibody titers are achieved” (Srivastava 2002). ZP vaccines have not been widely studied in cats. The
Wheir et al. (2005) reported on a study to evaluate the commonly used porcine ZP antigen is not effective when
efficacy of native and recombinant ZP protein in inducing used in cats. Although cats can react to PZP by producing
permanent sterility in female dogs aged 4-6 months at serum anti-PZP antibodies, these antibodies do not appear
study start. Three types of ZP (porcine ZP, native rabbit ZP,
and recombinant human ZP), and two types of adjuvant
(modified Freund’s Complete Adjuvant mFCA or CpG
(C-phosphate-G)-DNA, an adjuvant that is interpreted by
the immune system as a sign of bacterial invasion) were
involved.
Test articles were: (Group 1) PZP with mFCA, (n=6);
(Group 2) PZP, RZP (native rabbit ZP) + mFCA (n=6);
(Group 3) PZP + CpG-DNA; (Group 4) fZP3 (recombinant
human ZP) + mFCA; (Group 5a) mFCA control; and
(Group 5b) CpG-DNA control. Researchers found that all
the dogs receiving mFCA experienced “serious injection-
site lesions.” However the use of CpG-DNA did not result
to interact with feline ZP (fZP) (Jewgenow 2000). This
in adverse reactions; therefore, dogs immunized with
lack of effect of anti-porcine antibodies on feline fertility
vaccines containing mFCA did not receive boosters while
indicates that a more suitable antigen for cats may be cat
CpG-DNA dogs did. Dogs in Groups 1, 2, and 3 showed
ZP proteins, and some experimental evidence for this is
reduced follicular development and increased atretic
discussed below.
granulosa cell clusters. The implications of these results
were that “with time, the ovaries would be depleted of A study that evaluated a PZP vaccine (SpayVac) for
developing follicles … [and that] … further studies have to immunocontraception in domestic kittens indicated
be carried out for longer periods of time to evaluate fertility that although high anti-porcine ZP antibody titers
and time until full ovarian depletion and sterility are were achieved, the formulations tested did not
accomplished.” Titers in Group 4 animals were quite low prevent estrous cycling at maturity or reduce fertility.
but since a decrease in follicles and an increase in atretic Immunohistochemical assays indicated that the antibodies
granulosa cell clusters were seen, these effects might be produced by treated cats “recognized porcine ZP but not
improved via booster immunization. feline ZP” (Gorman et al. 2002).
In general, the main technical hurdles to A PZP vaccine study designed to test safety in zoo
commercialization of a ZP vaccine for dogs have been: felids (27 female felids representing 10 species) revealed

behavioral manifestations of estrus (15 animals) and an anti-fertility effect in vitro when antibodies against the
the six animals assayed for antibodies against PZP synthetic peptide were added to the fertilization medium.
showed antibody production. All the felids underwent Researchers concluded that the results were promising,
ovariohysterectomies 3-13 months post-treatment, and and that the specific immune response and anti-fertility
no histopathologic signs of inflammatory damage to properties of a synthetic vaccine would have to be
the ovaries were found. Although efficacy in terms of examined in vivo.
contraception was not assessed specifically, “two of the In a study at Murdoch University School of Veterinary
three felids housed with an intact male became pregnant and Biomedical Sciences (Eade 2007, Eade et al. 2009), PZP
during the study, one of which gave birth to healthy cubs” polypeptide and feline ZP A, B and C subunits expressed
(Harrenstien et al. 2004). by plasmid vectors were evaluated as anti-fertility vaccine
Levy et al. (2005) screened a panel of native ZP antigens candidates for domestic female cats. Cats received three
isolated from the ovaries of cows, cats, ferrets, dogs, and injections of the various ZP vaccines, and ZP-antibody
mink to ascertain immunocontraceptive activity in cats. response, ovarian histology and fertility after mating were
Vaccines (using the SpayVac formulation technology) were compared. Vaccination with native porcine ZP polypeptide
constructed and a breeding trial commenced 20 weeks induced anti-porcine ZP antibodies but these antibodies
post-immunization. All cats became pregnant, producing did not cross-react with feline ZP and no effect was seen
an average 4.1+/- 0.7 viable kittens per litter. Antibodies on fertility in vivo after mating. Vaccination with the feline
did not bind to feline ZP in situ. Fertility was not impaired. ZP vectors did elicit circulating antibodies specific for
In work reported in 2004 (Ringleb et al.), the impact feline ZP. Changes in ovarian histology were not elicited.
of feline ZP glycoprotein B-derived synthetic peptides Researchers noted that conception rates in mated females
on in vitro fertilization of cat oocytes was investigated. were 25% and 20%in the ZPA and ZPB+C vaccinated
Researchers hypothesized that an immune response groups respectively, compared with 83%in the control
against fZPB (one of three feline ZP proteins) increases group , but cautioned that samples sizes were small (7/8
the possibility of permanent contraception by destruction control cats mated, 4/7 fZPA cats mated; 5/5 feline ZPB+C
of intra-ovarian oocytes. The research sought to identify cats mated) and statistical significance was not achieved.
immunologically relevant epitopes of fZP, and to test Nonetheless, researchers concluded that feline ZPA and
the amino-acid sequence of these epitopes for their ZPBCC subunits are potential candidate antigens for
contraceptive potential in cats. One of six immunogenic immunocontraceptive vaccines in the domestic cat.
epitopes within the amino acid sequence of fZPB expressed

3.3.1.2.3 ZP Vaccines: Summary of Advantages and Disadvantages
Proven to suppress fertility in females (in some Ineffective in males
studies and not others); efficacy shown in equi-
ds, some ruminants, pinnipeds, and elephants
but not yet in carnivores
Reversible – when the vaccination boosters Reversible – when the vaccination boosters are discontinued, repro-
are discontinued, reproduction should resume duction should resume (irreversibility is preferred by many pet own-
(may depend on the antigen used); could be ers and for unowned and “community” dogs and cats)
used in pets intended for breeding
Immune response may be inconsistent in individual animals and will

vary depending on the preparation of the antigen
Depending on the formulation, can cause injection site reactions
Difficult to predict when reproduction would resume after cessation
of treatment, as this likely depends on the gradual decrease in circu-
lating antibodies to ZP
May require multiple boosters to maintain effect
Will not affect sexual behavior – dogs and cats will still come into
estrus and have normal cycles; in induced ovulators, this could lead
to repeated pseudopregnancies with associated elevations in proges-
terone that could cause uterine and mammary pathology
Difficult to purify the ZP under GMP conditions
Slow onset of activity (may be more than 2-3 months) as animal
May cause inflammation of the ovary
Response varies by species
3.3.1.3 Vaccination against Egg and Sperm Proteins Why is a recombinant antigen desirable? It is unlikely
Using proteins found exclusively in the ovum or on that ovary extracts would be a practical source of material
the sperm as vaccine antigens is another approach to for the type of manufacturing that would be required
immunocontraception. If antibodies can be raised to these to make an approvable product, which requires GMP
“self” proteins, they could theoretically interact with egg manufacturing. With a well-defined, simple recombinant
or sperm to inactivate fertilization. An advantage to this protein, manufacturing could be significantly more
approach is that the target protein can be chosen to be one straightforward.
that is only found in either sperm or eggs, and therefore, The original 2002 Contraception and Fertility Control in
“off- target” effects should be minimized. Animals report described the work of Dr. Scott Coonrod,
then at the Department of Cell Biology at the University
3.3.1.3.1 Vaccination against Egg Proteins of Virginia (UVA), who constructed dog and cat ovarian
Proteins within the mammalian egg might be used as cDNA libraries, and had begun the process of isolating
antigens in immunocontraceptive vaccines to elicit an proteins to be expressed for immunogenicity and fertility
immune response and cause infertility. It is important to trials (Coonrod 2002). Dr. Coonrod has since joined the
identify proteins that are only expressed in the egg. If target Baker Institute for Animal Health at Cornell University,
proteins are found in other organs as well, such as liver or where his work has identified an egg protein that plays
kidney, they could not be used for a vaccine because other an important role in reproduction. See section 3.6.3 for
tissues would be affected. If novel, egg-specific proteins information on this emerging area of research.
could be identified, they might be used to generate an Research on egg specific proteins for use as
immune response and inhibit fertility. If such proteins could immunocontraceptive antigens has not yet matured to the
be isolated and the cDNA cloned, it might be possible to point of identifying and testing protein targets in studies in
make a recombinant antigen to be used as a vaccine. cats and dogs.

3.3.1.3.2 Vaccination against Sperm Proteins could theoretically be applied to dogs and cats, the sperm
Researchers have been investigating proteins that antigen immunization approach has not resulted in a
are only expressed in sperm, with the goal of using satisfactory control of fertility.”
these proteins as the basis of anti-fertility vaccines (for Work reported at the 4th International Symposium on
an overview see Frayne 1999, Naz 2000). As is the case Non-Surgical Contraceptive Methods of Pet Population
with egg proteins, the idea is to find proteins that are Control involves landscape phage-peptide contraceptive
not expressed anywhere in the body, except sperm, to vaccine constructs in which the peptides “mimic sperm
decrease the potential side effects of using these vaccines to that bind to zona pellucida (ZP) proteins at fertilization.”
generate an immune response. Unlike the ZP or egg protein One of the benefits of such an approach might be reduced
vaccines, sperm vaccines aim to generate what is known cost since such vaccines should be reasonably stable
as a mucosal immune response, in which the lining of the and the components are expected to be readily available
reproductive tract in females produces anti-sperm IgA type at a reasonable cost. Researchers hypothesized that
antibodies, which could then bind the sperm and prevent “Administration of the vaccine would result in an anti-
conception. In studies in mice (Naz 2002), relatively long- sperm antibody response that would interfere with sperm
term contraception (approximately 300 days) was achieved delivery or function in the male or female genital tract,
after vaccination. leading to a contraceptive effect. Due to the natural ability
Some studies have shown that in laboratory animals, of phage to stimulate B and T cell responses (without
immunizing females with unique sperm proteins can cause adjuvants), the vaccine may also inhibit spermatogenesis
them to mount an immune response to sperm, which then and steroidogenesis via induction of cytokine reactions
inhibits fertility (hamsters: Gaudreault et al. 2002, monkeys: in males.” Four candidates were tested in year-old male
Deng et al. 2002). These antigens have been tested in males dogs, who received an initial intramuscular injection
as well, but caused testicular inflammation. followed by boosters at 3 weeks and 7 weeks. Analysis of
testosterone levels and sperm collected from study dogs
Since the immune system interprets sperm antigens as
indicated that all tested constructs “induce[d] production
“foreign,” they “are a target for contraceptive vaccines”
of high levels of serum IgG antibodies that persisted for
but because the spermatozoon “shares several antigens
at least 5-6 months. Testosterone levels varied during
with other somatic cells … [it] cannot be used for vaccine
the study … [and] testicular widths in all dogs were
development.” Because of this, researchers have sought
decreased when measured 2-3 months after the second
to find sperm-specific epitopes in order to improve
booster immunizations.” The study demonstrated that
vaccine immugenicity and efficacy. As of the date of the
“the identified phage-peptide constructs may be useful
publication quoted here (Kutzler and Wood 2006), two
in the design of immunocontraceptive agents for dogs
important sperm-specific antigens were isolated: lactate
(Samoylova 2010).”
dehydrogenase and acrosin, but “Although this approach

3.3.1.3.3 Egg and Sperm Proteins: Summary of Advantages and Disadvantages
Suppress fertility in females (in some studies Ineffective in males
and not others)
Reversible – when the vaccination boosters Immune response may be inconsistent in individual animals, and
are discontinued, reproduction should resume may vary depending on the preparation of the antigen
(may depend on the antigen used); note that
in instances in which permanent sterility is the
desired outcome, this approach would be a
disadvantage
Defined recombinant proteins easier to manu- Requires the development of an IgA response in the female reproduc-
facture under GMP tive tract, which is difficult to assess experimentally when compared
to a serum IgG response
Depending on the formulation, might cause injection site reactions
Difficult to predict when reproduction would resume after cessation
of treatment, as this would depend on the gradual decrease in circu-
lating antibodies
May require multiple boosters to maintain effect
Will not affect sexual behavior – animals will still come into estrus
and have normal cycles
Slow onset of activity (may be more than 2-3 months) as animal
3.3.2 Luteinizing Hormone (LH) Receptor Vaccines on Immunocontraceptive Approaches for Sterilization of
Dogs and Cats notes that “targeting LH or FSH receptors
Very little research has been done using LH receptor may not be practical since there are many tissues outside
protein as a vaccine adjuvant. The idea is that if an immune the reproductive system that contain receptors for these
response can be raised against the receptor of a hormone molecules and that might be affected adversely” (Golden
(such as LH), antibodies could block the action of that 2009).
hormone, by occupying the receptor and blocking its
interaction with the hormone. As hormone receptors are seen 3.3.2.1 LH Receptor Vaccines: Summary of Advantages
as “self” – that is, not a foreign protein – the immune system and Disadvantages
must be “fooled” into mounting an immune response,
creating challenges similar to those encountered in trying to
Suppresses estrus in Not shown to be effective in
generate an immune response to GnRH or ZP. This approach
females males
theoretically would be similar to vaccination with GnRH, in
Suppresses sexual be- Difficult to manufacture under
that both fertility and sexual behavior should be blocked.
havior GMP without defining recom-
When purified bovine LH receptor protein was used binant antigen
as a vaccine antigen in dogs, an immune response was
Reversible – when the Depending on the formulation,
mounted (anti-receptor antibodies were elicited), causing
drug is discontinued, might cause injection site reac-
a reduction in fertility (Saxena et al. 2002). Bovine LH reproduction should tions
receptor vaccine administered to cats suppressed corpus resume within a rea- Immune response may be
luteum function in cats for approximately 1 year; this effect sonable period of time; inconsistent in individual
was reversible (Saxena et al. 2003). In this experiment, an could therefore be used animals and may vary depend-
implant containing purified LH receptors from bovine in animals ultimately ing on the preparation of the
intended for breeding antigen
ovaries obtained from slaughterhouses was used, a difficult
approach to commercialize. Difficult to predict when re-
production would resume after
In 2006, Hao and Saxena discussed the potential for use of cessation of treatment, as this
chimeric proteins containing human lutropin receptor and would depend on the gradual
chorionic gonadotropin epitopes as an immunocontraceptive decrease in circulating
vaccine (Hao and Saxena 2006). antibodies to LH receptors
The report from the 2009 ACC&D Scientific Think Tank

3.4 Chemical Sterilants addition, Infertile’s formulation contains approximately
two times the concentration of zinc gluconate contained in
Current commercialized chemical sterilants for dogs
Esterilsol. Although arginine is not listed as an ingredient
and/or cats are administered via injection directly into
on the Infertile packaging, the product’s Sponsor and lead
the testis, though one approach under development
researchers confirm that it is included as a neutralizing
is administered via subcutaneous injection or orally.
agent. Concerns about this product include the relatively
One approach has been approved for use in male dogs
small sample sizes in the published studies and an efficacy
in various markets, including the US, where it was
rate less than that demonstrated in the pivotal effectiveness
taken off the market for business reasons, obtained by
study conducted to support the approval of Neutersol
another Sponsor, and is pending reintroduction. Another
by the CVM. With further study and possible refinement
formulation is approved for the Brazilian market.
of formulation, Infertile may have potential to aid in
advancing sterilization programs (ACC&D Preliminary
3.4.1 Zinc Gluconate
Statement on Infertile 2009). See Chapter 4, section 4.2.4.5.
Zinc solutions that cause testicular degeneration and
permanent sterility have been developed for direct intra-
testicular injection.
One such solution consisting of zinc gluconate and
L-arginine was developed, approved by the CVM under
the trade name Neutersol® in 2003, and then withdrawn
from the US market in 2005, apparently due to issues
between the manufacturing and marketing companies. The
formulation was approved by the FDA for use in male dogs
3-10 months of age for chemical (non-surgical) sterilization.
Ark Sciences, Inc., located in New York City, acquired
full rights to the original formulation in 2007 and has
renamed the product Esterilsol® in markets outside the
Another zinc gluconate-based product called Testoblock®
US and Zeuterin™ in the US. The company reports that
has been studied in dogs in the Brazil. A 2007 publication
Esterilsol is registered in four countries, and Zeuterin will
(Oliviera et al. 2007) describes the product as ”a proprietary
be launched in the US in 2013. In Mexico, Panama, Bolivia,
zinc-based solution containing 0.1 M of zinc gluconate
and Colombia, Esterilsol is approved for dogs 3 months
that is pH neutralized in BioRelease Technologies, LLC’s
and older. Ark Sciences indicates the cost to nonprofit
(Birmingham, AL, USA) physiological vehicle (13.1 mg
organizations will be, on average, $15 per dog (price will
zinc/mL), that is designed for intratesticular injection. The
vary based on dose, which depends on the size of the dog’s
vehicle is non-irritating and aids in sequestering the zinc
testicles). Although, as noted, the product to be launched
moiety within the testicular tissue. Testoblock is similar to
in the US is called Zeuterin, we will use the term Esterilsol
Neutersol in that it is a zinc gluconate formulation that is
to represent the product, since it is available in a number
neutralized by the amino acid arginine. The solution is then
of markets under that name (see Chapter 4, section 4.2.4.2).
mixed with a proprietary BioRelease Technologies vehicle
Esterilsol is approved for use in cats in Columbia, but not
which is formulated to deliver the zinc gluconate in a slow-
in other markets.
release pattern … (this was not evaluated in the present
A zinc gluconate/arginine/dimethyl sulfoxide (DMSO) experiment).”
product called Infertile® was launched by Rhobifarma
A zinc-based product called Talsur was developed by
Industria Farmaceutica Ltda in Brazil in March of 2009.
the National Institute of Immunology (NII) of India 1988
Available information indicates that a single treatment with
and tested in 1990-1991. The product was a zinc tannate
Infertile provides permanent sterilization for 72% of dogs.
formulation. Experimental use in a street-dog control
Dogs not responding within 30 days were treated a second
program revealed that 22% of treated dogs developed
time; the second treatment resulted in sterilization. Infertile
complications (Animal People October 1998); excessive
is similar to Esterilsol but with important differences. The
scrotal swelling was noted (Animal People May 2007). The
formulation contains a small amount of DMSO as a carrier
product was discontinued.
to aid in the distribution of the drug within the testicle. In

3.4.1.1 Zinc Gluconate in Dogs post-treatment activity restrictions. This field study was
Esterilsol is injected using a 28-gauge (or finer) needle conducted on Isabella Island in the Galapagos. Note that
directly into the testes, where it destroys sperm cells, dogs “of all ages” were included in the study and dosed
followed by eventual shrinking and scarring of the based on testicular size, per a dosing chart. Necrotizing
epididymis and seminiferous tubules. Dogs treated injection site reactions occurred in four large dogs (3.9%
before puberty never become fertile; however, dogs that of the treated population) “receiving injection volumes
are sexually mature at treatment may remain fertile for near the maximum label dose.” These reactions required
up to 6 weeks (the delay is due to the time required for orchiectomy and extensive surgical repair in two dogs.
passage of sperm from the epididymis and vas deferens Researchers concluded that “the use of zinc gluconate
that were produced prior to treatment. Studies described injection is particularly useful in situations involving
in the Neutersol Freedom of Information (FOI) summary “large-scale use in dogs, particularly in remote locations
(available on the CVM website, fda.gov/AnimalVeterinary) … [and that] further investigation is needed to identify
indicate this treatment is 99.6% effective in causing sterility risk factors in dogs for adverse reactions to zinc gluconate
in young male dogs (aged between 3 and 10 months; and to develop strategies for avoidance.” Researchers
n=270). (Success was defined as an animal that displayed emphasized the importance of proper injection technique
aspermia (no semen ejaculated), azoospermia (no to avoid exposing non-target tissue and noted “possible
spermatozoa in the ejaculate), necrospermia (spermatozoa contributing causes to complications … include …
in the ejaculate are dead or motionless), or oligospermia improper after-treatment management, and characteristics
(sperm concentration less than 20 million spermatozoa per unique to the Galapagos environment” (e.g., “the warm
mL) 6 months post-injection.) The studies also reported climate and habit of dogs to lie on the hot sand and lava
testosterone levels were reduced by 41%–52%, compared rocks”) (Levy et al. 2008).
with a much greater reduction caused by surgical See Chapter 5, section 5.4.1.3 for a discussion related to
castration. The “effects of Esterilsol on hormone-dependent programs involving the use of zinc gluconate (Esterilsol) in
diseases and behaviors have not been established … It is field studies in frontier markets.
important to note that testosterone levels range widely
In a study of the use of zinc gluconate “either associated
among dogs” (ACC&D Product Profile and Position Statement
or not to dimethylsulfoxide,” researchers divided 29
on Zinc Neutering April 2012). Safety was evaluated both in
“sexually mature” male dogs into 5 groups: Group 1
controlled laboratory conditions and in a large (270 dog)
(control; saline); Group 2 (zinc gluconate 13.1 mg); Group
pivotal field study. In the field study the majority (97.5%) of
3 (zinc gluconate 26.2 mg); Group 4 (zinc gluconate 13.1
dogs treated exhibited no sign of pain when zinc gluconate
mg and DMSO 0.5%); and Group 5 (zinc gluconate 26.2
was injected into the testicles using recommended
mg and DMSO 0.5%). Dogs were examined at Day 15,
procedures. Sedation and analgesics were used for some
Day 0, and every 15 days post-treatment for 6 months to
dogs to minimize stress and discomfort. Adverse reactions
assess testicular size and sperm quality and quantity. In
as reported in the FOI Summary occurred in approximately
Groups 3, 4, and 5, cell motility declined significantly at
6.3% of the dogs treated, including 1.1% that required
five collection points. Two control dogs and four Group 5
medical treatment. Local reactions included mild testicular
dogs were surgically neutered at 12 months post-treatment.
swelling, evidence of pain, swelling of the prepuce,
Histopathology indicated “testicular degeneration,
dermatitis, ulceration, infection, and bruising or drying of
decreased number of germ cells, areas of atrophy,
the scrotum. Systemic adverse reactions included elevated
disruption of seminiferous tubule architecture, and loss of
white cell count, vomiting, anorexia, lethargy, and diarrhea.
germ and Sertoli cells in Group 5 dogs … [indicating that]
Ark Sciences emphasizes the importance of following the
the association of DMSO (0.5%) to zinc gluconate (26.2 mg)
recommended treatment techniques to minimize adverse
may be indicated as a contraceptive method for male dogs”
reactions. Current administration protocol includes light
(Soto et al. 2007).
sedation and administration of a non-steroidal anti-
inflammatory drug (NSAID). In a study of Infertile, researchers concluded that zinc
gluconate formulated with DMSO was clinically safe
In a study of pet-owner acceptance, ease of use,
and effective and did not produce behavioral changes or
and short-term outcomes, 103 dogs were treated with
discomfort in dogs (n=11) treated with an injection of 26.2
Neutersol; treatment was “well accepted by the dogs.”
mg/mL zinc gluconate and 0.5% DMSO in both testicles.
Dogs went home to “their free-roaming environment” post-
Histology revealed lesions “compatible with permanent
treatment and their owners observed them. There were no
sterilization” (Soto et al. 2009).

Researchers studying Testoblock evaluated the testes. Treatment resulted in testicular atrophy, reduced
effectiveness of intratesticular injection as a contraceptive testosterone, and absence of sperm.
in 15 mixed-breed dogs. Five dogs served as controls,
five dogs assigned to Group 2 ranged in age from 8 3.4.2 Calcium Chloride
months to 1 year, and five dogs assigned to Group 3
ranged in age from 2 to 4 years. Dogs in Groups 2 and 3 Research on use of calcium chloride as an intratesticular
received 0.2–1.0 mL Testoblock depending on testicular injection for sterilization of dogs “and other large
width. Histopathological analysis revealed changes that mammals” was reported as early as 1978. Use in cats was
“suggested irreversibility” and researchers concluded that reported by Jana and Samanta at the 4th International
the use of Testoblock intratesticular injection “effectively Symposium on Non-Surgical Contraceptive Methods of Pet
impaired spermatogenesis” (Oliveira et al. 2007). Population Control in 2010, who noted that ease of injection
is the primary “practical advantage” of this approach,
A recently published study of Testoblock assessed
while “the primary disadvantage is slow onset of action
“whether the efficacy of zinc gluconate (Testoblock) as a
(4-6 weeks) and inter-individual variability in level of
chemical contraceptive in male dogs was compromised
discomfort during injection.” The latter may be addressed
in the presence of metamizole sodium (a nonsteroidal
by basing injection volume on testicular volume rather than
anti-inflammatory/analgesic agent).” Ten sexually mature
body weight.
mixed-breed dogs received intratesticular injection of
Testoblock at 0.2–1.0 ml/testis, based on testis width. For an ACC&D review article on the use of calcium
Five dogs also received metamizole sodium (aka sodium chloride for non-surgical contraception, see http://www.
dipyrone) orally at 25 mg/kg three times a day for 2 acc-d.org/ACCD%20docs/ACCD-RecommCalcChlor2.pdf.
days, starting 2–3 hours post injection. All 10 dogs had
transient testicular swelling for 3 days post injection.
All 10 dogs were azoospermic at Day 60 post injection;
seven dogs were azoospermic at 120 and 180 days post
injection and three had apparent aspermia. Researchers
found no significant differences in any clinical parameters
between the two groups and concluded that administering
“metamizole sodium concurrent with an intratesticular
injection of a zinc-based solution did not interfere with
chemical sterilization and it improved animal welfare”
(Oliveira et al. 2012). 3.4.2.1 Calcium Chloride in Dogs
The low cost, lack of need for anesthesia and relative In a study of sterilization of 24 male stray dogs with
safety involved in the proper use and administration of a single injection into each testicle of calcium chloride,
products containing zinc gluconate for sterilization of male a 5-, 10-, 15-, or 20-mg dose in dogs caused significant
dogs are characteristics that can be expected to be appealing atrophy of testicular tissue. Epididymal sperm counts and
to the shelter and related communities as well as clients and testosterone concentrations were significantly decreased
veterinarians. The effect of these treatments on behavior in at all doses. The 15- and 20-mg doses provided a higher
male dogs has not been evaluated, and there are few data on level of efficacy than the two lower doses. This method
the effects of surgical castration on male dogs. of chemical sterilization was found to be economical
and effective, with no adverse effects noted. All animals
3.4.1.2 Zinc Gluconate in Cats tolerated the intratesticular injections of calcium chloride
In a 2010 presentation at the 4th International Symposium and exhibited a slight increase in firmness of testis on
on Non-Surgical Contraceptive Methods of Pet Population palpation. Most dogs, including those injected with normal
Control summarizing potential options for non-surgical saline, displayed signs of mild discomfort approximately
approaches in cats, Dr. Julie Levy of the University of 1 to 5 minutes after injection. Researchers attributed this
Florida reported on unpublished data provided by Ark to fluid pressure. Every dog had mild testicular swelling
Sciences about the use of zinc gluconate (Esterilsol, Ark by 24 hours after injection, and swelling was most evident
Sciences) in cats. One hundred and fifteen cats were treated in treated dogs between 48 and 72 hours post-injection.
at 6 months of age and monitored for 12 months. Cats were The swelling decreased gradually at 3 weeks. Injection of
heavily sedated and treated with dosage of 0.2-0.4 mL/ 5 mg of calcium chloride did not induce uniform results
as evaluated by histology after removal of the testes.
Significant morphological changes were associated with the 0 and every 20 days for a 2-month period. Semen analyses
10 mg dose, and the 15 mg dose “resulted in total necrosis were done at these time points as well. Ability to collect
in seminiferous tubules and interstitial Leydig cells, with semen and analysis of semen collected at 20, 40, and 60
replacement by a fibrocollagenous band.” Researchers days post-injection were defined as the “primary indicators
were able to palpate only a “small testicular remnant” at 4 of treatment effectiveness.” Semen could not be collected
weeks after the 20 mg calcium chloride injection. Therefore, from the high-dose cat after injection, possibly because “the
“a dose-dependent relationship [resulted] when [calcium high dose of calcium chloride injected into the testes could
chloride] was used to induce sterilization in the male dog. have caused serious damage in seminiferous tubules.”
The maximum responses in both the biochemical and Collection from the other cats was successful.
histological parameters related to chemo-sterilization were The other three semen samples (two treated cats and one
noted at the 15- or 20-mg doses.” Researchers concluded control cat) contained live motile sperm; the two treated
“calcium chloride induces necrosis of the entire testicular animals were found to be oligospermic, with less than
tissue, [which is consistent] with previous studies with 20 million spermatozoa/mL of ejaculate, and the control
this chemical agent in the testis of the rat and in domestic animal was found to have sperm greater than 20 million
animals” and that “an intratesticular injection of CaCl(2) at per mL. Testicular histology showed dose-dependent
specified doses could be a suitable method of sterilization degenerative changes.
in preference to surgical castration of dogs“(Jana and
Samanta 2007). On Days 1-7 post-treatment, researchers assessed general
attitude, appetite, ability to walk, scrotal pain, rectal
3.4.2.2 Calcium Chloride in Cats temperature, and scrotal swelling. Although the scrotum
of all the cats was swollen or the testis was sore or irritated
In a study reporting on the use of calcium chloride in the
to a minor degree post-injection, researchers did not note
cat, cats (6/group) received a single bilateral intra-testicular
significant safety-related findings.
injection of 0.25 ml 5%, 10%, or 20% calcium chloride
dehydrate containing 1% lignocaine hydrochloride per Routine surgical castration was utilized at Day 60, and
testis: histomorphological analysis was conducted on the testes.
The authors concluded that “efficacy of calcium chloride
“At Day 60 post-injection, cat testes were col-
[at 40 mg] in inducing sterilization was supported by
lected and examined, and showed complete
the necrosis of the seminiferous tubules and interstitial
testicular necrosis and replacement by fibrous
cells, along with the significant fibrosis. Results indicate
tissue; very low sperm counts; and reduction
that intratesticular injection of calcium chloride (40 mg)
of serum testosterone by at least 70% in [the]
is a well-tolerated and effective method for non-surgical
20% dose. Androgenic enzyme activities and
chemical sterilization of male cats.”
their expressions were also reduced in all the
treated groups … intra-testicular testosterone 3.4.3 Chlorhexidine Digluconate
concentration was also low. Increased testicu-
lar lipid peroxidation, with reduced antioxi- In the 1980s work was done with chlorhexidine
dants and mitochondrial membrane potential, digluconate with or without DMSO injected into the
were evident following calcium chloride treat- epididymis of dogs and cats (Pineda and Hepler 1981,
ments” (Jana and Samanta 2011). Pineda and Dooley 1984, respectively).
� Injections of 3.0% chlorhexidine digluconate in 50%

A pilot efficacy and safety study of a single intratesticular DMSO in eight dogs resulted in azoospermia for
injection of calcium chloride in causing sterility of male all but one dog (which had low sperm count, low
adult cats was also reported at the 4th International motility, and many abnormal sperm) by Days 35 or
Symposium on Non-Surgical Contraceptive Methods of 42. Dogs were monitored for 952 days, and all dogs
Pet Population Control (Baran et al. 2010). Four male cats remained azoospermic. Injections of 4.5% chlorhexidine
were selected for this study; treated cats were injected with digluconate to dogs resulted in azoospermia by Day 28,
a 10-, 20-, or 40-mg concentration of calcium chloride at 0.2 but dogs were not monitored for long-term effects. Some
ml/per testis, and one control cat was injected with sterile transient edema was observed in dogs in both studies,
saline at the same rate. but no other adverse effects were observed.
Researchers assessed testicular size and serum � In eight cats, epididymal injection of 4.5% chlorhexidine
testosterone level was assessed prior to injection, on Day digluconate reduced or eliminated sperm production
for 140 days (the duration of the study) without major
adverse effects. The authors note that this method of developing this approach in dogs, is also working on a
“chemical vasectomy … appears to be safe and may be product to sterilize rat populations in Asian rice fields (see
suitable for large-scale sterilization programs … “ Chapter 4, section 4.2.4.6).
Recent work on a single testicular injection of VCD is an industrial chemical that is an intermediate
chlorhexidine solution as a chemical sterilant in male dogs related to production of a number of products including
was presented at the 4th International Symposium on synthetic rubber and flame retardants. VCD has been
Non-Surgical Contraceptive Methods of Pet Population shown to cause loss of small, preantral ovarian follicles in
Control (Aiudi et al. 2010). Forty-two healthy dogs were rodents and, since this occurs in vitro and in vivo models,
sedated and divided in two groups of 21 animals. One appears to directly act on those follicles. The literature
group was treated with 2 ml of 5% chlorhexidine solution contains reports of various pathological consequences
injected percutaneously into the dorsal cranial portion of the use of VCD in accelerated ovarian failure (i.e.,
of both testes, and the second group injected with 1 ml menopause) rodent models, but “these studies used higher
of saline solution. Researchers monitored testosterone in concentrations, longer duration, and different routes of
all dogs every week for 60 days. Chlorhexidine-treated administration (Van Kempen et al. 2011). Note that VCD
dogs showed testicular tenderness and local swelling is a known dermal carcinogen, as noted in the relevant
at 96 hours post-treatment, which regressed within 15 material safety data sheet (MSDS).
days. At Day 60, testicular ultrasonography revealed
bilateral nodular lesions. Libido was reduced and prostatic
volume and parenchyma were normal. Analysis of
semen indicated azoospermia and a substantial decrease
in the volume of ejaculate. Control animals showed no
changes in libido, semen quality, testicular, epididymal or
prostatic characteristics. Following surgical castration at
Day 60, “longitudinal sections of testes revealed an area
of necrosis and fibrosis beside the epididymis extended
to the tubuli seminiferi recti, rete testis and ductuli
efferentes; histological examination showed degeneration
of the seminiferous tubules associated with a significant
alteration of the germinal epithelium cells … [researchers
concluded that] a single percutaneous administration of
5% chlorhexidine digluconate solution into the testicular In a field study on a Navajo reservation in Arizona,
parenchyma should be considered an effective non-surgical researchers treated eight 12-week-old female puppies and
sterilization method without local or systemic adverse eight 6-month old female dogs with 80 mg VCD, 160 mg
effects.” VCD, 240 mg VCD or vehicle each day for 6 days. On Day
30 ovaries were removed for histopathology. Primordial
3.4.4 Vinylcyclohexene Diepoxide follicles in VCD-treated dogs were reduced significantly
compared to vehicle-injected control dogs. Researchers
The basis for the use of 4-vinylcyclohexene diepoxide reported that blood chemistry was normal, growth in
(VCD) as a sterilant for female dogs has been the puppies was not affected, the older dogs did not lose body
hypothesis that VCD treatment will accelerate elimination weight, and all animals were “healthy and active” at 2.5
of primordial follicles in dog ovaries leading to ovarian years post-treatment (Mayer 2006). There does not appear
failure, eliminate estrous behavior and cause permanent to be any additional publications describing research on
sterility. VCD works by up-regulating cellular and VCD to sterilize dogs.
molecular processes of apoptosis, thereby accelerating the
natural process of follicular atresia. In mice, it has been 3.4.5 Hypertonic Saline
shown that over 2 weeks of daily injections are required
to cause ovarian follicles to become atretic. The more A study conducted in 40 rats compared orchiectomy
practical preferable mode of delivery for causing sterility versus an injection of a hypertonic (20%) saline
in female dogs would be continuous release to attain 100% solution into the testicles of laboratory rats. Twenty rats
sterility and a hormone environment equivalent to that of were treated with hypertonic saline and 20 rats were
sterile individuals (Mayer 2006). SenesTech, the company orchiectomized. The study was undertaken to investigate

an alternative, minimally invasive approach to castration in
human patients with metastatic carcinoma.
At 30 days after injection, the rat testes were slightly
atrophied, and testosterone levels were similar to those
for animals that had an orchiectomy. Histologically, the
epididymis was unaffected by the saline injection. Adverse
effects were not observed in treated animals. Researchers
indicated that “intratesticular hypertonic saline injection
seems to be an alternative method in the future to its rivals
such as orchiectomy and medical castration” but that
further laboratory work would be required to ascertain the
potential utility of this approach in dogs (Emir et al. 2008).
Note that advantages and disadvantages may vary depend-
ing on the specific approach.
3.4.6 Chemical Sterilants: Summary of Advantages and Disadvantages

Permanent sterility Irreversible
Low cost Potential for improper administration and related side effects
Convenience Side effects may necessitate surgery and require provisions for follow up
Ease of use
Surgery and anesthesia not required (sedation
strongly recommended)
Potential for large-scale use in public health-
related settings
Note that continued testosterone production at some level, albeit reduced from normal (characteristic of use of zinc gluconate), and
presence of testicles in males may be viewed either as advantages or disadvantages in a given owner, population or situation.
3.5 Sex Steroids 3.5.1 Progestins

Hormonal down-regulation involving the administration
Progestins are a class of compounds that are structurally
of exogenous steroid hormones can serve as a method
similar to progesterone, and mimic its biological effect.
of suppressing fertility. These drugs act, in general, via
They are typically used to manage reproduction in
several mechanisms, which may include suppression of
female dogs and cats, and progestins may also be used
GnRH through negative feedback or by direct effects on the
for dermatological and behavioral indications in animals.
uterus, sperm transport, or other mechanisms.
Use of progestins in companion animals is subject to
A variety of modified versions of the sex steroids have “variability in individual animal response based on an
been synthesized and are used for therapeutic purposes animal’s genetic and metabolic characteristics … [and is]
in human and animal medicine (Okkens 1981). These cumbersome, in many instances unreliable, and subject to
drugs work through negative feedback at the level of the the timing at which the drug is administered. Thorough
brain and pituitary (see Chapter 2). They reduce the level assessment via physical and reproductive examination is
of GnRH, impair fertility and have local effects on the required prior to using progestins in companion animals,
reproductive tract that interfere with fertility. However, as is consistent follow-up monitoring” (Jöchle, personal
they may have a number of side effects which can make communication 2012).
them undesirable therapies for cats and dogs.
Side effects of the progesterone-type drugs vary
depending on when treatment is given in relationship to
stage of the estrous cycle and can include:
� Uterine hyperplasia and pyometra

been associated with side effects such as “increased
� Diabetes appetite leading to weight gain; lethargy or restlessness;
� Changes in hair coat (hair loss, discoloration) marked mammary stimulation with hyperplastic and/
� Increased incidence of mammary tumors or neoplastic changes; clinical and pathologic changes
� Increased sodium and water retention typical of diabetes mellitus … Similar side effects have
� Lethargy also been reported in queens” (Kutzler and Wood 2006).
� Weight gain The most serious side effect of megestrol acetate is
Use of progestins also “increases the tendency towards endometrial hyperplasia which favors pyometra (Asa,
diabetes, mammary tumors, fibroepithelial mammary personal communication 2012).
hyperplasia, [and] adrenocortical suppression” (Kutzler,
personal communication 2012), and Dr. Michelle Kutzler � Orally administered megestrol acetate for 1 week prior
maintains that “progestins should never be used in to and 1 week following deslorelin implant placement
cats” (Kutzler, personal communication 2012). Dr. can prevent the deslorelin flare and resulting estrus in
Sandra Goericke-Pesch notes that in cats “the [progestin- domestic dogs as well as wild canids and felids (AZA
related] risks of uterine disease, mammary tumours, Wildlife Contraception Database, St. Louis Zoo).
fibroadenomatosis or diabetes mellitus have to be taken � Plumb’s Veterinary Drug Handbook, 7th Edition lists the
into account – especially in predisposed animals. Modern, following additional adverse effects of megestrol acetate:
effective pharmacological alternatives are available for � In dogs – changes in behavior or hair color, mucometra,
managing oestrous suppression and unwanted pregnancy” endometritis, cystic endometrial hyperplasia,
(Goericke-Pesch 2010). acromegaly, adrenocortical suppression and, rarely,
lactation
There are species differences in response to the use of
progestins and a given dosage “will have different effects on � In cats – profound adrenocortical suppression, adrenal
atrophy, polydipsia/polyuria, personality changes,
the cycle depending on the time of treatment relative to the
possible hepatotoxicity
stage of the estrous cycle” that vary from days’ to months’
duration of effect (Romagnoli and Concannon 2003). � An unapproved product, FeralStat® (megestrol
acetate), was marketed over the Internet in the US for
Kutzler and Wood (2006) note that publications regarding contraception in feral cats from 2009-2011. The product
the use of “hormonal manipulation” for contraception in was produced by a compounding pharmacy to be added
cats and dogs date back to 1952, and much information canned cat food and fed to cats for fertility suppression.
related to side effects was generated in dog studies in The distributor characterized FeralStat as a “stop gap”
support of applications in humans. measure to prevent reproduction until a colony could
Progestins available for contraceptive use in the US be trapped and sterilized. The dose of megestrol acetate
include MGA, medroxyprogesterone acetate (MPA), and that was contained in FeralStat was significantly lower
proligestone; these and others are available outside the US. than that used historically; its safety and effectiveness do
MGA was approved by the FDA and marketed as Ovaban® not appear to have been studied (ACC&D 2010).
by Schering Plough Animal Health (it is known as Ovarid® � MPA has been administered to bitches and queens
in the UK and other parts of the EU). It is no longer on the as a long-acting injectable treatment, but this has not
market, but unapproved “copies “of this compound are suppressed estrus as effectively as MGA, and in bitches
available via the Internet. MPA was known by the trade was associated with a “high incidence of side effects”
names Provera® and Depo-Provera and is not approved by
the FDA but also is available on-line from compounding
pharmacies. Proligestone’s trade name is Delvosteron®.
It is not approved by the FDA and does not appear to be
available from compounders in the US.
3.5.1.1 Bitches and Queens
� Megestrol acetate “has been used extensively for

temporary estrus suppression in the bitch,” (Kutzler
and Wood 2006) and is also used to alleviate false
pregnancy in bitches and treat dermatological and
behavioral indications in queens. Megestrol acetate has

including uterine disease and skin- and hair-related insignificantly when MGA was administered orally;
manifestations. MPA should not be used in cats (Kutzler subcutaneous administration of MPA [medroxyprogesterone
and Wood 2006). acetate] at 4 mg/kg or 10 mg/kg did not affect sperm
� Plumb’s Veterinary Drug Handbook, 7th Edition notes that quality; “however, subcutaneous administration of MPA
“if MPA is administered subcutaneously, permanent 20 mg/kg produced rapid response (within 3 days) with
local alopecia, atrophy, and depigmentation may occur” significant decreases in sperm motility, morphology and
and recommends injecting subcutaneously in the output” (Kutzler and Wood 2006). Higher doses can be
inguinal area. expected to be accompanied by higher rates of side effects
� Proligestone is characterized by “weaker progestational (Asa, personal communication 2012). Use of progestins
activity than other synthetic progestins” (Kutzler and in male cats increases the tendency towards diabetes,
Wood 2006). (MSD/Merck Animal Health) is approved mammary tumors, fibroepithelial mammary hyperplasia,
in certain ex-US markets as an injectable contraceptive adrenocortical suppression, and other side effects seen in
for dogs. The label for the product in the UK notes queens (Kutzler, personal communication 2012).
“urine sugar levels [should be] observed carefully There have been no progestin drugs that have been
during the month after dosing” and “bitches may approved by regulatory bodies for use in male dogs or cats.
accept the male for some days after medication with the
product in pro-oestrus.” Proligestone can also be given 3.5.2 Androgens
to female cats … causing estrus suppression for about
6.5 months” (Kutzler and Wood 2006). Covinan® is a Androgens are natural or synthetic steroids that control
product previously marketed by the company Intervet and stimulate male sex characteristics. Mibolerone
(now Merck/MSD Animal Health). For bitches this (Cheque® Drops, an orally administered product formerly
proligestone is labeled for multi-dose treatment every 5 produced by Pharmacia, now part of Pfizer Animal
months. The label notes that “Return to normal oestrous Health), is a synthetic androgen that was used to prevent
[sic] activity occurred within 9 months in 75% of animals estrus in dogs. Mibolerone (MIB) works via negative
and within 12 months in 90% of animals following a feedback to block the release of LH and has been used
single injection of Covinan.“ For queens the label notes to lengthen the anestrous period to postpone estrus and
“Dosage regimes similar to those given for bitches are to treat false pregnancies. It was not recommended for
advised except that, for temporary postponement of use in dogs before the first estrous cycle because it can
calling, the injections may be given in either di-oestrus stunt growth, nor was it to be used in breeding bitches.
or anoestrus. Because cats are seasonally poly-oestrous, The Cheque Drops label stated that the product can be
the reoccurrence of calling after medication is very used daily as desired but should be discontinued after 24
variable. However, the majority of queens will call 6 ½ months of use, making it unsuitable for owners wishing to
months after injecting Covinan for the suppression or have continuous contraception for their bitches. Treatment
temporary postponement of calling.” must be started at least 30 days before the next estrus, or
the treatment may not be effective. MIB has been declared
a Class III drug in the US and is no longer marketed for use
as a commercial veterinary product, but it can be obtained
from compounders and “underground” producers, who
are providing this androgenic material to bodybuilders.
Side effects are numerous and may be acute; the drug is
contraindicated in Bedlington terriers (Kutzler and Wood
2006) and should not be co-administered with progestins
or estrogens (Plumb’s Veterinary Drug Handbook, 7th Edition).
Plumb’s lists the adverse effects of MIB in female dogs as
follows:
3.5.1.2 Male Dogs and Cats � Prepubertal female: premature epiphyseal closure,
“Based on the principles of negative feedback … clitoral enlargement, vaginitis
exogenous progestins should suppress gonadotropin � Adult bitch: mild clitoral hypertrophy, vulvovaginitis,
secretion in males, thereby disrupting spermatogenesis.” increased body odor, abnormal behavior, urinary
In male dogs, semen quality did not change or changed incontinence, voice deepening, riding behavior, enhanced

clinical signs of seborrhea, epiphora (tearing), hepatic 3.5.3 Anti-Androgens, Anti-Estrogens and
changes (intranuclear hyaline bodies), increased kidney Aromatase Inhibitors
weight (without pathology), hepatic dysfunction (rare)
Drugs have been developed for human use that either
MIB is contraindicated for use in cats because the interfere with the production of testosterone or estrogen,
effective dose is very close to the toxic dose (i.e., narrow or inhibit binding of testosterone or estrogen to their
therapeutic index) and “cervical skin thickening and receptors.
clitoral hypertrophy was observed in cats and did not
resolve after drug withdrawal” (Kutzler and Wood 2006). These compounds are mainly used to treat prostate
In addition, “mibolerone has been reported to cause or breast cancer in humans. They have not been used in
thyroid dysfunction in cats” (Plumb’s Veterinary Handbook, animals, so efficacy is unknown. Most of the compounds
7th Edition). for humans require daily pills or injections – in some
cases several times a day – and are impractical for
veterinary use. Although theoretically they could be used
as contraceptives, because of practicality and expense,
research on their veterinary use has not been done. They
are not discussed further in this document.
3.5.4 Progestational and Androgenic Drugs: Summary of Advantages and Disadvantages
Suppresses estrus and fertil- Unacceptable side effects
ity in both sexes (depending
on the drug)
Some approved veterinary Time of administration during the estrous cycle determines effectiveness, duration, and
drugs have regulatory ap- side effect profiles
proval and are available in
some markets5
Consistent veterinary monitoring required due to significant and sometimes life threaten-
ing side effects seen with use
Maximum duration of effectiveness is unpredictable
Lack of products for use in cats
Minimal effectiveness of progestins in male dogs
Minimal/inconsistent availability of approved veterinary versions
3.6 Miscellaneous Research of Interest oligonucleotides, such as antisense oligonucleotides, that

bind to complementary sequences in DNA and RNA and
3.6.1 Gene Silencing disrupt their transcription or translation.
At a 2009 ACC&D Scientific Think Tank, Gene Silencing
One potential approach to non-surgical contraception
Potential for Sterilization of Cats and Dogs, participants
is gene silencing, which essentially involves turning off
identified some of the ways that a gene silencing agent
genes that code for proteins essential for reproduction. It
is believed that gene silencing would be unlikely to reach might be delivered into a target cell, discussed the research
100% efficacy, although levels of 95% to 99% are regarded that would need to be undertaken to better understand
as quite possible (Whitcomb 2010, S. Johnston, personal the molecular aspects of male and female dog and cat
communication 2012). It is not known what level of reproduction, and discussed the potential regulatory and
silencing would be required for permanent sterilization. other practicalities involved in developing and obtaining
Agents that can be used for gene silencing include approval for a product whose activity is based on gene
small interfering RNA (siRNA) that can bind to specific silencing (see http://www.acc-d.org/ThinkTanks for more
messenger RNA (mRNA) molecules and increase information).
or decrease their activity; and chemically modified Researchers at the Oregon Health & Science University
5
At this time, availability of approved veterinary drugs is difficult to determine in a given market and varies
a great deal. In addition, a company with an approved drug may choose not to market that drug. Human
generics and compounded versions are typical (Jöchle, personal communication 2012).

(OHSU) and the University of Iowa (UI) (Dissen et al. 2012) pathology and also open new avenues for pharmacological
have conducted proof-of-principle work involving the use or vaccinal control of fertility.” (Fellman 2010)
of RNA interference to silence a gene needed for fertility. Both are members of a family of peptides known as
One of the issues related to gene silencing is the potential RFAmide or RFAmide-related peptides. (See Ebling and
for unintended silencing or repression of non-target genes. Luckman 2010 for a detailed technical discussion).
The team’s objectives were: Kisspeptins, which were identified in 2001, are expressed
in neurons of the hypothalamus.
1. “identifying a gene within the hypothalamic-hy-
pophyseal-gonadal axis that is required for fertility; “These neurons synaptically contact GnRH neurons and
they express steroid hormone receptors. Their responses to
2. choosing a method that can selectively silence the gonadal steroids suggest that [depending on their location],
gene of interest with minimal off-target effects; kisspeptin neurons … are involved in the negative
feedback regulation of gonadotropin secretion [or] … may
3. devising a minimally invasive method of silencing contribute to generating the preovulatory gonadotropin
genes of interest in a cell-specific manner; surge in the female” (Fellman et al. 2010).
There may also be a role played by “locally produced
4. utilizing a delivery vehicle that allows this silenc-
kisspeptins” as indicated by “the ability of the LH surge
ing effect to be maintained for the live [sic] span of
to induce ovarian expression of KiSS-1 at the preovulatory
the animal … “
period. … In the male, recent results suggested a down-
regulation of the hypothalamopituitary testicular
Two studies were conducted – one in rats and one in
axis response to kisspeptin following continuous
monkeys. The EAP1 (Enhanced at Puberty 1) gene was
administration” (Fellman et al. 2010).
selected as the target fertility-related gene. Suppressing this
gene disrupts reproductive cyclicity. A viral-based vector Researchers note that kisspeptins are also characterized
“that allows infection of a very broad spectrum of species by metastasis suppressor effects, “effects on motility,
and cell types” was used to contain and deliver specifically chemotaxis, adhesion and invasion have also been
engineered small inhibitory RNA (siRNA). Researchers documented” and a system in which kisspeptin is involved
concluded that the studies demonstrated “targeting RNAi affects certain secretory functions in the endocrine
to a gene required for reproductive fertility and delivered pancreas. Signaling in which kisspeptin is involved “may
to the hypothalamus is capable of suppressing fertility” and participate in implantation of the mammalian embryo,
noted that the development of delivery systems to target the placenta formation, and maintenance of pregnancy”
hypothalamus ought to enable the development of “the tools (Fellman et al. 2010).
to silence genes essential for reproduction in a non-invasive, GnIH, a hypothalamic neuropeptide that inhibits the
effective and sustained manner in dogs and cats.”The release of gonadotropin at the level of the pituitary, is
team included Dr. Beverly Davidson of UI, found in the pituitary, hypothalamus, and “several brain
who has received a Michelson Grant in regions.” It was discovered in quail in 2000. Researchers
Reproductive Biology to have identified its receptor and characterized its binding
conduct additional proof-of- activity, and have suggested “that GnIH acts directly on
principle work. the pituitary via GnIH receptors to inhibit gonadotropin
release. GnIH may also act on the hypothalamus to inhibit
3.6.2 Kisspeptin GnRH release” (Fellman et al. 2010).
and Gonadotropin-
Fellman et al. (2010) note that these peptides have
Inhibitory Hormone
(GnIH) “emerged as important regulators of the reproductive axis,
underscoring the importance of further investigations
Two peptides have been into the neural, cellular, and molecular mechanisms by
discovered “and have … emerged which [they] act. Their potential for the manipulation of
as important regulators of the the gonadotropic axis and gametogenesis deserves a very
reproductive axis.” They are kisspeptins particular interest.”
and gonadotropin-inhibitory hormone
(GnIH), and they provide “a novel 3.6.3 Egg Proteins and Peptides
approach to studying the physiological The 2002 Contraception and Fertility Control in Animals
regulation of reproduction, as well as its report described the work of researchers at the Department

of Cell Biology at the University of Virginia (UVA), who using vaccine formulations that contain hormonal and
constructed dog and cat ovarian cDNA libraries and had oocyte-restricted antigens that have been conjugated with
begun the process of isolating proteins to be expressed for these VLPs” (Coonrod 2010).
immunogenicity and fertility trials (Coonrod 2002). Dr. For dog and/or cat contraception, it is not known if
Scott Coonrod, previously at UVA, is currently working plateau antibody levels created by this type of vaccination
in this field at Cornell University College of Veterinary would be above or below those needed for contraception
Medicine Baker Institute for Animal Health, and Dr. John (Schiller 2010).
Herr has continued work in this area at UVA.
At the time of this update, Dr. Coonrod and his
Certain of these proteins are important because they colleagues are testing MATER expressed within a VLP
are required for the oocyte-[egg]to-embryo transition, protein in mice and assessing the immune response and
“which has the potential to make them good drug targets level of germ cell depletion, as a precursor to potential
or targets for autoimmune responses.” Two of the most studies in cats (Coonrod, personal communication 2012).
relevant proteins that have been isolated are peptidyl
arginine deiminase (PAD6) and maternal antigens that
embryos require (MATER). Researchers discovered that
in mouse models, removing the thymus gland in young
females produces an autoimmune response that results in
destruction of oocytes, completely depleting the germ pool
and causing infertility. “The key was figuring out what
the immune system is seeing in the egg, and it’s MATER.”
Therefore, if MATER can be expressed in a recombinant
form and injected into an animal, the animal’s immune
system could be “tricked” into destroying oocytes before
they can become fertilized. It may be possible to generate a
large amount of recombinant MATER that is identical to the
MATER that is expressed in the oocyte, take the MATER
and the gene that encodes MATER, and create a vaccine Dr. Herr and his colleagues are screening phage libraries.
(Coonrod, personal communication 2012). A phage is similar to a bacterial virus and “displays various
peptide structures on its surface.” The researchers are
In order to use egg-specific proteins as antigens seeking oocyte biomarkers – “peptides that bind to the
in vaccines that could result in single shot sterilant, surface of immature egg cells.” Dr. Herr has received a
innovations are required in vaccine construction, since Michelson Grant in Reproductive Physiology (see Chapter
vaccines used to date for immunocontraception require 4, section 4.3.3.2) to help fund the project. The team is
multiple booster injections to maintain effectiveness. One “screening [the peptides] against different organs to see
potential method of structuring a vaccine for longer-term which phage only targets the egg cell … [and] … plans to
effect involves the use of virus-like particles (VLPs). VLPs use those peptides as a drug to target the surface of the
are noninfectious particles that are similar in structure to eggs and deliver another peptide that will induce apoptosis
infectious viruses but are noninfectious because they don’t and kill the eggs.” This will involve what Dr. Herr calls
contain viral nucleic acid. Examples of human vaccines that “hunter and killer” peptides – the “hunter” will target the
use VLPs include FDA-approved human hepatitis B and surface of the oocyte, and the “killer” will cause the oocyte
human papillomavirus vaccines. Their small size facilitates to die. At this point, the “killer” peptide has been identified
their uptake by dendritic cells and macrophages and (Burnham 2011).
“enables diffusion to lymph nodes” (Schiller 2010).
In ongoing work at the Herr laboratory at the UVA
VLPs from the parvovirus capsid have a rigid School of Medicine, researchers are identifying, cloning,
conformation that makes them good candidates as and characterizing human testis genes and their proteins
immunogens or adjuvants. They have been used in dog in terms of their expression in human tumors. This area
and cat vaccine formulations to incite potent and long-lived of research is known as “cancer-testis antigens.” Whether
immune responses against a range of associated infectious- or not this approach will identify additional targets for
disease-based antigens. Therefore, it is hypothesized that immunocontraception of dogs or cats is unknown.
“permanent sterility can be achieved in dogs and cats by

3.6.4 Targeted mice reduced ovarian weight
Delivery of and endocrine hormones. The
Cytotoxins researchers’ goal is to develop
KUAS-272 as a single-dose
The use of targeted
sterilant in both male and
delivery of cytotoxins for
female dogs and cats (Tash
sterilization in dogs and
and Roby 2010). Gupta et al.
cats involves applying the
(2012) reported on the effects
power of potent biological
of several KU-AS-272 dose
toxins to kill just the cells
levels administered to rats
that are targeted, in this
and concluded that “the data
case specific sperm, egg, or
collected thus far indicate that
hormone-producing cells
KU-AS-272 at 12 mg/kg and
required for reproduction.
higher may have achieved the desired sterilizing block to
Three factors must converge for this approach to be effec- spermatogenesis with total loss of spermatogenic cells.”
tive (Rhodes 2010): Researchers are expecting 60-day data, pending at the time
of this publication, will ascertain whether sterilization was
1. A toxin has to be purified and attached to some- in fact attained. Mating trials in the rats and additional
thing that will take it to its target. This “transport proof-of-concept studies in dogs and cats are planned.
molecule” could be an antibody that binds to a
specific protein on a cell surface, or a hormone that 3.6.4.2 FSH Receptor Ligand-Cytotoxin Conjugates
binds to a specific hormone receptor. Cytotoxins that target the follicle-stimulating hormone
receptor (FSHR), a protein found in specific cells of the
2. The particular cell type to be destroyed has to have
male and female reproductive systems that are crucial
a specific “dock” for the deadly payload, to bind
for fertility, may act as potential chemosterilants. Dr.
tightly to the cell and deliver the toxin to that cell
William Ja, a professor at the Scripps Research Institute
alone. This “dock” could be a hormone receptor or
in Florida, has been working on such an approach for
a specific cell surface protein that an antibody can
developing cancer therapeutics, and is now applying the
grab onto.
same principle to ablating Sertoli and granulosa cells to
3. The researcher has to make sure that the “dock” is cause permanent sterility in animals. His work involves
only on the cells to be killed and nowhere else, so that developing a compound by combining a ligand, that
other “non-target” cells in other parts of the body are is, a molecule that binds to a receptor on a cell, with a
not harmed, causing unwanted side effects.” toxic molecule. Dr. Ja has received a Michelson Grant in
Reproductive Biology (see Chapter 4, section 4.3.2.1) to
In addition, if the effect is to be permanent, and only enable him to work on potential compounds that target the
require one treatment, the destroyed tissue must be unable FSHR.
to regenerate (Levy, personal communication 2012).
3.6.4.3 Reversible Inhibition of Sperm under Guidance
3.6.4.1 Single-Dose Non-Hormonal Male and Female (RISUG)
Sterilant
RISUG®, a chemical complex of styrene maleic
At the 4th International Symposium on Non-Surgical anhydride and DMSO, is being developed as a sterilant
Contraceptive Methods of Pet Population Control in for men under the trademark Vasagel™ (in the US). The
2010, Drs. Joseph S. Tash and Katherine F. Roby of the product is intended for contraception and suppressing
Center for Reproductive Sciences at the University of testosterone in men.
Kansas Medical Center (KUMC) described KU-AS-272,
Work in the rat and the monkey indicate that once the
an antispermatogenic targeting the testis and causing
drug is injected into the epididymis, a stable “implant” is
sterilization of male rats following a single high dose. Since
created, which leads to azoospermia and contraception.
the ovary contains the same protein KU-AS-272 protein
Delivery of the drug into the testes impedes testicular
targets and homologous granulosa cells, data have shown
blood circulation, “all of which together lead to regression
that a single oral administration of KU-AS-272 in female

of the seminiferous tubules along with the Sertoli cells spermatogenesis by blocking the ability of vitamin A to
and the testicular interstitial tissue and its contained drive germ cell developments.” The techniques utilized
Leydig cells. Thus, the source of testosterone production is in this study are expected to be helpful to researchers
depleted.” conducting screening for novel retinoic acid biosynthesis
According to the researchers “this method may inhibitors for possible development as male contraceptives.
potentially be a good technique for obtaining contraception (Hogarth et al. 2011).
and testicular tissue regression and may be quite effective Another publication (Chung et al. 2011) described a
in male dog sterilization” (Chauhan and Guha 2010). study that investigated the use of low doses of the pan-
retinoic acid receptor (RAR) antagonist BMS-189453.
3.6.5 Retinoic Acid Receptor Antagonists “Spermatogenesis was disrupted, with a failure of
spermatic alignment and sperm release and loss of germ
BDADs (Bis-(dichloroacetyl)-diamines) are compounds cells into lumen, abnormalities that resembled those in
believed to inhibit biosynthesis of testicular retinoic acid, vitamin A-deficient and RAR(alpha)-knockout testes.
resulting in reduced spermatogenesis. Importantly, the induced sterility was reversible.” Recovery
The BDAD WIN 18,466 has an interesting 50-year of spermatogenesis was seen at the histological level
history, summarized in a 2011 paper (Amory et al. 2011). after dosing at systematically modified dosing regimens.
Originally the compound was intended as an amebicide. Researchers noted that “Results suggest that testes are
Testing in rodents revealed that while the compound exquisitely sensitive to disruption of retinoid signaling and
caused marked impairment of spermatogenesis, it did that RAR antagonists may represent new lead molecules in
not affect other tissues significantly in vivo. Investigation developing nonsteroidal male contraceptives.”
in dogs and rhesus monkeys in the 1960s showed that
administering WIN 18,466 orally resulted in “a complete 3.6.6 Sperm Protein Reactive with Antisperm
arrest of spermatogenesis in testicular biopsies.” Work Antibodies (SPRASA)
by Asa et al. (1996) and Munson et al. (2004, see below)
In 2004, Chiu et al., University of Auckland, reported
indicated that WIN 18,446 was a safe, effective, reversible
on the discovery of SPRASA, which is a sperm protein
oral contraceptive in male wolves and cats. Development
targeted by anti-sperm antibodies in some men who are
of WIN 18,446 for contraception in men was discontinued
infertile. Since “only [antisperm antibodies] from infertile
upon the discovery that men taking WIN 18,446 experience
men react with SPRASA [it is suggested] that this novel
unpleasant side effects when they drink alcohol.
protein may be important in the processes of fertility.”
As noted, Munson et al. (2004) investigated whether The Department of Obstetrics and Gynecology at the
the particular drug metabolism of cats precludes university is studying the role of SPRASA in human
extrapolation of the safety and effectiveness of WIN and animal infertility. Dr. Larry Chamley, an author of
18,446 for contraception seen in other mammals, including the 2004 publication, has received a Michelson Grant in
humans. Researchers determined that WIN 18,446 was a Reproductive Biology to study the immunocontraceptive
safe and effective contraceptive for male cats; testosterone potential of SPRASA (see Chapter 4, section 4.3.3.1). A 2008
concentrations decreased during treatment (Munson et al. publication (Wagner et al.) coauthored by Dr. Chamley
2004). Based on this particular study of five male cats, it described SPRASA as highly conserved, demonstrated
appears that, in toms, inhibition of spermatogenesis lasts that SPRASA is expressed by oocytes as well as sperm, and
longer than approximately 2.5 months but not as long as suggested that “this protein has an important function in
5 months. No follow-up work in cats was discovered in fertility.” Dr. Chamley has also studied the responses of
a March 2012 Internet search; however, researchers are possums, considered an invasive pest in New Zealand, to
continuing to investigate the potential to utilize BDADs for immunocontraceptive vaccines. Responses were found to
contraception in men. vary (Holland et al. 2009).
In a more recent study, researchers sought to investigate
how a specific BDAD (WIN 18,466) “can inhibit

4.0 Overview of Companies, Pet owners and pet population management
organizations now have access to products that were
Organizations, Institutions, and unavailable just a few years ago. This overview describes
Agencies Involved in Researching those products and illustrates that success is possible. It
has been updated from the 2010 International Symposium
or Developing Approaches to version as appropriate.
Non-Surgical Contraception in As mentioned elsewhere in this report, for many years,
Dogs and Cats basic researchers and people and organizations working
Please note that some endeavors involve more than one on dog and cat population control have been interested in
entity or type of entity and that there may be others in the area developing an alternative to surgical spay and neuter for
of cat and dog population control not contained in this report. sterilization and/or contraception of animals.
Some may be proprietary and therefore no information is avail-
Hundreds if not thousands of research studies have
able publicly. Organizations and institutions sponsoring or
conducting relevant non-proprietary research not included here been published showing progress towards the goal of
are encouraged to contact Alliance for Contraception in Cats & non-surgical contraception, but until recently no products
Dogs (ACC&D) so that their projects may be included in future were available for use in dogs and cats, with the exception
updates. Please see Chapter 3, section 3.6, for additional informa- of progesterone-related drugs that provided short-term
tion on emerging areas of research that may provide approaches to fertility suppression, but usually at the expense of a risk of
non-surgical contraception in dogs and/or cats.
undesirable side effects.
When the 1st International Symposium was organized
4.1 Setting the Framework: Overview of by ACC&D in April of 2002, there were no new6 products
Existing Non-Surgical Products available for either contraception or sterilization of dogs
This overview was presented by Linda Rhodes, VMD, PhD, at and cats. Some information was presented on Neutersol®,
the 4th International Symposium on Non-Surgical Contraceptive an intra-testicular injectable zinc gluconate to sterilize male
Methods of Pet Population Control held in 2010 and organized dogs that would subsequently achieve Food and Drug
by ACC&D, which is profiled in section 4.3.3.1. At the time Dr. Administration (FDA) approval in 2003 and be marketed
Rhodes was chair of the board of ACC&D. to veterinarians in the United States (US). At that same
meeting, an Australian company, Peptech Animal Health,
Several small updates have been made. ACC&D (acc-d.org)
presented information on deslorelin, a drug in a
was founded in 2000 and incorporated as a nonprofit, tax-exempt
class called gonadotropin-releasing
organization in 2005. A key part of the ACC&D mission is to
hormone (GnRH) agonists. Data
bring together people at international symposia – people
showed suppression of fertility in male and
with a passion for more tools for pet population
female dogs for up to 12 months, but there was
control, people with knowledge of basic research
as yet no approved product. The deslorelin
and science, experts in drug and vaccine
product obtained its first approval and was
development and manufacture, and
launched in 2004 in Australia and New Zealand
companies interested in investing
as Suprelorin®, an implant labeled for use in
resources for new products – to talk and
male dogs for 6-month suppression of
collaborate, spark new ideas and make
fertility.
real progress, not just in demonstrating
that a technology works, but in developing At the 2nd International
technologies and drugs to the point at which Symposium in 2004, the landscape
they can achieve regulatory approval and can didn’t change. More information was
be used around the world. Proceedings of available on Neutersol and Suprelorin,
ACC&D’s four International Symposia and although several other seemingly
are available at acc-d.org/ACCD%20 promising technologies were
Symposiaacc-d.org. presented, they were all in the research stage – none was
“ready for prime time.”
6
Megestrol acetate and Depo-Provera® were available at
this time.

By the 3rd International Symposium in 2006, Neutersol States Department of Agriculture (USDA) National
was unfortunately no longer being marketed and was Wildlife Research Center (NWRC) developing GonaCon
unavailable for use; in 2005, production and distribution of (not to be confused with Gonazon), a GnRH vaccine for
Neutersol were discontinued. use in contraception in deer, announced that in the US
However, there was news from Dr. Marc Antoine the Environmental Protection Agency (EPA) would be
Driancourt, of the company then known as Intervet (and regulating contraceptives for wildlife. In 2009, the EPA
now part of MSD/Merck Animal Health). He presented announced approval of GonaCon for use in white-tailed
data on the use of another GnRH agonist implant, deer. Although not approved for use in companion animals,
containing azagly-nafarelin, called Gonazon™ (not to be research indicates that GonaCon may be an effective
confused with GonaCon™). This product was shown to contraceptive in cats, and may have some potential in dogs
suppress fertility in female dogs for up to 12 months. Dr. with adjustments in formulation.
Driancourt announced that it would achieve regulatory In summary, after many years of research on the use of
approval in Europe soon after the meeting, which it did. GnRH agonists for fertility suppression, two companies
During 2006, we waited to see the marketing of Gonazon have committed the resources to achieve regulatory
for bitches in the European Union (EU), but although it approval of products, and one is being marketed in major
was approved by regulatory agencies, it has never been markets. A sterilant that is effective for male dogs is
introduced. In the meantime, in September 2006, Peptech approved in four Latin American countries and is expected
Animal Health registered a 12-month version of Suprelorin to be available in the US in 2013; it is showing great
in Australia for use in male dogs. Approval followed in promise in sterilizing male dogs, and could be particularly
July 2007 in Europe for the 6-month version for male dogs useful in dogs that might never have been able to be
and in April 2010 for the 12-month version. Peptech Animal castrated surgically. A vaccine that is approved for use in
Health was acquired in 2011 by Virbac, putting a major deer may also be effective in cats and potentially dogs.
animal health company “in the game.” This progress, plus the exciting development of new
As of 2010, and still at the time of this publication, there interest in the area of research in cat and dog contraception
are no products with FDA approval for contraception or and sterilization inspired by the Michelson Prize & Grants
sterilization on the market in the US. Suprelorin 6- and/ (see section 4.3.3.2), indicate that strides are being made in
or -12-month implants are on the market in Australia, New providing safe and effective alternatives to surgical spay/
Zealand, and Europe for fertility control in male dogs. neuter for dog and cat population control (Rhodes 2010,
updated 2012).
Esterilsol® (ex-US)/Zeuterin™ (US), a product identical
to Neutersol and owned by Ark Sciences, Inc. is an intra-
4.2 Companies
testicular injection for sterilizing male dogs, and is used in
puppies and adults. Esterilsol was introduced 4.2.1 Major Animal Health Companies
in Mexico in 2008 and made available to
Historically, “big pharma” animal health has had an
private-practice veterinarians, government
“on again/off again” relationship with contraception and
programs, and non-governmental
fertility control in animals.
organizations (NGOs) in that country.
As of March 2012, Esterilsol was Although it is misleading to say large animal health
approved in Mexico, Columbia, Panama, companies have not been interested in contraception and
Bolivia and the US, and is scheduled fertility control in animals, societal factors as well as
to be launched in the US in 2013. Ark frustration with technological issues put the market
Sciences has announced plans to extend on the back burner while animal health companies
distribution to other countries. worked on antiparasitics, antimicrobials, anti-
inflammatories, and vaccines for
Another zinc gluconate product called
economically important diseases.
Infertile®, with a different formulation
There appear to be fewer major animal
than that of Esterilsol, was introduced in
health companies involved in non-surgical
Brazil in 2009 and is only available in Brazil.
contraception and fertility control in cats
Progress is illustrated by another and dogs today than there were at the time the
development, albeit in wildlife original Contraception and Fertility Control in Animals
contraception. The group from the United report was published in 2002.

4.2.1.1 Historical acquisition of Peptech.
Involvement � Pfizer Animal Health
Although at the time of obtained a GnRH vaccine
this update Virbac is the indicated for canine benign
only major animal health prostatic hyperplasia (BPH)
company with approved, in early 2004 as a result of
marketed non-surgical Pfizer’s acquisition of the
contraceptive products Australian company CSL and
(although none in the its US-based subsidiary Biocor.
US), there are a number USDA granted a conditional
of examples of animal license for use in treating
health company initiatives BPH in 2004, but a full license
undertaken in non-surgical was not obtained and the
contraception over the years: product is not available at this
juncture. See Chapter 3, section 3.2.4.1, for information
� Pharmacia, which ultimately became part of Pfizer on a canine contraception study involving this product,
Animal Health, provided funding support for research which was not labeled for use as a contraceptive. The
into a chemical sterilant in the late 1970s. product was known as Canine Gonadotropin Releasing
� Several large animal health divisions of major human Factor® Immunotherapeutic.
pharmaceutical companies pursued GnRH vaccines in � Protherics PLC formed an alliance with Janssen Animal
the 1970s and 1980s. One project, in the 1970s, led to Health for a GnRH vaccine for use in animals. Protherics
the discovery of the principle of down-regulation of PLC was acquired by BTG plc in December 2008. BTG
GnRH receptors caused by giving continuous GnRH focuses on development, manufacture, and marketing of
agonists, but the product concept was not deemed specialized hospital products for critical care and cancer
commercializable and the project was dropped. Another in humans, primarily in the UK, US, and Australia.
GnRH project in the late 1980s did not produce a � United Biomedical, Inc. (UBI) had an alliance focused
product felt to be reliable enough and was discontinued. on a GnRH vaccine, with an unnamed animal health
� The Carnation Company and Upjohn started to develop company. At this juncture UBI is not pursuing the GnRH
a mibolerone (MIB)-based contraceptive dog food in vaccine. See the table in section 4.2.3.
1975. Carnation was hopeful of quick approval from the � Intervet (now Merck/MSD Animal Health) developed
FDA, and planned to distribute the dog food through the GnRH agonist Gonazon which was approved in
veterinarians and, eventually, retail outlets. However, Europe for injection into salmonid fish and as an implant
the project did not come to fruition, at least in part for preventing gonadal function in bitches via long-term
because of fears that a product for animals might be blockade of gonadotropin receptors. Studies have been
used to induce abortions in women or cause abortions in done in cats as well. See Chapter 3 for information on
women who consumed pet food. the dog and cat studies. Unfortunately, as noted, the
� Pfizer Animal Health announced an agreement with product for dogs was never launched.
Peptech Animal Health (see section 4.2.3) in December of � In 2006, following the removal of the zinc gluconate
1998 by which Pfizer agreed to fund a 12-month period sterilant Neutersol from the market in 2005 (see Addison
of research as well of the development of methods Biological Laboratory, Inc., section 4.2.3), Abbott Animal
for scaling up manufacture of a long-acting implant Health announced the company’s intention to re-launch
for reversible castration of companion animals. Pfizer Neutersol; however, this did not occur. The product
did not continue this project, and the technology was was subsequently acquired by Ark Sciences, which has
eventually returned to Peptech. Note that the Peptech- re-launched the product as Esterilsol in several markets
sourced product eventually developed by Peptech and and is planning to re-launch the product in the US
acquired and marketed by Virbac is a version of the renamed Zeuterin (see section 4.2.4.2).
implant developed following the cessation of work by
Pfizer. See section 4.2.1.2 for details of Virbac’s eventual

4.2.1.2 Virbac Acquisition of Peptech Animal Health in animals, coupled with the fragmented nature of the
(Suprelorin) market, has presented opportunities for smaller animal
Peptech Animal Health launched Suprelorin (6-month health and life sciences companies to collaborate with
implant containing 4.7 mg deslorelin) in Australia in partners, or, in some cases, work on their own, to develop,
December 2004 and in New Zealand in September 2005. commercialize, and ultimately market products. It appears
Peptech Animal Health went on to register Suprelorin that fewer companies are engaged in development
12 (12-month implant containing 9.4 mg deslorelin) in and commercialization activities in the non-surgical
Australia in 2006. In July 2007, Suprelorin (6-month contraception and fertility control space as of the date of
implant) was approved in Europe; in May of 2008, it was this update than at the time of the original report. Note,
launched in Europe and Virbac became the exclusive however, that given the number of smaller life sciences
distributor there. Sales in Europe were initiated in 2008. and biotechnology companies working on reproduction
Virbac Australia was appointed to market Suprelorin in and related areas, it is possible that there are additional,
Australia in 2009. Suprelorin (12-month implant) was unannounced animal health projects underway.
approved for sale in Europe in April 2010. One year later,
Peptech Animal Health was acquired by Virbac. In May 4.2.3 Update on Entities Profiled in the
2010, Virbac presented a small animal symposium entitled 2002 Report
Deslorelin in Practice at the 7th EVSSAR Congress. For
The entities shown in Table 4-1 below were profiled in the
proceedings, see zoovet.ee/product/docs/2050981722.pdf.
original 2002 Contraception and Fertility Control in Animals
report, which covered horses, wildlife, and production
4.2.2 Smaller Companies
animals in addition to dogs and cats.
The fact that large animal health companies are not
pursuing basic R&D in contraception and fertility control
Table 4-1: Entities Profiled in the 2002 Report

Company Status

Addison Biological Addison Biological Laboratory is a private animal health company that manufactures and
Laboratory, Fayette, sells a number of veterinary products including production animal products and dental,
MO dermatology, otology, and wound care products. Neutersol was developed by Pet Health-
care International, Inc., and introduced in the US in 2003 by Addison Laboratories after
it was approved by the FDA Center for Veterinary Medicine (CVM) for permanent steril-
ization of male dogs from 3-10 months of age. In 2005, production and distribution were
discontinued after a business divorce between Pet Healthcare and Addison Laboratories.
Plans to reintroduce Neutersol by Abbott Animal Health in 2009 were cancelled for undis-
closed business reasons. Ark Sciences currently owns all Neutersol rights and intellectual
property and is re-commercializing the product. See section 4.2.4.2 and Chapter 3, section
3.4.1.
Aphton Corporation, At the time the 2002 report was developed, Aphton had been working on a GnRH vaccine
Miami, FL for treating human prostate cancer, and it was believed that the technology may have had
animal health potential. However, in May of 2006 Aphton filed a Chapter 11 petition. The
only additional reference to Aphton Corporation found in an Internet search notes that the
bankruptcy case had not been settled as of June 2010.
CSL (Commonwealth Pfizer Animal Health acquired CSL and its US operation Biocor in 2004, and obtained a
Serum Laboratories) and conditional license from the US Department of Agriculture (USDA) for the CSL GnRH
associated entities, Aus- vaccine for treatment of benign prostatic hyperplasia (BPH) in dogs. As noted earlier in
tralia and New Zealand this chapter, no permanent license was obtained and the product is not available. The
vaccine was not labeled for use as a contraceptive; an initial injection, booster after one
month, and subsequent boosters at 6-month intervals were required for treatment of BPH.
See Chapter 3, section 3.2.4.1, for information about a study of the potential of this vaccine
for fertility control.
Gonex, Inc., Gonex was launched in 1995, initially to develop GnRH-based technology invented by
Boulder, CO company founders Drs. Terry Nett and Michael Glode. In April 2002, then Gonex COO Dr.
Paul Jarosz noted that the objective at that time was to provide the market with an inject-
able product that can sterilize male and female companion animals via a single injection.
The company’s technology chemically linked GnRH to a protein synthesis inhibitor (poke-
weed antiviral protein). See Chapter 3, section 3.2.3.1, for information on this technology.
Gonex changed its name to Cedus, Inc. In 2009 Drs. Nett and Weber (then the COO) filed
a patent application, and Application Number 20110281299 was issued in November 2011.
The application notes “the present invention provides novel, modified pokeweed antiviral
proteins, nucleic acids that encode the proteins, conjugates that incorporate the proteins,
and methods to make and use the proteins. The present invention also provides methods
to administer the conjugates to animals, for the purpose of directing toxin to particu-
lar cells.” The application names Colorado State University Research Foundation (now
known as CSU Ventures) and Cedus, Inc. as assignees, but there appears to have been
no update to the Cedus/Gonex website since 2005. Cedus won 3rd place and an $18,000
prize in a 2006 national business plan competition sponsored by Purdue University Life
Sciences. The CSU Ventures website lists Gonex as one of the startups emerging from CSU
but as noted above, the associated URL is not up to date. In August of 2010, an article in
the Kansas City Business Journal quoted Cedus CEO Kevin Scott and noted that Cedus
had presented at the 2009 Kansas City Animal Health Investment Forum. The Morris
Animal Foundation (MAF) has funded a study undertaken by Dr. Nett and called Devel-
opment of New, More Efficacious Technology to Chemically Castrate Male and Female Dogs. The
study appears to have been extended in December 2011. Dr. Nett is a professor in the CSU
Department of Biomedical Sciences and a member of the university’s Animal Reproduc-
tion and Biotechnology Laboratory. His current research is focused on “obtaining a better
understanding of factors that regulate synthesis and secretion of hormones that control
reproduction, particularly the gonadotropins. Gonadotropin-releasing hormone (GnRH)
stimulates synthesis and secretion of gonadotropins by interacting with membrane recep-
tors in the anterior pituitary gland. Highly potent analogs of GnRH are being used to de-
liver cytotoxic moieties specifically to gonadotrophin-producing cells in the anterior gland
with the goal of developing a treatment to control reproductive rate of wild and selected
domestic animal populations to treatment of hormone-dependent cancers in humans”
(csuvth.colostate.edu/directory/person.aspx?m=NzMxNDE5OTI2).

Immucon, Immucon was specializing in reproductive technologies; specifically, the company devel-
oped the P34H Sperm Fertilizing Ability Test diagnostic test for infertility in human males
Montreal, QC, Canada and at the time of the 2002 report was working on oral contraceptives for men and women
and reversible contraceptive vaccines for men, women, and animals. A posting dated
April 21, 2011 on the Immucon website (immucon.com) notes that due to market uncer-
tainty and technical challenges, the shareholders had halted development of products
based on protein P34H.
Immunovaccine Technolo- Immunovaccine Technologies (IVT) began as an animal health company that successfully
gies (now called Immuno- developed SpayVac™, a contraceptive vaccine for use in seals, although the vaccine was
vaccine, Inc.), Halifax, NS, never approved or marketed. The vaccine is based on a proprietary vaccine develop-
Canada ment technology called DepoVax™. Pfizer Animal Health is developing two livestock
vaccines using the company’s proprietary vaccine delivery technology; however IVT is
now focusing on human health applications of the DepoVax technology, particularly in
oncology and infectious disease. In 2012 the company announced a collaboration with
an unnamed animal health company to use DepoVax in the development of companion
animal vaccines. Indications have not been specified publicly. See imvaccine.com/releases.
php?releases_id=274.
MetaMorphix, Inc. (Savage, MetaMorphix was a privately held animal health company with several technology
MD) and Metamorphix platforms. At the time of the 2002 report the company was pursuing immunocontracep-
Canada, Saskatoon, SK, tion for animals using technology they had obtained from Biostar. In February of 2011,
Canada the company announced its intention to sell all, or substantially all, of its assets as part of
reorganization under Chapter 11. The collateral subject to auction sales did not specifically
list any asset related to immunocontraception for animals. This GnRH vaccine technology
that had been under development was returned to the academic institution at which it
originated (personal communication 2012).
Peptech Animal Health, Peptech developed Ovuplant®, a sustained-release implant of the GnRH agonist deslore-
Milperra, NSW, Australia lin, for use in timing ovulation in horses, and Suprelorin, also a sustained-release GnRH
agonist implant, for 6-12 month suppression of reproductive function of male dogs. Ovu-
plant was first approved in 1995 in Australia and New Zealand, in the US in 1998, in the
UK in 2005, and several European countries in 2007. The 6-month version of Suprelorin
was approved in Australia in 2004, New Zealand in 2005, and Europe in 2007. A 12-month
version was approved in Australia in 2006 and Europe in 2010. Peptech Animal Health
was acquired by Virbac in May 2011. See Virbac, section 4.2.1.2.
United Biomedical, Inc., United Biomedical (UBI) is a privately held immunotherapeutics and immunodiagnostics
Hauppauge, NY company that employs proprietary processes to design and manufacture synthetic pep-
tide products for human and animal health. UBI technology is based on refining peptides
to act via the immune system. The pipeline is made up of biologicals for the treatment
and prevention of Alzheimer’s disease, AIDS, and allergy in humans, as well as animal
health vaccines. As of 2002, the company was working on a number of animal health
applications, including a long-acting immunocontraceptive for male and female com-
panion animals. Duration would be achieved via administration of annual boosters. The
company indicated it was conducting trials of the vaccine in dogs in collaboration with
an undisclosed animal health company. The current UBI website indicates a veterinary
portfolio consisting of a vaccine for growth promotion and boar taint (swine), PCV-2 vac-
cine (swine), PRRS vaccine (swine), FMD vaccine (cattle), and allergy vaccine (canine); and
refers to a longer longer-term plan to address health needs in companion animals. As of
August 2012, the company was not working on a pet contraceptive (Wang, personal com-
munication).

Zonagen, Zonagen was founded in 1987 topresentation,
commercialize10,000
work dogs
donehave been
by Dr. sterilized
Bonnie usingformer-
Dunbar, its
Woodland Hills, TX product in a field trial in Mexico to establish the
ly of Baylor University in Waco, Texas, on a zona pellucida (ZP) contraceptive vaccine for safety and
use in animals and possibly humans.effectiveness in adult dogs.
The collaboration Theincompany
ended also reports
an unfortunate examplethat
of technology transfer and intellectual
the US property
Army hasissues
takenthat
the can arise.toInearthquake-affected
product 2006, the company
name was changed to Repros Therapeutics, which
areas in Japan is reported
to sterilize dogsto bewithout
left workinghomes,
on drugs
andforthat
male fertility, type 2 diabetes, uterine fibroids, and endometriosis. There is no reference
Bangladesh has ordered 50,000 doses to be used in a dog
to animal health applications on the Repros website. Work related to non-human species
appears to have ceased. population control project.
4.2.4 Companies Currently or Recently Involved The company reports that post-treatment sterility
in Non-Surgical Contraception and Fertility is permanent, and although sedation is strongly
Control for Dogs and/or Cats
4.2.4.1 Amplicon Vaccine, LLC, Pullman, WA
The Amplicon Vaccine, LLC website (ampliconvaccine.
com) describes the composition of a vaccine called Repro-
Bloc™ as “a series of GnRH genes [which] are cloned
onto ovalbumin carrier gene which is held in an E. coli
based expression vector … the purified protein is added
to an emulsifying agent, oil, dead [M]ycobacterium
butyricum and a urea + phosphate buffer.” The company
website refers to studies in mouse, swine, dogs, cats,
lamb, caribou and cattle, and a PowerPoint® available recommended prior to administration, anesthesia is not
on the site describes several studies in heifers and bulls. required. In an experienced administrator’s hands, as
No information on studies in other species appears to be many as 12 dogs can be sterilized per hour. Post-treatment
available to the public. clinical observation is suggested for 10- 15 minutes when
dogs should be alert enough to be released. The company
4.2.4.2 Ark Sciences, Inc., New York, NY has developed training programs utilizing Master Trainers
Ark Sciences (arksciences.com) was founded in 2007 by (veterinarians) who train other veterinarians. See Chapter
Joseph Tosini, who has focused his career on the field of 3, section 3.4.1, for more details on use of this product.
community development. The company has resurrected An October 2012 Veterinary Information Network article
the zinc gluconate male canine sterilant formerly known as announced the impending return of the product to the US
Neutersol and has renamed the product Esterilsol (ex-US) market, renamed Zeuterin, and provides comprehensive
and Zeuterin (US). According to Ark Sciences the company information on how the product works, how to use it
now owns all intellectual property rights. The formulation properly, how Ark Sciences is training veterinarians and
has been approved for use in the US for male dogs from supporting the product, and how it has evolved since its
3- 10 months of age, and in Mexico, Bolivia, Panama and initial foray into the US market as Neutersol. See news.vin.
Colombia for dogs 3 months and older. In Colombia, it is com/VINNews.aspx?articleId=24708.
also approved for use in cats. Ark Sciences has announced
plans to expand to other countries in the future. Currently, 4.2.4.3 Crinetics Pharmaceuticals, Inc., San Diego, CA
the product can be used on a limited basis with special Crinetics Pharmaceuticals, Inc. (crinetics.com) specializes
permission in some countries in which it does not have in applications of neuropeptide-receptor targeted
regulatory approval. The US launch is expected in 2013. Ark therapeutics for the treatment of endocrine diseases
Sciences reports that the company expects the label claim to and cancers in humans. The company is researching an
be expanded to male dogs 3 months and older by that time. ovarian cancer drug candidate that can be expected to
Ark Sciences’ website describes the company as a social cause sterility as a side effect. Dr. Scott Struthers, who is
entrepreneurship venture that combines social impact Crinetics’ President and Chief Scientific Officer, believes
and investor return. The company’s strategy is to work that the drug may cause sterility in domestic animals as
with nonprofit animal welfare organizations involved in well. Crinetics has received two Michelson Prize grants
population control to make it possible to sterilize male (see section 4.3.3.2) to pursue the use of its technology in
dogs that would otherwise be contributing to homeless dogs and cats: a 2-year grant entitled Novel Toxin Conjugates
pet populations. According to a July 2011 Ark Sciences for Non-surgical Sterilization via Gonadotroph Ablation and a
3-year grant to study Targeted Ablation of GnRH Neurons for of Esterilsol/Zeuterin), argenine and dimethyl sulfoxide
Non-surgical Sterilization. (DMSO) as a “carrier” to aid in the distribution of the drug
within the testicle.
4.2.4.4 FeralStat, Old Lyme, CT
Development of Infertile was funded by an animal
Note that FeralStat® is not a company. Rather, FeralStat welfare advocate committed to advancing animal welfare
was the brand name of a megestrol acetate (MGA) oral by providing safe, effective, affordable, and easy-to-
contraceptive developed by the late Dr. John Caltabiano, a administer alternatives to surgical sterilization. The
product is approved by Brazil’s Ministry of Agriculture, the
Connecticut veterinarian, who during his career helped re- agency that oversees all veterinary products in Brazil. The
home unwanted pets and in the 1990s launched a nonprofit Sponsor plans to expand introduction to other countries,
mobile spay/neuter and vaccination clinic for cats (Tait’s but as of 2012 Infertile was only available and approved in
Every Animal Matters – TEAM). FeralStat appeared to Brazil.
be marketed independently of the organization; it was
The instructions for use of Infertile include a
available via a website.
recommendation to use an analgesic for post-injection pain
MGA has not been approved by the CVM or any management (see Chapter 3, section 3.4.1).
European regulatory agency as a contraceptive for cats,
In June of 2012 a research project at Universidade de
but has been used, most commonly in Europe, for this
Sao Paulo was launched to “evaluate and compare the
purpose. The particular dose of MGA in FeralStat has not
level of pain and inflammation that chemical sterilization
been studied for safety and/or effectiveness. According
by [Infertile]” may involve. Study dogs will be assigned
to the website, FeralStat was to be added to canned food
to one of four groups. Three groups will receive Infertile
weekly and positioned as a “stop gap” strategy to prevent
15 minutes after administration of dipyrone, tramadol,
reproduction in a feral cat colony until the colony could
or meloxicam. The fourth group will receive standard
be trapped and permanently sterilized. The product was
marketed over the Internet, prescribed over the telephone
and was not distributed wholesale to veterinarians for re-
sale. Although FeralStat is no longer available, numerous
feral cat caregivers have reported acquiring generic MA
from private veterinarians and administering it at the dose
level recommended for FeralStat. FeralStat came on and
went off the market during the period between the 2002
Contraception and Fertility Control in Animals report and this
update.
While FeralStat was still available, ACC&D did not
recommend use of the product in part due to the absence
of safety and efficacy studies, but did note that since the
dose of MGA was “significantly lower than that used
historically,” it may have been “possible that the lower anesthesia and undergo surgical orchiectomy. Dogs will be
dose is effective and not associated with significant side monitored for 7 days post-surgery and various scales will
effects.” The organization has developed a position paper be applied to assess pain in the four groups. The principal
on FeralStat (www.acc-d.org/ACCD%20docs/PPPP- investigator is D. T. Fantoni; the study is expected to end in
FeralStat.pdf). May of 2013 (study announcement, 2012).
See http://www.acc-d.org/About for ACC&D’s
4.2.4.5 Rhobifarma Industria Farmaceutica Ltda, Brazil
Preliminary Statement on Infertile.
In 2009, the Brazilian company Rhobifarma Industria
Farmaceutica Ltda launched Infertile, a zinc gluconate 4.2.4.6 SenesTech, Inc., Flagstaff, AZ
product with a different formulation than that of Esterilsol/
SenesTech, Inc. was founded in 2002 and products under
Zeuterin (section 4.2.4.2). The company distributes the
development are based on technology licensed from the
product. Infertile is an injectable sterilant for male dogs
University of Arizona. The technology involves the use
administered via a single injection into each testicle. The
of 4-vinylcyclohexene dipoxide (VCD) (see Chapter 3,
product consists of zinc gluconate (at twice the strength

section 3.4.4) to provide chemical acceleration of ovarian male and female dogs and cats is possible. Immunogenicity
senescence. SenesTech is currently working on two against antigenic epitopes of infectious agents has been
contraceptive products: ContraPest® for rice-rat control demonstrated to induce both humoral and cellular immune
and ChemSpay™ for contraception in bitches. According responses. Dr. Van Kampen noted that “the [potential for]
to its website (senestech.com), the company is developing application of this scientifically sound, proven technology
strategic partnerships with international industry partners for companion animal contraception” may be compromised
and nonprofit institutions to accelerate the translation of by factors that are not science related, such as regulatory
its platform technology into a marketable approach to requirements and funding issues (Van Kampen 2010).
the rice-rat problem. SenesTech currently regards rodent In December 2011, Vaxin and the Scott-Ritchey
management within agriculture as its primary market and Research Center at the Auburn University College of
chemical spay as its secondary market. Veterinary Medicine were awarded a Michelson Grant
Work on ChemSpay has been based on the hypothesis (see section 4.3.3.2) to continue development of a vectored
that VCD treatment will accelerate elimination of GnRH contraceptive vaccine to control dog and cat
primordial follicles in dog ovaries leading to ovarian
failure, eliminate estrous behavior and cause permanent
sterility. The preferable mode of delivery would be
continuous release to attain 100% sterility and a hormone
environment equivalent to that of sterile individuals
(Mayer 2006).
For a brief time, SenesTech had a relationship with an
organization called 600 Million Stray Dogs Need You,
which was founded by People for the Ethical Treatment
of Animals (PETA) co-founder Alex Pacheco, and claimed
to be developing an orally available compound that could
result in permanent sterilization, using VCD as the active
compound. In April 2011 SenesTech notified ACC&D
that they had severed ties with that organization and its
founder, and that “neither 600 Million nor Mr. Pacheco overpopulation. According to a Vaxin press release (vaxin.
[has] any right, title, license or interest in our ChemSpay com/FAFAuburnRelease.pdf), “the three-year project
product or any other [SenesTech] product” (acc-d. draws upon the science of Vaxin’s vaccine technology
org/600Million). already tested in humans for influenza and the Scott-
Ritchey Research Center’s commitment to develop
4.2.4.7 Vaxin, Inc., Birmingham, AL contraceptive vaccines for companion animals.” Drs. Van
Kampen of Vaxin and Henry Baker and Nancy Cox of
Vaxin, Inc. (vaxin.com) is a life sciences company with
Auburn University are the lead investigators.
a proprietary technology “that consists of non-replicating
adenovirus and bacterial vectors that can deliver antigens
non-invasively to the nasal passages or to the skin to elicit
4.3 Research: Organizations and Founda-
a protective immune response.” At the 4th International tions, Government Agencies, and
Symposium on Non-Surgical Contraceptive Methods for Academic and Research Institutions
Pet Population Control, Dr. Kent R. Van Kampen explained This section of the report deals with research sponsored
that research indicates use of adenoviral vectors that or undertaken by various organizations and research that is
express antigens to induce antibodies that block fertility in

emerging and may offer new approaches to contraception. We are pleased to report that there appears to be significantly
more research and involvement in this field by organizations, foundations, government agencies, and academic and
research institutions than there was when the original report was published. In some instances work will have been
mentioned in other sections of this report but is also mentioned here due to the nature of its sponsorship. See also Chapter
3, section 3.6.
4.3.1 Update on Research Described in the 2002 Report
The entities shown in Table 4-2 below were profiled in the original 2002 Contraception and Fertility Control in Animals
report, which covered horses, wildlife, and production animals in addition to dogs and cats.
Table 4-2: Research Profiled in the 2002 Report
Group and Investigator(s) (2002 Report) Update

AFSSA Nancy Wildlife Health and Man- Dr. Franck Boué presented work (Verdeir et al. 2002) related to developing
agement Unit, Malzéville, France a sperm-antigen-based immunocontraceptive vaccine for canine species.
Foxes were the model used in the study, in which several auto-antigens
Dr. Franck Boué et al. were identified as “potentially interesting for the development of a contra-
ceptive fox vaccine.” Researchers tested three types of vaccines for deliver-
ing the auto-antigens: synthetic peptides, recombinant proteins produced
in vitro by E. coli or baculovirus, and recombinant antigens inside a non-
replicating E. coli “ghost” containing only the protein of interest. While
these approaches “induce[d] immune response against the injected agent
… the antibodies did not recognize the native protein and no impact on
the ovary or on the spermatozoa was observed.” At the 2nd International
Symposium on Non-Surgical Methods for Pet Population Control in 2004,
Dr. Boué described efforts to develop immunological tools to assess the hu-
moral and cellular immune responses in sera and vaginal fluids, in support
of development of a canine immunocontraceptive vaccine (Boué 2004). See
section 4.3.4.4 for additional related research published in 2005. Current fo-
cus of the organization appears to be on wildlife issues. Further discussion
is beyond the scope of this update. See www.anses.fr/index.htm.
Baylor College of Medicine, Houston, TX See Zonagen, section 4.2.3.
Dr. Bonnie Dunbar (currently at the Uni-

versity of Nairobi)
Center for Reproductive Science/ The 2002 report described work done by Dr. Min Wang and based on ear-
Technology, University of Missouri, lier work by the late Dr. Mostafa Fahim on the safety and efficacy of zinc
Columbia, MO gluconate neutralized by arginine for use as an intra-testicular injection for
chemical castration in male dogs. This work was commercialized initially
Dr. Min Wang by Addison Biological Laboratory (Neutersol, see section 4.2.3) and, subse-
quently, by Ark Sciences (Esterilsol in ex-US markets, Zeuterin in the US).
Dr. Mostafa Fahim (deceased 1995) See section 4.2.4.2 for more information about the impending US recom-
mercialization of this zinc gluconate formulation.
College of Veterinary Medicine, Colorado See Gonex in section 4.2.3; see Chapter 3, section 3.2.3.1.
State University, Ft. Collins, CO
Dr. Terry Nett

College of Veterinary Medicine of the The Scott-Ritchey Center has been involved in research related to non-sur-
Scott-Ritchey Research Center, Auburn, AL gical contraception in animals for some time and, in fact, was instrumental
in starting ACC&D. The Center continues to be involved in research and is
Dr. Brenda Griffin (currently at University working with Vaxin on a project funded by a Michelson Grant. See section
of Florida) 4.3.3.2.
Dr. Henry J. Baker

College of Veterinary Medicine, University The 2002 report described Dr. Irwin K. Liu’s work on developing zona
of California, Davis (UCD) pellucida vaccines. At that time he had completed a study (Liu & Ball
2002) showing that dogs immunized with pig zona pellucida were not
Dr. Irwin K. Liu contracepted effectively. His group was working on developing a ZP-based
immunocontraceptive treatment for horses. Dr. Liu has continued to work
Dr. Linda Munson (deceased) on issues related to equine reproduction, which is beyond the scope of this
update. Dr. Linda Munson published her work on the use of GnRH agonist
Dr. Barry Ball (currently at the University
treatment in cats (Munson 2001) and a review article, Contraception in Felids
of Kentucky)
(2006), in which she indicated that limited availability of non-progestin
contraceptives and side effects associated with some agents in felids has
limited the fertility control options in felids. Unfortunately, Dr. Munson
passed away in 2010. Dr. Barry Ball was working to identify sperm pro-
teins in dogs (Sabeur et al. 2002) and to test the GnRH protein synthesis
inhibitor in male dogs (Ball 2002). Dr. Ball is now the first Albert G. Clay
Endowed Chair in Equine Reproduction at the University of Kentucky; he
is no longer involved in dog research.
College of Veterinary Medicine, University Dr. Julie Levy has continued to research the population dynamics of feral
of Florida, Gainesville, FL cats under various management situations and test potential approaches
to non-surgical contraception in cats. Her work and resulting publica-
Dr. Julie Levy tions have spanned approaches from GnRH and ZP vaccines to retinoic
acid receptor antagonists to chemical castration with zinc gluconate. See
www.vetmed.ufl.edu/about-the-college/faculty-directory/julie-levy/ for
a profile of Dr. Levy and a list of some of her publications. See Chapter 3,
sections 3.2.4.2, 3.3.1.2.2, 3.4.1.2, and 4.3.2 of this report.
College of Veterinary Medicine, University Dr. Richard Fayrer-Hosken continues his work on contraception in wild-
of Georgia, Athens, GA life, which is beyond the scope of this update.
Dr. Richard Fayrer-Hosken

Cornell University College of Veterinary Dr. Scott Coonrod, formerly of the University of Virginia, has joined Cor-
Medicine Baker Institute for Animal nell University College of Veterinary Medicine as an associate professor at
Health the Baker Institute for Animal Health. See Chapter 3, section 3.6.3 for an
update of Dr. Coonrod’s work in this area. See also University of Virginia,
Dr. Scott Coonrod below.
Cornell University Institute for Animal The 2002 report described wildlife-related work at the Cornell Institute for
Welfare, Cornell University, Ithaca, NY Animal Welfare, which is beyond the scope of this update. Note: See Dr.
Patrick Concannon listed below under New York State College of Veteri-
Dr. Paul Curtis nary Medicine, also affiliated with Cornell University.
Division of Veterinary and Biomedical Sci- The 2002 report noted that investigators were using naked DNA coding
ences and the Department of Microbiology, for zona pellucida proteins as an antigen for the immunization of the cat.
Murdoch University, Perth, Australia At that time T-cell responses were seen in a small group of animals, but no
long-term contraception trials had been reported. See Chapter 3, section
Investigator not specified at the time 3.3.1.2.2 for information about a 2007 Murdoch University study of the
contraceptive potential of porcine and feline zona pellucida A, B and C
subunits in domestic cats.
Institute for Zoo and Wildlife Research, Dr. Katarina Jewgenow continues to publish a range of research related
Berlin, Germany to fertility and contraception in animals. For example: reduced germ cell
apoptosis during spermatogenesis in the teratospermic domestic cat (2009);
Dr. Katarina Jewgenow functional role of feline zona pellucida protein 4 trefoil domain: a sperm
receptor or structural component of the domestic cat zona pellucida (2009);
seasonal profiles of ovarian activity in Iberian lynx based on urinary hor-
mone metabolite analyses (2009); cryopreservation of mammalian ovaries
and oocytes (2011); the molecular detection of relaxin and its receptor
RXFP1 in reproductive tissue of Felis catus and Lynx pardinus during preg-
nancy (2011).

Institute for Molecular Biology, National Dr. Jualang Hwang’s laboratory is focusing on 1) using linear array epit-
Chung Hsin University, Taichung, Taiwan ope (LAE) approaches to develop therapeutic vaccines and 2) studying the
post-translational modification of DNA topoisomerase. His web page notes
Dr. Jualang Hwang that an anti-GnRH vaccine has been developed using LAE technology,
and other molecular vaccines such as LAE vaccine against HER2 for HER2
over-expressed breast cancer therapy and LAE for Alzheimer’s disease
prevention are under development. There appears to be no activity related
to the application of this technology to develop a contraceptive vaccine for
dogs and/or cats.
Lethbridge Research Center, Lethbridge, The work described in the 2002 report involved the use of GnRH vaccines
Alberta, Canada in cattle. Updating is beyond the scope of this document.
Drs. Cook, Kastelic, and McAllister

National Wildlife Research Center, US De- The work described in the 2002 report involved wildlife. Updating wild-
partment of Agriculture, Ft. Collins, CO life applications is beyond the scope of this report; however the GonaCon
vaccine developed by NWFC for deer has been tested in dogs and cats and
Dr. Kathy Fagerstone has been administered with a canine rabies vaccine. See Chapter 3, section
3.2.4, and section 4.3.4.1.
Dr. Lowell Miller
New York State College of Veterinary Dr. Patrick Concannon has worked for many years on canine reproduction
Medicine, Cornell University, Ithaca, NY and the canine estrous cycle. In 2006 he made a presentation entitled Use of
GnRH Agonists and Antagonists for Small Animal Contraception (Concannon
Dr. Patrick Concannon 2006) at the ACC&D 3rd International Symposium on Non-Surgical Con-
traceptive Methods of Pet Population Control. He was also on the organiz-
(Also see others at Cornell University ing committee of the 7th International Symposium on Canine and Feline
above) Reproduction in July 2012, which included several reports on new research
in the area of contraception.
Norwegian School of Veterinary Science, The work described in the 2002 report was related to reproduction in the
Oslo, Norway fox and assisted reproduction in various canid species. More recent work
appears to have been undertaken in lambs. This work is beyond the scope
Dr. W. Farstad of this update.
Rutgers University, New Brunswick NJ The work described in the 2002 report related to various methods to ad-
dress deer overpopulation and is beyond the scope of this document. (Dr.
Dr. Larry Katz Katz no longer does research in reproduction.)
University of Liège, Belgium The 2002 report described work of Dr. John Verstegen on the use of GnRH
agonists in the bitch. As of 2010, Dr. Verstegen became the executive vice
Dr. John Verstegen (now at Minitube Inter- president of international research and development at Minitube Inter-
national) national in Wisconsin. Minitube specializes in assisted porcine, bovine,
equine, and canine reproduction technologies.
University of Pretoria, Ondertepoort, Re- Dr. Bertschinger’s present work includes the use of porcine zona pellucida
public of South Africa (PZP) in managing reproduction in elephants and Suprelorin (deslorelin)
GnRH agonist in managing reproduction in cheetahs. Further updating is
Dr. Henk Bertschinger beyond the scope of this report.
University of Virginia, Charlottesville, VA The 2002 report described oocyte-related work undertaken by Dr. Scott
Coonrod, then at the University of Virginia, on identifying oocyte-specific
Dr. Scott Coonrod (now at Cornell Univer- proteins in dogs and cats under Dr. John Herr. Dr. Herr is continuing work
sity College of Veterinary Medicine Baker on oocyte ablation and has received a Michelson Grant (see section 4.3.3.2)
Institute of Animal Health). See section to pursue work on egg ablating drugs for use in dogs and/or cats (Burn-
3.6.3 for an update of his work. ham 2011).
Current: Dr. John Herr

Vertebrate Biocontrol Cooperative Re- The 2002 report described work on various methods to address wildlife
search Centre (CRC), Commonwealth control. Updating is beyond the scope of this report. See CSIRO/CRC sec-
Scientific and Industrial Reseach Organiza- tion 4.3.4.3 for other information.
tion (CSIRO) Wildlife and Ecology, Can-
berra, ACT, Australia
Dr. Mark Bradley

Virginia-Maryland Regional College of The 2002 report described work by Drs. Stephen M. Boyle and Beverly Pur-
Veterinary Medicine, Virginia Tech, Blacks- swell to develop species-specific orally administered contraceptive baits. In
burg, VA the interim, Drs. Boyle and Purswell have retired. Dr. Boyle continues to be
involved in the development and testing of a contraceptive vaccine, in this
Dr. Stephen M. Boyle (retired) case for feral swine, using a live, attenuated strain of Brucellosis suis VTRS2
developed at Virginia Tech. Drs. Lowell Miller and Steven Olsen of the
Dr. Beverly Purswell (retired) National Wildlife Research Center are collaborating on this research (Boyle,
personal communication 2012). Further discussion of the swine project is
beyond the scope of this document.
4.3.2 Universities Working on Non-Surgical Approaches
Note that much of the work described in Chapter 3 has been done at universities so this table may not include all
universities at which work on non-surgical approaches is occurring. Since this field is evolving continually, ACC&D may
not be aware of every academic research project. Please notify ACC&D of any project that may be included in future
updates of this report.
An asterisk (*) in Table 4-3, below, denotes a Michelson Grant in Reproductive Biology recipient (as of July 2012). See
section 4.3.3.2 for information about the Michelson Prize & Grants in Reproductive Biology.
Table 4-3: Universities Involved in Researching Non-Surgical Approaches to Dog and Cat Contraception/Sterilization
University Researchers Area(s)
Auburn Univer- *Tatiana I. Samoylova, PhD Phage-GnRH constructs (see Chapter 3, section 3.3.1.3.2 for a de-
sity, Auburn, AL in collaboration with Drs. scription of Dr. Samoylova’s work on Phage-ZP constructs)
Nancy Cox, Valery Petren-
ko, Bettina Schemera, Frank
Bartol and Mark Carpenter
Baker Institute, Scott Coonrod Egg-ablating drugs delivered via virus-like particles (see Chapter 3,
Cornell University section 3.6.3)
Bose Institute, Dr. Kuladip Jana Calcium chloride as a sterilant (see Chapter 3, section 3.4.2)
Kolkata, India
Center for Repro- Joseph S. Tash and Kather- Antispermatogenic (see Chapter 3, section 3.6.5).
ductive Services, ine F. Roby. Note that Dr.
University of Gunda Georg at the College
Kansas Medical of Pharmacy, University of
Center Minnesota, is collaborating
with Drs. Tash and Roby on
this research.7
Interdisciplinary Joseph S. Tash and Gunda Under the auspices of the Contraceptive and Reproductive Health
Center for Male Georg Branch of National Institute of Child Health & Human Develop-
Contraceptive Re- ment (NICHD), the Center and collaborator Dr. Gunda Georg (see
search and Drug above) are spearheading a multi-university effort to develop revers-
Development ible non-hormonal male contraceptive agents.
7
Researchers listed in this table may have collaborators at other institutions.

Iowa State Col- *Douglas E. Jones, MS, GnRH vaccine delivery device. Dr. Jones has been involved in devel-
lege of Veterinary VMD, PhD oping mathematical models of immunity, which has led to research
Medicine, Ames, related to developing a vaccine implant that responds to the im-
IA mune status of the person or animal, enabling release of the vaccine
when the immune response is decreasing.
National Jewish *Phillippa Marrack, PhD Attenuated recombinant herpesviruses. Dr. Marrack’s research is
Health, Denver, and Michael Munks, PhD related to T-cell function.
CO (hospital and
medical research
facility)
National Univer- *Cristina Gobello, DrVet- Several, including GnRH agonists and antagonists. Dr. Gobello has
sity of La Plata, Med, Dipl ECAR. Also Drs. authored or co-authored a number of publications related to repro-
Argentina C.Valienta, and Y. Corrada duction and fertility control in companion animals. (See Chapter 3,
(and other publication-spe- sections 3.2.1 and 3.2.2 for examples of published work for which
cific authors) Dr. Gobello is the lead author.)
Oregon Health & Sergio R. Ojeda DVM and Interfering RNA/gene silencing (see Chapter 3, section 3.6.1)
Science University Gregory A. Dissen, PhD
School of Medi- Dr. Sujoy K. Guha Reversible inhibition of sperm under guidance – RISUG™ contra-
cal Science and ceptive polymer (see Chapter 3, section 3.6.4.3)
Technology
(SMST) and Na-
tional Institute of
Medical Science
and Technology,
Kharagpur, India
Scripps Research *William W. Ja, PhD Cytotoxin conjugates (see Chapter 3, section 3.6.4.2)
Institute, Jupiter,
FL
UMDNJ-Robert *Paul R. Copeland, PhD Targeting selenoprotein P for use in male contraception. Dr. Cope-
Wood Johnson land has identified and characterized important factors involved in
Medical School, programming ribosomes to incorporate selenocysteine, an amino
Piscataway, NJ acid involved in many human proteins. These proteins include glu-
tathione peroxidase 4, which is required for male fertility.
Université de D. Fellman, F. Pralong, P. Y. Kisspeptin and GnRH (see Chapter 3, section 3.6.2)
Franche-Comté, Risold
Besançon Cedex,
France
University of Aldo Dr. Raffaella Leoci Calcium chloride as a sterilant (see Chapter 3, section 3.4.2). Note
Moro of Bari, Va- that Dr. Leoci has also worked on the use of ultrasound for steriliza-
lenzano, Italy tion of male dogs. Note: As of November 2012, Dr. Leoci was in the
planning stages of a study to compare various visual identification
methods to mark dogs as sterilized (Lissner, personal communica-
tion 2012).
University of Ari- *Benjamin Renquist, PhD Interfering RNA/gene silencing (see Chapter 3, section 3.6.1)
zona, Tucson, AZ
University of *Larry Chamley, PhD Sperm protein (SPRASA, see Chapter 3, section 3.6.6)
Auckland, New
Zealand
University of Iowa *Beverly L. Davidson, PhD Interfering RNA/gene silencing (see Chapter 3, section 3.6.1)
Medical School,
Iowa City, IA

University of *R. John Aitken, ScD, FRSE Developing a humane non-surgical sterilization method for use in
Newcastle, Cal- domestic animals. Note that Dr. Aitken has published on a number
laghan, NSW, of topics related to reproduction, including the cell biology of male
Australia germ cells, particularly spermatozoa, and certain aspects related to
ovarian follicles.
University of Nathaniel Fried, Ph.D. Working on non-invasive laser vasectomy with funding from
North Carolina at NICHD. According to the university’s Biomedical Optics Labora-
Charlotte, Char- tory website: “Preliminary experiments … have demonstrated that
lotte, NC it is possible to use therapeutic focused ultrasound to noninvasively
target the vas deferens for thermal coagulation, scarring, and occlu-
sion.” Dr. Fried has co-authored a number of studies related to non-
invasive laser coagulation of the canine vas deferens. See maxwell.
uncc.edu/nmfried/index.html and maxwell.uncc.edu/bmolab/
pages/sterilization.html.
University of *Ralph G. Meyer, PhD Poly(ADP-ribose) metabolism-related pharmacological strategies

Pennsylvania, for treatment of male infertility and non-surgical sterilization of cats
Philadelphia, PA and dogs.
University of *John C. Herr, PhD Egg-ablating recombinant vaccines. Dr. Herr is focusing on work
Virginia (UVA), that could lead to the development of a non-surgical sterilant that
Charlottesville, VA targets oocytes before they become eggs (see section 3.6.3). His labo-
ratory is also working on understanding human testis genes and
how they are expressed in various types of human tumors.
University of *Megan Lloyd, PhD Recombinant viral vector. Note that Dr. Lloyd has published on
Western Australia, infertility caused by immunization with recombinant murine cy-
Crawley, Western tomegaloviruses expressing murine zona pellucida (O’Leary et al.
Australia 2009).
West Bengal Uni- Dr. P. K. Samanta (now Calcium chloride as a sterilant (see Chapter 3, section 3.4.2). Dr. Sa-
versity of Animal retired) manta is now partially retired, but still involved in a local field trial
and Fishery Sci- (Lissner, personal communication 2012).
ences, Calcutta,
India
Yale University. *Meenakshi Alerja, PhD Developing a non-surgical sterilization method in mice. Note that
New Haven, CT Dr. Alerja has published on activation of the G-protein-coupled re-
ceptor GPR54 by kisspeptins during puberty (Dumaiska et al. 2008).
4.3.3 Organizations and Foundations
There has been a significant increase in the level of nonprofit – and to some extent – government support of research
and general focus in the area of contraceptives for dogs and cats since the original report in 2002. At least one of these
entities has pledged to also play a role in commercializing new products.
One product, sponsored by The Humane Society of the United States™ (HSUS), received regulatory approval in
February 2012 from the EPA following years of use in the field on a research basis. The product is a vaccine, called
ZonaStat-H, intended and approved solely for use in fertility control in female wild horses. Although ZonaStat-H is not

a product for dogs or cats, it represents perhaps the first that can be developed into effective, safe products that meet
known animal health product sponsored by a nonprofit applicable regulatory standards, are commercializable,
to receive approval (see humanesociety.org/news/ and can be dispensed affordably and conveniently in
press_releases/2012/02/EPA_Announces_First_Fertility_ low-income and frontier market situations. Another focus
Control_Vaccine_for_Wild_Horses.html). (See section of the organization is providing scientifically-sound and
Chapter 3, 3.3.1 for a discussion of porcine zona pellucida- animalwelfare-oriented information about available
based vaccines.) products and work in this field to stakeholders in animal
Overviews of different organizations’ and foundations’ welfare, animal health, population management, and
involvement and approaches are reviewed below in public health. See acc-d.org for additional information.
alphabetical order. ACC&D has the support of its Council of Stakeholders,
See Chapter 6 for an overview of regulatory which provide multi-year operational financial support
considerations related to non-surgical sterilization and/or as well as strategic insight on stakeholder interests and
contraception products for use in dogs and cats, including networking. As of November 2012 the Council consists of
a discussion of issues related to un-approved products seven organizations: Amber and Adam Tarshis Foundation,
obtained from compound pharmacies or other sources in the ASPCA, The HSUS, Parsemus Foundation, Petco®
lieu of development under the prescribed pathways for Foundation, PetSmart Charities®, and the Regina Bauer
regulatory approval. Frankenberg Foundation. For updates, see acc-d.org.
4.3.3.1.1 ACC&D Symposia

ACC&D has organized and hosted four international
symposia focusing on non-surgical contraception in
companion animals. Proceedings of the 2002, 2004,
2006, and 2010 symposia are available for review and
downloading at acc-d.org/ACCD%20Symposia. A fifth
symposium will take place in June 2013.
4.3.3.1.2 ACC&D Think Tanks

ACC&D has held four “Think Tank” meetings since
4.3.3.1 Alliance for Contraception in Cats & Dogs, 2009 to bring together experts in a given field to discuss
Portland, OR specific opportunities relating to developing non-surgical
ACC&D was founded by contraceptive researchers Drs. contraception and fertility control for use in cats and dogs.
Henry Baker, Stephen Boyle and Brenda Griffin in 2000 as a Think Tanks convened to date include:
program of Auburn University and was then incorporated � Contolled Release for Depot and Implant Technologies,
as an independent 501(c)3 nonprofit organization in as it Applies to Developing Non-Surgical Alternatives
2005. The organization’s mission is to expedite the to Sterilize Cats and Dogs (April 2012, sponsored by
successful introduction of methods to non-surgically Found Animals® Foundation and the Animal Assistance
sterilize dogs and cats and to support the distribution Foundation)
and promotion of these products to humanely control cat � Population Dynamics Modeling and Field Studies
and dog populations worldwide. ACC&D represents the to Improve Development of Technologies for Non-
interests of the animal welfare community in obtaining Surgical Sterilization of Cats and Dogs (June 2011,
more efficient methods of preventing unwanted litters sponsored by Leonard X. Bosack & Bette M. Kruger
of cats and dogs. The Board of Directors and Scientific Foundation and PetSmart Charities; follow-up
Advisory Board include leaders and experts in veterinary development of a computer model to evaluate both
medicine, reproduction, animal health, drug development, surgical and non-surgical interventions in free-roaming
public health and animal welfare. Experts include senior cat populations funded by the ASPCA in 2012)
staff/scientific advisors for the American Society for the � Immunocontraceptive Approaches for Sterilization
Prevention of Cruelty to Animals® (ASPCA®), The HSUS, of Dogs and Cats (November 2009, sponsored by
Dogs Trust, and, formerly, the World Society for Protection Found Animals Foundation and the Animal Assistance
of Animals (WSPA). Foundation)
The organization advocates science-based approaches
in 2013. Ark Sciences, the company commercializing
� Gene Silencing Potential for Sterilization of Cats and Esterilsol, has provided training. A February 2012 visit
Dogs (October 2009, sponsored by Found Animals
report by then-ACC&D Senior Director Karen Green is
Foundation and the Animal Assistance Foundation)
available at http://www.acc-d.org/ACCD%20docs/
Think Tank summaries are available for review and VWBChileStudyKGReport.pdf.
downloading at acc-d.org/ThinkTanks.
Previous Projects
4.3.3.1.3 ACC&D-Sponsored Studies
Esterilsol Small Grants Program (ESGP)
ACC&D provided support in 2006 to SenesTech for This program was inaugurated in 2009 to help nonprofit
early work in efficacy and safety of its technology in dogs. organizations wishing to use Esterilsol in their sterilization
According to a position on research updated in 2012 and programs and to gather data regarding the field-based
available on ACC&D’s website, “ACC&D does not directly use of the product. Five grants, funded by a variety of
conduct or fund the research necessary in the development groups and individuals, were awarded to groups working
in Colombia, Dominican Republic, Samoan Islands,
Galapagos Islands, Chile, Sierra Leone, and Kenya. See
acc-d.org/EsterilsolGrants for specific information.
Sterilization Program and Field Study in Guatemala

ACC&D sponsored this 2009 VWB/VSF field-based
project in Todos Santos, Guatemala (with funding from
Parsemus Foundation – see section 4.3.3.4) in which 126
male dogs were sterilized using Esterilsol. (See www.acc-d.
org/ACCD%20docs/SummaryGuatemalaReportFinal.pdf
for a report and photos of the project.)
of new contraceptives and non-surgical sterilants.

4.3.3.2 Found Animals Foundation/Michelson Prize &
However, [ACC&D] may facilitate research on promising Grants in Reproductive Biology, Los Angeles, CA
formulas by providing counsel on study design, standards
Philanthropic investor Dr. Gary Michelson formed the
of animal use, and routes for potential funding. ACC&D
nonprofit Found Animals Foundation in 2005 to address
may conduct or fund non-terminal research involving
the problem of cat and dog overpopulation. In October
animals in field projects designed to increase learning about
of 2008 Dr. Michelson instituted the Michelson Prize in
existing products: those that have regulatory approval and
Reproductive Biology, a $25 million prize for the first
are commercially available for dogs and/or cats, or extra-
method shown to permanently sterilize cats and dogs
label use of other approved products.”
and to have a viable pathway to regulatory approval. The
Other grants awarded by ACC&D have supported field- prize is supported by the $50 million Michelson Grants
based efforts to “advance knowledge about [the] effective in Reproductive Biology program. Grants are intended
use of Esterilsol, the non-surgical sterilant for [use in] to fund promising research in pursuit of non-surgical
male dogs.” See Chapter 3, section 3.4.1 and section 4.2.3 sterilization products or technologies for use in dogs and
for information about the history of Esterilsol (known as cats. Found Animals Foundation seeks proposals from
Zeuterin in the US) and its precursor, Neutersol. researchers for up to $250,000 USD per year for up to 3
Ongoing Project: Esterilsol Behavior Study years of funding.
The goal of the Michelson Prize & Grants Program is
A current behavioral study in Puerto Natales, Chile seeks development and commercialization of a single dose,
to address the behavioral effects of Esterilsol compared non-surgical sterilant that could be administered in the
to those of surgical castration in male dogs. The study, an field at a reasonable cost. By offering the Michelson Prize
international collaboration among the Chilean National in Reproductive Biology, Found Animals encourages
Agriculture Service, the Italian Instituto G´Caporale, the researchers to take on the challenge of non-surgical
University of Pennsylvania, and the Canadian Atlantic sterilization for dogs and cats. Found Animals Foundation
Veterinary College and Veterinarians without Borders/ believes a low cost, non-surgical method of sterilization
Vétérinaires sans Frontières-Canada (VWB/VSF), is being would allow large populations of cats and dogs to be
carried out by VWB/VSF. A report on the study is expected
sterilized to reduce the number of homeless and unwanted
animals that are killed each year in shelters.
� Viable pathway to regulatory approval
• As defined by CVM as a prescription product in
Found Animals will award the $25 million Michelson Prize
dogs and cats
to the first entity to provide a product that has, at minimum,
the following characteristics (michelson.foundanimals.org/ • Regulatory approval will be sought by Found
michelson-prize/michelson-prize-criteria): Animals
� Single dose, non-surgical sterilant � Reasonable manufacturing process and cost

• Target is a low-cost product to deliver to shelters
• Administered in a single patient encounter
• Must be no greater than $50 cost per dose to
• Must not require general anesthesia
deliver labeled, packaged product to the
• May require sedation or local anesthesia Foundation or other distributor, with less than $25/
• Subcutaneous implant is considered non-surgical dose preferred when manufactured at commercial
for the purpose of the Michelson Prize scale
• Must induce permanent sterility for the • Importantly, Found Animals plans to license the
reproductive lifetime of the species, defined as prize-winning approach and then take it through
at least 10 years after administration the US regulatory approval process and to market,
with the goal of making a product available in a
• Will generally require 3 years of data with a trend
timely manner and affordably to the target market.
line with no expectation of recovery;
may require that study extends for additional time • The Michelson Grants also provide funds for
research with promise of leading to an approach
� Safe and effective in male and female, cats and dogs that meets their priorities. As of this update, 22
• Must be one product for both species and genders grants have been approved and 18 grants have
• Must be no more dangerous than surgical been awarded and announced publicly, totaling
gonadectomy more than $8.7 million (S. Johnston and K. Palfrey,
personal communication October 2012).
• Must be safe for treated animal, environment
(including predators), and person • Grant applications are (and future prize
administering the product applications will be) reviewed by the organization’s
Scientific Advisory Board under the leadership of
• Efficacy must be greater than or equal to spay/
the Michelson Prize & Grants’ Director of Scientific
neuter. For the purposes of experimental design, a
Research, Dr. Shirley Johnston, a veterinarian, with
lower standard of proof may be acceptable
a specialty in animal reproduction (theriogenology)
• Must not induce clinical abnormalities or the author of a textbook on canine reproduction,
pathological lesions at 1X dose and the founding dean of the College of Veterinary
in safety studies Medicine at Western University.
• Must not be carcinogenic, mutagenic, • Table 4-4, next page, provides information
or clastogenic regarding recipients of Michelson Grants.
• Must not be a “bait” formulation (i.e., Readers are advised to consult the Michelson
administered without handling of Grants in Reproductive Biology at michelson.
treated animals) foundanimals.org/for information on
� Ablates sex steroids and/or their effects grant amounts and durations, and periodic
additions to the grantee list. This table is
� Suitable for administration in a field setting taken directly from the Michelson Grants
• May require refrigeration/cold chain website (except for references to specific
but no frozen storage, water source, or sections of this report which provide more
other electricity than refrigeration detail on the work) and has been updated as
• Must have shelf life of at least 2 years of July 14, 2012.
• Must not require sterile environment/

surgical theater

Table 4-4: Michelson Grants in Reproductive Biology
Grantee Project Title8
R. John Aitken, ScD, FRSE, University of “Development of a human non-surgical sterilization method for domestic
Newcastle, Callaghan, NSW, Australia animals.”
Meenakshi Alfreja, PhD, Yale University, “Development of a non-surgical sterilization method in mice.”
New Haven, CT
Larry Chamley, PhD, University of “SPRASA – An Immunocontraceptive with a Difference.”
Auckland, New Zealand
Paul R. Copeland, PhD, UMDNJ-Robert “Targeting Selenoprotein P for male contraception in mammals.”
Wood Johnson Medical School, Piscat-
away, NJ
Beverly L. Davidson, PhD, University of “Inducing stable infertility by RNA interference – proof of principle
Iowa Medical School, Iowa City, IA studies.”
Cristina Gobello, DrVetMed, Dipl ECAR, “Prepubertal administration of GnRH agonists in domestic cats.”
National University of La Plata (FVS-
NULP), Argentina
John C. Herr, PhD, University of Virginia, “Oolysins: egg ablating drugs.”
Charlottesville, VA
William W. Ja, PhD, Scripps Research “FSH receptor ligand-cytotoxin conjugates for permanent chemosteriliza-
Institute, Jupiter, FL tion.”
Douglas E. Jones, MS, VMD, PhD, Iowa “Development of a vaccine delivery device that will maintain life-long high
State College of Veterinary Medicine, titers of anti-GnRH antibodies.”
Ames, IA
Megan Lloyd, PhD, University of Western “Contraception in companion animals using a recombinant viral vector.”
Australia, Crawley, Western Australia
Phillippa Marrack, PhD, National Jewish “Use of attenuated recombinant herpesviruses, expressing fertility antigens,
Health, Denver, CO to induce infertility in cats and dogs.”
Ralph G. Meyer, PhD, University of Penn- “Targeting Poly (ADP-ribose) metabolism for development of a non-surgical
sylvania, Philadelphia, PA sterilant.”
Michael Munks, PhD, and Phillippa “Use of attenuated recombinant herpesviruses, expressing fertility antigens,
Marack, PhD, National Jewish Health, to induce infertility in cats and dogs.”
University of Colorado Health Science
Center, Denver, CO
Benjamin Renquist, PhD, University of “Inducing stable infertility by RNA interference.”
Arizona, Tucson, AZ
Tatiana I. Samoylova, PhD, Auburn Uni- “Phage-GnRH constructs and their mimics for immunocontraception of cats
versity, Auburn, AL and dogs.”
A.C. Schaefers-Okkens, DVM, PhD Uni- “Kisspeptin: the Endocrinological Gatekeeper to Reproductive Function. A
versity of Utrecht, Netherlands Realistic Target for Non-Surgical Contraceptives in the Dog.”
R. Scott Struthers, PhD, Crinetics “Novel toxin conjugates for non-surgical sterilization via gonadotroph
Pharmaceuticals, San Diego, CA ablation.” See Crinetics, section 4.2.4.3.
R. Scott Struthers, PhD, Crinetics Pharma- “Targeted ablation of GnRH neurons for non-surgical sterilization.” See
ceuticals, San Diego, CA Crinetics, section 4.2.4.3.
Kent R. Van Kampen, DVM, PhD Vaxin, “A vectored GnRH contraceptive vaccine to control dog and cat overpopu-
Inc., Birmingham, AL; Drs. Henry Baker lation (with Scott-Ritchey Research Center, Auburn University).” See Vaxin,
and Nancy Cos, Auburn University, Au- section 4.2.4.7.
burn, AL
8
Note that in many instances, description of a given project beyond its title is not available.
Relevant publicly available information can be found in the sections referenced in the table.

Two additional grants have been awarded through the Michelson Graduate Student Challenge program:
� Joseph Rosenthal (Cornell University, Ithaca NY), a student in the Department of Biomedical Engineering, received a
$15,000 grant in the Materials and Science/Engineering Category
� Owen Siggs (Scripps Institute, La Jolla, CA), a student in the Department of Genetics, received a $15,000 grant in the
Depot Formulation Category
4.3.3.3 Morris Animal Foundation, Denver, CO

Over the years a number of reproduction- and overpopulation-related studies have been sponsored by Morris Animal
Foundation (MAF) to evaluate methods of non-surgical contraception in dogs and cats. Consult the MAF website
(morrisanimalfoundation.org/our-research/studies.html) for updates and for information on specific studies. The studies
below were conducted between the years 2000 and 2012; investigators received a combined total of $673,000 in grant
funding.
Table 4-5: Morris Animal Foundation Dog and Cat Overpopulation Projects
Division Primary Contact Project Title Organization Name Status

Canine Dr. Cristina Go- Use of the GnRH Antagonist, National University Completed 2007
bello, MV, DMV, Acyline, for Pregnancy Termina- of La Plata
DECAR tion (Pilot)
Canine Dr. Cristina Go- Use of the Non-Peptide GNRH National University Completed 2010
bello, MV, DMV, Antagonist, NBI-42902 on of La Plata
DECAR Pregnancy and Estrous Cycle
Interruption
Canine Dr. Terry M. Nett, Development of New, More Ef- Colorado State Uni- Project extended as of
Ph.D. ficacious Technology to Chemi- versity 12/31/2011
cally Castrate Male and Female
Dogs (see section 4.3.2, Gonex)
Canine Elisa Juarez Use of a GnRH Antagonist on National University Completed 2008
Estrous Cycle Interruption of La Plata
Canine Paul S. Cooke, PhD Use of Neonatal Progestin University of Florida Noted as Active but scheduled
Treatment as a Permanent, Non- to end 8/12
surgical Contraceptive Method-
ology in Dogs
Feline Dr. Julie K. Levy, Evaluation of SpayVac for Steril- University of Florida Completed 2001
DVM, Ph.D. izing Domestic Cats (Felis catus)
(see Chapter 3, section 3.3.1.2.2)
Feline Dr. Julie K. Levy, GnRH Immunocontraception University of Florida Completed 2006
DVM, Ph.D. for the Humane Control of Feral
Cats (see Chapter 3, section
3.2.4.2)
Feline Dr. Julie K. Levy, GnRH Immunocontraception University of Florida Completed 2009
DVM, Ph.D. for the Humane Control of Feral
Cats (continuation of study on
duration of effect) (see Chapter
3, section 3.2.4.2)
Feline Ana Cristina Effect of Exogenous Melatonin Catholic University of Completed 2008
Carranza Martin on Prevention of Breeding Sea- Cordoba
son in the Domestic Cat

Feline Mr. Jorge Diaz Effect of the GnRH Antagonist, National University of Completed 2009
Acyline, on Domestic Cat Preg- La Plata
nancy (Pilot)
Feline Mercedes Soriano Effect of Prepubertal Admin- National University of Completed 8//12
istration of a GnRH Agonist in La Plata
Domestic Cats
Feline Dr. Cristina Go- Effect of Neonatal Administra- National University of Extension – results due 2/13
bello, MV, DMV, tion of a GnRH Antagonist in La Plata
DECAR Domestic Cats
4.3.3.4 Parsemus Foundation, San Francisco, CA veterinary use of compounded calcium chloride injection
The California-based Parsemus Foundation’s website may be justified based on current published literature
(parsemusfoundation.org) describes its purpose as “finding and the publication of the Italian results expected in early
low-cost solutions neglected by the pharmaceutical 2013.” (See section 3.4.2 for more on calcium chloride and
industry.”Although the foundation is heavily involved an ACC&D-issued statement and review of current studies
in human health-related projects with special interest in on this technology (http://www.acc-d.org/ACCD%20
non-hormonal human male contraception, contraception docs/ACCD-RecommCalcChlor2.pdf), and Chapter 6
and fertility control in dogs and cats is also one of the for an overview of regulatory pathways for new drugs
foundation’s key areas of interest. The foundation website intended for use in dogs and cats.)
lists the following dog and cat projects as receiving its
support: 4.3.3.5 600 Million Stray Dogs Need You,
Pompano Beach, FL
� Use of calcium chloride testicular injection for neutering 600 Million Stray Dogs Need You (600 Million) was
male dogs and cats (several collaborators) founded and continues to be led by PETA co-founder Alex
� Confirmatory studies of ultrasound non-surgical Pacheco to address dog overpopulation, prevent deaths
sterilization (Dr. Raffaella Leoci, University of Bari) due to bites by dogs with rabies, provide “practical and
affordable alternatives to labor intensive and expensive
� Research into transcervical intrauterine contraception or surgical sterilization,” and “enable government animal
sterilization for medium and large female dogs (several
control and rabies agencies to reduce their use of
collaborators)
inhumane animal control methods.” The group’s focus is
� Promoting a transition from the use of on developing an oral, single-dose sterilant for dogs (or
ovariohysterectomy to ovariectomy to sterilize female “Super Birth Control Pill”). The website refers to “formulas
dogs which thus far are all safe when used as intended” and
� A demonstration video focused on ovary-sparing spay notes that due to expense “the work … is outside the
as an option in cases in which the health benefits of US.” Funds are actively sought on the group’s website to
keeping the ovaries are deemed to outweigh the health advance the research. No information on the approach(es)
risks (Dr. Michele Kutzler, Oregon State University) being worked on is provided. In 2010, 600 Million began
promoting its efforts, referencing a technology that was
The foundation’s most extensive involvement in non-
”in-hand.” At that time, the organization had a relationship
surgical spay and neuter has been in calcium chloride
with SenesTech, an Arizona-based company working on
testicular injection for male dogs and cats, specifically,
chemical-sterilant-based contraceptive products for use
funding completion and publication of studies in India
in rats and dogs (see section 4.2.4.6) but that relationship
(Dr. Kuladip Jana, Bose Institute) and independent
has since been terminated by SenesTech. The current 600
confirmatory trials in Italy (Dr. Raffaella Leoci, University
Million website refers to a relationship with Planned
of Bari). According to personal communication with
Pethood International, which is “the non-profit division”
Parsemus Medical Director, Elaine Lissner: “The
of Denver-based Planned Pethood Plus, Inc. These two
foundation seeks to raise awareness of the calcium chloride
entities appear to be focused on companion animal
approach and of the opinion of several regulatory experts
welfare, including encouraging and providing spay/neuter
that in certain circumstances and under certain conditions,
services.

4.3.4 Government “the use of … GonaCon did not affect the ability of dogs
to seroconvert in response to the rabies vaccine. Thus,
4.3.4.1 United States Department of Agriculture
GonaCon provides a potential immunocontraceptive for
National Wildlife Research Center,
Fort Collins, CO use in combination with rabies vaccine to increase herd
immunity and address dog population over abundance to
See information in Chapter 3, section 3.2.4, which is
better manage rabies (Bender et al. 2009).” A 2009 study
related to the GnRH vaccine GonaCon, developed by
(Wu et al.) described the development of a recombinant
NWRC, approved for contraception of white-tailed
combination rabies/immunocontraceptive vaccine. See
deer in the US and tested in cats and dogs. GonaCon
Chapter 3, section 3.2.4.1 for information on the Bender et
has also been incorporated into a simultaneous rabies/
al. study, the Wu et al. study, and a subsequent Lecuona et
immunocontraceptive vaccine protocol by researchers at
al. study (2012).
USDA, CDC in Atlanta, GA, and Navajo Nation Veterinary
Program. See below and also Chapter 3, section 3.2.4.1 for US patent application 13/062680, entitled Rabies Virus-
information about simultaneous use of GonaCon and a based Recombinant Immunocontraceptive Compositions and
commercially available rabies vaccine. Methods of Use, was filed on August 20, 2009 and published
on July 7, 2011. Inventors are listed as Xianfu Wu and
4.3.4.2 United States Centers for Disease Control Charles E. Rupprecht of the CDC, and the assignee is listed
and Prevention, Atlanta, GA as “The Government of the United States of America as
represented by the Secretary of the Department of Health
As described in Chapter 3, section 3.2.4.1, researchers
and Human Services, Centers for Disease Control and
at the CDC have been investigating simultaneous
Prevention.” The invention is characterized as follows:
administration of a canine immunocontraceptive vaccine
and rabies vaccine, as well as combining a canine “Described herein are recombinant rabies viruses
immunocontraceptive vaccine and rabies vaccine that comprising a heterologous nucleic acid sequence
can induce appropriate dual immunological responses encoding an immunocontraceptive protein, such
against both rabies virus and immunocontraceptive targets as gonadotropin-releasing hormone (GnRH) or
following a single administration in animals. A 2009 zona pellucida 3 (ZP3). The recombinant rabies
publication described a study in which GonaCon, USDA’s viruses disclosed herein are recovered by reverse
GnRH immunocontraceptive vaccine for white-tailed genetics, replicate efficiently, elicit rabies virus
deer, was administered simultaneously with a commercial neutralizing antibodies and immunocontracep-
rabies vaccine. In that study researchers concluded that tive peptide-specific antibodies in vaccinated

animals, and protect vaccinated animals against technologies to better target and monitor wild dog, fox and
wild-type rabies virus challenge. Further pro- feral cat control programs; to develop an integrated, cross-
vided is a method of immunizing a non-human tenure strategy, which manages or eradicates feral goat,
animal against rabies virus infection and simulta- deer, pig, and cat populations on Kangaroo Island using
neously inhibiting fertility of the animal, com- effective control measures, including new technologies
prising administering an immunogenic composi- PIGOUT® and HOG-GONE® [both poisons]; to test an
tion comprising one or more of the recombinant alternative approach to managing foxes and feral cats –
rabies viruses described herein” (freepatentson- automated control using spray tunnel technology through
line.com/y2011/0165189.html). targeting the propensity of both species to orally groom;
to understand community attitudes to fauna conservation,
Note that the invention described above refers to control of feral and stray cats, and containment of domestic
recombinant rabies virus being “combined” with either cats, to smoothly implement conservation policies (see
GnRH or ZP. invasiveanimals.com/wp-content/uploads/2011/11/
With the help of local animal welfare advocates, the Research-Portfolio-2010-11-Compressed.pdf for
CDC is striving to raise $125,000 for a field trial in dogs, information). The CRC is also working with SenesTech,
presumably related to the project described above. Few Inc. (see 4.2.4.6) on SenesTech’s rat contraception product,
details are available (Briggs, personal communication 2012). ContraPest.
4.3.4.4 AFSSA Nancy, Wildlife Health and

Management Unit, Malzéville, France
Dr. Franck Boué of Agence Française de Sécurité
Sanitaire des Aliments (AFSSA) Nancy presented
research related to development of a sperm-antigen-based
immunocontraceptive vaccine for canine species at the
1st and 2nd International Symposium on Non-Surgical
Methods of Pet Population Control (see section 4.3.1).
Later work by the AFSSA team (Verdier et al. 2005) was
carried out to clone and sequence the fox antigenic proteins
fSP8 and fSP13 as a precursor to developing methodology
4.3.4.3 Cooperative Research Centres, Australia to characterize the antigens identified in the study
The Cooperative Research Centres (CRC) program was described in 2002.
inaugurated by the Australian Federal Government in 1990
4.3.4.5 Food and Environment Research Agency,
to unite researchers from universities, government labs
United Kingdom
(including the Commonwealth Scientific and Industrial
Research Organization (CSIRO)), private industry, and The mission of the United Kingdom (UK) Food and
public-sector organizations in long-term collaborations to Environment Research Agency (FERA) is to “support
support R&D and education activities “that achieve real and develop a sustainable food chain, a healthy natural
outcomes of national economic and social significance.” environment, and to protect the global community from
At the time of the 2002 Contraception and Fertility Control in biological and chemical risks.” This includes dealing with
Animals report, there were three CRCs involved in work the challenge of “humane, effective and sustainable dog
in this area: CRC for Vaccine Technology, CRC for the population management.” In a 2010 joint FERA-USDA
Biological Control of Pest Animals, and Marsupial CRC. publication the authors noted that an estimated 75% of the
None of these appears in a listing of 2010-2011 CRCs on the approximately 500 million dogs in the world “are free to
Encyclopedia of Australian Science website (www.eoas. roam and reproduce and may have a negative impact on
info/bib/ASBS02735.htm). human activities” (Massei et al. 2010).
CRC work on contraception and fertility control involves In September 2012, FERA, in co-operation with the World
pest species only; the July 2012 CRC website refers to Health Organization (WHO), World Organization for
developing tools for “major pest species” which include Animal Health (OIE), Royal Society for the Prevention of
“wild dogs” and “feral cats.” Projects include but are not Cruelty to Animals (RSPCA), WSPA, International Fund for
limited to the following studies: to develop new monitoring Animal Welfare (IFAW), and Humane Society International

(HSI), sponsored the 1st International Conference on pathology from its Health Surveillance Program. A recent
Dog Population Management. At this conference, FERA project sought to better understand side effects related to
expressed its continued interest in being involved with use of deslorelin (Suprelorin) implants in female canids
research on the use of GonaCon in free-roaming dog through a “retrospective analysis of medical records
populations (see section 3.2.4.1). Conference abstracts are and pathology reports from more than 1000 subjects.”
available for download from https://secure.fera.defra.gov. The Center provides information about a variety of
uk/dogs2012/bookOfAbstracts.cfm. contraceptive interventions, including progestins, GnRH
agonists, vaccines, surgery, and nicarbazin (for birds).
4.3.4.6 The AZA Wildlife Contraception Center, Recommendations and cautions about products and their
St. Louis, MO use are included (www.aza.org/wildlife-contraception-
Based at the St. Louis Zoo, the AZA Wildlife center). For more information, visit stlzoo.org/animals/
Contraception Center (WCC) provides zoos with scienceresearch/contraceptioncenter/.
information regarding contraception of captive wildlife,
including numerous species of canids and felids. The
Center collects data on use of contraceptives in zoos
throughout the country and develops recommendations
based on its communications with zoos and tissue

5.0 Marketing Overview and Issues pursuing relatively early stage technologies as well, and
significant challenges to serving the broad market continue
5.1 Overview to exist.9
Non-surgical dog and cat contraception, whether The unmet needs in the companion-animal contraception
permanent or reversible, is regarded as a market with and fertility control market represent opportunities for
significant potential due to the sheer numbers of animals, animal health companies. Historically, however, “big
and the general commitment of a large number of pet pharma” animal health has been reluctant to develop
owners in many countries to control their animals’ fertility. products either for domestic dogs and cats or so-called low-
In addition, pet owners are increasingly expecting more profit segments, such as feral animals and wildlife. (Note
pet healthcare options, and although several products that wildlife is beyond the scope of this document.)
have emerged, historically there have been few choices for Aside from the traditional obstacles to developing,
non-surgical fertility control for the majority of pets. The delivering, and commercializing pharmaceutical and
market for non-surgical approaches also includes nonprofit biological products (e.g., cost, business and competitive
organizations and government agencies that commit risks, scale-up and manufacturing issues, overall length
resources to controlling populations of unowned pets; of time it takes to develop products and obtain regulatory
this market segment may be expected to appreciate and approvals), contraception and fertility control in dogs and
embrace the benefits of being able to achieve dog and cat cats present specific challenges.
population control without the need for surgery.
The combination of different technologies, diversity
among stakeholders, and the presence of very visible low-
margin segments presents a challenge that can be expected
to keep marketing managers awake at night. What kinds of
things will they be thinking about?
There is no single approach, formulation, technol-
ogy, or product to date for use in dogs and cats.
It is an understatement to say that the needs of dog and

cat owners, shelters and welfare groups, and the veterinary
The belief that non-surgical alternatives to pet population professionals who serve these groups differ.
control represent a viable market is illustrated by the
increasing extent of ongoing research and development There are important end-user preferences that affect
efforts to create products that offer non-surgical approaches the ultimate attributes of products – short-term, long-
for pets and stray or feral animals. In fact, since the original term, or permanent sterilization; injection, implant, or
Contraception and Fertility Control in Animals report was oral formulation; and suppression or maintenance of sex
published in 2002, several products have been approved, hormone influenced behaviors.
for male dogs at least, and are available in various markets The following assumptions have typically been made
The dog and cat “contraception and fertility control by individuals and groups interested in contraception and
market” is, in fact, a number of markets at various stages fertility control in dogs and cats:
of development. After some false starts and decades � Spay/neuter clinics and organizations sponsoring
of research, several commercially viable products for programs such as Trap-Neuter-Return (TNR) would
specific applications in contraception and fertility control like something inexpensive, easy to administer, 100%
in animals have been approved in certain markets (e.g., effective, and permanent or long lasting for feral and
Suprelorin® from Peptech/Virbac, Esterilsol®/Zeuterin™ adoptable animals. It should be possible to distinguish
from Ark Sciences – see Chapters 3 and 4). Because no treated animals from untreated animals.
single technology developed to date is suitable for cats � Companion animal veterinarians may value a treatment
and dogs and all segments of the market, researchers that brings pet owners back to the practice on a regular
are continuing to refine long-standing approaches and basis, and seek a treatment that is dependable, safe,
9
See Chapter 4, section 4.3.3.2, regarding the Michelson Prize
& Grants for information about a major effort to discover
and develop a commercially viable approach to permanent
sterilization that is effective in male and female dogs and cats.

profitable, simple and fast, and provides the presumed market research, targeting, prelaunch programs,
long-term health benefits associated with surgical and public relations will add to marketing costs
spaying and neutering. See Chapter 3, section 3.1.1 for and complexity.
a discussion of pros and cons of gonadectomy in dogs
Companies interested in pursuing opportunities for
and cats. It is interesting to note that in a 2007 survey
contraception or fertility control in animals will want to
of small animal veterinarians, 21% indicated that there
have a thorough understanding of market size and market
is a great need for a non-surgical alternative and 45%
characteristics. Knowledge about stakeholder interactions
indicated there is no need; 51% of shelter veterinarians
and factors that drive the price/value relationship for
surveyed in 2008 indicated there is a great need and 16%
each end-user segment under consideration will also
indicated they felt there is no need (see section 5.6 for
be important. Companies will need to consider which
more information on these surveys).
approach best fits where a given company is, where it
� Some pet owners may prefer a permanent solution, and
wants to be, and how it wants to get there. Deciding which
others object to the permanence of sterilization or may
technology to embrace and how to define and approach
wish to breed their animals someday and therefore
such a complicated marketplace can be a “balancing act”
would like an approach that “wears off.”
– weighing company culture, strategic direction, internal
� For many pet owners, suppression of sexual behavior is
resources, existing customer base, and product portfolio to
important – they don’t want their female dogs and cats
determine the most commercially and strategically viable
coming into estrus, and owners of male dogs want to
approach. In order to help optimize the potential of any
reduce marking, mounting and aggression. See Figure
opportunity, an analysis should be undertaken as a part of
5-2 and Tables 5-20 and 5-22 for reasons pet owners
the long-range planning process, ideally before initiating
do and do not have their dogs and/or cats spayed or
product development or forming alliances, but certainly
neutered.
before final decisions regarding product attributes are
� Breeders (i.e., reputable breeders) and owners of
made.
show animals need the flexibility of reliable fertility
control and reduced sexual behavior when an animal In summary: The attributes of a given product are a
is participating in a show or event, but want normal combination of the inherent characteristics of the science
fertility when their animals are scheduled for breeding, and technology behind that product; the needs, plans and
or have retired from competition, to produce future competencies of the organization involved in marketing
champions it; and the needs and economics of the mix of groups
that influence the dynamics of the particular market
There are many potential customer segments and
segment. There’s nothing unusual about that in and of
stakeholders – even within a given group there are
itself – but in a market as diverse as contraception and
different needs, and there are societal factors too.
fertility control in cats and dogs, each segment brings its
Just as there is a range of technologies at different stages, own set of challenges, and, in addition to the typical costs
there is a range of stakeholders, i.e., groups with an interest related to product launches, first-in-market companies
in contraception and fertility control in dogs and cats, can be expected to bear the market-definition, education,
including animal health companies; biotechnology and life and public relations costs inherent in bringing “pioneer”
sciences companies; nonprofit and governmental agencies products to market. This is further complicated by the
that sterilize animals for adoption or offer community complex mix of politics and advocacy associated with pet
sterilization services; veterinary schools and research population control and regulations aimed at dog and cat
institutions; veterinarians; pet owners; show animal sterilization.
owners; breeders; regulatory agencies; and animal welfare
and animal rights groups with a variety of philosophies –
not to mention the animals themselves.
Since stakeholder characteristics, beliefs, needs,
and wants vary among and within customer
and key influencer groups, the need for extensive

Potential customer segments have different used in shelter and spay/neuter settings once the products
expectations. they’ve help create are approved for commercial use in
much the way donors subsidize the cost of surgical spay
Technical characteristics, advantages, and disadvantages
and neuter now. Shelter and spay/neuter groups might
of approaches to non-surgical contraception and fertility
unite in buying groups that could bring volume business
control in dogs and cats vary from species to species (see
to companies that have products to sell. Joint ventures,
Chapter 3) and, as noted above, the profile of an “ideal”
partnerships, or businesses such as low-profit Limited
product differs among end-user segments (i.e., customer
Liability Companies (L3Cs) could be formed to take on
groups). There are also considerations that don’t relate
different aspects of the development, commercialization,
strictly to product attributes.
and marketing process – approaches that are already in use
For example, a contraceptive technology that produces in the human health arena.
permanent sterilization in male dogs will be effective for
Of course the opportunities for realignment and alliances
a pet dog as well as a stray dog. Some of the needs of the
will depend on who brings what products to market and in
nonprofit or governmental agencies that sterilize animals
what order, but these types of models will have to evolve
for adoption or offer community sterilization services
if important but traditionally nonprofit segments, such
are different than those of a veterinarian with only a
as “unowned” and feral cats and dogs, are to be served
percentage of clients who want permanent sterilization
meaningfully.
for their male dogs – the shelter needs to desex animals
quickly and economically before adoption or release; the 5.2 “Owned” Dogs and Cats
veterinarian needs a certain margin to cover overhead and The most obvious market to target is pet owners caring
make a profit. Consequently, cost is an issue that could for one or more cat or dog and willing and able to pay for
serve as a basis for realignment among stakeholders for treatment. This section reviews information on several
mutual benefit. world markets to provide a feel for the size of the owned
For instance, organizations that have helped fund pet market and trends in purchase of products and use of
research by academic institutions could reallocate some of veterinary services.
their resources to underwriting the costs of the products

5.2.1 Population and Spending Estimates
5.2.1.1 North America
5.2.1.1.1 United States
Sources vary slightly regarding the number of pet dogs and cats in the United States (US).
Table 5-1: Overview of US Pet Dog Population
APPA PFI AVMA Estimate or Average US Human Population Dogs/ Person

(if multiple)
In millions
1990 52.7 52.7 248.7 0.2119
1996 54.6 55.7 55.15
2000 68.0 68 281.4 0.2416
2001 61.6 61.6
2003 61.5 61.5
2004 73.8 73.8
2005
2006 74.8 72.1 73.45 298.6 0.2456
2007
2008 77.5 77.5 304.4 0.2546
2009
2010 65.5 65.5 308.7 0.2154
2011 78.2 65.9 69.9 71.3 310.5 0.2296
The growth in the population of dogs has roughly followed the growth in human population but as noted above,
statistics suggest that the rate of pet-keeping may have peaked in 2008 and declined a bit since that time.
Table 5-2: Overview of US Pet Cat Population
APPA PFI AVMA Estimate or Average US Human Population Cats/ Person

(if multiple)
(In millions)
1990 60.8 60.8 248.7 0.2444
1996 66.1 67.9 67.0
2000 72.9 72.9 281.4 0.2591
2001 70.8 70.8
2002 77.7 77.7
2003 78.35 78.35
2004 90.5 90.5
2005
2006 88.3 81.7 85.0 298.6 0.2847
2007
2008 93.6 93.6 304.4 0.3075
2009
2010 78.4 78.4 308.7 0.2540
2011 86.4 79.1 74.4 80.0 310.5 0.2576

Sources (Tables 5-1 and 5-2): Pet Food Institute (PFI) population between 2007 and 2011. This may have been a
website lists recent source of data as Euromonitor function of both economic factors during the recession, as
International. Earlier resources were Ipsos-NPD (2001);
American Pet Products Association (APPA) Executive well as changes in the US population demographics.
Summary, 2009; en.wikipedia.org/wiki/Demograph-
ics_of_the_United_States; 2011 US population US � Pet cats can be separated into two groups: cats that are
Census Bureau estimate (census.gov/population/ strictly indoor cats (~50%) and cats that are outside
www/popclockus.html); American Veterinary Medical at least part of the time (50%) (Rowan, personal
Association (AVMA) statistics (AVMA.org) communication 2012).
The growth in the population of cats has roughly

� In 2011, 62% of households had at least one cat or dog,
outnumbering households without a cat or dog (APPA
followed the growth in human population. However,
2011).
recent statistics suggest that the rate of pet-keeping may
have peaked in 2008 and declined a bit since that time. The APPA provides the following additional relevant
The most recent American Veterinary Medical Association statistics for 2011:
(AVMA) survey indicates a decline in the US dog and cat
Table 5-3: Miscellaneous Statistics
Dogs Cats
� 39% of US households own at least one dog � 33% of US households own at least one cat
� 60% of owners own one dog � 52% of owners own more than one cat
� 28% of owners own two dogs � On average, owners have two cats (2.2)
� 12% of owners own three or more dogs � More female than male cats are owned (80% vs. 65%)
� 21% of owned dogs were adopted from an � 21% of owned cats were adopted from an animal shelter
animal shelter
� On average, dogs owners spend $248 on � On average, cat owners spend $219 on veterinary visits per
veterinary visits per year year
� 78% of owned dogs are spayed or neutered � 88% of owned cats are spayed or neutered

Historically the trend in dog and cat population tends cats declined 6.2%, although cats still outnumber
to follow the increase in the total number of households. dogs as pets.
Household life stage is an important determinant of pet
“ownership.” Almost 80% of families with children aged “Changes in the total number of dogs and cats
5-17 have pet dogs or cats while only about 40% of single owned as pets are even more dramatic. There were
person households have dogs and cats (Rowan 2008). 69.9 million pet dogs at the end of 2011, a decrease
of 3% from 72.1 million in 2006, and 74.4 million
According to data from the AVMA US Pet Ownership and
pet cats in 2011, a decrease of 9.4% from 81.7 mil-
Demographics Sourcebook (2012) (veterinarynews.dvm360.
lion in 2006. The decline in the total number of pet
com/dvm/article/articleDetail.jsp?id=784088):
dogs and cats in the US from 2006 to 2011 is 6.4%.”
“The percentage of pet-owning households de-
These figures differ from the 2011 APPA figures presented
clined 2.4 percent over the last five years, accord-
in Table 5-4, which may be due to survey population
ing to a study of 50,000 pet owners conducted
demographics, methodology, and/or timing.
by the American Veterinary Medical Association
(AVMA). The percentage of households owning An analysis of data from several surveys provided the
dogs decreased 1.9%, while households owning following information regarding sources of pet dogs and
cats several years ago (Rowan 2008):
Table 5-4: Sources of Pet Dogs and Cats
Source Dogs (%) Cats (%)

Family/friend/neighbor, etc. 35% 28%
Stray 8% 28%
Offspring of own animal 9% 15%
Shelter/rescue/adoption 12% 12%
Pet store/newspaper 9% 3%
Breeder 17% 1.5%
Internet 0.5% 0%
Other (e.g., gift, veterinarian) 9.5% 12.5%
This source (Rowan 2008) indicated data such as these “adopt” their owners spontaneously (e.g., they wander in
should be used as a guide only. Generally it is reported that off the street and stay), and that breeders and pet stores are
somewhere around 15+ percent of animals are adopted a more important source for dogs than for cats.
from shelters or rescue centers, that a large number of cats

A survey commissioned by PetSmart Charities® (2009)
found that owners acquired their dogs and cats from the
following sources:
Figure 5-1: Sources of Pet Dogs and Cats in the US by
Percentage
Although figures tend to vary somewhat from source to

source, Pet Product News reports that in 2011, US pet owners
spent an estimated $51 billion on their animals, broken
Source: PetSmart Charities 2009
down as shown below (petproductnews.com):
Table 5-5: Pet Owner Expenditures
Category 2010 Actual 2011 Actual % Growth, 2010-2011 2012 Estimate % Estimated
Growth,
($ billions) ($ billions) ($ billions) 2011-2012
Food 18.76 19.85 5.8 20.46 3.1
Supplies/OTC 10.94 11.77 7.6 12.56 6.7
medications
Veterinary care 13.01 13.41 2.9 13.59 1.3
Live animal 2.13 2.14 0.5 2.15 0.5
purchases
Other services 3.51 3.79 7.9 4.11 8.4
Total 48.35 50.96 5.3 52.87 3.8

Source: americanpetproducts.org/press_industrytrends.asp

5.2.1.1.2 Canada Table 5-8: Annual Estimated Cost of Care (CA$)
At the 2006 Banff Summit for Urban Animal Strategies
Category Cats Dogs
(BSUAS), delegates indicated that a lack of reliable
Canadian statistics was hampering municipal leaders and Veterinary care $287-294 $360-451
legislators in their effort to develop urban animal strategies Kitty litter $91-100 -
(Perrin 2009). As a result, a national survey on urban Food $306-372 $510-514
animals was conducted in late 2008. The survey provided Collars, leashes, toys, $36-53 $36-53
the following information: miscellaneous supplies
Table 5-6: Overview of Dog and Cat Ownership in Canada Pet insurance $270-360 $408-455
Cats Dogs Licensing - $25-39

35.5% of Canadian house- 32.3% of Canadian house-
holds included a cat holds included a dog
• 4,820,085 households • 4,384,978 households 5.2.1.2 Outside of North America
• 1.76 cats/household • 1.38 dogs/household

5.2.1.2.1 Europe
• 8,510,021 cats in Canada • 6,070,783 dogs in
There are 84.7 million cats and 73.6 million dogs living
Canada
in European households; 64.4 million cats and 60.2 million
dogs are living in the European Union (EU) countries
Table 5-7: Age Breakdown of Canadian Dogs (FEDIAF Facts & Figures 2010).
Dogs � Estimated number of European households owning at

least one pet:
Average age 5.9 years
o 70 million (excluding Russia)
< 1 year 7%
� Estimated percentage of European households owning at
1-3 years 29% least one cat or one dog:
4-7 years 30% o EU
8-10 years 11%  Cats: 24%
 Dogs: 27%
10+ years 22%
o Europe
A total of 50% of cats and 22% of dogs had not been to  Cats: 25%
a veterinarian in the past 12 months. Of those that did  Dogs: 26%
receive veterinary care, 34% of all cats and dogs went only � In the United Kingdom (UK), the pet population in 2009
once during the 12-month period; 13% of cats and 34% of was 8 million dogs and 8 million cats. Approximately
dogs were seen 2-3 times. Seventy-nine percent of cats and 6 million households owned at least one dog and 5.2
69% of dogs were spayed or neutered. A total of 66% of million households owned one or more cats.
respondents acknowledged that spaying or neutering was
recommended by their veterinarian, was good value for
the money spent, and was done with the best interest of the
pet in mind. Sixteen percent of owners of “mostly indoor
pets” believed that sterilization was not necessary for their
animals.

Table 5-9: Top 10 European Countries: Dog and Cat Populations 2010
Country Dog Popu- % of Households Cat Population % of Households Owning at

(alphabetical lation Owning at Least One Dog Least One Cat
order)
Czech Republic 3,152,000 43% 1,750,000 22%
France 7,595,000 23% 10,965,000 26%
Germany 5,300,000 13% 8,200,000 16%
Italy 7,000,000 21% 7,400,000 19%
Netherlands 1,493,000 19% 2,877,000 26%
Poland 7,311.000 38% 5.550,000 30%
Romania 4,166,000 43% 3,891,000 42%
Russia 12,520,000 20% 18,000,000 33%
Spain 4,720,000 27% 3,385,000 21%
United Kingdom 8,000,000 22% 8,000,000 18%
Source: FEDIAF Facts & Figures 2010

female respondents. Dog ownership significantly decreased
5.2.1.2.1.1 United Kingdom the likelihood of cat ownership, and respondents aged
65 years or more were less likely to report that their
Dog ownership has been declining, while cat ownership
household owned a cat than younger respondents.
is increasing. Surveys conducted between 2008 and 2010
Households with one or more dogs and children aged 11-15
indicate that 46% of households in the UK own either a dog
years were more likely to own a cat than other households.
or cat or both (pfma.org.uk/statistics). Among dog-owning
The likelihood of dog ownership increased as household
households, 78.5% have one dog; the rest have two or
size increased. Dogs were more likely to be owned by rural
more. Among cat-owning households, 62.2% have a single
households, and less likely to be owned by households
cat and the rest have two or more. More people between
with cats or children aged 10 years or younger. Female
ages 35 and 44 are cat owners while more people between
respondents and those aged 55 or less were more likely to
45 and 54 are dog owners. The bulk of owned dogs are
report dog ownership than other respondents (Murray et
medium (26%) and large (43.6%) sized. Small dogs (20.8%),
al. 2010).
toy dogs (5.7%), and giant dogs (3.8%) round out the
population. Dog ownership is higher in urban locations.
5.2.1.2.1.2 France
Approximately 59% of pet dogs are purebreds.
There is at least one pet cat or dog in more than 50% of
A paper summarizing the results of a random sample
households. Forty-one percent of dogs and 37% of cats
of 2,980 UK households indicated that in 2006, 26% and
live in rural households; 30% of dogs and 28% of cats live
31% of households owned cats and dogs, respectively. The
in cities and towns with fewer than 100,000 residents;
actual populations extrapolated from the data collected
and 29% of dogs and 35% of cats live in cities of 100,000+
showed a virtually equal number of owned cats (9.34
people. About 53% of families that own companion
million) and dogs (9.62 million) in the survey timeframe.
animals have one dog or cat; 45% have a dog and a cat.
Notably these earlier data are higher than the 2010
The majority of people who own a dog and/or cat say they
estimates of 8 million each of dogs and cats in the UK.
acquired the animal(s) because they love animals, like the
Households with outdoor space were more likely to own
company, and/or want the pets for their children (FEDIAF
cats and dogs than households without outdoor space
Facts & Figures 2010, Reichler 2008).
(i.e., “garden”). Households that were classified as more
educated were more likely to own cats and less likely to 5.2.1.2.1.3 Germany
own dogs than other households. Cats were more likely to
The number of dogs is declining while the number
be owned by semi-urban and rural households and by
of cats is increasing. There is at least one dog in
approximately 13% of German households, and 16% of
German households have one or more cats (FEDIAF Facts
and Figures 2010, Reichler 2008). Dog and cat owners in

Germany spent $2.7 billion on pet food in 2009 (FEDIAF the US was reported to be just over $50 billion in 2011, and
Facts and Figures 2010). FEDIA Facts and Figures 2010 is $1 billion-to-$2 billion in China, the US is a far more pet-
available at: www.fediaf.org/fileadmin/user_upload/ oriented culture, as evidenced by the per capita pet-related
facts_and_figures_2010.pdf. spending (Rowan, personal communication 2012).
It is also interesting to understand what those numbers
5.2.1.3 Cat and Dog Populations vis-a-vis Human
mean in terms of the human population. Given that some
Populations: Europe and US
people have more than one cat or dog, these numbers are
One way to look at the value of pets in a given society is indicators, not precise measures of animals/person or
to look at pet spending per the total human population, i.e., people/animal (FEDIAF Facts and Figures 2010); however
per capita. For example, spending on pets is about $100/ they do indicate the place a pet dog and cat holds in a
person/year in the US; $20/person/year in Brazil, which is given culture (Rowan, personal communication 2012).
rapidly growing into a pet culture; and about $1/person/
year in China. So although the total spending on pets in
Table 5-10: Dogs/Person and People/Dog and Cats/Person and People/Cat in the Top 10 European Countries and the US
Country Humans Dogs Dogs/Person People/Dog
Russia 142,905,208 12,520,000 0.0876 11.4
United Kingdom 62,041,708 8,000,000 0.1289 7.8
France 63,460,000 7,595,000 0.1197 8.4
Poland 38,192,000 7,311,000 0.1914 5.2
Italy 60,418,711 7,000,000 0.1159 8.6
Germany 81,757,600 5,300,000 0.0648 15.4
Spain 47,150,800 4,720,000 0.1001 10.0
Romania 19,042,936 4,166,000 0.2188 4.6
Czech Republic 10,535,811 3,152,000 0.2992 3.3
Hungary 9,979,000 2,856,000 0.2862 3.5
Humans Cats Cats/Person People/Cat

Russia 142,905,208 18,000,000 0.1260 7.9
France 63,460,000 10,965,000 0.1728 5.8
Germany 81,757,600 8,200,000 0.1003 10.0
United Kingdom 62,041,708 8,000,000 0.1289 7.8
Italy 60,418,711 7,400,000 0.1225 8.2
Poland 38,192,000 5,550,000 0.1453 6.9
Romania 19,042,936 3,891,000 0.2043 4.9
Spain 47,150,800 3,385,000 0.0718 13.9
Netherlands 16,696,700 2,877,000 0.1723 5.8
Hungary 9,979,000 2,240,000 0.2245 4.5
United States Humans Dogs Dogs/Person People/Dog

308,745,538 78,200,000 0.253283 3.9
United States Humans Cats Cats/Person People/Cat
308,745,538 86,400,000 0.279842 3.6
Source: FEDIAF Facts and Figures 2010, APPA 2011

5.2.1.4 Other Areas Table 5-11. Overview of Consumer Expenditure on Pets in
5.2.1.4.1 Australia Australia in 2009
According to 2009 figures, there are 3.4 million pet dogs Category AU$ million % of total
and 2.35 million pet cats in Australia. Pet population
Veterinary services $2,219 36.9%
numbers in Australia fluctuated during the 15 years prior
Pet food $1,826 30.3%
to the 2009 assessment, with a moderate decline in dogs
numbers noted since 1998, when the dog population was Pet care services $1,041 17.3%
estimated at 4 million. Cat numbers rose in 2009 following Pet purchases $616 10.2%
a 23% decline in cat numbers from 1994 to 2007. In 2009, Pet care products $319 5.3%
consumers spent AU$6.02 billion on pets, pet care products, Total $6,021
and services. Spending on dogs accounted for almost Source: acac.org.au
60% ($3.6 billion); cats accounted for 24% ($1.4 billion).
Veterinary services represented the largest segment at 5.2.1.4.2 Asia (Japan and China)
$2.22 billion. Pet food was the second largest section, with 5.2.1.4.2.1 Japan
consumer expenditures totaling $1.83 billion. The market The Japanese pet market has become a trillion-yen
appears to be transitioning to premium pet foods, which (US$12.7 billion at September 2012 conversion rate) industry;
is believed to be the result of pet owners prioritizing the in fact, there are now more pet dogs and cats in Japan than
health and well-being of their pets. There are pet dogs children under the age of 15 (Japan Pet Food Association).
in 6 million households (23%) and pet cats in 5.2 million Pets are becoming valuable members of the family, a
households (20%) (Australian Companion Animal Pet phenomenon unheard of 30 or 40 years ago.
Population Trends, 2009 at acac.org.au/pdf/ACAC%20 Today, there are about 13.1 million pet dogs in Japan,
Report%200810_sm.pdf). compared to 6.6 million in 2006 and 3.7 million in 1989.
In Tokyo, 410,000 dogs were registered in 2005, 1.6 times
higher than in 1995. Shukan Economist traces the origin of the
pet boom to the 1980s when the Japanese economy began
to grow and Golden Retrievers become status symbols. A
subsequent economic downturn caused the pet boom to
subside. A 2000 TV commercial featuring a Chihuahua is
believed to have reignited the pet boom, which continues,
particularly for small dogs. There are pet spas, gyms,
nursing care, hotels, insurance, funerals, and clothing and
accessories. Dog parks apparently serve as places for pet
owners to meet one another, and koen debut is a term used
In 2009, Australian pet owners contributed AU$3.6 to describe the first visit for a dog owner and pet to a new
billion to the country’s economy. Australians spent a yearly dog park – dog owners even have business cards printed
up with pictures of their dogs (factsanddetails.com/japan.
average of AU$135 per pet dog and AU$33 per pet cat
php?itemid=795&catid=21...145).
(acac.org.au). Overall, consumer expenditures on pets in
Australia in 2009 can be broken down as follows: In a survey conducted by a pet food company in 2004,
Japanese dog owners provided the following reasons for
having pet dogs (multiple responses permitted):
Table 5-12: Reasons Japanese Dog Owners Have Dogs (2004)

Reason % of Owners Citing
They like dogs 66.3%
Dogs are fun to be around 65.6%
Dogs are affordable 50.4%
Dogs enrich daily life 50.4%
Dogs contribute to family life (“are indispensable for family 42.1%
communication”)
Dogs guard the home 28.7%
Source: factsanddetails.com/japan.php?itemid=795&catid=21...145

Information for the year 2009 indicates that the total owners have sprung up in cities, and there is at least one
value of the “pet market” was 1.2 trillion yen, which dog park in Shanghai (factsanddetails.com/china.php?item
includes companion animals, fish, birds, and reptiles. id=266&catid=12&subcatid=81).
One-third of that amount is spent on pet food – food for In recent years the image of dogs has improved as the
dogs comprises 53% of the market, cats 40%, and other Chinese middle class grows. In 2011, the Beijing-based
pets 7%. Pet-related expenses per household averaged magazine Dog Fans estimated that the pet dog population
18,323 yen (US$233 at September 2012 conversion rate). In was growing at about 30% per year; French Poodles and
single-person households, women spent more than men Rottweilers are among the popular breeds. In an October
on their pets, with women 35-39 spending the most money 24, 2010 New York Times article, writer Michael Wines
on their pets. Small-breed dogs are the most popular, with notes that “people used to be focused on improving
nearly 70% weighing less than 10kg (22 lbs); 73% of these their own lives, and they weren’t really acquainted with
dogs are indoor dogs. The residential housing market raising dogs. But with the improvement in the economy,
appears to be keeping up with the trend – in 1999 only 3% people’s outlooks have changed. There’s a lot of stress
of condominiums allowed pets, a figure that had increased in people’s lives and having a dog is a way to relieve
to 75% in 2005. The rental housing market, however, is still it.” Another factor may also be at work in the increasing
not a pet-friendly market and this may account at least in popularity of pet dogs: “Many owners also say China’s
part for the popularity of “cat cafes,” where people can go one-child policy has fanned enthusiasm for dog ownership
to visit with cats for a fee of about 100 yen/hour. These as a way to provide companionship to only children in
establishments typically serve drinks or coffee, and offer young households and to fill empty nests in homes whose
Internet access and other amenities (factsanddetails.com/ children have grown up. As the younger generation waits
japan.php?itemid=795&catid=21&subcatid=145). longer to marry and put careers ahead of having children,
parents of only children are increasingly lavishing attention
5.2.1.4.2.2 China
on furry companions as a stand-in for the grandchildren
In 2008, the New York Times reported “Keeping pets has they do not have” (nytimes.com/2010/10/25/world/
become all the rage among the affluent in China, even asia/25dogs.html?pagewanted=all).
though some Chinese still consume dog and cat meat.”
Euromonitor International, a market intelligence firm, 5.2.1.4.3 Latin America
forecast spending on pet food and pet care in China at an The Brazilian market is leading the development of the
estimated $870 million in 2008, up about 15% from the pet food and pet care products markets in Latin America.
$757 million spent in 2007. Note that a large percentage of It appears that, as in other geographic areas, the expansion
that figure is related to pet birds, fish, and reptiles (Cheney of the middle class is one of the major drivers. During the
2008). period 2005-2010, sales of pet food and pet care products
Estimates of the number of pet dogs and cats in China rose from $4.8 billion to $8.3 billion (Euromonitor). This
can vary greatly, so greatly, in fact that it is difficult to represents a compound annual growth rate (CAGR) of
even settle on a range for this report. The New York Times 11.9%. As a result, the Latin American market proportion
article cited above noted that China estimates it has 150 of global pet care sales rose from 7.6% in 2005 to 10.2% in
million pet dogs (2008). Statistics are scant because many 2010. Brazil is by far the largest market in the region, with
pets are unregistered. Euromonitor puts the figure at 26.8 pet care sales valued at $5.2 billion in 2010, followed by
million, and says China has 10.7 million pet cats. Mexico ($1 billion) and Argentina ($645 million). In 2010
In Beijing, where about 900,000 dogs were reported to
be registered as of 2010, dog owners are not allowed to
have dogs taller than 36 centimeters (just over 14 inches)
out of concern that large dogs might frighten people;
according to one source, this has led to an overpopulation
of Pekinese, Pomeranians, and Chihuahuas. In Shanghai,
home to an estimated 60,000 pet dogs in the early part of
the 2000s, officials estimate the city was home to 740,000
pet dogs in 2011. Officials have proposed a one-dog policy
and mandatory registration of dogs. Owners would also
be required to sterilize their dogs. Stores catering to dog

there were 155 million pets in Argentina, Brazil, Chile, is what is known about the actual impact of removing an
Colombia, Mexico, and Venezuela combined, compared animal’s sources of reproductive hormones. We have a fair
with 116 million in 1999 (Euromonitor). Chilean households idea of what they provide relative to reproduction, with
were expected to overtake pet-owning households in several yet unidentified shared functions of hormones
Argentina and Brazil in terms of spending on dog and cat for an animal’s well-being (Root Kustritz, personal
food. It is estimated that there are 30 million dogs and 12.5 communication).
million pet cats in Chile. There is speculation that the dog There is an ever-growing body of literature regarding
figure includes unowned dogs. the benefits and risks of spay/neuter (see summary below)
and the optimal age for gonadectomy, but the overall
5.2.2 Dynamics of the Spay/Neuter Decision conclusion appears to be that there is no single answer. As
non-surgical alternatives are available it is important to be
One of the first questions that comes to mind when
able to compare them objectively to surgical methods of
spay/neuter versus non-surgical sterilization is considered
sterilization.
5.2.2.1 Summary of Pros and Cons of Spay or Castration in Dogs and Cats
Pros Cons
dog Decreased incidence of mammary neoplasia Increased incidence of urinary incontinence
(depending on timing of gonadectomy) Increased incidence of hematologic, bone, and bladder
Decreased incidence of reproductive tract tumors
(ovarian/uterine) disease Increased disposition to knee injury
Decreased incidence of reproductive behaviors Obesity
Eliminates the risk of difficult birth (dystocia) Possible breed-related decreased lifespan
Male dog Completely effective sterilant Surgical complications
Decreased incidence of reproductive tract Increased incidence of hematologic, bone, and prostate
(testicular and prostatic) disease (except tumors
prostate tumors) Increased predisposition to knee injury
Decreased incidence of reproductive behaviors Obesity
Possible increased lifespan
cat Decreased incidence of mammary neoplasia Obesity
(depending on timing of gonadectomy) Possible increase in diabetes mellitus
Decreased incidence of reproductive tract
(ovarian/uterine) disease
Decreased incidence of reproductive behaviors
Eliminates the risk of difficult birth (dystocia)
Source: Derived from Root Kustriz 2007 and personal communication 2012, Reichler 2009, and Rhodes, personal communication 2012).
Note that this table also appears in Chapter 3, along with supporting documentation.

Marketers will need to realize that perceptions of pet and perhaps efforts to escape outdoors in order to mate.
owners may not reflect what is actually known about non- The impact of sterilization on canine behavior is less clear,
reproductive effects of spay/neuter surgery. and may be breed dependent. Sterilized males will be less
For example, pet owners may have expectations that likely to fight other male dogs when estrous females are
spaying and neutering will change the behavior of their present, and will likely roam less in search of females in
pets. In some cases, that change would be desirable; in estrus. No clear relationship has been established between
others, there is concern that the animal’s personality will aggression towards people and canine neuter status.
change from the personality the pet owner knows and
5.2.2.2 What Drives Owners’ Decisions and What Are
loves.
Some Statistics?
Historically, the animal welfare and veterinary
Information regarding what factors encourage and
communities have promoted positive behavioral changes
discourage pet owners from having their pets spayed or
as a benefit of spaying or neutering dogs and cats; however,
neutered is useful to entities developing or considering
there is a fairly small body of research literature addressing
developing non-surgical approaches – which factors
this assumption.
might be ameliorated by non-surgical alternatives and
In reality, the only behavioral change for which there which might not. Information about spay/neuter rates,
are data following surgical castration of dogs indicate costs, and programs are likely to affect development,
that castration is associated with decreases in indoor commercialization, and marketing decisions.
urine marking, roaming, sexual mounting, and dog-to-
dog aggression around females in estrus; however, it 5.2.2.2.1 In the United States
does not always decrease these behaviors. Studies report A 2011 survey of pet owners in the United States (US)
inconsistent findings on how castration status may by American Pet Products (americanpetproducts.org/)
correlate to aggressive behavior towards humans. estimates that 22% of owned dogs and 12% of owned cats
A study of more than 6,000 dogs suggested “that spayed have not been spayed or neutered.
female dogs tend to be more aggressive towards their Studies show that many are unclear on the appropriate
owners and to strangers than intact females, but that the age for sterilization. In one survey, 17% of the people
effects of spaying on behavior appear to be highly breed- contacted regarding the appropriate age to spay or neuter
specific.” Results of the study indicated that, contrary to did not know. In that survey, 29% of the people contacted
popular belief, there is little evidence that castration is an believed it was not appropriate to spay a female before the
effective treatment for aggressive behavior in male dogs, first estrus and 8% felt it was necessary to wait until the
and [castration] actually may exacerbate other behavioral animal had produced at least one litter (PetSmart Charities,
problems”( Hsu and Serpell 2003, cited by Duffy 2006). 2009).
Spayed female dogs and cats will not exhibit estrous Using the percentages of intact pet dogs and cats
behavior or vaginal discharge and bleeding, and it seems (22% and 12% respectively) and the overall pet dog and
to be widely accepted that male cats will be less likely cat population figures (78.2 million and 86.4 million
to roam, urine spray, vocalize, and fight when they are respectively) from the 2011-2012 APPA National Pet
sterilized. One study (Finkler and Terkel 2010) concluded Owners Survey (americanpetproducts.org/press_
that the 36 neutered females living in a managed Trap- industrytrends.asp), we can calculate the number of intact
Neuter-Release (TNR) and feeding program had lower pet dogs at 17.2 million and the number of intact pet cats
levels of aggression and cortisol compared to a control at 10.4 million – significant numbers in the eyes of any
group of 15 intact females. Researchers note that this study business development or marketing manager.
makes it “possible to suggest for the first time a possible
While there is certainly room to convert pet owners
relationship between cortisol levels and aggression in free-
currently choosing surgery to non-surgical methods, these
roaming female domestic cats” and that therefore it may
same managers will wonder why these animals haven’t
be “possible that TNR has an added beneficial role in cat
been spayed or neutered, and what the chances are that
welfare in addition to that of control of population size.”
alternatives to surgery would encourage their owners to
In summary, credible studies indicate that neutering embrace contraception and fertility control for their pets.
reduces urine spraying and roaming in search of mates
Two surveys help provide insight into why dog and cat
by male cats, and spaying eliminates estrous-associated
owners in the US have not spayed or neutered their
behaviors in female cats, including aggression, vocalization

animals: a 2009 study commissioned by PetSmart Charities, as noted above; and a 2000 study commissioned by Ralston
Purina®.
The 2009 PetSmart Charities study indicated the following reasons pet owners haven’t spayed or neutered their dogs
and cats. Responses were not broken out on a per species basis. Figures represent the percentages of respondents choosing
a given reason; multiple answers from a given respondent are included.
Figure 5-2: Summary of Reasons Pet Owners Have Not Spayed or Neutered Their Dogs and Cats in the US (%)
In a 2000 State of the American Pet study sponsored by Ralston Purina, dog and cat owners who had not had their pets
spayed or neutered were asked why. Although respondents were allowed to provide more than one reason, figures
represent what percentage of the time a given answer was provided compared to all answers.
Table 5-13: Summary of Reasons Pet Owners Have Not Spayed or Neutered Their Dogs and Cats in the US
(2000 Ralston Purina Study)
Justification for Inaction Dog Owners Cat Owners Dog/Cat Owners as a Single Group
Just haven’t had it done yet 30% 27% 29%

Want to breed the animal(s) someday 21% 5% 16%
Animal(s) too young 13% 20% 15%
Procedure is cruel 5% 5% 5%
Can’t afford 5% 18% 9%
Not “natural” 3% 7% 4%
Other 16% 12% 15%
Not sure 6% 9% 7%
Totals 99% 103% 100%

The table below provides the authors’ subjective input regarding whether or not owners falling into a given group
might or might not embrace non-surgical approaches as an alternative to spay or neuter surgery.
Table 5-14: Potential Acceptance of a Non-Surgical Alternative to Spay/Neuter
Justification for
Would They Accept a Non-Surgical Alternative?
Inaction
Just haven’t had it Depends on the real reason(s). These owners might:
done yet
� view spaying or neutering as too inconvenient and time consuming
� dislike the idea of major surgery even though they don’t consider it cruel
� believe that their animals should produce one litter before they’re sterilized
The availability of effective, safe alternatives to surgical spaying and neutering can be expected
to appeal to pet owners who are uncomfortable with surgery or believe it’s too inconvenient or
cruel, but such products will not counter the “one litter” myth. Once products are available, com-
panies, veterinarians, and advocacy groups that want to target the “one litter” consumer group
will collaborate to educate owners who are holding off until their pets have a litter – according
to one source, such litters are the source of an estimated 400,000 relinquished puppies in the US
each year, which account for 10% of the dogs that enter the shelter system (naiaonline.org). This
is likely an even bigger issue with cats.
Want to breed the Yes. Dogs and cats whose owners wish to breed them eventually are good candidates for non-
animal(s) someday permanent (aka “reversible”) contraceptive products that eliminate undesirable mating-related
behavior but permit a return to fertility and normal mating behavior at some time in the future.
Such an approach can be expected to appeal to owners of show dogs, who understandably do not
want to have to handle sexually related behaviors during competitions.
To be commercially viable, such products will have to cause no harmful effects in either males or
females but particularly on the treated female and on subsequent litters. Issues related to use of a
given product on a pregnant animal will have to be addressed, including:
� how the pregnancy would be affected

� how to manage the pregnancy
� how to address this issue in conjunction with pregnancy testing and/or ultrasound.
Animal(s) too young Yes. However, for companies that will be marketing products shown to be safe for use in young
dogs and cats, the marketing challenge will be fourfold:
� teaching owners that animals younger than 6 months of age can be treated without ill effects
� educating owners about the benefits of non-surgical approaches
� demonstrating that the long-term health benefits of surgical sterilization also apply to non-
surgical approaches (if they do)
� gaining the confidence of veterinarians who have not begun to alter dogs and cats younger
than ~6 months of age.
Procedure is cruel Maybe, if the pet owner views the surgical procedure, rather than the outcome, negatively.

Can’t afford Maybe. This will depend in part upon the pricing of non-surgical alternatives relative to surgery.
Maybe, especially if the reluctance reflects a combination of affordability and concerns about
surgery, rather than a reluctance to spend money on the pet. Some pet owners, for whom the
charge for a spay or neuter in a veterinarian’s office would be too high, may be concerned about
the quality of procedures done in clinics or shelters.
In fact, there is a wide range of spay/neuter options and pricing available for pet owners from
free or low-cost clinics and shelters to private veterinarians. When the cost of surgery is divided
by the average life span of a pet dog or cat, the annualized expense is negligible.
Pet owners who don’t spay or neuter their animals due to expense may not have thought about
the potential costs of that decision – for example, the costs of: repairing property damage caused
when a male dog digs his way out of the yard to pursue a female in estrus; injuries to or from a
competing male dog, necessitating veterinary care; getting picked up by the local “dog catcher”
and impounded; female animals damaging furniture or carpeting when in estrus (spcala.com/).
While companies marketing contraception and fertility control products should be aware of the
price/value concerns of pet owners, it may be difficult to capture those pet owners who have not
even taken advantage of free or low-cost surgical spaying or neutering programs that, in some
cases, even include other important health services.
Not “natural” Depends on what “not natural” means to individual owners. Is it the cessation of sexual func-
tion and/or sexual behaviors, the changed appearance in males, or a presumption that animals
should be left “as nature intended?”
� sexual function: If it is important that the pet has the potential to reproduce, the owner could
consider products that are nonpermanent
� sexual behaviors: If it is important that the pet behave “naturally,” the owner could consider an
approach that prevents reproduction but does not alter behavior
� appearance of male dogs: There is a product called Neuticles®, testicular implants that can
be used to preserve the appearance of male dogs and cats that have been surgically castrated.
Intratesticular injections that sterilize without requiring removal of the testicles may help
address this concern.
� nature no matter what: Responsible pet ownership requires management of reproduction and
sexually related behaviors.
The 2009 PetSmart Charities survey also examined reasons people do have their dogs and/or cats spayed or neutered:
Table 5-15: Reasons Pet Owners Have Had Their Dogs or Cats Spayed or Neutered in the US
Rationale Male (dogs and cats) Female (dogs and cats)

It’s the right thing to do 70% 67%
To prevent unwanted pets 63% 73%
To keep my pet from reproducing 64% 71%
To reduce pet overpopulation 62% 62%
For the health benefits 35% 43%
To eliminate certain behavioral issues 50% 21%
To stop my female pet from going into estrus 7% 69% (mainly cats)
Recommended by my veterinarian 22% 21%
It helped my pet roam less 24% 17%
It helped my pet become less aggressive 27% 10%
Recommended by the place I acquired my pet 11% 12%
ß
License fee is lower for sterilized pets 7% 8%
Recommended by my friend/family 6% 5%
Mandatory spay/neuter law in my area 3% 4%
Landlord required it 2% 2%
In the US, at least two significant surveys have indicated that pet
owners consider pet overpopulation to be an important issue to them. Estimated size of the United States market for
Positioning non-surgical sterilization options as tools to better combat pet sterilization of dogs and cats
overpopulation could be meaningful to consumers, given the importance of (includes “owned” and “unowned” animals; see
this issue to them. section 5.4 for information related to “unowned” dogs
and cats)
The Ralston Purina State of the American Pet (2000) study indicates that One analysis estimated the annual size of the US mar-
new tools to address pet overpopulation will address the issue of most ket for surgical sterilization of cats and dogs at 12.5
importance to pet owners. Purina asked pet owners a range of questions, million surgeries (Briggs 2006). Of these surgeries,
including, “Thinking about our country’s pet population, which of the approximately 11 million were performed by private
veterinarians, and 1.5 million were performed on a
following issues is most important to you?” subsidized basis by ”shelters” for re-homed pets and
Pet owners ranked the following statements in terms of importance: through community outreach. An estimated 200,000
subsidized surgeries were estimated to be associated
� Reducing the pet overpopulation problem 60% with feral cat Trap-Neuter-Release (TNR) programs for
� Promoting a more pet-friendly society 15% maintained colonies.
� Increasing preventive healthcare for pets 11% The analysis was based on American Pet Products As-
� Increasing funding for research to improve pet health 9% sociation (APPA) population data as of 2004. Note that
� Not sure 5% some sources indicate a somewhat higher dog and cat
population at that time than the population estimates
as of 2011, but this may be balanced by a rising
In the 2009 PetSmart Charities study, 29% of pet owners said they were rate of sterilization since that time. Nonetheless, the
familiar with the issue of overpopulation of dogs and cats and 39% had analysis described here did not involve an assumption
seen campaigns providing information about it or asking for support; 52% related to overall pet population growth.
of respondents cite dogs/cats not being altered leading to unwanted litters This estimate includes replacing the population of
as the main source of overpopulation and homelessness, by far the most dogs and cats that are forecast to die annually, in part
frequent answer given. with unaltered puppies and kittens and in part with re-
homed pets, a percentage of which are already altered.
New non-surgical sterilization options may be effectively marketed as An analysis of shelter intake and adoption rates was
tools to better combat pet overpopulation and reduce euthanasia, given the used to determine number of surgeries performed by
importance of this issue to consumers. that sector, estimating the number of re-homed pets
altered. Specifics of the analysis are available at (acc-
d.org/2006%20Symposium%20Docs/4Briggs.pdf).
5.2.2.2.1.1 Legislation
Briggs reports that at the time, an independent
For decades, many communities have offered a discounted license rate for analysis done of this market for a completely separate
pets that have been sterilized. This strategy, called “differential licensing,” project arrived at a similar figure.
aims to raise more funds from an audience whose animals, or their animals’ Average pricing for spay/neuter surgeries in the US
offspring, are more likely to contribute to animal-control costs. nationally is not generally available. Typically the
In the US, mandatory spay/neuter laws in many states require at least nonprofit sector prices surgery at cost or below and
subsidizes delivery with charitable dollars. (Note that
re-homed animals from shelters to be sterilized. According to a 2010 “price” referred to the price paid for the surgery; “cost”
summary on www.animallaw.info, “Releasing agencies (animal shelters, refers to the cost to the provider of the services.)
control agencies, etc.) are required in approximately 32 states … to provide
To get a rough estimate of potential market value,
for the sterilization of all dogs or cats they transfer or adopt out. Generally, Briggs assumed an average price of $200 for private
releasing agencies are required to have a sexually mature dog or cat (usually practice and $50 for nonprofit clinics. Note that these
six months of age or older) sterilized by a licensed veterinarian prior to averages were derived from a fairly wide range of
releasing it to a new owner.”   prices for dog/cat and male/female surgeries. Under
these price assumptions, the market as described
Looking ahead to a time when alternatives to surgery exist to sterilize cats above may be as large as $2.95 billion ($2.2 billion in
and dogs, or to when contraception may be an alternative, “It will be important private practices, and $751.5 million in the nonprofit
to develop interpretation of these regulations that accept non-surgical forms of sector). Charges related to current surgical methods
are largely for labor, anesthesia and surgical overhead.
sterilization” (Zawistowski, personal communication 2012).
Progressive communities have already revised the 5.2.2.2.2 Outside the United States
language of laws to specifically state that dogs and cats There appears to be no single, reliable source delineating
must be surgically sterilized, spayed or neutered. In spay/neuter rates in European countries.
conjunction with the initial launch of Neutersol, Texas was
This section provides input on spay/neuter practices
the first state to preemptively revise the Texas Sterilization
from a variety of sources. Information regarding a given
Act (Nordyke P, see specifics at acc-d.org/2006%20
country may therefore be separated.
Symposium%20Docs/Posters.pdf). Arizona followed suit
with revisions to its state language in 2011 to open doors to In a report of the results
future non-surgical methods. of a 2006-2007 survey
of stray animal control
5.2.2.2.1.2 Economic/Price Sensitivity practices in 32 countries/
In the 2000 study sponsored by Ralston Purina and regions in Europe, the World
described above, 9% of US dog and cat owners surveyed Society for the Protection of
reported they had not had their dog or cat sterilized Animals (WSPA) and RSPCA
surgically due to cost. In the 2009 study sponsored by International (Tasker 2008)
PetSmart Charities, also described above, the combined selected four locations –
figure was 31%. Slovenia, Sweden, Switzerland, and the UK – as “success
stories” in terms of dealing with stray dog populations.
Affordable programs continue to be available, and in fact
The report describes the landscape in regards to neutering,
the Alliance for Contraception in Cats & Dogs (ACC&D)
which is typically defined as including males and females.
estimates that there are more affordable programs in 2012
In Slovenia:
than there were in 2002. It is unclear whether differences
in study design affected the answers or if there was actual “Bitches are more likely to be neutered than male dogs.
significant growth in the number of people seeing expense Although estimates of the percentage of dogs that are
as a major challenge. This could relate to differences in neutered are not available, the member society reports
the sample or changes in the economy (Briggs, personal that a high percentage of sexually mature females are
communication 2012). neutered and the number of dogs castrated is increasing
Respondents in the PetSmart Charities survey provided year over year. It should be noted that the cost of
the following information when asked how much they neutering is relatively high, e.g., it costs approximately
would spend on a spay/neuter surgery for their pets. 200 EUR (~US$285 on October 14, 2012) to spay a large
Note that gender and species do not appear to have been female dog (e.g., German Shepherd) through a private
specified: veterinary clinic.
� Average for a cat: $109 “Although there is no nationally operating, reduced-

� Average for a dog: $144 cost neutering scheme [i.e., program], a large number
� 33% would spend $100 or more of municipalities run twice yearly schemes that they
� 37% would spend $51-$100 subsidise, and owners can have their pets neutered at
� 29% would spend $1-$50 greatly reduced cost. All dogs in animal shelters are
neutered prior to re-homing, with the exception of
Respondent age and region had an influence on the
very young animals whose adopters are issued with a
amount a given respondent would be willing to spend to
neutering voucher permitting them to return the dog
spay/neuter a dog or cat:
to the shelter at a later date for neutering at no extra
� Respondents aged 18-24: $133 charge.
� Respondents aged 35-54: $128 “Veterinary practitioners working in rural regions
� Respondents aged 55+: $101 run mobile clinics at certain times of the year; they
� Northeast: $164 actively publicise the need for annual rabies vaccination
� Midwest: $121 and promote the routine neutering of pets during their
� South: $103 clinics. This activity is supported by the veterinary
� West: $145 administration of the Ministry of Agriculture.”

In Sweden: last option (Reichler 2008). In some European countries,
“There is an enormous commitment by the Swedish surgical contraception is seen as a form of mutilation. In
people and authorities for strict dog control and an Norway, it is considered unethical to neuter animals to
impressive degree of social responsibility where dog make them easier to handle. In spite of a relatively common
ownership is concerned. Owners readily comply disposition among pet owners against surgical sterilization
with the law. Furthermore the high investment and of their pets, younger veterinarians in Europe are
status of dogs within Swedish household means that performing spays and neutering and can be expected to do
they are not readily disposed of or abandoned … The so as long as the procedures are profitable (Jöchle, personal
routine neutering of dogs of either sex is uncommon in communication 2012).
Sweden; less than 7% of bitches and 4% of male dogs In a 2012 publication, Palmer et al. note that the
are neutered. Consequently there are no subsidized American notion that spaying and neutering pets is a
neutering schemes in Sweden … Responsible ownership component of responsible ownership of cats and dogs “is
and enforced leash laws mean that animals that aren’t not a view shared by veterinarians all over the world. In
neutered do not breed uncontrollably.” large parts of Europe … veterinarians are traditionally
much more reluctant to neuter, particularly to neuter
In Switzerland: dogs.” The authors continue:
“… 33% of males and 50% of female dogs are neutered “In Sweden, for example, it was illegal to castrate a
… Restrictive dog ownership and enforced leash laws male dog until 1988, unless there was a specific medical
control against accidental matings. Moreover, owners reason for doing so. And the official view of Swedish
are required by law to avoid uncontrolled reproduction veterinarians is still much more restrictive than that of
of their pets … Subsidised neutering schemes, run by their American counterparts. The section of the Swedish
animal welfare charities operate across Switzerland for Veterinary Association (SVF) dealing with companion
owners who are in receipt of social benefit.” animals issued a statement (last revised in 2011) in
In the UK: which routine surgical neutering of dogs is rejected
as sound policy (SVS 2011). This statement maintains
“There are no published estimates of the proportion
that culturally based differences between countries
of dogs that have been neutered … Most sexually
concerning how dogs are kept affect the extent to which
mature animals being re-homed from animal shelters
unwanted puppies are a problem. It’s claimed that in
are neutered prior to being placed in their new home.
Sweden, despite that only about 7% of bitches and an
In addition, sexually immature animals leave shelters
even smaller percentage of male dogs are neutered, any
with a “neutering” voucher for low-cost neutering at a
problem with unwanted stray dogs is insignificant.”
later date. The majority of animal welfare organizations
operate subsidized neutering schemes [i.e., programs] The burgeoning pet insurance industry in Sweden is
for owners who are in receipt of … state benefits or are adding a new dimension to the discussion about spaying
low-income. Local authorities run subsidized neutering bitches because records on health issues for pets are
schemes that operate year-round for owners on … available. The database of a well-established pet health
benefit.” insurance company in Sweden indicates that “on average
23-24% of the bitches in the database will have experienced
In the Scandinavian countries and in Germany, where
pyometra by 10 years of age” (Egenvall et al.2001) .
pets are typically left intact and the emphasis is on
responsible pet ownership and managing the reproductive As a result of the access to this specific information,
behaviors of pets, spaying and neutering are somewhat “there has been growing interest in that country in spaying
rare (Jöchle, personal communication 2012). In Germany, bitches as a means of preventing pyometra” (Zawistowski,
castration of male dogs is the first choice for treatment of personal communication 2012).
prostate hyperplasia, but in France, it is regarded as the

In a presentation at the 7th International Symposium attitude. Through shared international media—such as
on Canine and Feline Reproduction in 2012, Jitpean et television channels focused on animal issues—the idea
al. noted that because only a small percentage of the is spreading that routine neutering is the normal thing
dog population in Sweden is spayed “a large number to do. Some small animal clinics in Denmark, which
of dogs are susceptible [to] diseases of the genital tract likely have a vested interest in the matter, have started
or that are associated with production of reproductive to advertise and advise accordingly.”
hormones.” In a study to determine the occurrence of According to Kirpensteij (2008), “Although most
the two most significant canine diseases that can be countries will allow elective neutering of dogs and
prevented by spaying, researchers utilized the database cats, regional differences exist. In Nordic countries
of Agria, a Swedish pet insurance company. The records (Sweden) elective neutering practices have been strongly
of 20,423 bitches diagnosed with pyometra and 11,758 discouraged, while in Holland, for instance, public opinion
diagnosed with mammary tumors were reviewed, and of castrating a male dog seems to be more problematic that
“the combined risk of contracting either of the two diseases spaying a bitch. Many factors associated with the client’s
was studied.” In this particular group of bitches, 30% had background and beliefs and the type of animal play a role.
developed either pyometra or mammary tumors at 10 For instance a cat spay or castration is commonly more
years of age. Occurrence of the two conditions among the acceptable than and dog spay or castration” (Kirpensteij,
110 breeds represented in the database varied with breed, International Congress of the Italian Association of
and researchers noted that the occurrence was “>50% for Companion Animal Veterinarians, 2008).
over 20 breeds in the studied dog population. The results
regarding age and breed differences in the incidence of In the UK, 80%-85% of cats are sterilized (Rowan,
both diseases were, on the whole, in accordance with personal communication 2012), but “there are no published
previous reports.” The researchers concluded that “these estimates of the proportion of dogs that have been neutered
data may be valuable when deciding whether or not to [includes spay] in the UK” although there has “been a shift
perform elective spaying for individual dog[s] of different in the attitudes of veterinarians to the routine neutering of
breeds” (Jitpean et al. 2012). pets since … 1969” (Tasker).
Table 5-16: Dog Populations in European Countries and Rates of Spay/Neuter

France Spain Germany Switzerland
Dog population (000’s) 8,508 4,510 6,473 480
Spayed females 25% 18% 28% 62%
Neutered males 12% 6% 25% 32%

Source: Reichler 2008
Palmer et al. (2012) also note: It has been observed that in Latin America, surgical
“In other parts of Europe the position is somewhere sterilization, particularly of male dogs, is generally not
between that expressed by the American and the accepted culturally (Veterinarios sin Fronteras); however,
Swedish veterinary associations. In Britain, a position this is not always the case. For example, experience in a
paper developed by the Ethics and Welfare Group Costa Rican program that sterilizes 10,000-15,000 dogs
of the British Veterinary Association (BVA 2011), and annually indicated “a slight reluctance, but by and large the
policy statements issued by the British Small Animal people are more than willing to have their pets sterilized”
Veterinary Association (BSAVA 2006a, 2006b and 2006c) (Rowan, personal communication 2012).
unanimously recommend neutering of male and female More than 53% of Australian households own a dog
cats and of female dogs, but argue that decisions about and/or a cat (Australian Companion Animal Council,
castration of male dogs should be taken on a case- 2009). In 2007, the dog population was estimated to
by-case basis. In Denmark … common practice has be approximately 3.7 million, and cats numbered
traditionally been much like that in Sweden. However, approximately 2.2 million. In both 1994 and 2006, over 80%
the Danish Veterinary Association has no official policy of dog and cat owners believed that pets should be spayed
on the issue, and some of its members seem to be or neutered unless specifically intended for breeding
increasingly influenced by the American

(petnet.com.au/sites/default/files/National_People_and_ from breeders and other sellers. In the final phase, all cat
Pets_2006.pdf). Attitudes were similar from 1994 to 2006; owners will be obligated to have their cats sterilized and
however, owner behavior appears to have undergone a registered, at a cost of about 130 Euros (~US$172 as of
change. In 1994 only 61% of dogs actually had been spayed December 18, 2012) for a female cat and 50 Euros ($66 as
or neutered. By 2006 this had risen to 78%. The number of of December 18, 2012) for a tom. Officials from several
spayed or neutered cats had also risen slightly, from 91% in rescue groups have commented that “they’ll never be able
1994 to 93% in 2006. to sterilize all the cats” and “pet owners will refuse to do
In Belgium, the government announced the Multi-annual it”; however, the animal welfare lobby appeared to be
Cat Plan 2011-2016 in September 2010. The plan is intended supportive of the plan (www.guardian.co.uk).
to sterilize all but a select few of the country’s estimated 1.7
5.2.2.3 A Sample of Spay/Neuter Costs
million cats (the human population is 11 million). At that
time it was assumed it would be passed into law, but there Please note that much of this information comes from organi-
zation websites and that some of it is undated. If these figures
has been no follow-up information on the Internet. Culling
are to be used for planning purposes they should be verified via
had become common, with 13,000 cats killed in animal additional sources. Also please note that cost basis, and therefore
refuges in 2009, amounting to about a third of the country’s prices, vary by country and by source of surgery (e.g., subsidized
strays. The initial phase of the plan called for sterilization program versus spay/neuter clinic versus private veterinary
of all cats in shelters, followed by neutering of cats sourced practice).
Table 5-17: Examples of Spay/Neuter Costs (Non-Subsidized)
Species Procedure Country Cost*

Cat Spay France $250
Dog Spay UK $350-$400
Dog Spay Japan $385-$650
Dog Spay USA $150-$300
Dog Neuter USA $200
Cat Spay USA $150
Cat Neuter USA $75
*Costs for countries other than the US are converted to US$ based on January 2012 conversion rates.

Table 5-18: Examples of Subsidized or Low-Cost Spay/Neuter Services in the US
Area Program
DFW Humane Society, Dallas, TX The Dallas-Fort Worth Humane Society sells certificates that enable dog and
cat owners to go to one of several area veterinary clinics where they can
redeem them for spay/neuter services.
� Female cats: $40
� Male cats: $30
� Dogs under 20 lbs: female $55; male $50
� Dogs 21-35 lbs: female $60; male $55
� Dogs 36-50 lbs: female $65; male $60
� Dogs 51+ lbs: female $70; male $65
Broward, Miami-Dade, and Palm Beach The Pet Aid League has agreements with 20 veterinarians who will perform
counties, FL spay/neuter surgery.
� Female cats: $35 (+ $5-$15extra if the cat is pregnant)
� Male cats: $25
� Female dogs (based on weight): $39-$89 +$5 if the dog is in estrus or
pregnant
� Male dogs (based on weight): $39-$64)
Humane Society of Northeast Florida � Cat neuter: $35; cat spay: $45
Putnam County Spay/Neuter Assistance
Program, Hollister, FL
� Dog neuter: $45; dog spay: $65 (dogs under 85 lbs)
� Additional cost for dogs over 85 lbs
Sacramento ASPCA, Sacramento, CA � Female cat: $45 (+$10-$30 if pregnant)
� Male cat: $30 (+$10-$74 if cryptorchid)
� Female dog: $50-$100 depending on weight; + $10 for female in estrus; + $
$20-$60 if pregnant)
� Male dog: $40-$110 depending on weight; + $10-$75 if cryptorchid)
Oregon Spay/Neuter Fund The fund provides coupons redeemable at participating veterinary clinics.
Portland, OR greater metro area � Female cat: $49 (no extra charges)
� Male cat: $33
� Female dog: $60 (+ $1 for every pound >60 lbs at some participating
clinics)
� Male dog: $49 (+ $1 for every pound >49 lbs at some participating clinics)
Animal Shelter Alliance of Portland � $10 for all cats owned by people on a form of government assistance
Portland, OR greater metro area � $20 for all cats owned by people meeting low-income requirements (but
not on public assistance)
� By donation for feral cats that must be trapped to be sterilized

Chicago, IL Friends of Animals Certificates
� $51: Male cat

� $64: Male dog
� $65: Female cat
� $90: Female dog
Anti-Cruelty Society Low-Cost Clinic
� $15: Cat (feral cats are free)

� $90: Female dog (pit bull/pit bull mix dogs are always free)
� $70: Male dog (pit bull/pit bull mix dogs are always free)
Tree House Humane Society Low-Cost Spay/Neuter Surgery
� Pet or stray female cat: $75*

� Pet or stray male cat: $50*
� Pet or stray female dog: $135* (under 50 lbs only)
� Pet or stray male dog: $95* (under 50 lbs only)
� TNR Feral Cat Package: $30 (includes vaccinations, parasite treatment, ear-
cleaning and more)
* Low-income individuals on public assistance receive reduced rates - call for full details
Animal Welfare League

Cats Male Female
• Any weight $50.50 $75.25

Dogs Male Female
• <51 lbs $95.75 $137.50
• 51-70 lbs $140.75 $153.00
• 71-90 lbs $155.75 $175.75
• > 90 lbs $170.75 $189.75
The Humane Alliance, � $65: Neuter male dog

Ashville, NC � $65: Spay female dog
� $50: Spay female cat
� $35: Neuter male cat
These costs appear to be unchanged since they were cited in the 2002 Contra-
ception and Fertility Control in Animals report.
Note that the Humane Alliance model is structured to be “breakeven” and

thereby sustainable, given surgery revenue and expenses to run the clinic.
ASPCA® and PetSmart Charities have helped the organization expand this
model. As of November 2012, this includes a network of 110 mentored clinics
using the Humane Alliance’s approach in the US (humanealliance.org).
WSPA and RSPCA International (Tasker 2008) report notes that 58% of the European/Eurasian countries surveyed
“had some form of subsidized neutering scheme … offered to people on low incomes or people with a large number of
animals. However, the majority of schemes were available to owners who were resident at specific locations and were
not, therefore, in operation nationwide. In most instances it was animal welfare organizations that provided this service
to owners.” WSPA/RSPCA International Report can be found at: www.fao.org/fileadmin/user_upload/animalwelfare/
WSPA_RSPCA%20International%20stray%20control%20practices%20in%20Europe%202006_2007.pdf.

Dr. Andrew Rowan, CEO of Humane Society supported was, on average, US$7.50 ($3-$15) for medicine
International™ (HSI), notes that in Costa Rica, between costs and US$30 ($10-$52) for the full costs, including staff
10,000 and 15,000 dog sterilizations are being performed and clinic operations costs for each dog or cat. At that time,
annually at a cost (not price) of US$8-$12 per procedure. the majority of WSPA’s funds were spent on delivering
In India, a humane organization is spaying dogs for surgical sterilization. Consideration of emerging and future
US$15-$20 dollars per procedure (Rowan, personal approaches will hinge on approvability by regulatory
communication 2012). In 2009, WSPA supported 10 projects authorities, safety, permanence, ability to generate sterility
that provided working models of humane dog and cat in male and female animals in a single treatment, and
population management in different regions of the world; economic feasibility (Hiby 2010).
together these projects have sterilized nearly 20,000 The organization Animal People compiled the following
dogs and cats, vaccinated more that 35,000 and provided examples of other non-US costs (ACC&D, 2008):
veterinary treatment for more than 15,000. As of 2010, the
cost of surgical sterilization in the projects WSPA
Table 5-19: Spay/Neuter Costs in Non-US Markets (Expressed in US$)
Location Organization Cost Range Spay Cost Range Neuter Avg Cost Avg Cost Excluding
Dog Cat Dog Cat Sterilization Boarding/Food
Philippines Palawan Animal $11.02

Welfare Ass’n.
Thailand SCAD $23.25 $17.96
(Bangkok)
China ARB $72.81- $13.11- $43.69- $7.280-
(Beijing) $203.89 $47.33 $131.07 $40.05
India Blue Cross of India $14.11 $10.36
Other sources provide the following examples: camiguin%E2%80%99s-free-spay-neuter-for-pets-

benefits-157-pet-owners-2/).
� The Philippine Veterinary Medical Association (PVMA)
holds a free, annual spay/neuter event funded by the � The Philippine Animal Welfare Society (PAWS) provides
local Camiguin government. The 2012 event targeted spay/neuter services for dogs and cats at its PAWS Animal
200 animals; 157 animals were sterilized in the 2011 Rehabilitation Center (PARC), which also serves as a shelter,
event. If surgical sterilization is performed in a private in Quezon City. Costs are shown in the table below (paws.
clinic, the average price to owners is estimated at P 5,000 org.ph):
(US$120) (piacamiguin.wordpress.com/2011/09/30/
Table 5-20: Spay/Neuter Costs in the Philippines
Animal Cost Additional Information

Female cat P 1,000 (US$24) Extra charge for purebreds and cats with pyometra or who are
pregnant
Female dog P 1,500 (US$36) Extra charge for purebreds and cats with pyometra or who are
pregnant. Additional P500 for every 10 kg in excess of 15 kg body
weight.
Male cat P 700 (US$18) Additional charge for purebreds
Male dog P 1,000 (US$24) Additional P500 for every 10 kg in excess of 15 kg body weight

� The Soi Dog Foundation (Thailand) carries out and fuel (5%), and darts and anesthetics (12.5%). The
sterilization and vaccination programs for stray and remainder of the cost is not broken out (soidog.org/en/
owned dogs and cats. Costs, covered by a “sound about-soi-dog/).
financial plan,” are approximately US$30 to spay or Readers wishing to learn about programs and costs in
neuter one animal. The cost includes drugs/surgical their areas are encouraged to consult local sources for up-
supplies (40%), veterinary fees (15%), clinical overhead to-date information.
(5%), nurse fees (5%), dog catcher fees (10%), vehicles
Table 5-21: Spay/Neuter Costs in Thailand
Location Animal Cost

Pets Are Wonderful Veterinary Clinic Male cat 600 yuan (US$96)
Female cat 750 yuan (US$120)
Male dog 800 yuan (US$128)
Female dog 1,000+ yuan (US$160)
St. Anthony Animal Recovery Hospital (SAARH) Male cat 400 yuan (US$64)
Female cat 800 yuan (US$128)
Male dog > 10kg 1,000 yuan (US$160)
<10kg 800 yuan (US$128)
Female dog >10kg 1,200 yuan (US$192)
<10kg 1,000 yuan (US$160)
5.3 Show Animal Owners and Dog (GnRH) agonist implants, (Suprelorin, Peptech/Virbac), are
and Cat Breeders available for use in male dogs in Australia, New Zealand,
and Europe; however, the period after which a given dog
Responsible commercial breeders, owner/breeders, and
regains fertility after treatment is variable (see Chapter 4).
owners of show dogs and cats who wish to control when
their animals come into estrus are likely to prefer a fertility
control method that has a predictable duration and is
5.4 “Unowned” Dogs and Cats
not permanent. In addition, any contraception or fertility The groups that deal with “unowned” animals are
control product for female cats and dogs whose owners diverse, and their needs are diverse. Some serve owner-
want to breed them at some time in the future will have relinquished animals only, but many are involved
to be shown to be free of negative effects on subsequent in dealing with issues presented by the presence of
fertility, litter size, and quality, or on the long-term health abandoned, stray, free-roaming, and feral animals. There
and fertility of the offspring. Furthermore, products that do is long-standing global debate about how many dogs and
not also suppress sexual behaviors would generally appear cats make up these populations, how many “adoptable”
inappropriate for this market, although some show animal and “unadoptable” animals are euthanized each year, what
owners may prefer a treatment that does not affect sex- can and should be done about it, and the degree to which
hormone-influenced morphology (e.g., toms are expected contraception and fertility control can influence the overall
to have “jowls”). dynamics of what is typically called “overpopulation.”
Currently some owners of show dogs use progesterone- There is general agreement, however, that the number
type products to suppress the estrous cycles of animals that of unowned animals is large – and that many adoptable
are likely to come into season at inconvenient times. Using animals are euthanized. Furthermore, many of these
progesterone type drugs in dogs successfully requires close animals are sexually intact. Dr. Andrew Rowan10 estimates
monitoring of the estrous cycle and is labor intensive. (See that there are 400 million “pet” dogs and 300 million
Chapter 4, section 4.1.5 for a discussion of progesterone- “street” dogs worldwide. While in some parts of the world,
type drug use in dogs. Progesterone-type drugs as
Dr. Rowan is President and Chief Executive Officer of Humane
10
injections are also available for cats. See Chapter 4, section
Society International (HSI) as well as Chief International Officer
4.2.3 for a discussion of progesterone-type drugs used in and Chief Scientific Officer for Humane Society of the United
cats.) Six- and 12-month gonadotropin-releasing hormone States (HSUS).

poisoning, and/or shooting stray and feral cats and dogs their survival. The reproduction rates of these
are accepted practices (albeit becoming less accepted), dogs and their rearing success has the potential
groups in many countries attempt to deal with issues of to be high because care given by humans offers
population control, abandonment, and relinquishment of the necessary protection for puppy survival …
cats and dogs in ways that are regarded as more humane. The relationship between cats and their caretak-
WSPA and RSPCA International explain that: ers is intrinsically different to dogs, although
the same set of associations may apply but to
“Definitions of stray dogs are inherently prob- varying degrees” (Tasker 2008).
lematic and judgments regarding when a dog
is considered to be a stray varies from country The World Health Organization (WHO) developed
to country and may be subject to local and four categories to characterize dog populations (cited on
national regulations … any dog found unac- jeevashram.org):
companied by a responsible person in a public � Restricted/supervised: pets; dogs that are dependent
place may, in some countries, be considered on owners who keep them under supervision
as stray and collected accordingly. Conversely, � Family dogs: dependent on owners, who restrict them
at the other end of the scale, unwanted dogs only partially
– dogs, whose owners have revoked all care- � Neighborhood or community dogs: partially
giving responsibilities – may, if they survive dependent on people; movement unrestricted
for long enough, be able to reproduce and rear � Feral dogs: independent or dependent on human-
young. Though this generation of dogs may generated waste and garbage; movement unrestricted
be considered to be genuinely ownerless and The Humane Society of the United States™ (HSUS)
in some instances feral, their survival rates are includes the following cats in its “free-roaming” category:
invariably low and their reproductive success is
likely to be poor. They are therefore not consid- � Owned cats that are allowed to roam
ered to be the main source of overpopulation. � Owned cats that have become lost
Somewhere between the two examples, dogs � Previously owned cats that have been abandoned [as
may be cared for by one or more members of well as their offspring]
a community, allowed to roam, and permitted � Quasi-owned cats that roam freely and are fed by
to reproduce. Nevertheless, they are genuinely residents
dependent upon human caregivers, as humans � So-called working cats that serve as mousers
provide access to the resources essential for

WSPA and RSPCA International have classified dogs and cats by the nature of their dependence on humans (Tasker
2008):
Table 5-22: Classification of Dogs and Cats by Their Dependence on Humans
Classification Dogs Cats

Stray: feral
� No owners or caretakers � Unowned, independent of human control
� Generally derived from dog � Poorly socialized to human handling
populations under some degree of � Sub-population of free-roaming cats (may be
human care “gone wild” offspring from owned or abandoned cats)
� Found on the outskirt of urban and � Survive through scavenging and hunting
rural areas
� Poorly socialized to human
handling
� Survive by scavenging
� Poor survival rates
� Low reproductive capacity
Stray: abandoned/ un-
wanted by owners � Were once dependent on an owner � Were once dependent on an owner for care
for care � Owner is no longer willing to provide resources
� Owner is no longer willing to � May or may not be fed by other members of the
provide resources community (food may be delivered intermittently)
� May or may not be fed by other � Survive by scavenging or hunting
members of the community (food � May or may not be socialized to human handling
may be delivered intermittently)
� Survive by scavenging or hunting
� Poor survival prospects once there
is no longer a caretaker to provide
food or shelter
Stray: owned, not
controlled � Free-roaming dogs � Free-roaming cats
� “Latch-key” dogs � “Kept” outdoors
� Community or neighborhood dogs � Either entirely free to roam or may be semi-
� Either entirely free to roam or may restricted at particular times of the day
be semi-restricted at particular � Dependent upon humans for resources
times of the day � May or may not be sterilized
� Dependent upon humans for � Potential for high reproductive capacity and
resources rearing rates
� May or may not be sterilized
� Potential for high reproductive
capacity and rearing rates
Owned, controlled
� Totally dependent upon an owner � Totally dependent upon an owner for care and
for care and resources resources
� Generally under close physical � May vary from totally indoor to indoor/outdoor,
control of the owner outdoor but confined to pen or garden
� Confined to the owner’s property � Generally reproduction may be controlled through
or under control when in public sterilization or confinement
places
� Reproduction usually controlled
through sterilization, chemical
means, or confinement
HSUS notes that feral cats are unsocialized animals “who may be one or more generations removed from a home
environment and who may subsist in a colony of similar cats,” and that it can be difficult to differentiate between free-
roaming and feral cats (hsus.org).
The popular and professional literature is rife with statistics and although there is some – and even great – semantic and
numerical disparity among them, it is agreed that shelter and “street” or “feral” populations consist of owned animals

at large, previously owned animals, free-roaming animals indicates that 55% of surrendered dogs and 47% of
that are fed by humans, “unsocialized” animals that surrendered cats are intact (ohlonehumanesociety.org).
receive some support (e.g., food and even medical care) Although these statistics focus on the US, it is likely that
from humans, and “unsocialized” animals that haven’t owner failure to neuter pets that are unsupervised at
had homes or support from people. While it is difficult least part of the time is an important contributing factor
to find reliable information regarding abandoned, stray, to shelter populations in general. Therefore shelters are
or feral animal populations worldwide, a few estimates interested in sterilization to address a demographic of
are given below. Note that a detailed examination of the animals more likely to contribute to shelter intake to
issues related to feral animals is beyond the scope of this well as to prevent litters.
report, but some information is included at the end of this
Outside the US:
section on lessons learned as a result of the use of chemical
castration to help manage unowned or “community-
owned” dog populations.
� An estimate of 2 million “strays” on UK streets is
considered low (celiahammond.org).
In the US: � Cats are not native to Australia. They were introduced
probably around the time of first European settlement.
� Estimates of the number of abandoned, stray, or feral During the 19th century, thousands of cats were released
cats in the US vary. Feralcat.com estimates that there are in the gold fields to control mice. Cats were also popular
60-100 million; Alley Cat Allies (alleycat.org and www. with settlers to keep down the number of rabbits and
alleycat.org/page.aspx?pid=667) estimates the number
at between 30 and 60 million; and Centonze and Levy
estimate that stray and feral cats account for 35% to
45% of the entire known cat population (Centonze and
Levy 2002). According to the American Society for the
Prevention of Cruelty to Animals® (ASPCA®), it is
impossible to determine how many stray dogs and cats
live in the US; estimates for cats alone range up to 70
million (ASPCA 2012).
� An estimate presented in 2010 indicates that
approximately 50 million feral cats produce
approximately 145 million kittens in the US.
This compares to 26 million kittens produced by
approximately 88 million owned cats in the US. The
sterilization rate among the feral cats is estimated at native rats. Many were released – or escaped – into
1.2%; it is 85% among owned cats. (Levy 2010). the bush, where they were able to fend for themselves.
� In 2002, it was estimated that 5% of pet dogs in the US These cats did not depend on humans for food or shelter
are acquired by their owners as strays; 24% of pet cats and in effect became wild, or “feral.” They spread
are taken in as strays (purina.com). A PetSmart Charities rapidly across most of the continent. It is estimated that
survey indicated that 19% of dogs and cats are taken is there could be 400,000 feral cats in New South Wales
as strays but did not separate data by species (PetSmart and around 12 million across Australia. Cats in NSW are
Charities 2009). categorized as domestic, stray, or feral. Feral cats have
� A survey showed that “sexually intact” dogs and cats been declared a pest species and are subject to abatement
were 2-3 times more likely to be relinquished by owners programs (www.environment.nsw.gov.au 2011).
in the US than dogs and cats that had been spayed or � There are an estimated 3,000,000 street dogs in Bulgaria
neutered (New 2002). (bulgarianstreetdogs.com) and a March 2012 census is
� The National Council on Pet Population Study and expected to provide an estimate of 11,000 stray dogs in
Policy (NCPPSP) Shelter Statistics Survey 1994-97 found the capital city Sofia (animalmedicalcarefoundation.
that approximately half of the pets (42.8% of dogs, com/bulgaria.html).
50.8% of cats) surrendered were not neutered (www. � In Japan, according to the Japanese animal health
petpopulation.org/statsurvey.html). Another source company Nippon Zenyaku Kogyo (Zenoaq)

(www.zenoaq.jp/english/aij/1201.html, www.zenoaq. to emerge will likely play a role in population control and
jp/english/aij/1102.html): general health programs for free-roaming dogs and cats.
� 112,690 “unwanted” dogs and 228,373 “unwanted” cats One can envision their use, for example, in rabies programs
were euthanized by Japanese animal control agencies that involve dog population control. See section 5.4.1.3
in 2008, which constitutes a dramatic decrease from the for information about the use of Esterilsol in population
1997 level of between 600,000 and 700,000 for dogs and control programs for male dogs and “lessons learned” by
cats combined. The decrease in euthanasia of unwanted groups involved in non-surgical projects.
dogs is greater than the decrease in cats.
� 81% of abandoned dogs are adults; 71% of abandoned 5.4.1.1 A Look at Methods of Dealing with
cats are kittens. Free-Roaming Dogs
� 80% of cats euthanized by animal control agencies are The following information and reported methods of stray
kittens. dog control were noted in the Europe Stray Animal Control
� Less than 5% of owners surveyed in 2008 adopted their Practices (Europe) document cited above. Information
dogs from a public or private shelter. was derived from questionnaires distributed to 34 animal
� The reason most given for relinquishing a dog is owner welfare groups operating in 30 countries located in Europe
death or illness; this justification accounts for about and Eurasia during 2006-2007:
one-third of canine relinquishments; the second most
cited reason is that the owner is moving. These two � Statutory holding periods varied from 3-60 days in the
countries capturing stray dogs.
reasons taken together account for one-half of the dog
relinquishments. � 32% of countries capturing stray dogs euthanized
animals that were not returned to owners or placed in a
� Puppy mills are a source of animals brought to
new home.
shelters; although puppy mills must register with local
authorities, “the standards for registration are still � 6% of countries capturing stray dogs euthanized all
animals upon capture, without waiting for the holding
minimal and inspection infrequent due to a lack of
period to end.
manpower.” More than 88% of abandoned dogs (~2,700
dogs) at the rural Tokushima Animal Welfare Center � 3% of countries capturing stray dogs legally forbid
euthanasia of healthy stray dogs and mandate life-
were euthanized in 2008 (Hoon and Fabre 2010).
long care for those healthy stray dogs for which homes
� Most stray dogs are abandoned rather than relinquished
cannot be found.
to shelters and are the sources of “dogs that have gone
wild” (Hoon and Fabre 2010). � There appears to be a general lack of numerical data
collected by “authorities” in responding countries
� Some hunters abandon hunting dogs after the hunting
season and purchase new dogs the following season � No country reported centralized monitoring of
(Hoon and Fabre 2010). dog populations, demographics, or ownership
trends.
5.4.1 Dealing with “Free-Roaming” Animals � Methods of controlling stray dogs
and cats vary “greatly” among surveyed
A thorough review of this topic is beyond the scope
countries
of this document; however, comprehensive sources,
not limited to the US, can be found at: www.vetmed. � Stray cats are “more likely to be culled than
ucdavis.edu/strays.htm. For a summary document, stray dogs.”
developed by WSPA and RSPCA International and � 22 countries (70% of those surveyed) have
describing stray dog control practices in Europe laws requiring licensing
Stray Animal Control Practices (Europe), see: fao. or registration of dogs. In 15 of those countries,
org/fileadmin/user_upload/animalwelfare/ this was considered ineffective in helping to
WSPA_RSPCA%20International%20stray%20 reduce stray numbers … “because the law
control%20practices%20in%20Europe%20 was neither enforced nor adhered to by owners.”
2006_2007.pdf. There are numerous examples
Discussion of country-specific information
of TNR programs to be found on the Internet.
generated by the survey is beyond the scope of this
Availability of current (e.g., zinc gluconate document; however, the full report contains a great
[Esterilsol/Zeuterin – see Chapters 3 and 4]) deal of interesting input and can be accessed
non-surgical sterilization methods and those expected

at: fao.org/fileadmin/user_upload/animalwelfare/ be known prior to use in the field or in veterinary practices
WSPA_RSPCA%20International%20stray%20control%20 (Briggs, personal communication 2012).
practices%20in%20Europe%202006_2007.pdf. Although less humane methods are also employed, many
In a review of Capture, Neuter and Return/Release communities and organizations deal with free-roaming cats
(CNR) programs in developing areas, Jackman and Rowan in one of four ways (definitions from Slater 2002):
(2005) point out that the “free-roaming dog populations
have emerged as both animal welfare and public health
� Trap, remove, euthanize – This is regarded as a short-
term approach unless the sources of food and shelter
problems in developing countries. Free-roaming dogs that attracted the cats in the first place are removed.
face high mortality, malnutrition, starvation, disease, and Otherwise, any cats that avoid the process remain in the
abuse; account for 99% of cases of rabies transmission area and continue to reproduce and the trap-remove-
worldwide (WHO 2004); and are associated with more than euthanize cycle can continue.
60 other diseases (Beck 2000, Reece 2005). Additional social
problems with free-roaming dogs include road accidents,
� Trap, remove, and relocate to another colony or a
sanctuary – This is a difficult process because suitable
fighting, noise, fecal contamination, spread of rubbish, and locations must be identified and obtained, and the stress
uncontrolled breeding.” Dog attacks on livestock are also of relocation can compromise the health of the cats. In
considered a serious issue in many communities. some cases, cats can be socialized and adopted, but the
Human public health preventive measures should be socialization process is time consuming.
paralleled by programs for dog rabies control (WHO 2004, � Trap, neuter, and return/release (TNR) – This alternative
cited in Jackman and Rowan 2005). While sterilization of requires the assistance of veterinarians, who surgically
free-roaming dogs appears to be a desirable added tool sterilize the cats and notch or tip the ear for identification
to reduce the dogs needed to treat in rabies vaccination purposes, as well as caretakers, who feed and monitor
programs, capture-and-kill methods used historically the colony on an ongoing basis. Monitoring is necessary
have been condemned as “ineffective and cruel,” and in to identify any new cats moving into the colony. At
some instances those practices began to decrease in the its most comprehensive, this strategy is extended to
late 20th century. CNR programs are modeled on Trap- TTVARM, which stands for Trap, Test, Vaccinate, Alter,
Neuter-Release (TNR) programs for feral cats. Sterilization Release, Maintain, and is geared towards stabilizing
via CNR, along with “vaccination, habitat control, and and managing feral/unowned cat colonies to help
responsible pet ownership … are now replacing … capture- reduce unwanted reproduction and control disease
and-kill” (Jackman and Rowan 2005). (Cat Fanciers Association, cfainc.org). Research for this
The benefits of CNR programs for dogs include (Jackman update appears to indicate that TNR is emerging as
and Rowan 2005): the preferred method of managing feral colonies. It is
important to note that there is an excellent opportunity
� Controlled population and reduced mortality for these cats to receive additional veterinary care while
“discourage migration and compensatory breeding … they are being sterilized, which is also an opportunity
to fill ecological niches left by dog losses.” New dogs are for animal health companies interested in developing
less attracted to a given territory. non-surgical approaches to market other feline products.
� Puppy populations are reduced. As an example, in addition to being spayed or neutered,
� Less post-sterilization-procedure stress occurs because each cat receiving treatment from the Feral Cat Coalition
dogs are returned to their own territory. of Oregon receives “FVRCP (distemper) and rabies
� There is significant public support in areas in which vaccines, flea treatment, ear cleaning and ear mite
there is opposition to catch-and-kill programs. treatment if necessary, fluids if dehydrated, treatment
for minor medical conditions if present, his or her right
5.4.1.2 A Look at Methods of Dealing with
ear tipped for future identification. Cats that appear to
Free-Roaming Cats
be suffering, as determined by a veterinarian, are tested
In the US, the sterilization rate in the feral/free-roaming for feline leukemia (FeLV) and feline immunodeficiency
cat population is very low – about 2%. A large virus (FIV). Any cat testing positive is
percentage of cats are pregnant – 15% on average euthanized” (www.feralcats.
– and there is a seasonal pattern; therefore, effects com/FAQ.html). For a summary
of any non-surgical approach on pregnant queens of studies on use of TNR to
and their fetuses would have to

manage feral cat populations, see www.alleycat.org/ an approximate 3-year mean life span. After
page.aspx?pid=667. the population stabilizes, this would equate
to sterilizing approximately 14% of the total
� Wait and see – This strategy, which typically occurs by female population per year or having approxi-
default, makes no effort to manage populations and can
result in the growth of colonies to crisis level, when any mately 71% of the total female and 81% of the
type of intervention can be more costly and a greater adult female population sterilized at all times.
animal welfare challenge. In the absence of juvenile sterilization, 91% of
adult intact females would need to be sterilized
One of the issues discussed among stakeholders annually to halt population growth. In compari-
advocating the development of non-surgical methods of son, with a 3-year non-surgical contraception
population control in cats relates to whether or not a given program, an annual contraception rate of 60% of
approach must provide permanent sterilization. Indeed, the female juvenile and adult intact cats would be
Michelson Prize & Grants program of the Found Animals® required to halt population growth, assuming
Foundation (see section 5.9.1) is focusing on discovery and that treated cats were retrapped at the same rate
development of a single approach to permanent, non- after 3 years.”
surgical sterilization that will work in male and female cats
and dogs. For some time, the working assumption made Animals returned to feral colonies should be vaccinated
by many stakeholder groups concerned with unowned against rabies and, if possible, identified in some way to
populations of cats and dogs was that since animals such as prevent their recapture and re-treatment. Some programs
feral cats may only be able to be treated once, sterilization use ear tipping for this purpose; however, identification
was required to have significant impact on population of animals sterilized non-surgically is typically regarded
control. as a barrier to acceptance of non-surgical approaches. In
fact, effects of accidental re-treatment would have to be
Given that several of the non-surgical contraceptives
understood and addressed to the satisfaction of regulatory
that have been developed may allow long-term fertility
agencies before a product could be labeled for use on
suppression, ACC&D was interested in understanding
feral animals and before organizations using TNR and
the impact of a treatment that could cause a long-term
similar strategies would actually use it. A panel discussion
suppression of fertility on a feral population when
entitled “A Focus on Feral and Free-roaming Felines,” held
compared to surgery, which offers a permanent solution.
during the 4th International Symposium on Non-Surgical
Because there was some information available that a
Methods of Pet Population Control in 2010, pointed out
deslorelin implant might result in up to 3 years of fertility
the challenges related to how the unique characteristics
suppression in cats, preliminary modeling work was done
of feral/free-roaming cat populations affect the structure
to evaluate population impact of a 3-year contraceptive
and implementation of management strategies. The issues
treatment in feral cats. This work resulted in a study that
include (Green 2010):
was published in 2009 that modeled the impact of 3-year
contraception vs. surgical sterilization on the population � Feral/free-roaming cats can be thought of as a “herd”
of feral cats. Results indicated that both were similarly in terms of the health of the group. This
effective and far more effective in population control than may mean that lower response rates
no intervention (Budke and Slater 2009): to a non-surgical approach
than the response
“This study constructed matrix population rate expected by
models to explore feral cat population growth a pet owner could
for a hypothetical population (a) in the absence be effective in
of intervention; (b) with a traditional surgi- managing a
cal sterilization-based trap, neuter, and return colony.
program; and (c) with a single-treatment 3-year � There may
non-surgical contraception program. Model be potential
outcomes indicated that cessation of population liability
growth would require surgical sterilization for involved in
greater than 51% of adult and 51% of juvenile capturing
(<1 year) intact female cats annually, assuming and

sterilizing cats that are owned but are free-roaming. Frontières Canada (VSF) used chemical castration in males
� There is a wide range of surgical spay/neuter services and surgical sterilization in females and has contributed
from a variety of sources. A subsidized, high-volume, to an overall reduction in population density of dogs in 12
high-quality spay/neuter program may be available in communities of Todos Santos, Guatemala, a community
some situations while in others, the only surgical option in a remote mountain region. This particular project was
available (e.g., private practice veterinarian) may be cost in part supported by ACC&D, underwritten by Parsemus
prohibitive for cats in a colony. Foundation and The Pegasus Foundation.
� Effectiveness of approaches may vary depending on In Phase 1 of the program, VWB/VSF assessed the
variability in fertility, fecundity, and mortality in a situation in the area and met with public health, veterinary
given colony – “a shorter acting product could be very professionals, and public stakeholders to develop the
effective in areas [in which feral/free-roaming cats have] relationships necessary to move from an unsuccessful
low life expectancy, but ineffective in areas [in which approach that involved using strychnine poisoning and
feral/free-roaming cats have] high life expectancy.” killing puppies to a more humane and successful approach
� Programs currently depend on ear tipping to identify in the future. In Phase 2, owned dogs were counted and the
treated cats; ear tipping requires anesthesia, while non- number of stray dogs was estimated using mark-recapture
surgical sterilization may not methodology. Results of a household
require anesthesia. survey indicated a slight preference
� Financing programs (“there is no for chemical sterilization over surgical
owner to ‘foot’ the bill”). castration.
� There is a wide range of
Phase 3 focused on sterilization
population sizes, depending on
colony location. and education, and occurred during
January of 2009. In preparation, two
� Cats are not easy to count,
VWB/VSF veterinarians traveled
observe, and track.
to Mexico, where they were trained
� Stress involved to cats and
in Esterilsol administration by Dr.
handlers in the capture,
handling, and surgical recovery Carlos Esquivel of Ark Sciences, Inc.,
process. the company currently marketing the
product. These veterinarians in turn trained veterinarians
� Potential opposition to permitting cats to remain in
in Guatemala, including one of the veterinarians closest to
colonies.
Todos Santos. A total of 216 male dogs were brought to the
5.4.1.3 Advocacy and Population Management Projects clinic for examination and vaccination; 126 male dogs were
Utilizing Non-Surgical Methodology: Lessons neutered with Esterilsol. Reasons dogs were identified as
Learned ineligible or not treated included too young or too old, and
Since most TNR programs utilize surgical spay/neuter, cryptorchid or scrotal pathology. The owners of 17 dogs
a full review of TNR programs is beyond the scope of this did not want the procedure done. The team encountered
document on non-surgical approaches. Readers wishing challenges with handling unsocialized and aggressive stray
to learn more will be able to find information about these dogs; VWB/VSF plans include pursuing new methods
programs on the Internet. As permanent non-surgical for handling these dogs so that they can eventually be
options such as Esterilsol (zinc gluconate, see Chapter 3) sterilized.
emerge, they can be expected to play increasing roles in Minimizing the incidence of injection site reactions that
community-based population control projects that now rely have occurred in up to 4% of dogs in other campaigns
primarily on surgery. was a critical objective. Using precise injection techniques
Experience with non-surgical sterilization is largely and ensuring that dogs remain still during the procedure
limited to the use of zinc gluconate in male dogs. In reduce the incidence of these reactions. Sedation was used
2009 and 2010, ACC&D sponsored several programs during the procedure and owners received specific home-
involving the use Esterilsol (Zeuterin in the US) (acc-d.org/ care instructions. Only two dogs experienced adverse
EsterilsolGrants). effects – one dog’s scrotum was more dry/scaly than
For example, a three-phased, community-based normal and treatment resolved the condition; the other
approach to canine population management conducted by dog developed a draining tract requiring scrotal ablation.
Veterinarians without Borders (VWB) and Vétérinaires Sans Although male dogs were the target population for this

phase of the project, 12 female dogs were surgically spayed. 23,000 people reside, cases continue.
This allowed the team to understand the conditions under As noted above, information on ACC&D’s Esterilsol
which this type of surgery is carried out in this particular Small Grants Program undertaken in 2009 and 2010, is
setting. available at acc-d.org/EsterilsolGrants.
During a November 2011 visit to Todos Santos, VWB/ ACC&D has summarized “key learnings” related to
VSF evaluated the current situation with respect to free- introduction and implementation of non-surgical methods
roaming dog status in the town, cases of rabies in dogs and based on the organization’s Esterilsol Small Grants
humans, and to obtain community recommendations for Program experience. Although the “learnings” are related
next steps. Feedback obtained by the community was very to the use of zinc gluconate to sterilize male dogs, the
positive and suggested that inhabitants were less fearful of information is expected to be of value as additional non-
the free-roaming dogs. Data from the municipality showed surgical methods emerge. A distillation is presented below.
that there had been no cases of rabies in the previous two
years; however, in the outlying agricultural area in which Levy et al. (2008) compared the use of intratesticular
injection of zinc gluconate versus surgical castration to
Table 5-23: ACC&D Summary of “Key Learnings”

Lesson Description
Public health concerns may In areas in which rabies or other zoonotic disease is a significant public health issue, “opportunities to
facilitate use attract government officials and pet owners with rabies control/vaccination activities can provide op-
portunities to engage these organizations and individuals in conversations about humane dog popula-
tion control on a community or individual-animal level.”
Local buy-in is a must Organizations involved in local sterilization programs “must be able to communicate effectively with
the local population. This includes proficiency in the local language as well as familiarity with cultural
norms.” The local population must also understand and be able to comply with post-administration
care requirements, which can be challenging in areas in which “veterinarians are in short supply; dogs
are often ‘loosely owned’ and lack supervision and access to clean, dry, and temperature-controlled
housing, as well as good nutrition and fresh water; dog owners often lack telephones and vehicles,
making it difficult to contact veterinarians with questions or concerns.” In instances in which teams
that are not locally based leave too soon after providing services, follow-up care may not be adequate,
which can compromise effectiveness and lead to adverse events.
Logistics are important An understanding of specific requirements is important. Areas of interest include, but are not limited
to, regulatory requirements for approved or unapproved products in a given country, and import and
customs permission regulations, policies, practices, and timelines.
Record-keeping and accu- Many dog and cat sterilization programs are conducted under field conditions and involve the use of
racy of records are critical; volunteers. Because tracking the effectiveness of these programs is critical to funding, maintaining, and
planning is important improving them, collecting and organizing treatment records should be emphasized and related pa-
rameters predefined. Experience has revealed that in field studies, “even for those organizations which
clearly understand the importance of record-keeping, it is not uncommon for some paperwork to be
lost or incomplete. Expectations for the amount and accuracy of data collected must be reasonable.”
Preparation can prevent Experience with Esterilsol indicates that the project preparation phase can take longer than estimated.
problems While some types of delays cannot be foreseen, delays that can be minimized have related to obtain-
ing the permissions noted above; delivery of products and related supplies; seasonal weather patterns,
and “bottlenecks in local, regional, or national bureaucratic systems.” Training of veterinarians and
other project personnel should occur within a reasonable time before the start of a project. In the case
of Esterilsol, Ark Sciences recommends that no more than 2 months elapse between the veterinarian’s
training and the use of the product. “It is critical that administration protocol (including but not lim-
ited to injection technique) be followed precisely, and specific instructions may be forgotten if there are
long delays between training and use.”
Proper handling and Lessons learned during the Esterilsol Small Grants Program include ensuring that product integrity is
administration are key to maintained (e.g., following label instructions regarding storage, product expiry, product life after open-
optimizing effectiveness ing); and using proper administration technique. In the case of Esterilsol, improper injection technique
and minimizing adverse is believed to account for a wide range of project-specific adverse reaction rates. “For example, a 2004
events project in the Galapagos Island of Isabella had four adverse reactions out of 103 dogs (3.9%). (Adminis-
tration protocols were further refined after this project.) A 2009 project in Todos Santos, Guatemala had
only one major and one minor reaction in 126 treated dogs (1.6%). And a 2010 project in Peru had three
reactions in 249 dogs (1.2%).”

sterilize male dogs in a project in Isabel Island in the
Galapagos archipelago. The project was a cooperative
effort between Animal Balance, the Galapagos National
Park Service, the Galapagos Quarantine and Inspection
System, and the municipal Control and Management
of Introduced Species Committee. The 4-week project
provided not only neutering but also an education program
“developed to promote responsible pet ownership and
encourage residents to restrict their dogs from roaming in
environmentally sensitive areas.”
The market served by the shelter community
Researchers reviewed medical records of 161 male dogs
is complex for a number of reasons. Any company, large
that were sterilized during the program. Fifty-eight of the
or small, established or new, that contemplates marketing
dogs were castrated surgically and 103 were sterilized
products for use in shelter-type situations will want to be
using injectable zinc gluconate:
aware of some of the forces that influence how nonprofit
“Dogs were returned to their owners for organizations such as shelters view contraception and
observation following castration. Wound fertility control for dogs and cats.
dehiscence occurred in two skin incisions,
A 2004 study attempted to determine the number of
representing 3.4% of the 58 dogs that under-
“animal organizations” in the US (Rowan 2008). The list
went bilateral orchiectomy. Necrotizing zinc-
contained approximately 9,500 independent entities.
gluconate injection-site reactions occurred in
four dogs receiving injection volumes near the � 3,352 characterized themselves as shelters, (defined as
maximum label dose (0.8 to 1.0 mL), repre- organizations with a building at their official address
senting 3.9% of the zinc-gluconate procedures. that housed animals).
Surgical wound complications were treated by o Of these, 1,554 (46%) identified themselves as being
superficial wound debridement and resutur- municipal.
ing. In contrast … [the 4 dogs with necrotizing o 1,809 (54%) identified themselves as being private
injection-site reactions] required orchiectomy 501(c)3 (i.e., nonprofit) organizations. Though these
and extensive surgical debridement, including may have a wide variety of names, many are of the
scrotal ablation in two dogs … Low cost, ease type the public thinks of as ”humane societies” or
of use, and cultural acceptance of a castration SPCAs. These shelters may or may not have animal
technique that does not require removal of the control contracts or agreements to house animals for
testes make zinc gluconate a valuable option municipal agencies.
for large-scale use in dogs, particularly in � About 75% or more of the animal protection
remote locations lacking sophisticated clinical organizations concentrate on companion animal rescue,
facilities or skilled surgeons and staff.” housing, and disposal (e.g., adopting out, returning to
owner, and/or euthanasia).
Researchers recommended that “further investigation is Although sterilization as a condition for adopting dogs
needed to identify risk factors in dogs for adverse reactions and cats is not universal, surgical spaying is encouraged in
to zinc gluconate and to develop strategies for avoidance.” countries such as the US and UK. A number of US shelters
“and virtually all rescue groups sterilize dogs before
5.5 “Shelters” making them available … and many shelters that do not
A thorough review of the dynamics and services of do the surgery before the animals leave do require that the
the shelter community, defined as animal shelters and new owner do so. Some advocacy groups … demand laws
nonprofit or governmental agencies that sterilize animals that require spay and neuter of all dogs and cats unless
for adoption or offer community sterilization services, people buy permission to keep their animals intact. Others
is beyond the scope of this document; however, the seek to require shelters to spay and neuter all animals
emergence of non-surgical approaches to sterilization of that leave their premises to avoid unwanted litters in the
cats and dogs is clearly relevant to this market segment. future” (dogsonly.org/spayfaq.html).
Non-surgical sterilization may be acceptable in some
countries and to animal welfare groups that oppose

surgical procedures on the grounds that the procedures viewed hand in hand, but not necessarily combined.
are “mutilation.” In European countries, pharmacological Non–surgical sterilants or contraceptives that can be
approaches to population control have focused on the delivered simultaneously with a rabies vaccine can be
use of oral and injectable progesterone-type drugs in attractive. If not permanent, then a duration of similar
female dogs and cats because “surgical intervention … time to a rabies vaccine could have potential.
is often regarded by owners as inhumane and degrading o Better tools to guide interventions: Several initia-
to a companion animal” (Jöchle 1994). Currently used tives are underway to develop simulation models to
progesterone-type drugs have significant drawbacks for better predict and guide interventions in populations
shelter situations because they require careful monitoring of free-roaming cats and dogs. Initially developed
over time of the estrous cycle of the bitch or queen to be around spaying and neutering, these can be used also
effective, and are not effective in males. to predict the impact of deploying non-surgical tools
For animal shelters and nonprofit or governmental when available.
agencies that sterilize animals for adoption or offer
community sterilization services, there are various issues
� Location (e.g., rural, suburban, urban; local economics).
and considerations affecting their decisions and practices.
� Differentiating among intact animals and stray,
abandoned, and feral animals that have already been
These may in turn affect their embrace of alternatives to sterilized. It can already be difficult to identify a
surgical sterilization. These include, but are not limited to: previously spayed female cat or dog visually, and even
� Ascertaining which reproduction control technologies by examination. Additional tools for variable levels of
best fit the needs of shelter and feral animals. birth control, delivered without the need for anesthesia,
� Availability of funding: Agencies are typically trying to bring up the need for means of readily identifying
stretch resources to help the most animals. Economical animals as having been treated, especially those without
means of safely sterilizing animals will be popular if the an owner to oversee their care.
agencies’ criteria for performance are met. � Degree of community, governmental, and local
� Type of organization and staffing decisions: Some veterinary participation and support, which can vary
organizations sterilize the animals they are placing for widely.
adoption only; others have subsidized programs for pet � Potential to collaborate with other organizations to
owners, often requiring proof of low income or need. provide a wider range of services.
Increasingly, agencies have one or multiple veterinarians
on staff and involved in medical protocol decisions.
� The field of shelter medicine has grown dramatically in
the past decade. The Association of Shelter Veterinarians
(ASV) has grown from a grassroots group of shelter
vets founded in 2002 to a formal organization with
750 members, 22 student chapters around the globe, a
range of published position statements and expanded
continuing education. Shelter Medicine for Veterinarians
and Staff, edited by Miller and Zawistowski of the
ASPCA, the first real text in the field, was first published
in 2004 with a second edition to be published in January
2013. The second edition has a chapter on non-surgical
sterilization.
� Emphasis on birth control vs. other factors: the
percentage of time, funds and focus agencies give
sterilization vs. their other roles including adoption and
preventing relinquishment.
� Better scientific guidance and changes in practice/
funding related to how to intervene in rabies and
population control, especially of free-roaming cats and
community dogs:
o Rabies and population control programs are often

5.6 How Do Practicing and Shelter The majority of veterinarians included in this study
Veterinarians Feel about Pet firmly believe that surgical spay/neuter provides clear
Sterilization and Potential benefits beyond non-surgical sterilization, helping to
prevent health problems and behavior problems in cats and
Non-Surgical Approaches?
dogs of both sexes. (While new products target comparable
The 2002 Contraception and Fertility Control in Animals benefits, this was not stated in the survey and the
report noted that veterinarians are key to the commercial respondents’ assumption may or may not be accurate.) In
success of new animal health products – they have to addition, the majority of veterinarians place at least some
embrace a product and use it in their practices, or in importance on the contribution spay/neuter procedures
shelters where they work, and they are often on the front make to revenues, though only a small percentage views
line. As of the 2002 publication, there was no research these procedures as ”very profitable” relative to other
available on veterinarians’ attitudes towards non-surgical procedures. Importance was also placed on the role of
alternatives to spay/neuter in cats and dogs. A variety of spay/neuter in attracting new clients to the practice.
assumptions had been made concerning veterinarians’
Due to the low level of perceived need for an alternative
beliefs regarding non-surgical contraception and fertility
and the value placed on a range of benefits associated
control in dogs and cats. These assumptions have ranged
with spay/neuter surgeries, research concluded that
from “spay/neuter works and is a profit center so why
private practice veterinarians – also referred to as “general
would I give it up?” to “it would be great to give clients
practice” veterinarians – will need to be convinced to
choices” as representative attitudes among private practice
consider an alternative. However, the data also suggest
veterinarians. Concerns among shelter veterinarians have
there is perceived value in some of the benefits that
been believed to relate to whether cost, permanence, and
a non-surgical sterilant may be able to provide their
ease-of-use characteristics could compete with surgical
clients. For instance, the majority felt it could be a better
sterilization.
option for shelters to use and may increase the number
In 2007, ACC&D commissioned a study of dog and of sterilizations performed in the community overall. For
cat contraception and fertility control attitudes in their own practice, respondents recognized the value in
private practice veterinarians in the US, and in 2008 the offering a non-surgical alternative to clients who are averse
organization collaborated with ASV on a similar study to surgery or who have pets that are not good candidates
of shelter veterinarians in the US. Note that some ASV for surgery. It also is valued as a lower-cost option for pet
veterinarians are in private practices but were included in owners with barriers to the price of surgery.
the shelter veterinarians surveys.
There does appear to be some interest among these
Summaries of key findings are provided below. To review veterinarians in the concept of a single-treatment female cat
the complete reports, see www.acc-d.org/ACCD%20 contraceptive with a duration of 3 years, with 52% overall
docs/VetResearchWebReport.pdf and www.acc-d.org/ ”somewhat or very likely to recommend” and 75% in the
ACCD%20docs/ASVResearchwebreport.pdf. northeastern US the most ”likely to recommend.“ The main
attraction of this product is the lower cost and the ability
5.6.1 Private Practice Veterinarians to offer another option to clients who are averse to surgery;
however, veterinarians are concerned about
According to the 2007 survey of private
the need to repeat the treatment, expressing
practice veterinarians, there is a fairly
doubt that pet owners would remember
low level of perceived need among
to bring their cat in for another treatment
veterinarians for an alternative to surgical
every 3 years. It is fairly clear that, in order
spay and neutering for use in the larger
for any sterilant or contraceptive product to
community and in their own practices.
be broadly considered by veterinarians as
Surgery was described as sufficient. Low
a viable alternative to surgical sterilization
awareness and unknowns about potential
(in more than just special circumstances),
non-surgical sterilant alternatives created
it will need to deliver many of the same
some skepticism. Among those who did see
benefits attributed to surgical procedures,
a great need, comments including “more
preventing health and behavior problems,
affordable,” “less risk with no anesthesia,”
providing permanent sterilization and
and “good for use in pet population
requiring only one treatment.
campaigns” were mentioned.

5.6.2 Shelter Veterinarians Shelter veterinarians were more likely to categorize the
following attributes as very important components of a
The results of the 2008 shelter veterinarian survey were non-surgical sterilant or contraceptive product than private
assessed in comparison to the 2007 survey of private practice veterinarians:
practice veterinarians, summarized in the section above.
While veterinarians in both surveys agreed that unplanned litters
� Requires only one treatment (86% vs. 70%)
are the major cause of unwanted pets, there was a significant
� Provides permanent sterilization (93% vs. 78%)
discrepancy in how shelter vets versus private practice vets felt
� Reduces unwanted behaviors of sexually intact pets (83%
vs. 72%)
about the potential for non-surgical sterilants as a solution.
� Protects against some reproductive tract and hormone-
related diseases (78% vs. 65%)
Nearly all veterinarians surveyed (96% shelter vets,
94% private practice vets) agreed that “unplanned litters While shelter veterinarians indicated a greater need for non-
contribute significantly to the number of unwanted pets in surgical sterilants to control the feral cat population in particular
our community.” than private practitioners, the shelter veterinarians were much
less likely to recommend a temporary (i.e., three year) contracep-
Six in 10 veterinarians working in animal shelters
tive out of concern that the cats would not receive a repeat treat-
indicated that there is a need for non-surgical sterilization
ment. More than 7 in 10 shelter vets were concerned that their
alternatives to control the pet population; however, 6 in
clients would forget to repeat the treatment.
10 private practice veterinarians felt just the opposite,
indicating that there was little or no need for non-surgical � Fewer than a third (30%) of shelter veterinarians
alternatives because surgical sterilizations are adequate and surveyed, compared to just over half (52%) of private
provide additional behavior and health benefits to pets. practice veterinarians, said they would recommend this
Shelter veterinarians were almost twice as likely as private prac- product to their clients.
tice veterinarians to recognize possible benefits of non-surgical � More than 7 in 10 shelter veterinarians said they were
sterilizations. concerned that pet owners would forget to have their
cats treated again in 3 years (82% versus 72%).
In a side-by-side comparison of input from shelter � All veterinarians saw the greatest need for sterilants to
veterinarians and general practice veterinarians, be available for female cats compared to male cats and
respectively, shelter veterinarians were more likely to find female and male dogs; however, shelter veterinarians
the following possible benefits of non-surgical sterilizations rated the need much greater, with 62% ranking it a 6
highly valuable (i.e., a rating of 6 or 7 on a 7-point scale): or 7 on a 7-point scale compared to general practice
� Could increase the number of sterilizations performed in veterinarians, of whom 22% gave such a sterilant a
the community (68% vs. 50%) rating of 6 or 7.
� Could increase the number of sterilizations
5.6.3 Key Messages from the Surveys
performed in the shelter/clinic (64% vs.
34%) In order for any pet sterilant or contraceptive
� Reduces the time and resources required product to be broadly considered by veterinarians in
by the veterinarian and shelter (62% vs. the US as a viable alternative to surgical sterilization
32%) under more than just “special” conditions, the
� Provides a lower-cost alternative to offer surveys appear to indicate that the product(s)
clients (53% vs. 30%) will have to deliver many of the same
� Is a safer alternative for the animal due to benefits attributed to surgical procedures,
fewer risks and side effects than surgical i.e, preventing both health and behavior
spay/neuter (45% vs. 35%) problems, providing permanent
More shelter veterinarians than private practice sterilization and requiring only one
veterinarians indicated that it was very impor- treatment.
tant that a non-surgical product requires only
Research, development, and
one treatment, provides permanent sterilization,
successful commercialization of non-
reduces unwanted behaviors of an intact pet, and
surgical sterilants will require educating
protects against hormone-related diseases.
veterinarians regarding the potential use
of these products as a means of reducing

the pet population and as an alternative or supplement to An unfavorable comparison will create barriers to
surgical sterilization. acceptance.
While the labeling required by regulatory authorities will
5.6.4 Other Issues Veterinarians Can Be Expected help veterinarians understand the expected effectiveness
to Consider of new contraceptive and fertility control products, in-
office testing that can assess continued effectiveness (e.g.,
What are the key characteristics that any product for serum anti-GnRH antibodies in the case of a GnRH
intended for use by companion animal veterinarians will vaccine) to monitor how well products are working may
require to be successful? help vets gain confidence and minimize concerns about
� Profitability – Veterinary practices are businesses and liability.
therefore must be profitable. Operating a veterinary Companies developing and marketing such products can
practice entails carrying a variety of fixed costs, and also help build confidence by ensuring that veterinarians
although those costs vary depending on the location have client education tools that set appropriate
and nature of a given practice, surgical sterilization expectations for the performance of a given product.
consumes time and resources that could be
employed more effectively. A product that enables
5.7 Owner Willingness to Pay for a
veterinarians to make a good margin and frees time to
see additional patients could turn a relatively expensive
Non-Surgical Alternative
procedure for the veterinarian into a solution that Will clients be willing to pay for an innovative non-
benefits owner, pet, and veterinarian alike. It would surgical contraceptive or fertility control product?
appear likely that given the inherent costs and time In the US, there are relatively recent, reliable data that
requirements of performing sterilization surgery, non- show that dog and cat owners are willing to take their
surgical alternatives offer the potential for greater animals to the veterinarian and pay reasonable costs for
margin. treatment.
� Safety to humans – Veterinary professionals
� Annual expenses in 2010-2011 for surgical visits for
administering contraceptives must be assured that these
dogs in the US averaged $407 and routine veterinary
products can be used safely. Companies contemplating
visits averaged $248 .americanpetproducts.org/press_
developing and/or marketing such products may also
industrytrends.asp)
wish to consider including a delivery device that would
limit the possibility of accidental self-injection or other � Annual expenses in 2010-2011 for surgical visits for
cats in the US averaged $425 and routine veterinary
exposure as part of the product concept.
visits averaged $219 (americanpetproducts.org/press_
� Animal safety – Veterinarians are charged with
industrytrends.asp)
protecting the welfare of the animals they treat, and
products must be proven to be safe to their satisfaction. An AVMA survey (AVMA Center for Information
� Minimal liability – Liability is clearly a concern of Management 2012) indicates that in 2011:
veterinarians in instances in which an animal does not
respond to a product as expected. In addition, products
� “The mean veterinary expenditure per household [for
dogs] was $378 in 2011 … the mean expenditure per visit
with durations that vary according to the responses was $146 … the mean expenditure per dog was $227
of individual animals (e.g., contraceptive vaccines)
should be labeled so that they can be re-administered
� “The mean veterinary expenditure per household [for
cats] was $191 in 2011 … the mean expenditure per visit
at the minimum effective time frame safely in all target was $122 … the mean expenditure per cat was $90
animals.
� 81.3% of dog-owning households visited a veterinarian
� Documented effects on behavior and health that at least once in 2011,
compare adequately to spaying and neutering – compared with 82.7%
There are positive non-reproductive effects of surgical in 2006
sterilization which are documented and other “effects”
which are essentially widely held beliefs. These effects
� 55.1% of cat-
owning households
range from decreased incidence of disease to behavior visited a veterinarian
often felt to be more likely to preserve the pet-owner at least once in 2011,
bond. Veterinarians value these effects and will need compared with
to understand how a contraceptive product compares. 63.7% 2006

switch the method by which they control reproduction
� 26.9% of dog-owning households reported spending in their pets as well as customers who would not choose
between $200 and $499 on veterinary services in 2011
surgical sterilization. In the past, researchers and animal
compared to 29.4% in 2006; 17.9% reported spending
welfare advocates tried to define the “ideal” non-surgical
between $100 and $199, compared to 15.8% in 2006;
contraceptive, with a long list of attributes such as
20.1% of dog owning households reported no veterinary
“cheap” and “completely safe” and “100% effective.”
expenditures in 2011, compared to 20.9% in 2006
Paradoxically, creating such a high bar for a new product
� 15.4% of cat-owning households reported spending
discouraged both research and investment into dog and
between $200 and $499 on veterinary services in 2011
cat contraception, as various stakeholders realized the
compared to 19.1% in 2006; 13.3% reported spending
difficulty of creating such an ideal product. ACC&D has
between $100 and $199, compared to 15.3% in 2006;
encouraged stakeholders to consider a ”tool box” approach
46.1% of cat-owning households reported no veterinary
– i.e., that there may be many different approaches to
expenditures in 2011, compared to 39.2% in 2006
companion animal contraception, and each may have its
� Total expenditures on veterinary services for dogs and
uses, limitations, and strengths in different situations.
cats in the US in 2011 were ~$26.43 billion
o Total expenditures on veterinary services for dogs That said, it is useful to consider what types of issues
were ~$19.07 billion could affect the “ideal” product characteristics for various
o Total expenditures on veterinary services for cats potential customers and stakeholders. Below are some
were ~$7.36 billion examples of these considerations.
In addition, Permanent versus nonpermanent (“reversible”) versus long-term
� 37% of caretakers of feral animals are willing to pay for • Permanent: pet owners who do not wish to breed their
veterinary services, including sterilization (Centonze animals
and Levy 2002). • Nonpermanent: pet owners who plan to breed their
animals, show animal owners, responsible breeders
The 2011 AVMA survey indicated that 9.7% of the most
recent veterinary visits by US dog owners and their dogs • Long-term: pet owners who prefer a non-surgical
were to have the dog spayed or neutered, up from 7.3% in approach and do not wish to have their pets sterilized;
the 2006. Among cat owners, 13.1% of the most recent visits TNR programs (see section 5.4) serving populations
to the veterinarian were to get the cat spayed or neutered, for which modeling studies have demonstrated
compared to 14% in 2006. effectiveness equivalent to surgical sterilization
Veterinarians can enhance the level of services they
provide by playing a role in educating new pet owners Contraception/fertility control with or without sexual behaviors
about what to expect from sterilization or contraception • For many pet owners, one of the reasons for using a
in terms of dog and cat behaviors and strengthening the contraception or fertility control product for their pets
human-animal bond, thereby contributing to a decrease is to eliminate unwanted sexual behaviors
in relinquishment and abandonment rates. It is estimated • Some pet owners may wish to avoid unwanted litters,
that in the US, preserving the human-animal bond could yet feel that it is inappropriate to interfere with an
increase veterinary income by at least $2 billion a year.
animal’s natural behaviors
“Simply put, if animals
don’t remain in their homes, Method of administration: implant
they can’t be cared for by versus injection versus oral
veterinarians as [the animals]
age. They also can’t use • Injection: Injections can
or consume products sold cause transient pain to
by pharmaceutical or pet the animal, though it can
industries” (Olson 2002). be mitigated by the body
location of the “shot.”
5.8 The “Ideal” Reports of vaccine-associated
Product fibrosarcoma have made some
cat owners more aware of the
Companies that will market
potential for problems at the
new non-surgical products will
injection site. Ideally, marketed
be courting customers who may
products will be based on
formulation technology that will minimize injection contraception in pets will increase, animal health in general
pain and injection site reactions. will improve, and, hopefully, there will be fewer unwanted,
• Implant: Implants have the same potential for transient stray, relinquished, and abandoned animals.
pain as injections. In addition, owners may find it (See section 5.10 for a summary of technologies and
unacceptable to feel an implant beneath the skin when marketing issues that are likely to occur as products are
they pet their dog or cat, so a rigid or large implant developed for the pet owner market.)
may be unacceptable for some owners. However,
should “soft” implants be developed and approved, 5.8.1 An Initiative to Develop a Single, Permanent,
they may be more difficult to feel, and therefore, Non-Surgical Sterilant for Male and Female
more acceptable. (This is not likely to be an issue Dogs and Cats
for population control in feral animals.) Should an
owner wish a soft implant removed, for instance, In the past several years there has been a renewed
to breed the animal, the implant may be located via interest in developing a single sterilant that would be
ultrasonography. effective in male and female dogs and cats. This objective
has been made more attractive to researchers and
• Oral: Although oral contraceptives for bitches and
organizations that may not have targeted this opportunity
queens have been developed, they have offered no
previously by the establishment of the Michelson Prize
more than 6 months of fertility control and require
& Grants in Reproductive Biology. The program was
precise, repeated administration. The side effects of
launched in October 2008 and first grants awarded in 2009.
these progesterone-based products include increased
risk of conditions such as pyometra and diabetes; The $25 million Michelson Prize in Reproductive Biology
thus their acceptance is very poor in the US and is offered to incent researchers to develop an ideal non-
variable internationally. In order to be approvable surgical sterilant for dogs and cats. The competition
by regulatory authorities, an oral formulation will is open to any qualifying entity from any country. The
have to be demonstrated as safe for animals, humans, program has been established to develop a low-cost,
and the environment. This is particularly true of bait non-surgical method of cat and dog sterilization that will
formulations. enable nonprofit organizations, animal care centers, and
Dogs versus cats non-governmental agencies (NGOs) to sterilize large
populations of cats and dogs and reduce the number of
• Variation in cultural attitudes towards dogs and
homeless and unwanted animals that are killed each year
cats may influence the ultimate product mix. Some
in shelters.
cultures “value” one species more than the other,
and expenditures not only by owners but also by As stated on its website (michelson.foundanimals.org/
animal health companies may reflect that. Owners about-michelson). The foundation recognizes that research
may demonstrate more resistance to contraceptive required to develop and test pharmaceuticals takes time
technologies for male dogs than for the tomcat, as is and money, and many interested parties may not have
the pattern in some parts of the world with regards to access to the resources needed to initiate and maintain this
surgical castration. research. For that reason, Found Animals also offers the
• Physiological differences between dogs and cats may companion Michelson Grants in Reproductive Biology,
affect the relative viability of a given technology. For research funding for promising proposals in pursuit
instance, cats appear to be more sensitive to adjuvants of non-surgical sterilization technology. See Chapter 4,
present in certain formulations. section 4.3 for information on projects that have received
• Less research on these technologies has been grant funding as of the publication of this document,
undertaken in cats than in dogs, so it is unclear and michelson.foundanimals.org/grant-winner-bios for
whether the technologies that appear most promising updates.
in dogs will be applicable to cats. The $25 million Michelson Prize
Despite the difficulty posed by the will be awarded to the first entity
variability in pet owner preferences, to provide the foundation with a
the fact that more than one approach technology proven to have defined
to contraception and fertility control in characteristics. Specific parameters
dogs and cats is being developed may can be found in Chapter 4, section
mean that ultimately, overall rates of 4.3.3.1.

The Found Animals Foundation are actually subsidized, which
(foundanimals.org) is supporting means the difference in what the
and managing the process shelter, pet owner, or prospective
(michelson.foundanimals.org/ pet owner pays and the actual
about-michelson). Importantly, they cost is made up in some way
also plan to fund and be involved (Slater 2002).
in the commercialization and In addition, once several
introduction of the technology of non-surgical approaches are
any winning application. Pursuing commercialized and approved
product development as a private for use, competition may bring
foundation for charitable purposes pricing down. This would enable
may well result in different business the shelter community to take
plan and requirements for return on advantage of affordable products
investment than those of a for-profit company. that will then have a history of safe and effective use by the
Note that technologies for which Michelson Grants have veterinary community behind them.
been received that do not ultimately meet all Michelson For some time, the non-surgical dog and cat
Prize criteria, but are effective for a given population or contraception community has operated under the premise
a given length of time, may be developed or licensed for that a “silver bullet” single approach is not feasible due
development by their inventors. A brief perspective for to differences in canine and feline physiology as well
animal health companies looking to advance this category as gender differences. Does the new Michelson Prize &
of products follows. Grants initiative to find and advance a single, permanent,
approvable, and commercializable non-surgical approach
5.9 Commercializing, Manufacturing, and for male and female cats and dogs lessen the opportunity
Marketing Products Profitably to develop other approaches? To the contrary; in fact, the
Companies that advance non-surgical technologies will quest for a single, permanent approach can be expected
need to make sufficient profits to amortize years of R&D to encourage research in this area and it has. As noted
and regulatory approval, as well as current operating and previously in this chapter, grantees whose approaches do
product costs. not ultimately meet the criteria for winning the prize will
have developed intellectual property that could result in
Companies may target nonprofit or governmental
value to licensees or acquirers of those technologies as
agencies and their veterinarians – especially those who
candidates for further development (Jöchle and Rhodes,
are treating a large number of animals annually – as
most receptive to non-surgical alternatives; however, the
assumption that low price is a priority may be a barrier, While a single, permanent solution may fit the needs of
and may not always be correct, as the cost will need to be some dog and cat population management stakeholders,
compared with costs of surgical alternatives. there will be veterinarians and owners who prefer reliable
non-permanent approaches, as indicated by the commercial
Animal health companies’ primary focus is on pet
success in Europe, Australia, and New Zealand of the
owners and the veterinary community that treats their cats
6- and 12-month Suprelorin (deslorelin) GnRH agonist
and dogs. Companies might see opportunities to partner
implants marketed by Virbac (see Chapters 3 and 4).
with private practitioners with both a higher wholesale
price and ultimate retail than would be seen at the shelter,
where little mark-up would likely be taken. Animal
5.10 Marketing Issues in Cats and Dogs:
health companies may fear a tiered-pricing structure that the Bottom Line
veterinarians could feel puts them at a disadvantage with As discussed earlier in this report, the history of research
”shelters.” in contraception and fertility control for cats and dogs is
However, alliances among animal-related funding a long one. Researchers have continued to explore non-
sources, the shelter community, and animal health surgical alternatives, knowing that such products could
companies could help create a structure in which the cost of offer significant advantages in population control for dogs
contraception and fertility control could be subsidized – in and cats. This research has been of interest not only to
fact, many existing “low-cost” spay and neuter programs organizations that have long been involved in the welfare
of animals and creating awareness of population control
issues, but also to the new organizations that continue to These include:
be founded worldwide. Research continues, the quest for
funding of low-profit or nonprofit segments continues, and
� Dealing with an unusually fragmented market in terms
of customer groups, cultures, societal factors, and
debate about population figures and the relative value of desired product profiles
population control strategies continues.
� Understanding clearly the profile, including the
Non-surgical contraception of dogs and cats is regarded limits of a given technology in terms of the marketing
as a market with significant potential due to the sheer opportunities it presents – and doesn’t present
numbers of animals, the percentage of animals that are � Implementing public relations and education activities
not spayed or neutered, the fact that pet owners spend an that target each customer group and its key influencers
increasing amount of money on their animals, and focus of • Being open to mutually beneficial collaborations,
governments on broadscale population control programs of partnerships and unique business models, especially
both dogs and cats to address zoonotic disease and public to serve the large market for unowned pets
health. There are some common factors that marketers may
want to consider when assessing what would be required 5.10.1 Issues that Affect Marketing of Contracep-
tion and Fertility Control for Dogs and Cats
to serve pet owners and the ”shelter” community.
The following table is intended as a guide and is not to be
considered exhaustive.
Table 5-24: Issues Affecting Marketing of Contraception and Fertility Control for Dogs and Cats
Customer Group What’s Important to Them
Owners and all other stakeholder
groups
� Human and animal safety
� Reassurance that there are no harmful effects on treated animals, including
very young animals and animals that are pregnant when treated
� Reassurance that new technologies and products are effective
� Clarity on the non-reproductive effects on behavior and health and believing
they compare adequately to surgical sterilization
� Eliminating “objectionable” behaviors (e.g., yowling, spraying, roaming,
fighting) that contribute to pet abandonment
� Ease of use
� Predictable duration of effect
� Predictable onset of effect
Nonprofit organizations and
government agencies
� Single treatment
� Effectiveness (likely permanent sterilization) for adoptable animals and
animals treated in Trap-Neuter-Release (TNR) programs
� Trained technician can perform the procedure
� Low cost
Reputable breeders and show ani-
mal owners
� Flexibility (showing schedule vs. breeding schedule)
� Full understanding of effects, if any, on treated animals, subsequent litters
Veterinarians
� Client choice (permanent sterilization or predictable length of control)
� Protects against some reproductive and hormone-related diseases
� Trained technician can perform the procedure as a cost savings
� Is profitable
� Has regulatory approval and is backed by clinical safety and effectiveness data

6.0 Regulatory Issues: Some Understanding (MOU) stating the decision.
Considerations for Evaluating The following is an example of a murky regulatory

area – the regulation of immunocontraceptive vaccines for
Contraceptives for Dogs and Cats fertility suppression in wildlife. In the past, the CVM has
indicated that it will regulate all immunocontraceptive
Regulatory requirements for approval of contraceptives
products for all species. A regulatory decision was made
for dogs and cats differ depending on the mechanism of
in 2006 to clarify the role of the FDA, USDA and the
action of the contraceptive approach, as well as the country
Environmental Protection Agency (EPA) in regulating
in which approval is sought. The purpose of this chapter is
contraceptives for use in wildlife and free-roaming animals.
not to serve as a detailed guide for regulatory approval of
A draft MOU between the FDA and the EPA was developed
specific products, but to give an overview of the regulatory
in which the EPA agreed to register contraceptives
processes and issues.
and immunocontraceptive vaccines for wildlife and
Regulatory requirements generally fall into three major feral animals (e.g., white-tailed deer, wild horses). In
categories for companion animal products: particular the EPA agreed to regulate GonaCon™, the
� Effectiveness gonadotropin-releasing hormone (GnRH) vaccine labeled
� Safety as an “immunocontraceptive vaccine for use in white-
� Manufacturing (also called chemistry, manufacturing tailed deer,” and the label, as approved by the EPA, further
and controls or CMC) defines the product as a “restricted use pesticide.”
Note that there are additional requirements for products In 2006, at the Alliance for Contraception in Cats &
intended for animals used for food, (e.g., meat and milk). Dogs (ACC&D) 3rd International Symposium on Non-
Discussion of these requirements is beyond the scope of Surgical Contraceptive Methods of Pet Population Control,
this document. representatives of the National Wildlife Research Center
(NWRC), a governmental agency within USDA Wildlife
The company that is developing the product is called the
Services (WS) that developed GonaCon, announced that, in
Sponsor, and it is responsible for submitting all information
addition to agreeing to review the application for GonaCon
required for review by regulatory authorities prior to
for white-tailed deer, the EPA would register fertility
approval. In addition, most regulatory bodies that review
control products targeted at feral cats based on an EPA-
data submissions to support regulatory approval require
FDA MOU (acc-d.org).
payment of significant fees (hundreds of thousands of
dollars) as part of their review requirements. The FDA agreed to retain authority over drug-based
contraceptive and immunocontraceptive vaccines for use
6.1 United States Regulatory Agencies in captive and pet animals, including livestock, companion
animals (dogs and cats) and zoo animals (Fagerstone,
The regulatory landscape for dog and cat contraceptives
in the United States (US) is complicated.
NWRC recently indicated that it is interested in
Contraceptives can be divided into two broad categories:
seeking EPA registration of GonaCon for use in feral
drugs and vaccines. Drugs to be used for contraception
and loosely owned dogs on Native American tribal
are regulated by the Food and Drug Administration
lands in the US. Additionally, approval by the
(FDA) Center for Veterinary Medicine (CVM). Although
EPA is considered a step towards a new fertility
vaccines for animals are usually approved by the United
control tool for free-roaming dogs internationally,
States Department of Agriculture (USDA) Center for
where the dog rabies problem is far greater than in the
Veterinary Biologics (CVB), in the past the FDA has
US, because often international regulatory agencies
indicated that the CVM will regulate vaccines used for
will accept approval by US regulatory agencies
immunocontraception for dogs and cats.
as a basis for approval in their countries. NWRC
For situations in which regulatory authority may be provided a letter from the EPA, dated December
unclear, the Sponsor may contact the agency of its 28, 2012, that states: “We have reviewed your
choice and which it believes is most appropriate, and request for a determination of whether EPA would
that agency will then confer with the other agencies have regulatory oversight for a new proposed use of
to make a decision as to which one will Gonacon™ for use in wild and feral
regulate. The convention is that the Sponsor free-roaming dogs. This proposed
will then be sent a Memorandum of use of Gonacon™ will be targeted

for wild and feral free-roaming dogs on
tribal lands. We discussed this proposed
� How the product will be packaged
use internally and with the Food and
� Draft labeling
Drug Administration. It was decided that
� Where the product will be used (e.g.,
states, locations, rural/urban areas)
this is a pesticidal use that EPA will have
regulatory jurisdiction over.” NWRC
� Opportunities that may exist for
human exposure and potential effects;
has also requested an Experimental
and whether restricted use would be
Use Permit from the EPA to conduct a
appropriate to minimize likelihood of
large-scale efficacy study on US Indian
such exposure and effects
reservations to collect the necessary field
effectiveness data for a registration”
� How long the contraceptive/sterilant
effect lasts in target animals
(Fagerstone, personal communication
2012).
� Opportunities that may exist for
environmental exposure
There are two interesting issues � Effective measures of package disposal;
here. First, how will it work if the EPA indicate return to manufacturer if
regulates immunocontraceptives for feral appropriate
cats and dogs, and the FDA regulates the same product � Identify and analyze potential effects in humans should
used in pets? Second, how would “feral” be defined? In the exposure occur; develop method of treatment for any
case of dogs, it appears that the EPA regulatory authority human exposure; include a telephone emergency
will only apply to feral dogs on tribal lands – a significant response number
restriction of the target population.
An example of a contraceptive drug that EPA regulates
Advocates are leery of feral cats being defined as “pests” is OvoControl® for control of wild pigeons, geese and
as a condition for a feral cat contraceptive to be approved ducks. This product is delivered as bait and distributed
by the EPA. The worry is that defining feral cats as pests in the environment, which reduces the hatchability of the
would then allow eradication programs and might affect eggs. The EPA took regulatory jurisdiction of this product
the Trap-Neuter-Return/Release (TNR) programs that are because it is distributed in the environment, and also
currently used. This concern was raised in considering EPA because it is used for wildlife management.
registration for the wild horse contraceptive ZonaStat-H,
The way to confirm the regulatory assignment of future
and ultimately it was concluded that EPA registration
products is for a Sponsor to undertake the process, navigating
offered benefits that outweighed the concerns (Hazard11,
through the complexities and politics as they unfold.
If the EPA is the regulatory review body for a new 6.2 European Regulatory
product and classifies it as a pesticide under the Federal Agency
Insecticide, Fungicide and Rodenticide Act (FIFRA), data
requirements might be abbreviated based upon proposed Europe in particular is an attractive market for non-
labeling and the method of application – for example, an surgical contraceptive products for pets due to what is
injection or implant. Data requirements for pesticides are characterized as a historical and general reluctance to
determined by use and likelihood of exposure to humans, surgically alter dogs and cats (see Chapter 5 for further
domestic animals, and the environment. Appropriate discussion). The European Medicines Agency (EMA,
waivers from the requirements for individual studies may previously known as the EMEA) regulates companion
be accepted by the EPA based on the lack of exposure animal drugs and vaccines for the European Union (EU).
potential, e.g., when use of an implant is involved. There is a centralized procedure for the approval of
innovative new drugs, so that a Sponsor can submit one
A strategy for conducting studies for any pesticide set of required documents (dossier) to achieve approval
and requests for waivers should be based on a thorough in all the member EU countries. Note that Suprelorin®
understanding of how the product would be used. For (deslorelin) 6- and 12-month implants have been approved
example, for the subject product to sterilize feral cats, in the EU for fertility control in male dogs; the product
consideration should be given to the following: is marketed by the animal health company Virbac (see
11
Holly Hazard is Senior Vice President, Programs and Chapter 4).
Innovations, at Humane Society of the United States (HSUS).

6.3 Rest of World best label claim for these products. There is an effort to
harmonize registration requirements in the major markets –
Review of all international regulatory considerations
the US, EU, Japan and other countries are working together
and procedures is beyond the scope of this document. In
to draft guidelines (Veterinary International Committee on
general, each country has its own procedures for meeting
Harmonization).
requirements, and it cannot be assumed that registration
(i.e., regulatory approval) is assured in other markets once
CVM or EPA requirements are met. For example, Canadian 6.5 Time Frame for Regulatory Approval
and Japanese registration often has requirements that differ How quickly regulatory approvals can follow after
from those in the US. submission of all required documentation varies
widely depending on the country, the product, and the
6.4 General Considerations and quality of the submission. Working closely with a given
Harmonization Efforts regulatory body during the development of a drug or
immunocontraceptive can speed up the process in some
For each country, a full regulatory submission has to
cases, but it would not be unusual for the entire approval
be prepared to achieve approval for marketing. Typically,
process, including required studies and regulatory review,
agencies require that additional clinical trials be conducted
to take up to 6 to 10 years, and the process could be longer
in their own countries, and additional safety testing may
for long-acting products. Nonetheless, products have been
be needed, even though regulatory approval may have
approved, as shown in Table 6-1.
been attained in other countries. Considerable effort is
required to reformat regulatory submissions and meet all Products listed below received regulatory approval
requirements. In general, studies are designed to prove between 2003 and 2012. The list does not include older
safety, efficacy and environmental safety, and achieve the products based on progesterone or related compounds.
Table 6-1: Contraceptive Products Approved by Regulatory Authorities in the US and EU
EPA FDA USDA EMA

Dogs - Neutersol® (2003), also - Suprelorin® (males)
called Zeuterin™ (males) Gonazon™ (females)
Intra-testicular sterilant (Both products are GnRH agonists)
Cats - - - -
White-tail Deer Gonacon™ (females) - - -
GnRH vaccine
Canadian Geese, OvoControl®
Wild Pigeons and Nicarbazin
Ducks
Wild Horses ZonaStat-H (females)
Porcine zona pellu-
cida vaccine

Note that the following sections pertain specifically to the ages and breeds should be used for the clinical work, as
US regulatory landscape but can be expected to be similar some veterinarians might want to use a contraceptive in
to the general requirements of any regulatory agency with adult animals, while others will be interested in treating
responsibility for products for dogs and cats. very young animals, should owners not want their bitches
to exhibit even one estrus.
6.6 Effectiveness Duration and potential reversibility of effect will need to
What claims can the label of a contraceptive product be measured in clinical trials.
contain? The claims are based on the effectiveness of the If the label claim is intended to be “effective
product and are backed up by clinical data in the relevant contraception for a year,” breeding studies of at least a
species. Design of the efficacy claims and clinical trials to year’s length will be necessary. How will efficacy be proven
prove them must be coordinated with a clear strategy so if the label claim is permanent sterilization? Multi-year
that at the end of the development process, the market is trials over the lifetime of a pet are not practical, and so it
defined and communication with customer groups can be is unlikely that a label claim such as this would be realistic
effective. unless the product showed actual tissue destruction of
For contraceptives and fertility control agents, claim the testicles or ovaries. One strategy that companies
structure must include: developing these types of products might want to take is to
initiate launch of the product with a label defining duration
� The species in which the product will be used as 6-12 months, and then continue the studies, filing label
� Definition of the population that the product is useful for extensions to increase the duration claim, if possible, or to
(e.g., for male and female dogs greater than 6 months of
demonstrate that repeat treatment extends the duration of
age)
effect.
� How quickly the product will show its effect (e.g., for
vaccines, how long is it from the initial injection and any What about products that may have a variable onset
follow-up boosters to full contraceptive effect) of and decline in efficacy, such as a GnRH vaccine or ZP
� The length of time for which the product is proved to vaccine that may provide 6 months of contraception in one
work (duration of effect) animal and 2 years in another? Even in the best of cases,
� The potential reversibility of the treatment (e.g., will individual animals in a clinical trial will probably have to
animals regain their ability to breed when treatment is be followed for at least a year, making clinical efficacy trials
discontinued, and if so, in how long a time) long, labor intensive, and expensive. If claims for continued
� How the product is used (injections, oral dosing, effects based on booster immunizations are desired, multi-
implants) year trials may be needed.
� The schedule of use (e.g., once every 6 months) For vaccines, co-development of a serum antibody
� Dose (if applicable) test may be helpful, if serum antibodies can be shown to
For both dogs and cats, it is important for a developer of directly correlate to suppression of fertility. This type of
a contraceptive product to make sure that the clinical trials correlation would have to be demonstrated adequately in
are conducted in the widest possible population in order to large clinical trials. The veterinarian could then periodically
achieve the broadest claim. For example, dogs of various test an animal for anti-zona pellucida (ZP) or anti-

GnRH serum antibodies to or inflammation. During the
predict the need for booster study, blood tests are usually
vaccinations. For GnRH performed to measure
agonist implants, efficacy any drug effects on serum
should be dose-related and chemistry and hematology
easier to predict than that of parameters.
immunocontraceptive agents, At the end of the target
which rely on an animal’s animal safety study, animals
innate immune response to are euthanized, and full
treatment. necropsies are performed
One of the major reasons pet – gross pathology and
owners spay or castrate their histopathology are required,
pets is because the animals along with serum hematology
are exhibiting unwanted sexual behaviors such as estrous and chemistry, and other, more specialized measurements
behavior in females, and mounting and territory marking depending on the product. All procedures must be done
in males. To include label claims on their contraceptive under good laboratory practice (GLP) guidelines, which
products such as “use of this product will reduce sexual increases the costs. Designing the protocol for the study,
behavior,” sponsoring companies may have to conduct having the study reviewed and agreed to by the CVM in
well-controlled, blinded behavioral evaluations. Even if the case of drug approvals, completing the study (including
it can be demonstrated that the proposed contraceptive the histopathology), and writing up a final report can take a
suppresses serum sex steroids, such as testosterone in year and up to $500,000 or more, depending on the species
males, it is unlikely that regulatory authorities will allow and duration of the experiment.
using this surrogate endpoint to make behavior claims. Many agencies also require “field safety” to be evaluated
Suppression of estrous behavior may be easier to document in a wider population of breeds and ages, in a “real-world”
than reduction in aggression. If behavioral claims are situation. To satisfy this requirement, safety information
desired, clinical trials to evaluate behavior will have to be (side effects, also known as adverse events) are required to
designed carefully. It is interesting to note, however, that be collected during field trials and reported to regulatory
the package insert for Neutersol, which was approved by authorities.
the FDA without behavior studies being required, includes
the following statement: “As with surgical sterilization, Finally, after a product is approved, the FDA and other
secondary male characteristics (roaming, marking, regulatory bodies worldwide require post-approval
aggression, or mounting) may be displayed.” monitoring for safety, called “pharmacovigilance.” This
means that the Sponsor is required to put in place a way to
collect reports of problems or side effects seen in animals
6.7 Target Animal Safety
treated with the product, and these adverse events must be
Contraceptive products must be safe for the target reported regularly to regulatory agencies to monitor safety
animals, but what exactly does “safe” mean? Safety is in the actual population of dogs and cats being treated with
generally proved by doing a study in the “target” animal the product.
– i.e., the animal species in which the product will be used.
Ideally the resulting study shows that the normal dose 6.8 Human Safety
and higher doses, sometimes given multiple times, cause
no adverse effects. The study must include a reasonable In all cases, the safety of the person handling products
number of animals of the appropriate ages. For example, in is a concern. If a vaccine or other injectable product has a
the Veterinary International Committee on Harmonization long-lasting or permanent effect, the people administering
Guidelines for Target Animal Safety, eight animals per the product will be at risk for self-injection and compromise
group are suggested – four males and four females, and of their own fertility, and the labeling will have to reflect
guidelines suggest inclusion of 0, 1, 3 and 5X groups12; total these issues. It may be that some types of products could
animals used may be limited to no more than 32. Animals be restricted to use by veterinarians only. For Gonacon,
are observed for any behavioral changes, and injection or regulated by the EPA, the label states: “Restricted use
implant sites are monitored for any signs of irritation, pain pesticide: due to non-target injection hazard. For the
use by USDA-APHIS wildlife services or state wildlife
12
1, 3, and 5X refer to multiples of the expected dosage.

management agency personnel or persons working under 6.10 Manufacturing
their authority.” These types of requirements would have
In the case of drugs, manufacture of the active
to be worked out with regulatory agencies.
pharmaceutical ingredient and the formulated product
Exposure to toxic substances such as chemotherapeutic must be conducted under good manufacturing practice
agents, and worries about HIV and other infectious agents (GMP). For vaccines, similar quality standards apply. Below
in human blood, have prompted a number of companies are some brief observations on some of the key regulatory
to develop injection technology that protects the person issues in meeting the manufacturing requirements.
giving the treatment. It should be possible for some type
Probably the least appreciated but most important step
of device to be developed for veterinary contraceptive
in bringing a product through commercial development
injections that would similarly protect the veterinarian or
successfully is developing a formulation – that is, the
technician giving the injections to animals.
active ingredient in combination with excipients that help
This could become an issue even in the development of keep it stable, in solution, buffered appropriately, etc.
immunocontraceptives that may be entering clinical (field) Formulations that are used for ”proof-of-concept” research
trials. Veterinary clinics could be reluctant to participate or early stage efficacy studies rarely are suitable for full-
in a clinical trial in which their staff members may be scale development. The final formulation needs to be stable
exposed to an experimental contraceptive. Certainly it – i.e., the active drug or antigen has to remain intact over a
would decrease the risk of participation if the experimental reasonable shelf life. It must be determined if the product
immunocontraceptive were to be delivered via a device needs special storage requirements (such as refrigeration),
that minimized the possibility of human exposure. In fact, which may impact practical use in the field. If a proposed
the company that launches its contraceptive vaccine or injectable is to be delivered in a multi-dose vial, the
injectable product along with a safe mode of administration stability of the remaining product after the first dose is
should have a definite commercial advantage. removed must be determined.
Concerns over liability will need to be addressed both The formulation must be non-irritating to tissue when
in the clinical development of the product and in its injected or implanted, especially if multiple applications
commercial use, and this may be one reason companies are required (e.g., boosters or repeat implants). The
have been reluctant to develop these types of products. formulation must be inexpensive enough to enable a
market appropriate price and deliver a reasonable profit
6.9 Environmental Assessment margin (which may vary depending on the Sponsor’s
objectives and situation). Sterilization methods must be
Particularly for the EPA, but also for other regulatory
developed that are effective and do not degrade the active
agencies, the environmental impact of contraceptives must
antigen or drug. Analytical methods must be developed
be evaluated, and the scope of this assessment will depend
under GLP conditions to measure the antigen or drug. If an
on the specific product. Oral, implanted or injected drugs
implant is being developed, release rates of the active need
that are given to individual animals that therefore have
to be demonstrated under a variety of conditions, and if the
limited effects on the environment generally will receive
product is to be an injectable, syringeability must be good.
a waiver from conducting an extensive environmental
assessment. Once a few possible formulations have been defined
that meet these criteria, efficacy must be confirmed in a
Over the years, various research approaches to
reasonable number of animals. For a contraceptive product,
contraception for wildlife and feral animals have included
these efficacy tests can take 6
attempts at designing baits to place in the area
months to a year, assuming the
where feral animals live. Baited contraceptives are
product claim is for that length
very unlikely to be approved, since the probability
of time. Depending on the
of “off-target” animals or humans – including
fragility of the product (antigen
children – being exposed is high. Development
or GnRH agonist), the process
efforts are underway to achieve a species-specific
of reaching a final formulation
result, in which only the target species will
can take several years, and cost
respond to or be able to access the bait, but species
several million dollars.
specificity is a significant obstacle.
Separate formulations may
be needed for various species,

especially for products requiring adjuvants in order to be to meet regulatory requirements, and its profitability. Fail to
effective. Even if the active drug or antigen is the same, if fulfill any of the requirements, and no matter how well the
the formulation is different, all requirements must be met product works, it will not be approved for sale.
for each formulation. During formulation development, it The costs and timing of meeting the requirements and
is necessary to begin to think about how the product will be getting successfully through the approval process with
manufactured and who will actually do the manufacturing. the CVM and other regulatory agencies worldwide vary
Some larger animal health companies have manufacturing depending on the complexity of the product. Experienced
facilities and have experience in putting together the companies know that assembling the necessary
data that the regulatory bodies requires, but smaller documentation for manufacturing can take a minimum
companies may have to locate toll manufacturers. For of 2-3 years, and carries a multi-million dollar price tag.
vaccines, Sponsors often use contract manufacturing sites In some cases, a factory needs to be built, requiring large
that have the capability of meeting and experience with capital investment.
USDA requirements. For the two wildlife vaccine products
approved by the EPA, each is made by the research
6.11 Conclusions
organizations that originally developed the products.
There is a long road from demonstrating that a certain
Many requirements need to be fulfilled, and the details
contraceptive approach can suppress fertility in a dog or a
will not be reviewed here. In general, packaging, sterility,
reproducibility from lot-to-lot, stability under a variety of cat, and achieving regulatory approval for a product that
handling conditions, cleaning requirements, and labeling can be marketed. Although some approaches can be shown
need to be worked out. Data may need to be generated on to be safe and effective, the time and technical expertise
the safety of the product and its raw materials for people required for developing a manufacturing process that can
exposed in the manufacturing process. The impact of be scaled up and result in a stable, reproducible product is
manufacturing on the environment must be defined. Enough often the main obstacle to regulatory approval.
product must be made under GMP conditions to conduct
In the last 10 years, we have seen only three products
the pivotal safety and field studies. Manufacturing must be
(Suprelorin, Gonazon, Neutersol/Zeuterin) achieve
scaled up to meet demand once the product is launched.
regulatory approval for contraception in cats and dogs.
Each formulation of a product needs its own Gonazon was only approved for use in female dogs in the
manufacturing process and documentation, so it is
EU (and not commercialized). Suprelorin is approved for
desirable to decrease development time and costs by
use in Australia, New Zealand and the EU and is reported
developing one formulation that can be used in multiple
to be a commercial success. The product Neutersol has also
species. Sterilization of the final product is also important
for injectable or implantable products, and methods need been approved in several Latin American countries under
to be established and proven not to degrade the active the name Esterilsol, and is being re-launched as Zeuterin in
ingredients. the US in the near future.
For GnRH agonists and antagonists, much of this For each potential product, the regulatory path is
information has been developed and approved for unique. The information presented here should be used
products used in humans, so GMP-manufactured only as historical background and general guidance.
bulk drug should be readily available, and In order to understand the path for a new product,
development could be restricted to identifying there is no substitute for expert regulatory advice by an
a final formulation and manufacturing process. experienced consultant. This scarcity of cat and
For immunocontraceptives, manufacturing may dog contraceptives approved for use reflects
be more of an issue, particularly since there how difficult the regulatory hurdles can be,
may be some antigen preparations that are but one can hope that these products and
extremely difficult to purify in bulk under GMP Sponsors have pioneered the way for future
conditions. For example, using pig ovaries from products.
slaughterhouse material as the source for porcine
ZP proteins is an example of a process that may be
useful for research purposes, but is hard to scale up
for commercial use under GMP.
Selecting the right manufacturing process or toll
manufacturer can make or break a product, its ability

Glossary
Given the easy Internet availability of detailed descriptions of the terms used in this report, this glossary is the glossary
of basic terminology related to fertility control and reproduction that was included in the 2002 Contraception and Fertility
Control in Animals report. It does not attempt to include all terms used in this document.
ablation – removal of a part (usually by cutting)

antibody – an immunoglobulin that is made by white blood cells in response to exposure to an antigen
antigen – a substance that is administered to an animal to elicit an immune response (usually refers to a protein substance)
bulling – when cows in estrus mount each other as if to breed; this can cause excessive activity and bruising of the hind
quarters (bulls and steers may also show this behavior)
castration – technically, removal of either the ovaries of females or the testicles of males, but the term is commonly used to
apply to males and is considered synonymous with “neuter”
cDNA – complementary DNA, which defines the DNA coding sequence of a gene and can be used to define the amino
acid sequence of a protein
cell-mediated immune response – specific acquired immunity in which the role of small lymphocytes (white blood cells)
of thymic origin (T-lymphocytes) is predominant
depot injection – an injection of a drug that is absorbed slowly over a period of time; this allows a drug to have its effect
over days rather than hours
down regulation – in the context of reproduction, used to mean that sensitivity to a hormone is decreased, usually due to
a reduction in the number of receptors but sometimes due to the unavailability of receptors to respond to the hormone
estrus – also known as “heat”; the time during which an female animal is ovulating and receptive to breeding by a male; it
is characterized by specific hormonal and behavior changes
follicle-stimulating hormone (FSH) – one of the hormones of the anterior pituitary that stimulates the growth of ovarian
follicles in females and spermatogenesis in males
gonadotropin-releasing hormone (GnRH) – the hormone that is produced in the brain, released in a pulsatile manner, and
stimulates the pituitary gland to release luteinizing hormone and follicle-stimulating hormone. It is a small, 10-amino-acid
peptide
gonadotroph – specific cells in the pituitary gland that have receptors that bind the peptide GnRH; these cells produce
follicle-stimulating hormone and luteinizing hormone
good laboratory practice (GLP) – a framework for non-clinical studies conducted for the assessment of the safety or
efficacy of chemicals (including pharmaceuticals) to man, animals and the environment
good manufacturing practice (GMP) – the list of practices to be followed in manufacturing pharmaceutical products to
meet worldwide regulatory requirements
heat – also known as estrus (see estrus above)
histopathology – a study of the microscopic appearance of tissues to look for any pathological changes caused by an
illness, toxin, drug treatment, etc.
IgA – immunoglobulin type A; made by immune cells in response to exposure to an antigen; this type of immunoglobulin
is usually secreted onto mucous membranes of the reproductive tract, nasal passages, etc.
IgG – immunoglobulin type G; made by white blood cells in response to exposure to an antigen; this type of
immunoglobulin is circulated in the blood
immunocontraception – causing an animal to become infertile by injecting it with an antigen that causes an immune
response to some component of the reproductive system, such as eggs, zona pellucida, sperm or GnRH
glycosylate – to add various types of sugar molecules to a protein; many proteins are glycosylated.
luteinizing hormone (LH) – one of the hormones of the anterior pituitary that acts to cause ovulation of mature follicles
and the secretion of estrogen in females, and stimulates the testes to produce testosterone in males
luteinizing hormone-releasing hormone (LHRH) – another name for gonadotropin-releasing hormone (GnRH)
necropsy – dissection of an animal’s body after death to examine organs and tissues; usually done to determine the cause
of death or to study the effect of treatments (called autopsy when referring to humans)
neuter – common term usually used to mean removal of the testicles of male animals, but can also mean spay in females
oligonucleotide – a relatively small fragment of DNA (usually about 2-20 bases)
ovariectomy – surgical removal of the ovaries; generally called a “spay” when referring to female cattle
ovariohysterectomy – surgical removal of the ovaries and uterus; generally referred to as spay when referring to female
companion animals
spay – when used in reference to dogs and cats, spay means ovariohysterectomy, or surgical removal of the uterus and
ovaries; when used in reference to cattle, spay means surgical removal of the ovaries
zona pellucida – a transparent, non-cellular layer or envelope of uniform thickness surrounding an ooctye (egg); made up
of glycosylated protein

Guide to Acronyms
ACC&D – Alliance for Contraception in Cats & Dogs
AFSSA – Agence Française de Sécurité Sanitaire des Aliments
APHIS – Animal and Plant Health Information Service (US Dept. of Agriculture)
APPA – American Pet Products Association
ASPCA – The American Society for the Prevention of Cruelty to Animals
ASV – Association of Shelter Veterinarians
AVMA – American Veterinary Medical Association
AZA – Association of Zoos and Aquariums (at St. Louis Zoo)
BLM – Bureau of Land Management (US Dept. of Interior)
CAP – chlormadinone acetate
CDA – Centers for Disease Control and Prevention (US Dept. of Health and Human Services)
cDNA – complementary DNA
CNR – Capture, Neuter and Return/Release
CRC – Cooperative Research Centres (Australia)
CSIRO –Commonwealth Scientific and Industrial Research Organization (Australia)
CVB – Center for Veterinary Biologics (US Dept. of Agriculture)
CVM – Center for Veterinary Medicine (US Food and Drug Administration)
DMA – delmadinone acetate
DMSO – dimethyl sulfoxide
dZP – dog-specific zona pellucida
EMA – European Medicines Agency
EPA – Environmental Protection Agency (US)
EU – European Union
FDA – Food and Drug Administration (US Dept. of Health and Human Services)
FERA – Food and Environment Research Agency (UK)
FIFRA – Federal Insecticide, Fungicide and Rodenticide Act
FSH – follicle-stimulating hormone
FSHR – follicle-stimulating hormone receptor
fZP – feline zona pellucid
GLM – good laboratory practice
GMP – good manufacturing practice
GnIH – gonadotropin-inhibitory hormone
GnRH – gonadotropin-releasing hormone
GnRH(F) – Canine Gonadotropin Releasing Factor®
HSHVSN – High Quality High Volume Spay Neuter
HSI – Humane Society International
HSUS – The Humane Society of the United States
IFAW – International Fund for Animal Welfare
LH – luteinizing hormone

MAF – Morris Animal Foundation
MATER – maternal antigens that embryos require
MGA – megestrol acetate
MIB – mibolerone
MPA – medroxyprogesterone acetate
NCPPSP – National Council on Pet Population and Policy
NICHD – National Institute of Child Health & Human Development
NII – National Institute of Immunology (India)
NSAID – non-steroidal anti-inflammatory drug
NWRC –National Wildlife Research Center (US Dept of Agriculture)
OIE – World Organization for Animal Health
PAD6 – peptidyl arginine deiminase
PAP – pokeweed antiviral protein
PFA – Pet Food Association
PRO – proligestone
PZP – porcine zona pellucida
RSPCA –Royal Society for Prevention of Cruelty to Animals (UK)
SPRASA – sperm protein targeted by anti-sperm antibodies
TCC – transitional cell carcinoma
TNR – Trap-Neuter-Return; also Trap-Neuter-Release
TTVARM – Trap, Test, Vaccinate, Alter, Release, Maintain
UBI – United Biomedical, Inc.
UCD – University of California, Davis
UI – University of Iowa
UK – United Kingdom
US – United States
USDA – United States Department of Agriculture
USGS – United States Geological Service
UVA – University of Virginia
VCD – vinylcyclohexene diepoxide
VLP – virus-like particles
VSF – Vétérinaires sans Frontières-Canada
VWB – Veterinarians without Borders
WCC – Wildlife Contraception Center (St. Louis Zoo)
WHO – World Health Organization
WS – Wildlife Services (USDA APHIS)
WSPA – World Society for the Protection of Animals
ZP – zona pellucida

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Websites
This list of websites cited in this document is provided as a convenience to readers. Note that ACC&D does not guarantee
the continued functionality, safety, or availability of specific material on a given website.
1st International Conference on Dog Population Management, https://secure.fera.defra.gov.uk/dogs2012/

bookOfAbstracts.cfm
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FEDIAF (The European Pet Food Industry) Facts and Figures, www.fediaf.org/fileadmin/user_upload/facts_and_
figures_2010.pdf
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Wu and Rupprecht, freepatentsonline.com/y2011/0165189.html

Trademarks and Registered Trademarks
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property of their respective owners.
Please note that photographs appearing in this document are either royalty-free or used with permission.
AdjuVac PIGOUT
Antagon PowerPoint
ASPCA Promone-E
Banfield Provera
Canine Gonadotropin Releasing Factor Ralston Purina
Cetrotide Repro-Bloc
ChemSpay RISUG
Cheque SpayVac
ContraPest Suprelorin
Covinan Testoblock
Defensor 3 The American Society for the Prevention of Cruelty to Animals
Delvosteron The Humane Society of the United States
Depo-Provera Vasagel
DepoVax Zeuterin
Equity
Esterilsol
FeralStat
Found Animals
GonaCon
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Improvac
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Contraception and

© 2013. All rights

2.0 The Physiology of Reproductive Control in Mammals –

3.2 Gonadotropin-Releasing Hormone (GnRH)..................................................................................... 23

3.3 Other Vaccine Approaches................................................................................................................. 43

3.5 Sex Steroids.................................................................................................................................. 55

Contraception and Fertility Control in Dogs and Cats 3

4.0 Overview of Companies, Organizations, Institutions, and Agencies Involved

Contraception and Fertility Control in Dogs and Cats 4

5.0 Marketing Overview and Issues.................................................................................. 87

Contraception and Fertility Control in Dogs and Cats 5

5.5 “Shelters”......................................................................................................................................... 121

5.7 Owner Willingness to Pay for a Non-Surgical Alternative.......................................................... 125

6.0 Regulatory Issues: Some Considerations for Evaluating Contraceptives

Contraception and Fertility Control in Dogs and Cats 6

Contraception and Fertility Control in Dogs and Cats 7

Contraception and Fertility Control in Dogs and Cats 8

� Elaine Lissner, Medical Director, Parsemus Foundation, San Francisco, CA

Contraception and Fertility Control in Dogs and Cats 9

Thanks are also due to our proofreader, Julie Snyder.

This project was supported by a generous grant from

Design donated by MoldaveDesigns LLC. www.moldavedesigns.com.

Contraception and Fertility Control in Dogs and Cats 10

Contraception and Fertility Control in Dogs and Cats 11

Contraception and Fertility Control in Dogs and Cats 12

Contraceptive medications in dogs and cats have only

Contraception and Fertility Control in Dogs and Cats 13

Contraception and Fertility Control in Dogs and Cats 14

Contraception and Fertility Control in Dogs and Cats 15

Table 1-1: Summary of Characteristics Required for Commercialization

Contraception and Fertility Control in Dogs and Cats 16

Contraception and Fertility Control in Dogs and Cats 17

Contraception and Fertility Control in Dogs and Cats 18

Table 3-1: Pros and Cons of Gonadectomy in Dogs and Cats

Contraception and Fertility Control in Dogs and Cats 20

Contraception and Fertility Control in Dogs and Cats 21

Contraception and Fertility Control in Dogs and Cats 22

3.2 Gonadotropin-Releasing Hormone A disadvantage of the GnRH agonist approach to

Contraception and Fertility Control in Dogs and Cats 23

Contraception and Fertility Control in Dogs and Cats 24

Contraception and Fertility Control in Dogs and Cats 25

Contraception and Fertility Control in Dogs and Cats 26

Contraception and Fertility Control in Dogs and Cats 27

Table 3-2: Use of Deslorelin for Contraception in Cats and/or Dogs4

Effect of deslorelin acetate (Suprelorin) in domestic cat testicular morphology

Postponement of puberty using GnRH agonists implants in bitches of different breeds

Contraception and Fertility Control in Dogs and Cats 28

3.2.1.2 Nafarelin “Control dogs received a placebo implant and

Contraception and Fertility Control in Dogs and Cats 29

3.2.1.4 GnRH Agonists: Summary of Advantages and Disadvantages

Slow onset of activity (generally a few weeks) and variable

Contraception and Fertility Control in Dogs and Cats 30

3.2.2.1 GnRH Antagonist Peptides

Contraception and Fertility Control in Dogs and Cats 31

Contraception and Fertility Control in Dogs and Cats 32

Contraception and Fertility Control in Dogs and Cats 33

3.2.2.5 GnRH Antagonists: Summary of Advantages and Disadvantages

Contraception and Fertility Control in Dogs and Cats 34

Contraception and Fertility Control in Dogs and Cats 35