International Journal of Womens Health Dovepress

open access to scientific and medical research

Open Access Full Text Article Review

Dienogest in long-term treatment of endometriosis

This article was published in the following Dove Press journal:

International Journal of Womens Health
5 July 2011
Number of times this article has been viewed

Adolf E Schindler Abstract: Endometriosis is a chronic disease primarily affecting women of childbearing age,
Institute for Medical Research and in which endometriotic lesions form outside the uterus, typically leading to painful symptoms,
Education, Essen, Germany fatigue, and infertility. The symptoms of endometriosis may cause significant impairment in quality
of life and represent a substantial economic burden to patients, families, and society. There is no
cure for endometriosis; management consists of alleviating pain and other symptoms, reducing
endometriotic lesions, and improving quality of life. Recurrence after surgical intervention is
common, while the clinical evidence to support the efficacy and safety of many medications cur-
rently used in endometriosis is limited. Dienogest is an oral progestin that has been investigated
extensively in the treatment of endometriosis in two clinical programs performed in Europe and
Japan, including dose-ranging, placebo-controlled, active comparator-controlled, and long-term
(up to 65 weeks) studies. These studies demonstrated that dienogest 2mg daily effectively alleviates
the painful symptoms of endometriosis, reduces endometriotic lesions, and improves indices of
quality of life. Dienogest showed a favorable safety and tolerability profile in these studies, with
predictable adverse effects, high rates of patient compliance, and low withdrawal rates. This review
article describes the clinical trial evidence that characterizes the efficacy and safety of dienogest
in endometriosis, including two studies characterizing dienogest in long-term use. The relevance
of these findings to the management of endometriosis in clinical practice is discussed.
Keywords: dienogest, endometriosis, progestins, long-term treatment, quality of life, symptoms,
pain

Endometriosis: a chronic, painful disease

Endometriosis is a chronic, estrogen-dependent disease that affects approximately 10%
of women of reproductive age, with a peak incidence in the age range of 2530 years.13
Endometriosis is characterized by the formation of endometriotic lesions outside the
uterus, including the ovaries and other pelvic structures. These lesions cause a chronic,
inflammatory reaction, which can lead to the formation of scar tissue and adhesions.4
Women with endometriosis frequently experience symptoms of dysmenorrhea, premen-
strual pain, dyspareunia, and chronic fatigue.5 Endometriosis can also interfere with
functioning of the bowel or bladder, depending on the site where endometriotic lesions
Correspondence: Adolf Schindler develop. Up to 50% of women with endometriosis experience infertility.6 However,
Institut fr Medizinische Forschung the clinical presentations of endometriosis can vary widely, and many affected women
und Fortbildung, Universittsklinikum,
Hufelandstrasse 55 D-45122 Essen, are asymptomatic.7 No clear relationship exists between the extent of endometriotic
Germany lesions and a womans symptoms.
Tel +49 201 799 1833
Fax +49 201 749 9533
Quality of life studies show that symptoms of endometriosis impact on many aspects
Email [email protected] of a womans life, including work and education, relationships, and social functioning.814

submit your manuscript | www.dovepress.com International Journal of Womens Health 2011:3 175184 175
Dovepress 2011 Schindler, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
http://dx.doi.org/10.2147/IJWH.S5633 which permits unrestricted noncommercial use, provided the original work is properly cited.
Schindler Dovepress

As symptoms become more severe, quality of life is reduced quality of life of affected individuals. A number of medical
further. In a recent international survey, women with endo- and surgical therapies are available to treat endometriosis,
metriosis reported a substantial 38% reduction in work pro- which may, on occasion, be used in combination. No single
ductivity, which was attributable primarily to reduced work treatment is ideal for all patients and the management
effectiveness in the presence of pelvic pain.15 Endometriosis approach chosen should be directed to the individual needs
also impacts mental health, with one study showing that 87% of each patient. As endometriosis is a chronic disease, con-
of the women investigated with endometriosis had depressive sideration should be given not only to the efficacy but also to
symptoms and 88% had anxiety.16 The severity of anxiety the long-term safety and tolerability of the treatment options
symptoms correlated with the intensity of pain. that are available.
Endometriosis places a considerable economic burden
on families and on society. Delays in diagnosis, high rates Surgery
of hospital admission, surgical procedures, and incidences Surgical intervention includes ablation of endometriotic
of comorbid conditions contribute to make endometriosis a lesions, removal of endometriotic cysts, and division of
more costly public health problem than other chronic condi- adhesions. Surgery can provide pain relief and enhance
tions such as migraine and Crohns disease.9,1721 fertility, but this approach should be delayed for as long as
possible due to the high risk of recurrence, which attains a
Diagnosis and treatment rate of 40%50% at five years.24 Medications administered
of endometriosis postoperatively may reduce the risk of recurrence.
Diagnosis
Due to the variable presentation of endometriosis, there is Medical therapy
typically a delay between the first appearance of symptoms Nonsteroidal anti-inflammatory drugs are frequently used by
and an accurate diagnosis. An international survey reported women with endometriosis in an attempt to achieve analgesia,
that this delay is, on average, seven years.15 Early diagnosis although clinical trial evidence to support the efficacy of these
is an important objective, as endometriosis typically follows agents in endometriosis is lacking.25 A major limitation to the
a progressive course characterized by a worsening of symp- long-term use of nonsteroidal anti-inflammatory drugs is their
toms in the absence of effective treatment. Errors in diag- significant side effects, including the risk of gastric ulceration
nosis, with the potential for inappropriate therapy, are also and an antiovulatory effect when taken at mid-cycle.4,25
common, creating anxiety and frustration, and contributing Specific medical therapies that are approved for the
further to the burden of endometriosis. treatment of endometriosis include gonadotropin-releasing
A definitive diagnosis of endometriosis requires lap- hormone (GnRH) agonists, danazol, and certain progestins.
aroscopy, ideally combined with confirmatory histology, to These agents and the combined oral contraceptives
characterize endometriotic lesions.4,22 In practice, however, (COCs) share a common hormonal mechanism of action in
this invasive approach is considered unnecessary or inap- endometriosis.
propriate for many patients, and a presumptive diagnosis of COCs are widely used to treat the symptoms of endo-
endometriosis can be made from the symptoms alone.4 metriosis, although they are not approved for this indica-
tion in the majority of countries because of the absence of
Treatment supportive trial evidence.26 For the same reason, practice
There is no permanent cure for endometriosis. As stated guidelines can offer limited guidance on the optimal COC
by the American Society for Reproductive Medicine, regimens in endometriosis.27 A recently published review
Endometriosis should be viewed as a chronic disease that notes that the putative biological effects for COCs include
requires a life-long management plan with the goal of maxi- both inhibition of endometrial cell implantation but also
mizing the use of medical treatment and avoiding repeated a protective effect against endometrial lesion necrosis. 28
surgical procedures.23 Women with endometriosis require Clinical experience indicates that COCs may be used
ongoing, collaborative, supportive management of their con- with safety in many women for the long-term treatment of
dition, as well as an understanding of the significant impact endometriosis. However, a common problem with long-term
that the condition can have on their quality of life. continuous COC regimens is breakthrough bleeding. This is
The main aims of treatment are to alleviate pain and other often treated by discontinuing the COC for a few days and
symptoms, reduce endometriotic lesions, and improve the then restarting therapy.

176 submit your manuscript | www.dovepress.com International Journal of Womens Health 2011:3
Dovepress
Dovepress Long-term dienogest in endometriosis

GnRH agonists are an established therapy for endometriosis When administered continuously, progestins are effective in
that can be administered via either intramuscular, subcutaneous, many women for the management of pain and other symptoms
or intranasal routes.29 Depot formulations are available. of endometriosis, with beneficial effects also relating to amenor-
Although GnRH agonists provide effective pain relief and rhea and anovulation. However, certain progestins are effective
reduce the progression of endometriotic implants,29 the hypo- in endometriosis only at high doses when compared with use
estrogenic state that they induce is associated with effects in other indications,33,34 which may increase the likelihood of
such as accelerated bone mineral density loss, hot flushes, and adverse effects, such as weight gain and androgenic effects, and
vaginal dryness.30 In consequence, the use of GnRH agonists elevate the risk of cardiovascular adverse events.
is limited to six months in the absence of add-back therapy
with steroids. The optimal regimens for add-back therapy are Dienogest in endometriosis
not yet established.18,31 For younger women who have not yet Dienogest is an oral progestin that has been investigated sys-
reached maximum bone density, guidelines recommend a tematically for the treatment of endometriosis in dose-ranging,
careful consideration of the use of GnRH agonists due to their placebo-controlled, active c omparator-controlled, and
bone demineralizing effects.4 long-term trials performed in Europe and Japan (Figure1).
Danazol is an androgenic steroid that is effective in treat- Based on this trial evidence, dienogest has received approval
ing the signs and symptoms of endometriosis, but its use is as a monotherapy for the treatment of endometriosis in
limited by adverse effects on lipid metabolism and by weight Europe, Japan, Australia, and Singapore.
gain, edema, acne, vaginal dryness, hot flushes, oily skin,
hirsutism, liver toxicity, and breast atrophy.18,32 Because of Preclinical studies
these effects, danazol has today been superseded in many Dienogest demonstrates a number of characteristics in pre-
countries by alternative agents. clinical studies that are relevant to its use in endometriosis.
Oral, parenteral, intrauterine, or implantable progestins Pharmacologically, dienogest combines the advantages of the
have been used for decades in the treatment of endometriosis, 19-norprogestin and the progesterone derivative classes.35,36
although for many of these agents there is a lack of support- Dienogest binds to the progesterone receptor with high
ive evidence from controlled clinical trials. Dose-finding specificity, and produces a potent progestogenic effect related
data are lacking for most progestins, and there are few to the high circulating levels of the unbound molecule.37
comparative data to indicate the benefits of one progestin Binding affinities of dienogest for estrogen, glucocorticoid,
over another. and mineralocorticoid receptors are negligible. Unlike other
The progestins that are approved for use in endometriosis agents in the 19-norprogestin class, dienogest lacks andro-
vary between countries. A notable example is medroxypro- genic effects; rather, dienogest has beneficial antiandrogenic
gesterone acetate injectable suspension (Depo-subQ Provera properties typical of the progesterone derivatives, which are
104, Pfizer, New York, NY), which was approved recently associated with minimal changes in lipid and carbohydrate
by the US Food and Drug Administration for the treatment levels.38,39
of endometriosis based on active comparator-controlled trial Dienogest is almost completely absorbed, and has a high
data. This medication carries a black box warning concerning bioavailability after oral administration, similar to other
possible bone mineral loss. The preparation is not available 19-norprogestins. Its relatively short half-life of 10 hours
in Europe. means there is no risk of accumulation after repeated dosing.

Dienogest Progesterone
COCH3
OH
CH2CN H

O O

Figure 1 Structural formula of the progestin, dienogest, compared with naturally occurring progesterone.

International Journal of Womens Health 2011:3 submit your manuscript | www.dovepress.com

177
Dovepress
Schindler Dovepress

The majority of orally administered dienogest is excreted prematurely because of unsatisfactory bleeding patterns.
within 24hours, mainly in urine. Laparoscopy showed that dienogest at 2mg and 4mg daily
Dienogest reduces endometriotic lesions through a num- significantly reduced endometriotic lesions. In addition,
ber of biological mechanisms. Dienogest is associated with dienogest at both these doses improved patient-reported
relatively moderate inhibition of gonadotropin secretion, symptoms, including the intensity of dyspareunia, dysmenor-
leading to a modest reduction in the endogenous production rhea, and diffuse pelvic pain. The 2mg and 4mg dienogest
of estradiol.40 When given continuously, dienogest induces doses were generally well tolerated and rates of discontinua-
a hypoestrogenic, hypergestagenic local endocrine envi- tions due to adverse events were low. Irregular uterine bleed-
ronment, causing a decidualization of endometrial tissue ing was experienced by 55.2% in the 2mg group and 68.6%
followed by atrophy of the endometriotic lesions. Animal in the 4mg group, with a trend to decreased intensity over
studies indicate that dienogest may also reduce plasma estra- time in both groups. Based on these outcomes, dienogest at
diol levels directly, through inducing apoptosis of granulosa 2mg once daily was recommended as the optimal dose in
cells in the ovary.41 the treatment of endometriosis.
A recent pharmacokinetic study confirmed the moderate In support of these findings, a Japanese study investi-
suppression of estradiol levels, remaining within the lower gated dienogest at daily doses of 1mg, 2mg, and 4mg for
end of the normal physiological range, in women volunteers 24 weeks in 183 women with endometriosis.52 The 2mg and
administered dienogest at doses of 0.53mg daily.42 In this 4mg daily doses were equivalent in efficacy, measured as a
study, ovarian activity was effectively suppressed by the global improvement in subjective symptoms. While safety
2mg and 3mg doses, with a rapid return to ovulation after assessments indicated no dose-related differences, reductions
cessation of dienogest administration. in estradiol levels associated with the 4mg dose indicated
In exploratory models of endometriosis, dienogest also that 2mg daily may offer least potential for adverse effects
demonstrates antiproliferative, anti-inflammatory, and on bone mineral density. Mean serum estradiol concentra-
antiangiogenic effects.36,4345 In vitro and animal studies tions at between eight weeks and the end of treatment in this
show that dienogest has a direct inhibitory effect on the study were 84.5, 37.4, and 26.2 pg/mL for dienogest doses of
proliferation of endometrial-like tissue that is independent 1, 2, and 4mg/day, respectively. A serum estradiol concen-
of actions via the progesterone receptor.4649 Indirect anti- tration in the range of 3050 pg/mL is considered to fulfill
inflammatory activity through modification of proinflamma- the requirements of the estrogen threshold hypothesis,53 by
tory markers has been demonstrated for dienogest in in vitro which estrogen levels are suppressed sufficiently to inhibit
and in vivo experiments.50 A further potential mechanism endometriotic lesion growth, but are adequate to prevent
of action for dienogest is inhibition of angiogenesis, which hypoestrogenic side effects such as bone mineral loss. Of
represents an essential stage in the development of endo- relevance to long-term compliance, 77% of the patients com-
metriotic lesions. Oral administration of dienogest signifi- mented that they wanted or definitely wanted to use the
cantly suppressed angiogenesis in a mouse model.45 The dienogest 2mg daily dose again.
molecular mechanisms underlying these effects continue The effectiveness of dienogest at the 2mg daily dose was
to be explored.4851 compared against placebo in a 12-week, randomized trial
using a range of tools for measuring changes in symptoms
Clinical studies and quality of life. The study enrolled 198 women with
Clinical studies of dienogest with durations between 12 and stage IIV (ie, minimal to severe) endometriosis and an
24 weeks have provided information on optimal dosing and endometriosis-associated pelvic pain score of at least 30mm
on efficacy and safety characteristics that are relevant to the on a visual analog scale (measured on a scale of 0100mm),
long-term management of endometriosis. which represents a well validated tool for the measurement
The optimal daily dose of dienogest for treating endo- of pain.54,55 Dienogest produced a statistically significant
metriosis was investigated in an open-label, randomized, decrease in the mean visual analog score compared with
multicenter, 24-week, dose-ranging study in Europe. 39 placebo, with a between-group difference of 12.3mm in favor
S ixty-eight women with endometriosis stage IIII at of dienogest (P , 0.0001). Biberoglu and Behrman scale
laparoscopy (ie, with minimal to moderate disease) were scores supported the visual analog scores by demonstrating
randomly assigned to treatment with dienogest 1, 2, or 4mg greater reductions in the intensity of symptoms and signs in
once daily. Randomization to the 1 mg group was halted the dienogest group compared with placebo. The Clinical

178 submit your manuscript | www.dovepress.com International Journal of Womens Health 2011:3
Dovepress
Dovepress Long-term dienogest in endometriosis

Global Impression scale, a measure of overall improvement, The third comparative trial including a GnRH agonist
showed that 52.9% of the patients treated with dienogest were was a 24-week, randomized, double-blind, multicenter
assessed by physicians to be very much improved/much study c omparing dienogest 2 mg once daily against
improved at week 12, compared with 22.9% in the placebo intranasal buserelin acetate 300g three times daily, which
group. Quality of life analyses based on the Short Form 36 was performed in Japan in 271 women with confirmed
Health Survey questionnaire, a non-disease-specific tool used endometriosis.58 Dienogest was as effective as buserelin
widely in clinical trials, showed that dienogest was associated acetate in reducing endometriosis symptoms and lesion size
with significantly greater improvement in bodily pain than at laparoscopy. Greatest changes in quality of life (assessed
placebo treatment. Dienogest was generally well tolerated in by Short Form 36 Health Survey score) in both groups
this trial, with no serious or unexpected adverse events, and were improvements in bodily pain, with a trend to greater
few events related to therapy. Estradiol levels were modestly improvement in the dienogest group. Mean lumbar bone
suppressed, and profiles of uterine bleeding in the dienogest mineral density decreased in both groups in this population,
group were comparable with the placebo group. with a significantly greater reduction in the buserelin acetate
Three studies of 1624 weeks duration have directly group (P=0030). Consistent with the other comparative tri-
compared dienogest against GnRH agonists, a standard als, dienogest was associated more frequently with irregular
therapy in endometriosis.5658 In a 24-week, randomized study bleeding but less frequently with hot flushes than the GnRH
of 252 women with endometriosis in Europe, dienogest 2mg agonist.
once daily and leuprolide acetate at standard dose (3.75mg, Notably, each of the trials that investigated dienogest
depot intramuscular injection every four weeks) provided 2 mg daily described adverse effects of generally mild to
comparable, continuous reductions in pelvic pain measured moderate intensity which were associated with low rates
by visual analog score. By week 24, reductions in mean visual of treatment discontinuation (eg, 5.0%57 and 4.4%58 over
analog score were 47.5mm for dienogest and 46.0mm for 24-week treatment durations). Bleeding episodes decreased
leuprolide acetate. Consistent with the visual analog score in number and intensity over time, and were associated with
changes, dienogest and leuprolide acetate induced similar no discontinuations in these trials.57,58
decreases in the intensity of symptoms and physical findings An open-label pilot study of dienogest at the higher
assessed by Biberoglu and Behrman scores. Short Form 36 dose of 10mg twice daily for 24 weeks provides additional
Health Survey scores showed a trend to greater improvement information on the safety of this medication.59,60 Dienogest
in both physical and mental health in the dienogest than the at 20mg daily had no clinically relevant effect on thyroid or
leuprolide acetate group. Effects of estrogen deprivation adrenal function, electrolyte balance, or hematopoiesis in the
were substantially more common in the leuprolide acetate 21 women with stage IIV endometriosis who participated. In
group than dienogest group, including numbers of days with addition, dienogest at this high dose had no adverse effects on
hot flushes/week (mean 4.7 versus 0.82, respectively), while lipid metabolism, liver enzymes, fasting insulin, or glucose.
bleeding episodes were suppressed less with dienogest than No menopausal symptoms and no adverse androgen-related
leuprolide acetate. The leuprolide acetate group showed a effects were reported. These observations, demonstrating
reduction in mean lumbar bone mineral density, while, in that dienogest has a favorable safety and tolerability profile
the dienogest group, lumbar bone mineral density showed a even at 20mg daily (ie, 10 times the recommended dose),
small increase (P=0.0003 versus leuprolide acetate).57 support the conclusion that the recommended dose of 2mg
Dienogest 1mg twice daily was compared with triptorelin once daily will have a similar beneficial profile.
3.75mg (depot intramuscular injection every four weeks)
as a postoperative medication in a 16-week, multicenter, Dienogest and fertility
open, randomized trial of 142 women with stage IIIV considerations
endometriosis.56 The two medications were equally effec- The majority of women suffering from endometriosis are of
tive in improving endometriosis symptoms and signs, and reproductive age and so may require contraception. Based
laparoscopy scores. Hot flushes were reported in 61.2% of on the available data, dienogest provides complete ovulation
women receiving the GnRH agonist compared with 9.6% of inhibition at a daily dose of 2mg.37,42,61 However, dienogest
women treated with dienogest. Irregular bleeding was the monotherapy was not developed as a contraceptive, and
most common complication in the dienogest group (61.6% women taking dienogest as a treatment for endometriosis are
versus 25.4% with GnRH agonist). advised to use nonhormonal methods of contraception.

International Journal of Womens Health 2011:3 submit your manuscript | www.dovepress.com

179
Dovepress
Schindler Dovepress

Women with endometriosis may desire pregnancy once after treatment cessation. Short Form 36 Health Survey
sufficient pain relief is achieved. Recent pharmacodynamic scores during the treatment-free period indicated minimal
data in volunteers indicate that ovarian activity resumes changes in physical or mental indices of quality of life over
rapidly (range 143 days) after cessation of dienogest.42 six months after cessation of dienogest.
These observations support studies that describe a prompt During the long-term study, laboratory parameters,
return to fertility (eg, mean about 30 days) and include vital signs, and body weight remained stable or underwent
cases of successful pregnancy in women with endometriosis minimal changes. Adverse effects considered potentially
following the cessation of dienogest treatment 2mg daily for treatment-related developed in 16.1% of women, including
durations up to one year.52,62,63 breast discomfort (4.2%), nausea (3.0%), and irritability
As with other progestins, there are limited data on the use (2.4%). The maximal intensity of treatment-related adverse
of dienogest in pregnant women. The available data do not events was mild or moderate in 92.5% of cases. In agreement
indicate harmful effects for dienogest with respect to repro- with trends observed in the 12- and 24-week studies, the
ductive toxicity and reveal no special risks on pregnancy. intensity and frequency of bleeding reduced progressively
However, dienogest should not be administered to pregnant over the course of the long-term study. During post-treatment
women because there is no need to treat endometriosis dur- follow-up, bleeding returned to normal intensity and cyclic
ing pregnancy.64 patterns resumed within 46 weeks. Treatment compliance
during the long-term study was high (98%) and discontinua-
Dienogest for the long-term tion rates due to adverse events or lack of efficacy were both
treatment of endometriosis low (2.4% and 0.6%, respectively).
Effective management of endometriosis over the longer term The results of this long-term study performed in Europe
is an important objective. The painful symptoms and impair- are supported by a 52-week, nonrandomized trial of dienogest
ment in quality of life associated with endometriosis may 2mg daily conducted in Japan on 135 women with confirmed
persist or deteriorate in the absence of effective treatment. endometriosis.63 Global improvement was measured by
Recurrence is frequent even after successful surgery, while change in the severity of five subjective symptoms (lower
there are only limited trial data to confirm the efficacy and abdominal pain, lumbago, dyschezia, dyspareunia, and pain
safety of long-term treatment for many medications used in on vaginal examination) and two objective findings (indu-
endometriosis. ration involving pouch of Douglas and uterine mobility).
Dienogest has been investigated as a long-term treatment Moderate or marked global improvement was recorded in
of endometriosis in two large trials performed in Europe and 72.5% of patients after 24 weeks and in 90.6% after 52 weeks
Japan, which included assessments of efficacy, change in of dienogest treatment (Figure3). Changes in visual analog
quality of life, safety, and tolerability. score for lower abdominal pain and lumbago decreased pro-
Women who completed the 12-week placebo-controlled gressively, while the proportion of patients demonstrating a
study in Europe54 were offered the opportunity to enter reduction in cyst size.25% was 85% at 52 weeks. Quality
an open-label extension study of dienogest for up to 53 of life assessments using the Short Form 36 Health Survey
additional weeks, providing an overall treatment period of score indicated improvements in bodily pain by 23.57 and
up to 65 weeks.62 Notably, of the 188 women completing 27.37 points (on a 100-point scale) at 24 and 52 weeks,
the placebo-controlled study, a large proportion (n = 168, respectively, compared with baseline. Patient satisfaction
89%) consented to enter the long-term extension study. The with dienogest at the end of treatment was high, with 88.9%
intensity of pain showed significant, sustained improvements of women responding that they were certainly willing or
during the long-term study, in addition to the improvements would prefer to use dienogest again.
associated with dienogest during the placebo-controlled The most commonly reported treatment-related adverse
phase. Mean visual analog scores decreased from 56.9mm event was metrorrhagia (71.9%), followed by headaches
at baseline of the placebo-controlled study to 34.1mm at (18.5%) and constipation (10.4%). None of the treatment-
baseline of the long-term study, to 11.5mm at the end of related adverse events was rated as serious. Metrorrhagia
the 53 additional weeks of treatment (Figure2). During a resolved in 96 of the 97 affected patients either during
24-week treatment-free period following the long-term study, the study or within two months of study cessation. The
visual analog scores increased only moderately, suggesting frequency of bleeding lessened as treatment progressed,
that dienogest induces a beneficial effect that may persist so that 40.5% of women were experiencing no bleeding by

180 submit your manuscript | www.dovepress.com International Journal of Womens Health 2011:3
Dovepress
Dovepress Long-term dienogest in endometriosis

P < 0.0001
A B
60 60

50 50
VAS (mm, mean SEM)

VAS (mm, mean SEM)

40 40

30 30

20 20

10 Dienogest 2 mg (n = 102) 10 Total population (prior-dienogest and

Placebo (n = 96) prior-placebo groups combined)

0 0
0 4 8 12 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks of treatment Weeks of treatment
Figure 2 Change in visual analog scale (VAS) score during the placebo-controlled (A) and the extension (B) studies.54,62
Note: Reprinted in part from Strowitzki T etal,54 with permission from Elsevier.

4952 weeks. Resumption of menses was confirmed in all 2mg/day for 12months (n=33 women) in comparison with
women at the end of the study. The discontinuation rate due sequential treatment including GnRH agonist (leuprorelin
to treatment-related adverse events was 5.2%. Lumbar bone acetate or buserelin acetate) for 46 months followed by
mineral density decreased by 1.72.2% between baseline dienogest 1 mg/day for 12 months (n = 38).65 Continued
and week 52, with the greatest change in the first 24 weeks. dienogest significantly reduced the mean visual analog scores
The authors noted that this bone mineral density change may for dysmenorrhea, nonmenstrual pelvic pain, and dyspare-
be considered mild and not significantly greater than that unia at six and 12months, equivalent to the score reductions
observed in untreated women of similar age. No biochemical achieved with GnRH agonist followed by dienogest. For
markers of bone metabolism indicated changes outside the approximately 40% of women in the sequential treatment
normal reference range. group, the dienogest dose was increased from 1 mg to
Recently, a small open-label, nonrandomized study 1.52mg/day to optimize bleeding control. Consistent with
performed in Japan has investigated continued dienogest other studies, uterine bleeding was significantly reduced in

100
Proportion of improvement (%)

90

80

70

60

50

40

30 Global improvement
Overall improvement of subjective symptoms during non-menstruation
20
Overall improvement of objective findings

10

0
0 4 8 12 16 20 24 28 32 36 40 44 48 52

Observation period (weeks)

Figure 3 Increase over time in the proportion of cases assessed as marked or moderate for global improvement, overall improvement of subjective symptoms during
non-menstruation, and overall improvement of objective findings.58
Note: Reprinted from Momoeda etal63 with permission from John Wiley & Sons.

International Journal of Womens Health 2011:3 submit your manuscript | www.dovepress.com

181
Dovepress
Schindler Dovepress

the second compared with the first six months of dienogest Together, the dienogest study programs performed
treatment. The divergence in dienogest dose hinders the inter- in Europe and Japan indicate that dienogest represents a
pretation of bleeding rates across the treatment groups. The promising new medication for the long-term management
authors concluded that dienogest represents a practical and of endometriosis.
efficient long-term therapy in patients who respond to GnRH
agonist therapy. The data may be interpreted also to indicate Disclosure
that continued long-term dienogest is as effective for pain The author declares that he has no conflict of interest in this
relief as a GnRH agonist followed by dienogest therapy. work.

Discussion References
1. Rogers PA, DHooghe TM, Fazleabas A, et al. Priorities for endo-
Effective long-term management of endometriosis is a sig- metriosis research: Recommendations from an international consensus
nificant clinical objective in view of the debilitating nature workshop. Reprod Sci. 2009;16(4):335346.
2. Nasir L, Bope ET. Management of pelvic pain from dysmenor-
of this often chronic condition. Among current management
rhea or endometriosis. J Am Board Fam Pract. 2004;17 Suppl:
approaches, recurrence is common after surgery, while evi- S43S47.
dence to support the efficacy and safety of many medications 3. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet
Gynecol Clin North Am. 1997;24(2):235258.
is lacking. GnRH agonists, a standard medication in endo- 4. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for
metriosis, may not be administered continuously for more the diagnosis and treatment of endometriosis. Hum Reprod. 2005;
20(10):26982704.
than six months in the absence of add-back therapy because
5. Sinaii N, Plumb K, Cotton L, etal. Differences in characteristics among
of the deleterious hypoestrogenic effects. 1,000 women with endometriosis based on extent of disease. Fertil
Dienogest is a progestin investigated for the treatment of Steril. 2008;89(3):538545.
6. Holoch KJ, Lessey BA. Endometriosis and infertility. Clin Obstet
endometriosis. Dienogest at a dose of 2mg daily has been Gynecol. 2010;53(2):429438.
studied extensively in clinical trial programs performed in 7. Fagervold B, Jenssen M, Hummelshoj L, Moen MH. Life after a diag-
nosis with endometriosis a 15 years follow-up study. Acta Obstet
Europe and Japan, including two studies with treatment
Gynecol Scand. 2009;88(8):914919.
durations of up to 65 weeks. These studies demonstrated that 8. Huntington A, Gilmour JA. A life shaped by pain: women and endo-
dienogest has an efficacy, safety, and tolerability profile that is metriosis. J Clin Nurs. 2005;14(9):11241132.
9. Fourquet J, Gao X, Zavala D, et al. Patients report on how endo-
favorable for long-term use. The intensity of pain associated metriosis affects health, work, and daily life. Fertil Steril. 2010;93(7):
with endometriosis decreased progressively, adverse events 24242428.
(mostly mild or moderate in intensity) were predictable and 10. Kennedy S. What is important to the patient with endometriosis? Br J
Clin Pract Suppl. 1991;72:810.
associated with low discontinuation rates, and bleeding 11. Jones G, Jenkinson C, Kennedy S. The impact of endometriosis upon
irregularities reduced in intensity and frequency over time. quality of life: A qualitative analysis. J Psychosom Obstet Gynaecol.
2004;25(2):123133.
Following cessation of dienogest treatment, menses returned 12. Lemaire GS. More than just menstrual cramps: Symptoms and uncer-
to normal. tainty among women with endometriosis. J Obstet Gynecol Neonatal
The impact of endometriosis on a womans quality of life Nurs. 2004;33(1):7179.
13. Kjerulff KH, Erickson BA, Langenberg PW. Chronic gynecological
is substantial and wide ranging. Quality of life assessments conditions reported by US women: Findings from the National Health
in the dienogest studies indicated that improvements in both Interview Survey, 1984 to 1992. Am J Public Health. 1996;86(2):
195199.
physical and mental indices were attained within 12-week 14. Denny E. Womens experience of endometriosis. J Adv Nurs. 2004;
and 24-week treatment durations, and that these benefits were 46(6):641648.
sustained in studies of up to one year. 15. Nnoaham KE, Sivananthan S, Hummelshoj L, et al. Global study
of womens health: A multi-centre study of the global impact of
Also of major significance to clinical practice, compli- endometriosis. Human Reproduction. 2010;25 Suppl 1:i9i11.
ance with dienogest treatment was high and rates of discon- 16. Sepulcri RP, do Amarai VF. Depressive symptoms, anxiety, and qual-
ity of life in women with pelvic endometriosis. Eur J Obstet Gynecol
tinuation due to adverse events were low in these studies. Reprod Biol. 2009;142(1):5356.
Contributors to this favorable compliance may include the 17. Gao X, Outley J, Botteman M, etal. Economic burden of endometriosis.
efficacy of dienogest for symptom control and the predict- Fertil Steril. 2006;86(6):15611572.
18. Winkel CA, Scialli AR. Medical and surgical therapies for pain asso-
ability of adverse effects, which can be communicated to ciated with endometriosis. J Womens Health Gend Based Med. 2001;
patients before treatment initiation. Large proportions of 10(2):137162.
19. Heinrichs WL, Henzl MR. Human issues and medical economics of
the women who were questioned expressed a willingness to endometriosis. Three- vs six-month GnRH-agonist therapy. J Reprod
continue dienogest treatment. Med. 1998;43 Suppl 3:299308.

182 submit your manuscript | www.dovepress.com International Journal of Womens Health 2011:3
Dovepress
Dovepress Long-term dienogest in endometriosis

20. Mathias SD, Kuppermann M, Liberman RF, Lipschutz RC, Steege JF. 42. Klipping C, Duijkers I, Faustmann T, Klein SF, Schuett B. Pharmacodynamic
Chronic pelvic pain: Prevalence, health-related quality of life, and study of four oral dosages of dienogest. Fertil Steril. 2010;94
economic correlates. Obstet Gynecol. 1996;87(3):321327. Suppl 1:S181.
21. Mirkin D, Murphy-Barron C, Iwasaki K. Actuarial analysis of private 43. Katayama H, Katayama T, Uematsu K, et al. Effect of dienogest
payer administrative claims data for women with endometriosis. administration on angiogenesis and hemodynamics in a rat endometrial
J Manag Care Pharm. 2007;13(3):262272. autograft model. Hum Reprod. 2010;25(11):28512858.
22. No authors listed. Revised American Society for Reproductive 44. Harada T, Taniguchi F. Dienogest: A new therapeutic agent for
Medicine classification of endometriosis: 1996. Fertil Steril. 1997; the treatment of endometriosis. Womens Health (Lond Engl). 2010;
67(5):817821. 6(1):2735.
23. The Practice Committee of the American Society for Reproductive 45. Nakamura M, Katsuki Y, Shibutani Y, Oikawa T. Dienogest, a
Medicine. Treatment of pelvic pain associated with endometriosis. synthetic steroid, suppresses both embryonic and tumor-cell-induced
Fertil Steril. 2008;90 Suppl 5:S260S269. angiogenesis. Eur J Pharmacol. 1999;386(1):3340.
24. Guo SW. Recurrence of endometriosis and its control. Hum Reprod 46. Okada H, Nakajima T, Yoshimura T, Yasuda K, Kanzaki H. The
Update. 2009;15(4):441461. inhibitory effect of dienogest, a synthetic steroid, on the growth of
25. Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal anti- human endometrial stromal cells in vitro. Mol Hum Reprod. 2001;
inflammatory drugs for pain in women with endometriosis. Cochrane 7(4):341347.
Database Syst Rev. 2009;2:CD004753. 47. Katsuki Y, Takano Y, Futamura Y, etal. Effects of dienogest, a syn-
26. Schindler AE. Non-contraceptive benefits of hormonal contraceptives. thetic steroid, on experimental endometriosis in rats. Eur J Endocrinol.
Minerva Ginecol. 2010;62(4):319329. 1998;138(2):216226.
27. Davis L, Kennedy SS, Moore J, Prentice A. Modern combined oral 48. Fu L, Osuga Y, Morimoto C, et al. Dienogest inhibits BrdU uptake
contraceptives for pain associated with endometriosis. Cochrane with G0/G1 arrest in cultured endometriotic stromal cells. Fertil Steril.
Database Syst Rev. 2007;3:CD001019. 2008;89 Suppl 5:13441347.
28. Vercellini P, Eskenazi B, Consonni D, etal. Oral contraceptives and 49. Shimizu Y, Mita S, Takeuchi T, Notsu T, Mizuguchi K, Kyo S.
risk of endometriosis: A systematic review and meta-analysis. Hum Dienogest, a synthetic progestin, inhibits prostaglandin E(2) production
Reprod Update. 2011;17(2):159170. and aromatase expression by human endometrial epithelial cells in a
29. Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues spheroid culture system. Steroids. 2011;76(12):6067.
for pain associated with endometriosis. Cochrane Database Syst Rev. 50. Tatsumi H, Kitawaki J, Tanaka K, Hosoda T, Honjo H. Lack of stimu-
2010;12:CD008475. latory effect of dienogest on the expression of intercellular adhesion
30. Sagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing molecule-1 and vascular cell adhesion molecule-1 by endothelial cell
hormone analogues for endometriosis: Bone mineral density. Cochrane as compared with other synthetic progestins. Maturitas. 2002;42(4):
Database Syst Rev. 2003;4:CD001297. 287294.
31. Mounsey AL, Wilgus A, Slawson DC. Diagnosis and management of 51. Horie S, Harada T, Mitsunari M, Taniguchi F, Iwabe T, Terakawa N.
endometriosis. Am Fam Physician. 2006;74(4):594600. Progesterone and progestational compounds attenuate tumor necro-
32. Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic pain sis factor alpha-induced interleukin-8 production via nuclear factor
associated with endometriosis. Cochrane Database Syst Rev. 2007; kappa B inactivation in endometriotic stromal cells. Fertil Steril.
4:CD000068. 2005;83(5):15301535.
33. Muneyyirci-Delale O, Karacan M. Effect of norethindrone acetate in 52. Momoeda M, Taketani Y. Randomized double-blind, multicentre,
the treatment of symptomatic endometriosis. Int J Fertil Womens Med. parallel-group doseresponse study of dienogest in patients with endo-
1998;43(1):2427. metriosis. Jpn Pharmacol Ther. 2007;35:769783. Japanese.
34. Telimaa S, Puolakka J, Ronnberg L, Kauppila A. Placebo-controlled 53. Barbieri RL. Hormone treatment of endometriosis: the estrogen thresh-
comparison of danazol and high-dose medroxyprogesterone acetate in the old hypothesis. Am J Obstet Gynecol. 1992;166:740745.
treatment of endometriosis. Gynecol Endocrinol. 1987;1(1):1323. 54. Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treat-
35. Lippert TH, Mueck AO. The clinical importance of dienogest. In: ment of endometriosis-associated pelvic pain: A 12-week, randomized,
Teichmann AT, editor. Dienogest Preclinical and Clinical Features double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod
of a New Progestogen. Berlin, Germany: Walter de Gruyter; 1995. Biol. 2010;151(2):193198.
36. Mueck AO. What makes dienogest a unique progestogen for the treat- 55. Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically
ment of endometriosis? Gynaecol Forum. 2010;15(2):1823. important changes in pain severity measured on a visual analog scale.
37. Oettel M, Breitbarth H, Elger W, etal. The pharmacological profile of Ann Emerg Med. 2001;38(6):633638.
dienogest. Eur J Contracept Reprod Health Care. 1999;4(S1):213. 56. Cosson M, Querleu D, Donnez J, et al. Dienogest is as effective as
38. Herkert O, Kuhl H, Sandow J, Busse R, Schini-Kerth VB. Sex steroids triptorelin in the treatment of endometriosis after laparoscopic surgery:
used in hormonal treatment increase vascular procoagulant activity by Results of a prospective, multicenter, randomized study. Fertil Steril.
inducing thrombin receptor (PAR-1) expression: role of the glucocor- 2002;77(4):684692.
ticoid receptor. Circulation. 2001;104(23):28262831. 57. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is
39. Khler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. A dose- as effective as leuprolide acetate in treating the painful symptoms of
ranging study to determine the efficacy and safety of 1, 2, and 4mg endometriosis: A 24-week, randomized, multicentre, open-label trial.
of dienogest daily for endometriosis. Int J Gynaecol Obstet. 2010; Hum Reprod. 2010;25(3):633641.
108(1):2125. 58. Harada T, Momoeda M, Taketani Y, et al. Dienogest is as effective
40. Sasagawa S, Shimizu Y, Kami H, et al. Dienogest is a selective as intranasal buserelin acetate for the relief of pain symptoms associ-
progesterone receptor agonist in transactivation analysis with potent ated with endometriosis a randomized, double-blind, multicenter,
oral endometrial activity due to its efficient pharmacokinetic profile. controlled trial. Fertil Steril. 2009;91(3):675681.
Steroids. 2008;73(2):222231. 59. Schindler AE, Christensen B, Henkel A, Oettel M, Moore C. High-dose
41. Sasagawa S, Shimizu Y, Nagaoka T, Tokado H, Imada K, Mizuguchi K. pilot study with the novel progestogen dienogestin patients with
Dienogest, a selective progestin, reduces plasma estradiol level through endometriosis. Gynecol Endocrinol. 2006;22(1):917.
induction of apoptosis of granulosa cells in the ovarian dominant fol- 60. Schindler AE, Henkel A, Moore C, Oettel M. Effect and safety of
licle without follicle-stimulating hormone suppression in monkeys. high-dose dienogest (20 mg/day) in the treatment of women with
J Endocrinol Invest. 2008;31(7):636641. endometriosis. Arch Gynecol Obstet. 2010;282(5):507514.

International Journal of Womens Health 2011:3 submit your manuscript | www.dovepress.com

183
Dovepress
Schindler Dovepress

61. Moore C, Carol W, Graser T, Mellinger U, Walter F. Influence of 64. Visanne. Summary of Product Characteristics. 2010. Available from:
dienogest on ovulation in young fertile women. Clin Drug Invest. 1999; http://visanne.com/en/auth/prescribing-essentials/spc/index.php.
18:271278. Accessed May 25, 2011.
62. Petraglia F, Hornung D, Seitz C, et al. Reduced pelvic pain in women 65. Kitawaki J, Kusuki I, Yamanaka K, Suganuma I. Maintenance therapy
with endometriosis: efficacy of long-term dienogest treatment. Arch with dienogest following gonadotropin-releasing hormone agonist treat-
Gynecol Obstet. June 17, 2011. [Epub ahead of print.] ment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol
63. Momoeda M, Harada T, Terakawa N, etal. Long-term use of dienogest Reprod Biol. April 5, 2011. [Epub ahead of print].
for the treatment of endometriosis. J Obstet Gynaecol Res. 2009;
35(6):10691076.

International Journal of Womens Health Dovepress

Publish your work in this journal
The International Journal of Womens Health is an international, peer- Endocrine and autoimmune syndromes; Sexual and reproductive
reviewed open-access journal publishing original research, reports, health; Psychological and psychosocial conditions. The manuscript
reviews and commentaries on all aspects of womens healthcare includ- management system is completely online and includes a very quick
ing gynecology, obstetrics, and breast cancer. Subject areas include: and fair peer-review system. Visit http://www.dovepress.com/
Chronic conditions (migraine headaches, arthritis, osteoporosis); testimonials.php to read real quotes from published authors.
Submit your manuscript here: http://www.dovepress.com/international-journal-of-womens-health-journal

184 submit your manuscript | www.dovepress.com International Journal of Womens Health 2011:3
Dovepress