CHAPTER 4

GnRH Analogs (Mechanism, Past

Studies, Drug Options, Use in
Precocious Puberty, Use in Gender-
Nonconforming Youth)
ANISHA GOHIL, DO • ERICA A. EUGSTER, MD

HISTORICAL PERSPECTIVE In the following years, potential applications of

The history that led to the discovery and development GnRHas were investigated in numerous clinical set-
of gonadotropin-releasing hormone analogs (GnRHas) tings, including central precocious puberty (CPP),
is a fascinating one. Gregor Popa and Una Fielding female and male contraception, endometriosis, uterine
discovered the hypophyseal portal system in 1930, fibroids, polycystic ovarian disease, hirsutism, men-
originally describing this network of blood vessels in strual cycle disorders, prostate cancer, and assisted
the rat.1,2 In 1937, Geoffrey Harris demonstrated that fertilization.6,8 GnRHas transformed the treatment of
the anterior pituitary was controlled by the central CPP since their first reported use in 1981 and quickly
nervous system, and his later research in the 1940s became the standard of care for this condition. By
and 1950s showed specifically that this control came 1993, three different GnRHasdleuprolide, nafarelin,
from the hypothalamus via the hypophyseal portal and histrelindhad each received the Food and Drug
system.1e3 In 1971, Schally et al. discovered that one Administration’s (FDA) approval for the treatment
polypeptide, gonadotropin-releasing hormone (GnRH), of CPP. The initial routes of administration were
when isolated from porcine hypothalami stimulated restricted to intranasal and subcutaneous, both of
the release of follicle-stimulating hormone (FSH) and which required daily dosing.9 Subsequently, a depot
luteinizing hormone (LH) from the pituitary gland form of leuprolide was developed that allowed for
across species. They not only identified the structure monthly intramuscular administration, and additional
of this polypeptide but also created a synthetic form of extended-release formulations of GnRHas continue to
it that exhibited the same downstream effects.4 Roger emerge.9e11 Currently, 3-monthly intramuscular injec-
Guilleman worked independently in a competitive race tions, 6-monthly intramuscular injections, and yearly
with Andrew Schally in the discovery of hypothalamic subcutaneous implants are also available.12,13 Intra-
regulatory hormones.1,5 In 1977, both were awarded muscular preparations have also been administered
the Nobel Prize in Physiology or Medicine for their subcutaneously with good success by some providers
scientific discoveries.6 A more refined physiological (personal communication).
understanding of GnRH was attained in 1978 when The use of GnRHas to block puberty and suppress the
Belchetz discovered that the pattern of GnRH delivery HPG axis in patients with gender dysphoria is associated
affected gonadotropin secretion. Intermittent administra- with improved physical and psychological outcomes.14
tion stimulated gonadotropin secretion while constant Following the first published case of the successful use
administration resulted in a paradoxical downregulation of the GnRHa, triptorelin, in a female-to-male (FTM) in-
of the hypothalamicepituitaryegonadal (HPG) axis.7 It dividual in 1998, this class of medications became
was this seminal discovery that paved the way for the established as the treatment of choice for pubertal sup-
development of the GnRHas and their subsequent utili- pression in the gender dysphoric patient.14e16 Fig. 4.1
zation in the clinical arena. illustrates a historical timeline of the discovery of

25
26 Pubertal Suppression in Transgender Youth

GnRH First published case of

Hypophyseal smulates First reported use GnRHa for pubertal
portal system release of LH of GnRHa in CPP suppression in gender
discovered and FSH dysphoria

1930 1940 1970 1980 1990 2000

Anterior Paern of GnRH Leuprolide

pituitary delivery affects receives FDA
controlled by gonadotropin approval for CPP
hypothalamus secreon

FIG. 4.1 Timeline of significant landmarks in the history of gonadotropin-releasing hormone (GnRH) analogs
(GnRHas). CPP, central precocious puberty; FDA, Food and Drug Administration; FSH, follicle-stimulating
hormone; LH, luteinizing hormone.

GnRH and the clinical use of GnRHas in pediatric pa- at the receptor by GnRH,17 which in turn is thought to
tients throughout the past century. inhibit the release of LH.8 Another important mecha-
nism is related to an alteration in the levels of LH alpha
PHYSIOLOGY AND MECHANISM OF ACTION and beta subunits in the presence of continuous GnRH
exposure. While alpha subunit levels increase, the bio-
GnRH is synthesized in the hypothalamus and secreted
logically active beta subunit levels decrease.17 When
into the hypophyseal portal system where it travels to
used therapeutically, gonadal suppression is entirely
the anterior pituitary. Here it acts at the GnRH receptor
reversed upon removal of GnRHa treatment.18
to stimulate the release of LH and FSH from the gona-
dotrope cells. The gonadotropins act on the ovary and
testis to stimulate production of sex steroids, which in USE IN CENTRAL PRECOCIOUS PUBERTY
turn leads to the development of secondary sexual char- By far, the greatest source of knowledge regarding the
acteristics. Sex steroids exert regulatory positive and clinical use of GnRHas in the pediatric population
negative feedback at the level of the hypothalamus comes from experience with its use in CPP. When pu-
and pituitary.8,17,18 berty develops prior to the onset of norms for racial
Pulsatile release of GnRH is required for production of background and ethnicity, it is considered precocious.19
LH and FSH. Pulses are released every 30e120 min. In Specifically, CPP involves premature activation of the
men, there is a consistent frequency of pulses, but in HPG axis21 and has traditionally been defined as
women, the frequency varies depending on the phase of puberty starting before the age of 8 years in girls and
the menstrual cycle.17 Several neuropeptides have been before the age of 9 years in boys.19 In addition to the
identified that exert a modulatory influence on GnRH age criteria, assessment for rapid progression, linear
secretion. Kisspeptin, which affects GnRH release, is widely growth acceleration, and advancement of bone age are
acknowledged to be the initial trigger involved in the initi- important aspects of the evaluation.12,19 Many girls
ation of puberty. Neurokinin B and dynorphin are involved with idiopathic CPP will have a gradual progression
in the regulation of kisspeptin, and collectively, these three of puberty with no compromise in final adult height.
neuropeptides are known as KNDy neurons.19 The major rationale for treatment is preservation of
GnRHas differ from native GnRH due to a chemical adult height potential, as there is a lack of evidence to
amino acid substitution at positions 6 and 10 in the support using GnRHas to delay menarche or ameliorate
GnRH molecule. This molecular change increases affin- psychological outcomes. Girls younger than 6 years and
ity for the GnRH receptor and decreases clearance by boys younger than 9 years with rapidly progressive
enzymatic removal.20 When GnRH is present at a sus- puberty have the greatest improvements in final height
tained continuous concentration, desensitization of as a result of GnRHa treatment.12
the GnRH receptor occurs. It appears that multiple Since the mid-1980s, long-acting GnRHas have been
mechanisms may play a role in desensitization, one of the standard of care for the treatment of CPP world-
which includes decreased mobilization of intracellular wide.22 They have been shown to be effective and safe.
calcium. This occurs secondary to sustained stimulation Rapid-acting intranasal and subcutaneous forms are
 CHAPTER 4 GnRH Analogs 27

TABLE 4.1
Gonadotropin-Releasing Hormone Analogs
(Limited to United States
Formulations) Brand Name Formulation Dosage Route
Leuprolide Lupron Monthly 0.2e0.3 mg/kg per month Intramuscular injection
3-monthly 11.25 mg or 30 mg every Intramuscular injection
3 months
Triptorelin Triptodur 6-monthly 22.5 mg every 6 months Intramuscular injection
a a
Histrelin Supprelin Yearly 50 mg every 12e24 months Subcutaneous implant
Nafarelin Synarel Twice daily 800 mg twice daily (starting dose) Nasal spray
a
Can be left in place for 2 years.

available, but depot formulations are recommended as regarding long-term follow-up of treated patients.26
compliance is improved with this method.12 Monthly Reproductive function in girls treated with GnRHas is
depot intramuscular injections are typically given at not impaired. There are very limited data on outcomes
a dose of 0.2e0.3 mg/kg per month.9,19 However, in boys, but three small studies show intact reproduc-
3-monthly and 6-monthly forms are also now avail- tive function in them as well at the age of 15e18 years.
able.12,13 An additional option for extended release is While average time to menarche is approximately
the histrelin subcutaneous implant which can be left 16 months after stopping treatment, there is a wide
in place for 2 years.19,23 Table 4.1 summarizes formula- variation of 2e61 months.12 Time to menarche after
tions available in the United States.12,13,24e27 treatment cessation appears to be inversely propor-
Initiation of GnRHa treatment results in cessation tional to age,26 whereas other factors such as bone
of pubertal progression, a return to a prepubertal age, breast Tanner stage, uterine development, or fre-
growth velocity, and a decrease in the rate of skeletal quency of injections have not demonstrated unifor-
maturation.22 There is no evidence to support the mity with regard to affecting this interval of time.20
need for routine laboratory monitoring while on treat- The regularity of menstrual cycles in treated girls
ment as long as clinical parameters indicate pubertal appears to be comparable to that observed in the
suppression. Response to treatment should be followed normal adolescent population.26 Although more data
clinically with physical examination, assessment of are needed to assess newer extended-release formula-
growth, and intermittent determination of bone age.12 tions, the mean time to menarche appears to be
Apparent clinical progression of puberty can indicate equivalent or slightly shorter on average in those
poor compliance, but treatment failure or the presence treated with a histrelin implant compared with depot
of an alternate diagnosis should be considered.22 intramuscular GnRHas.20,28 Fertility appears to be
GnRHas are extremely well tolerated, and most side normal in women who were treated for CPP. In fact,
effects are transient including rash, headaches, gastroin- GnRHa treatment appears to improve reproductive
testinal issues, or hot flashes. Vaginal bleeding can occur function in patients with a history of CPP, as those
after administration of the first dose in girls due to an who are untreated require reproductive assistance
initial flare in HPG axis activation with a concomitant in- more frequently.20,29 Rates of pregnancy and live
crease in sex steroid levels prior to suppression.22 Local births do not appear to differ from those seen in the
reactions can occur in about 10e15% of cases and sterile general population.19
abscesses have been reported. Anaphylaxis is very rare.12 The best height outcomes are achieved when
The decision to stop treatment is individualized in treatment is initiated in girls who start treatment
each patient and incorporates consideration of the prior to the age of 6 years,19,20 with height gains of
timing of normal puberty, individual height potential, 9e10 cm,12 recognizing that height outcomes are vari-
psychological components, and patient and family pref- able among studies.19 Evidence demonstrates that
erence. The average age of treatment cessation is GnRHas are successful in halting further bone age
10.6e11.6 years.12,22 advancement.20 Girls treated between the age of 6 and
8 years show a moderate benefit in height outcome,12
OUTCOMES IN CENTRAL PRECOCIOUS whereas those older than 8 years do not appear to
PUBERTY benefit in terms of an increase in adult height.19 There
Suppression of the HPG axis is reversible after discon- are insufficient data to allow for the establishment of anal-
tinuation of a GnRHa, but variable information exists ogous age cut-offs regarding height outcomes in boys.12
28 Pubertal Suppression in Transgender Youth

It is known that girls with CPP have higher rates of Typically, the first stage of hormonal intervention
overweight and obesity prior to starting treatment consists of a puberty blocker to halt the progression of
with a GnRHa. This weight status continues throughout physical changes that are discordant with gender identity.
treatment and therefore does not appear to be second- It is not recommended to treat prepubertal children since
ary to the treatment itself. Body mass index does not intensification of gender dysphoria at the onset of pu-
increase further during GnRHa treatment.19,26 berty serves to reinforce the diagnosis. In addition,
Although only a few studies are available, bone min- many children who are diagnosed in childhood ulti-
eral density (BMD) does appear to decrease during mately desist and do not end up as transgender adults.
GnRHa treatment, but once therapy is stopped, BMD Although a variety of strategies for suppressing endoge-
returns to normal and ultimate accumulation of bone nous sex steroids are available, GnRHas are the preferred
mass during adolescence is sufficient.12,20,26 approach. This allows the patient more time to reflect on
There is controversy regarding an increased risk of their gender identity prior to embarking on the next
polycystic ovarian syndrome (PCOS) in girls with CPP phase of physical transition which consists of gender-
since studies suggest an increased incidence compared affirming hormone (GAH) treatment which is consid-
to unaffected individuals, but not necessarily attributed ered only partially reversible.14 When started in the early
to the treatment itself.19 There is a similar prevalence of stages of puberty, GnRHas also prevent the development
PCOS in untreated patients with CPP which speaks of secondary sexual characteristics, which often brings
against GnRHas as the cause.26 about an escalation in feelings of gender dysphoria,
While it is known that girls with early puberty have resulting in worse psychological outcomes in a popula-
earlier sexual risk-taking behaviors, it is unknown if tion already at high-risk for psychopathologic comorbid-
this also applies to the CPP population and how ities.33 Some characteristics such as the Adam’s apple,
GnRHas play into psychological outcomes.12,19 While deeper voice, taller stature, male hair pattern, and body
existing literature pertaining to psychosocial sequelae habitus in male-to-female (MTF) patients and breast
of early puberty in girls is inconsistent, studies have development, female body habitus, and shorter stature
failed to find evidence of negative psychological conse- in FTM patients are difficult or impossible to reverse
quences of CPP either at baseline or after 1 year.30,31 once they have occurred. Thus, preventing these physical
Further studies are needed to investigate this topic. changes is associated with a more successful transi-
There has been considerable interest in the poten- tion.14,34 Another advantage of GnRHas is the fully
tial use of GnRHas in children with normally timed reversible nature of this intervention. Once treatment is
puberty in whom the prognosis for adult height is withdrawn, endogenous puberty concurrent with the pa-
deemed to be poor. This includes children with short tient’s natal sex will resume and progress.14,15
stature, growth hormone deficiency, congenital adre- Eligibility criteria for GnRHa treatment includes the
nal hyperplasia, and profound primary hypothyroid- presence of a long-lasting and intense pattern of gender
ism. Currently, there are insufficient data to support dysphoria that worsens with the start of puberty, the
the use of GnRHas for any of these indications absence of significant psychosocial or medical prob-
in routine clinical care, although more research is lems, sufficient medical capacity on the part of the pa-
indisputably needed.32 tient and parent or guardian to give informed consent,
and the presence of Tanner stage 2 or greater of pubertal
development confirmed by a pediatric endocrinologist
USE IN GENDER-NONCONFORMING YOUTH or other clinician.14,15 Criteria for hormonal treatment
While awareness of gender dysphoria increased in the also include confirmation of the diagnosis of gender
second half of the 20th century, recent years have dysphoria by a qualified mental health provider, and
witnessed an exponential rise in the number of referrals ongoing counseling during the period of transition is
for gender-related concerns to pediatric endocrine and considered essential. Part of the informed consent pro-
adolescent medicine clinics.15 The World Professional cess should involve the discussion of side effects and
Association for Transgender Health provides updated options for fertility preservation.14 See Table 4.2 for a
standard-of-care guidelines for the treatment of gender- list of these eligibility criteria.14,15
nonconforming youth. Additionally, the Endocrine Soci- When GnRHas are prescribed during the early stages
ety released updated clinical practice guidelines in of pubertal development, regression of existing physical
2017.33 Both recommend GnRHas as the preferred changes often occurs, and any further progression is
method for pubertal suppression.14,15 halted. For example, breast tissue and testicular size
 CHAPTER 4 GnRH Analogs 29

TABLE 4.2
Eligibility Criteria for Pubertal Suppression in Gender Nonconforming Youth
1. The presence of a long-lasting and intense pattern of gender dysphoria that worsens with the start of puberty.
2. Psychosocial or medical problems that could interfere with treatment are addressed such that the adolescent is
considered stable to start treatment.
3. The patient and parent or guardian has sufficient medical capacity to give informed consent. The discussion of side effects
and options for fertility preservation should be involved.
4. The presence of Tanner stage 2 or greater of puberty confirmed by a pediatric endocrinologist or other clinician.
5. There are no medical contraindications to gonadotropin-releasing hormone analog treatment.

may decrease.14 Monitoring during treatment includes addition to intramuscular formulations is the subcu-
anthropometric parameters (height, weight, Tanner taneous histrelin implant. The version marketed for
staging) and laboratory assessments (LH, FSH, testos- children under the brand name Supprelin was approved
terone in MTF, estradiol in FTM) at baseline and every by the FDA for use in CPP in 2007 and has been shown
6 months. Determination of bone age X-ray in patients to be safe and effective.36 This device is associated with
with remaining growth potential and BMD assessed via favorable patient and parent satisfaction compared with
dual-energy X-ray absorptiometry are recommended depot intramuscular injections. The implant is generally
yearly.14,34 well tolerated with the most common side effect, a local
The age of initiation of GAH treatment varies, but reaction at the implantation site, being temporary and
typically occurs around the age of 16 years. The optimal self-limited. Retrieval of the device can be challenging
length of time that a GnRHa should continue once GAH due to a 22%e39% chance of breakage.24 Despite
therapy has been initiated is unknown. As initial doses this, fragments are easily retrievable through the orig-
of testosterone or estrogen are not high enough to sup- inal incision without the need for additional imaging
press gonadotropin production, it is important to or a different anesthetic technique.36 The vast majority
continue the patient on a GnRHa at least during the of implants can be placed and removed in the outpa-
early stages of GAH therapy. Current recommendations tient clinic under local anesthesia with child-life distrac-
include continuing GnRHa treatment until gonadec- tion and general anesthesia almost being never
tomy. However, alternate options are available for required.24,36
patients in whom gonadectomy is not desired or pro- Another version of the histrelin implant that is
longed treatment with a GnRHa is not feasible. Adult marketed for adults is known by the brand name Vantas.
doses of testosterone may be sufficient monotherapy Although only FDA approved for prostate cancer
in FTM patients with the addition of a progestin if treatment in adult men,37 it has been used successfully
menstrual periods occur.14,33 In MTF patients, an anti- for pubertal suppression in transgender youth.38 Both
androgen can be added to an estrogen regimen in lieu implants contain a total dose of 50 mg of histrelin ace-
of a GnRHa.14 tate, but Supprelin releases 65 mg per day while Vantas
Although initiating GnRHa therapy early in puberty releases 50 mg per day. Both are inserted subcutaneously
is considered optimal, many transgender youth do not into the upper arm, are FDA approved for 1 year, and
seek medical intervention until well after endogenous decrease sex steroids to goal level by 1 month.37,39 How-
puberty is essentially complete.35 GnRHas are still ever, Supprelin contains enough medication to last for
considered appropriate in this setting as they represent 2 years and provides effective suppression of the HPG
the most potent means of rendering endogenous sex axis for at least 24 months in children with CPP.40
steroids to prepubertal values.

OUTCOMES IN GENDER-NONCONFORMING
OPTIONS FOR TREATMENT YOUTH
The exact same therapeutic armamentarium of GnRHa The current landscape regarding outcomes of pubertal
preparations are available for use in gender-variant suppression in transgender youth is rife with large
patients as in those with CPP. One attractive option in gaps in knowledge, and more long-term data regarding
30 Pubertal Suppression in Transgender Youth

the safety of GnRHas in this setting are badly needed.41 Treatment with a GnRHa will suppress spermatogen-
While much of what we know about these drugs can esis and oocyte maturation. Suspending treatment for
be inferred from their use in CPP, it is important to fertility preservation is an option but is complicated
consider that their use in children with gender dysphoria by the fact that gametogenesis occurs during the later
occurs on an entirely different physiological and devel- stages of puberty, at which time substantial progression
opmental background.34 However, the limited evidence of secondary sexual characteristics has already occurred.
that is currently available suggests that when used appro- The time to onset of gamete maturation after GnRHa
priately in gender-variant patients, they are safe and effec- cessation as well as the potential effects of prolonged
tive at least in the short term.33 Long-term effects are GAH treatment on germ cell viability is currently un-
briefly reviewed here, with further discussion in subse- known.14 Surgical outcomes can also be impacted by
quent chapters. GnRHa treatment in MTF patients who pursue creation
While gender dysphoria does not resolve completely of a neovagina, as sufficient phallic and scrotal skin may
with GnRHa therapy, its use has been associated with not be present. However, alternative surgical techniques
improved psychological functioning in areas of depres- using intestinal tissue have been successful.33,46
sion, anxiety, anger, overall functioning, and life satisfac-
tion.33,42 One argument against the use of GnRHas is
that natal sex hormones are important for the develop- CHALLENGES IN CARE
ment of gender identity and that adolescents may not Transgender youth may face many barriers to care
possess the developmental foresight to understand the including uninformed providers, long distance to cen-
potential effects of pubertal suppression. However, the ters providing transition services, lack of insurance
very real risk of increased psychological distress and con- approval for hormonal therapies, discrimination even
current rise in depression and suicidality caused by the within the medical environment, and/or lack of care-
development of secondary sexual characteristics that giver support and willingness to provide consent. Cur-
are inharmonious with gender identity is thought to riculum for the care of transgender patients in current
outweigh this concern according to experts in the field.43 medical education is lacking with only a few medical
GnRHas result in adequate suppression of the HPG schools providing this type of instruction.38,47 While
axis in transgender youth and can be used to manipu- GnRHas are the standard of care for pubertal suppres-
late adult height standard deviation score in patients sion, the FDA has not approved their use for pubertal
in whom epiphyseal fusion has not yet occurred. Bone suppression for gender dysphoria, so current prescrip-
density z-scores appear to decrease significantly during tions are all considered “off label.”38
pubertal suppression, but subsequently, bone accretion Insurance denial for hormone treatment is a substan-
normalizes once GAH treatment is added. Studies are tial barrier leading to large out-of-pocket expenses for
needed to assess long-term effects on bone health.44 families. The high costs of GnRHas make them out of
Changes in body composition include an increase in reach for many. Compounding the burden is the large
fat mass and a decrease in lean body mass during treat- cost differential between GnRHa formulations that are
ment.14,33,44 It is unknown whether and in what way marketed for pediatric versus adult use.48 For example,
GnRHas may affect brain development.44 the cost difference between the 3-monthly formulation
The first reported long-term follow-up of an FTM of Lupron Depot ($4800) compared to the 3-monthly
patient treated with a GnRHa and GAH with subse- preparation of Lupron Depot-Ped ($9700) is approxi-
quent gender reassignment surgery was published in mately $4900. The cost of the pediatric subcutaneous
2011 from the Netherlands. After 22 years of follow- histrelin implant (Supprelin) is approximately $35,000
up, this patient was doing well psychologically and compared with the adult subcutaneous histrelin implant
had normal physical health, bone density, and body (Vantas) which is approximately $4400, resulting in a
proportions. His final height was just below
2 stan- difference of approximately $30,600.49,50 The use of
dard deviations compared to natal males, and he some mail order pharmacies or Vantas represents poten-
wished to be taller. However, he had no regrets about tial ways of limiting costs for families paying out of
his treatment process.16 Similar findings were reported pocket for hormonal treatment.38,48
in a cohort of 55 young transgender adults who were
evaluated approximately 7 years after completing tran-
sition and were found to have rates of well-being equiv- CONCLUSION
alent or better than their peers in the general In conclusion, within the historical context of GnRHa
population.45 use in the pediatric population, the employment of
 CHAPTER 4 GnRH Analogs 31

this class of medications in gender-variant children 14. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endo-
and adolescents represents a new frontier. While crine treatment of gender-dysphoric/gender-incongruent
initial knowledge is reassuring, many important persons: an endocrine society clinical practice guideline.
questions remain pertaining to both physical and psy- J Clin Endocrinol Metab. 2017;102.
15. World Professional Association for Transgender Health.
chological consequences of suppressing normally
Standards of Care for the Health of Transsexual, Transgender,
timed puberty, sometimes for upwards of 7 years, in and Gender Nonconforming People 7th Version; 2011. http://
these vulnerable patients. Long-term, carefully con- www.wpath.org/site_page.cfm?pk_association_webpage_
ducted prospective studies are needed to further menu¼1351.
delineate the risks and benefits of GnRHas in trans- 16. Cohen-Kettenis PT, Schagen SE, Steensma TD, de Vries AL,
gender youth. Delemarre-van de Waal HA. Puberty suppression in a
gender-dysphoric adolescent: a 22-year follow-up. Arch
Sex Behav. 2011;40(4):843e847.
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