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Puberty suppression in gender identity disorder: The Amsterdam experience

Article in Nature Reviews Endocrinology · May 2011

DOI: 10.1038/nrendo.2011.78 · Source: PubMed

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Baudewijntje P C Kreukels Peggy T Cohen-Kettenis

Amsterdam University Medical Center Amsterdam University Medical Center
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This paper has been published in: Kreukels, B. P. C. & Cohen-Kettenis, P. T. Nat. Rev.

Endocrinol. 7, 466–472 (2011); published online 17 May 2011;

doi:10.1038/nrendo.2011.78

Puberty suppression in gender identity disorder: the Amsterdam

experience

Abstract

The use of gonadotrophin releasing hormone analogs (GnRHa) to suppress puberty in

adolescents with gender dysphoria is a fairly new intervention in the field of gender identity

disorders or transsexualism. GnRHa are used to give adolescents time to make balanced

decisions on any further treatment steps, and to obtain improved results in the appearance of

those who continue with sex reassignment. The effects of GnRHa are reversible. However,

concerns have been raised about the risk of making the wrong treatment decisions, as gender

identity could fluctuate during adolescence, the adolescents’ might have poor decision-

making abilities, and there are potential adverse effects on health and on psychological and

psychosexual functioning. Proponents of puberty suppression emphasize the beneficial effects

of GnRHa on the adolescents’ mental health, quality of life and of having a physical

appearance that makes it possible for the patients to live unobtrusively in their desired gender

role. In this Review, we discuss the evidence pertaining to the debate on the effects of GnRHa

treatment. From the studies that have been published thus far, it seems that the benefits clearly

1
outweigh the risks. However, more systematic research in this area is needed to determine the

safety of this approach.

Introduction

Gender identity disorder (GID) is characterized by a persistent cross-gender

identification and discomfort with one’s natal sex, or a sense of inappropriateness in the

gender role of that sex (as defined in the DSM IV-TR).1 Individuals who suffer from extreme

forms of GID usually pursue hormone treatment and sex reassignment surgery. For patients

with this condition, the ICD-10 uses the term transsexual.2 The patient’s distress caused by

the subjective experience of persistent cross-gender identification and discomfort with one’s

natal sex can be described by the term gender dysphoria.

Although the etiology of GID is still far from clear, the results from several studies

indicate that biological factors are involved. For instance, in the central portion of the bed

nucleus of the stria terminalis and the interstitial nuclei 3 and 4 of the anterior hypothalamus a

sex reversal has been found in the volume and number of neurons in male-to-female (MtF)

transsexuals and a female-to-male (FtM) transsexual.3–5 Neuroimaging studies indicate that

the microstructure pattern of white matter in untreated FtM transsexuals was similar to the

usual pattern in men,6 and that the gray matter volume of the putamen in untreated MtF

transsexuals resembled the volume usually seen in women.7 In addition, cerebral activation

patterns in transsexuals prior to treatment seem to share more features with those of the

experienced gender than those of their biological sex. These patterns were observed during

the processing of pheromones8 and while participants viewed erotic film excerpts.9 Finally,

differences have been found within the cortical network between MtF transsexuals (prior to as

2
well as during hormonal treatment) and control males while the participants are engaged in

mental rotation tasks.10 In addition to the brain studies, findings from behavioral–genetic

studies indicate that a genetic component in gender development can not be ruled out,11,12 and

polymorphisms in genes related to sex steroids have been found to differ between transsexual

and nontranssexual groups,13–15 but see.16,17 These findings are in line with our clinical

experience that GID in adolescents and adults is extremely resistant to change.

Clinicians generally use the Standards of Care of the World Professional Association

for Transgender Health (WPATH)18 as a guideline for their diagnostics and clinical

interventions. Hormone treatment guidelines have been formulated by the Endocrine

Society.19

Most transsexual adolescents have shown atypical gender development,20 including

gender dysphoria, since early childhood. For them, the first signs of puberty are invariably a

source of distress, and puberty might have a strong negative effect on their emotional and

social functioning, and school career. Even adolescents who previously functioned well might

react with oppositional behavior, depression and/or anxiety once they enter puberty.

Therefore, the suppression of puberty, followed by cross-sex hormone treatment and surgery

seems to have undeniable benefits for transsexual youths. However, strong objections against

puberty suppression have been raised by those who fear that the disadvantages of this approach

outweigh the advantages.21,22 In this Review, we will first describe the development of the

current approach and then discuss the dilemmas associated with the treatment of this young

group of transsexual individuals.

Protocol development

The practice of puberty suppression in young adolescents, developed by the team at

the Amsterdam Gender Identity Clinic, The Netherlands, was not introduced overnight. Two

3
clinical observations, made in the late 1980s, were relevant to this change in practice. The

first was that, often despite many years of psychotherapy, the gender dysphoria of most

adolescents with GID does not abate. The second was that many problems (e.g. depression

and difficulties in their relationsships with peers) the adolescents were struggling with seemed

to be the consequence, rather than the cause, of their GID. At the time, hormone treatment

was not started in patients <18 years old, therefore, the above observations resulted in a

change of clinical policy at the Amsterdam Gender Identity Clinic.

Staged hormonal treatment from 16 years old

The first treatment protocol developed at the Amsterdam Gender Identity Clinic

consisted of a staged hormonal treatment in patients ≥16 years old. MtF transsexuals were

initially given antiandrogens and if they responded positively to this first phase, estrogens

were prescribed. FtM transsexuals received progesterone first and then androgens. The

diagnostic procedure that was followed for adults was adjusted to select good candidates for

this staged hormonal treatment. The adjustment included more involvement of the family,

more extensive psychological testing and stricter eligibility criteria than the adult diagnostic

procedure. The eligibility criteria were age >16 years, a clear early-onset (before puberty)

GID, persisting gender dysphoria upon entering puberty, no comorbidities or other

circumstances that could interfere with the diagnostic work or treatment, support from parents

or caretakers and a good understanding of the effects of the treatment.

Before treatment started, ample attention was given to the effects and limitations of all

treatment steps, and to factors that could seriously jeopardize treatment (for example,

smoking or being overweight) to enable a truly informed consent. Treatment decisions were

always taken by the whole team.

4
Evaluation of the first treatment protocol

Over the years, the protocol was evaluated in a number of follow-up studies. These

studies showed that the treatment resulted in the disappearance of gender dysphoria, and that

none of the participants regretted undergoing treatment as assessed by interviews and

questionnaires 23,24 The psychological and social functioning of the adolescents who received

treatment also seemed to be comparable to that of their peers. Naturally, using a randomized

double-blind design would have been preferable, but for obvious ethical and practical reasons

such a design is not an option. In the group of 27 who were not accepted for early treatment or

withdrew from the diagnostic procedure, 6 pursued sex reassignment in adulthood, usually

after some other form of treatment and some still with considerable problems such as bipolar

disorder or a chaotic family situation. However, the large majority of adolescents who did not

receive early treatment never reconsidered undergoing sex reassignment.24 When conducting

these follow-up studies, the team at the Amsterdam Gender Identity Clinic became aware that

the appearance of those participants who had not reached Tanner stage 5 (the last phase of

puberty development) at the start of the treatment, was much more in accordance with the

new gender than the usual appearance of individuals who were treated in adulthood. Early

intervention not only seemed to lead to a better psychological outcome, but also to a physical

appearance that makes being accepted as a member of the new gender much easier, compared

with those who began treatment in adulthood.

Staged hormonal treatment from 12 years old

As these first studies favored early, rather than late, interventions, the team at the

Amsterdam Gender Identity Clinic decided to reduce the age limit for starting hormonal

treatment. In the first protocol, the adolescents were initially treated with medications that

either blocked the effects of all androgens (antiandrogens in MtF transsexuals) or only

5
suppressed menstruation (progesterone in FtM transsexuals), before they received cross-sex

hormones. Preventing the development of secondary sex characteristics in the early Tanner

stages (not later than Tanner stage 2/3) seemed to be the most advantageous approach, as the

adolescent would not experience the alienating effects of a body that changed in an unwanted

direction. For this purpose, gonadotropin-releasing hormone analogs (GnRHa; triptorelin,

3.75 mg every 4 weeks) were used.25 An extra dose was given after 2 weeks of GnRHa

treatment26 to counteract the initial surge of sex hormones. If treatment with GnRHa is

stopped, puberty in line with the natal sex will continue to develop. In this sense the treatment

is reversible. If the adolescent still wanted to start the actual sex reassignment when they were

16 years old, a feminizing puberty was induced in boys by prescribing 5 μg/kg 17 β estradiol

per day and increasing the dose every 6 months by 5 μg/kg. An adult dose of 2 mg per day

was given when the patient reached 18 years of age. In girls, a male puberty was induced with

testosterone esters, starting at 25 mg/m2 per 2 weeks intramuscularly, increasing the dose

every 6 months by 25 mg/m2. At age 18 years an adult dose was given of 250 mg per 3–4

weeks. Further information about the treatment procedure can be found in the guidelines of

the Endocrine Society on the endocrine treatment of transsexual persons.19

After the first experience with an FtM transsexual who responded to the treatment

exceptionally well,27 it was decided to start treatment in a large number of carefully selected

adolescents. In addition to the criteria that have been set for the ≥16 year olds (clear early-

onset GID, persisting gender dysphoria upon entering puberty, no comorbidities or other

circumstances that could interfere with the diagnostic work or treatment, support from parents

or caretakers and a good understanding of the effects of the treatment), eligible participants

now have to be at least 12 years old. Because it seems to be important that adolescents

experience some of the physical effects of puberty to make a well-informed decision on

whether to suppress these effects, they have to be in Tanner stage 2 of their pubertal

6
development before starting treatment. By providing extra time to enable further exploration

of the desire for irreversible interventions (cross-sex hormones and surgery) without the

distress of puberty, GnRHa treatment is considered to be a diagnostic aid.

Evaluation of the second treatment protocol

Thus far, two studies, both from the Amsterdam Gender Identity Clinic, have

evaluated the psychological functioning of adolescents with GID after the use of GnRHa to

block puberty.28,29 140 of the 196 adolescents who were consecutively referred to the

Amsterdam Gender Identity Clinic between 2000 and 2008 were considered eligible for

treatment. Of the eligible adolescents, 111 received GnRHa, 29 had already reached the age of

16 years and were prescribed cross-sex hormones according to the first treatment protocol.28

None of the participants dropped out of the treatment protocol and stopped taking GnRHa. In

the first study that examined the initial 70 candidates eligible for puberty suppression (33

natal males and 37 natal females), it was found that psychological functioning improved

considerably during treatment, but, as expected, the gender dysphoria did not change.28 In the

second study, 27 young adults were interviewed ≥1 year after surgery that was preceded by

treatment with GnRHa and cross-sex hormones; the gender dysphoria disappeared and their

quality of life was good.29 No one regretted treatment and the participants were similar to

their peers with regard to relationships, education and/or career. At the moment the

adolescents who have not been considered eligible for treatment with GnRHa have not been

examined systematically. The inclusion of these adolescents in future follow-up studies

would clearly be worthwhile

Dilemmas

7
 The dilemmas associated with GnRHa treatment for young adolescents with GID are

about the potential harm this strategy could cause—is more harm done by abstaining from

medical interventions or by interfering medically? The concerns of those who support not

intervening medically focus on the risk of making incorrect decisions, because in adolescence

gender identity might still be fluctuating;22,30 the inability of adolescents to make far-reaching

decisions and to understand the effect puberty suppression will have on their lives;21

potentially adverse effects of GnRHa treatment on psychological or psychosexual

functioning;22 and the possibility that puberty suppression before Tanner stage 4 or 5 is

medically unsafe.31

Proponents of early treatment emphasize the suffering of those who were treated as

adults, the poor mental health and distress of adolescents who are denied treatment before

adulthood, the risks a delay might involve, the advantage of ‘buying time’ in the diagnostic

phase and the advantage of having a physical appearance in accordance with the desired

gender.32–35

Harmfulness of interference

Can a diagnosis be made in adolescence?

Some researchers state that suppressing puberty results in an increased risk of

misdiagnosis because the patient’s gender identity might still change.22,30 In the evidence that

supports this argument, however, usually no distinction is made between child and adolescent

studies. Only a fairly small number of children with GID (20–25%) seem to have a persisting

GID after the first pubertal stages.36–38 This figure might be related to the current broadness of

GID criteria. According to the child DSM-IV-TR criteria for GID, even children who only

show gender variant behavior can obtain a diagnosis.39 Yet, after puberty has started,

persistence of GID is considerably higher than in children. Although no long-term studies in

8
large numbers of adolescents with GID have been published, clinically one rarely comes

across adolescents with early-onset GID who experienced an increase in gender dysphoria in

the first stages of puberty and pursued sex reassignment in adolescence, in whom the GID

then reversed. In one qualitative study, older adolescents with an age range of 14 to 18 years,

who had been children with a GID diagnosis but whose GID reversed, reported that their

gender dysphoria had disappeared shortly after the first physical signs of puberty, and the first

sexual feelings and sexual attractions.40 So it seems very unlikely that adolescents who have

been through the first stages of puberty and responded to it with an increased intensity of

gender dysphoria rather than a (new) enjoyment of their gender of rearing and developing

sexuality, will experience a reversal of their GID in the late pubertal stages.

The first studies by the Amsterdam group, described above, indicate that participants

did not regret treatment. This finding suggests that a selection of ‘good candidates’, is

possible if the diagnostic procedure has been meticulous. However, further studies are

required to confirm these findings in different populations.

Can adolescents make complex life decisions?

The legal minimum ages differ between countries for many behaviors or rights, such

as smoking, drinking, voting, marrying or driving vehicles. Apparently there is not much

agreement on the age of discretion. Adolescents themselves consider it essential to have a

voice in important treatment decisions, such as end-of-life decisions.41 In some countries,

such as The Netherlands and the UK, adolescents are allowed to make medical treatment

decisions without parental approval from the age of 16 years. In the UK, following the Gillick

case it was established that a minor <16 years can give informed consent to medical

interventions when the minor has reached sufficient understanding and intelligence to be

9
capable of making such a decision (Gillick competence).33 In The Netherlands, the consent of

parents as well as the child is needed between the ages of 12 and 16 years.

Some clinicians might fear that the decision to pursue hormone treatment is taken on

impulse. From the brain development literature, it seems that during adolescence there is a

change in the ratio of grey to white matter in prefrontal areas, an increase in connectivity

between prefrontal and other regions, and an increase in dopaminergic activity in prefrontal–

striatal–limbic pathways.42 These processes are hypothesized to lead to an increased

likelihood of engaging in risky or impulsive behavior (which is characteristic of adolescence).

However, the desire for sex reassignment never arises abruptly in early-onset transsexual

adolescents. They and their parents usually report that the wish to have treatment has been

present for many years before the actual referral to the clinic. To consider their desire for

treatment a whim would be erroneous. The studies in brains, however, do identify another

source of concern. Adolescents with GID who are kept from treatment in this already

vulnerable period might engage in risky behaviors because of their despair. Trying to fulfill

their goals they might seek other ways to obtain treatment and as a consequence engage in

prostitution to earn money to pay for the treatment, or buy illegal hormones.43 Not willing to

wait too long for their sex reassignment, they might even engage in self-harm or become

suicidal.44

It is essential that adolescents understand the long-term consequences (such as

infertility) of their sex reassignment and make a balanced decision that takes the risks and

benefits into account. Even if they are in principle able to make such decisions by themselves,

it seems important that they are well informed and carefully guided by their clinicians and

caretakers.

Are there negative effects of treatment?

10
 The fear that GnRHa treatment might have a negative effect on the patient’s

psychological functioning has thus far not been supported by the few studies that have been

conducted at the Amsterdam Gender Identity Clinic.28,29 However, confirmation of these

results is needed from other clinics.

The conjecture of some clinicians that puberty suppression hinders the formation of a

normal or a natural gender identity, and that one should not interfere before psychosexual

development is complete22 seems to be of little use in solving the clinical dilemmas. First, no

criteria are given for ‘complete psychosexual development’. If, for instance, having sexual

relationships would be considered important in these criteria, it is unlikely that untreated

adolescents with GID will ever reach such a stage, as they would consider having sexual

relationships unattainable without having undergone sex reassignment. Similarly, they would

never choose to undergo the puberty of their natal sex to become more certain about their

‘ultimate gender identity’, as they feel that they are already certain. Persons with GID cannot

take the usual psychosexual steps to attain a complete psychosexual development. Therefore,

requiring youngsters with GID to await complete psychosexual development before they can

receive treatment places them in an impossible position. Second, it is unclear what a ‘natural

gender identity’ consists of for an adolescent who, since early childhood, had a gender

identity that was not congruent with his or her natal sex. Considering the etiological studies

that suggest early biological influences, the cross-gender identity might be more natural than

the gender identity associated with the natal sex.

What are the medical risks?

Medical concerns about GnRHa treatment include the effects on bone mass

development, height, body segment disproportion and metabolism. Again, only a few studies

have been done that assess these risks and many more are needed to corroborate the existing

11
findings. The studies report that, although puberty suppression results in a decrease in the

speed of growth, the introduction of cross-sex hormones will result in a final height

appropriate for the desired gender.26 When cross-sex hormone therapy is initiated within a

few years of GnRHa therapy the negative impact upon accrual of BMD should be

neutralized.30 Indeed, BMD, as well as metabolic parameters, seem to normalize after

initiation of cross-sex hormones.26 The results of a study on the effects of puberty suppression

on bone mass development showed that bone mass development is not jeopardized by the

treatment (Schagen, Cohen-Kettenis, van Coeverden-van den Heijkant, Knol, Gooren,

Delemarre-van de Waal, unpublished work). As puberty suppression might also have a

negative effect on brain development,45 the effects of puberty suppression (as well as cross-

sex hormone treatment) on brain development need to be evaluated. Results of a functional

MRI study that explored the effects of GnRHa and subsequent cross-sex hormones on brain

activation during particular tasks will be published in the near future by the Amsterdam

group. Clinically, adolescents who have received GnRHa therapy and have been followed into

adulthood do not seem to function very differently from their peers.29

Harmfulness of abstinence

Emotional problems and other risks

Retrospective accounts of adult transsexuals indicate that psychological problems,

such as depression and anxiety, often arise during puberty as a consequence of the distress

that accompanies their bodily changes. For many adolescents, being refused treatment during

this difficult period is a form of psychological torture. Providing such adolescents with early

interventions might be viewed as harm reduction. As stated previously, not giving these

youngsters treatment might lead to risky behaviors (for example, prostitution, self-mutilation,

12
self-medication or suicide).43,46 They might also alienate themselves from professional health

care and follow their own risky routes to live as a member of the desired gender. By contrast,

those who are treated with GnRHa often view the therapy as more than just buying time to

make careful decisions. They are confident that this treatment is a first step towards their

desired sex. Psychopathology as a result of the untreated gender dysphoria might thus be

prevented.47

In adults, an unfavorable outcome after surgery seems to be related to late, rather than

early, treatment.48,49 Similarly, the psychological functioning of adult transsexuals is worse

than in adolescent transsexuals from the same clinic who had been treated in early

adolescence.29,50,51 The poorer psychological functioning of adult transsexuals compared with

adolescent transsexuals could partly result from the enduring distress the adults had

experienced in their lives.

Physical outcome

The bodies of adolescents with GID who not do receive puberty suppression will

develop in a direction that is unwelcome to the adolescents. For example, during puberty natal

boys will develop a low voice, an Adam’s apple, stronger facial features, a beard and body

hair, and they will be taller than if they receive the treatment. These features give them an

appearance that is contrary to their gender identity and can cause the adolescent distress when

they start living in the female gender role. For natal girls, breast development, a female fat

distribution and menstruation are highly distressing. Breasts in particular lead to an

undeniable feminine appearance that has to be re-directed afterwards by means of surgery.

Surgery will be less invasive and will leave fewer scars when puberty is halted than if the

patient has undergone their natal puberty. In patients who have received puberty suppression,

13
some of the unwanted sex characteristics (such as a beard or breasts) do not need to be

‘corrected’ at all which will give an improved outcome..

Not allowing adolescents to take GnRHa might result in an appearance that could

provoke abuse and stigmatization. As the level of gender-related abuse is strongly associated

with the degree of psychiatric distress during adolescence,52 withholding GnRHa treatment

does not seem to be a neutral option for adolescents with GID.

Conclusions

With our current knowledge, it seems to be appropriate to intervene with GnRHa

(followed by cross-sex hormones and surgery) in carefully selected young adolescents with

GID. Although psychological interventions might be useful in patients who also have

psychological problems, there is little evidence that these interventions can undo the effects of

‘transsexualogenic factors’22 and reverse the gender dysphoria in adolescents with early-onset

gender dysphoria. In our opinion, to deny these youngsters GnRHa treatment is unreasonable.

Although the physical effects of puberty suppression are reversible, it has been argued that the

effects on psychosexual development are not reversible: the adolescents will miss puberty that

is a result of their own natal sex hormones. However, in this sense denying GnRHa treatment

is equally irreversible: the adolescents will never know how puberty in accordance with their

gender identity will be, because that is made impossible by the effects of their own sex

hormones. Transsexual adolescents often consider not experiencing the puberty of their

desired sex more harmful than missing their natal puberty. Because puberty suppression

generally results in a physical appearance that makes it possible to live unobtrusively in the

desired gender role, withholding GnRHa treatment is also harmful because of the potential

life-long social consequences (such as stigmatization).

14
 The protocol for puberty suppression and subsequent cross-sex hormone treatment in

adolescents with GID was developed in the Amsterdam Gender Identity Clinic. At the

moment, the Amsterdam Gender Identity Clinic is the only center that has treated a sufficient

number of adolescents for long enough to assess the effects of this treatment. Although the

first results of puberty suppression are promising it is clear that we still have a long way to go

in further developing evidence-based clinical care in this area. The effects of GnRHa

treatment need to be investigated or replicated in centers outside The Netherlands before this

therapy can be widely recommended. Conceivably, some effects will be less positive than

expected. Protocols will then have to be adjusted. However, the field has moved beyond

clinging to theories without collecting evidence to improve treatment.

15
Review criteria

For this review we have searched the literature database PubMed (Medline) with the

terms “adolescence” OR “puberty” AND “gender identity disorder” OR “gender dysphoria”

OR “transsexual*” AND “treatment” OR “puberty suppression” from 1998 onwards, because

in this year the first paper was published reporting on pubertal delay as part of the clinical

management of gender identity disorder in adolescence in the English language. We excluded

papers focussing on disorders of sex development and papers focussing on surgery/surgical

techniques. We have also checked reference lists of retrieved papers for further leads. The

majority are full-text papers.

[box]

First protocol

Staged hormonal treatment in patients of 16 years or older.

MtF transsexuals antiandrogens first, followed by estrogens after 3-6 months.

FtM transsexuals progesterone first, folowed by androgens after 3-6 months.

Eligibility criteria were:

 age 16-18 years

 a clear early-onset (before puberty) GID

 persisting gender dysphoria or even an increase in gender dysphoria upon entering

puberty

 no comorbidities or other circumstances that could interfere with the diagnostic work

or treatment

 support from parents / caretakers

 good understanding of the effects of the treatment.

16
[box]

Second protocol

Staged hormonal treatment in patients of 12 years or older.

MtF transsexuals gonadotropin-releasing hormone analogs first, followed by estrogens at 16

years or older.

FtM transsexuals gonadotropin-releasing hormone analogs first, followed by androgens at 16

years or older

Eligibility criteria:

 age 12 years or older

 pubertal development > Tanner stage 2/3

 clear early-onset GID

 persisting gender dysphoria or an increase in gender dysphoria upon entering puberty

 no comorbidities or other circumstances that could interfere with the diagnostic work

or treatment

 support from parents / caretakers

 good understanding of the effects of the treatment

17
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Author contributions

Both authors contributed equally to all aspects of this review.

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