Puberty suppression in transgender children and adolescents

Review

Puberty suppression in transgender children and adolescents Simone Mahfouda, Julia K Moore, Aris Siafarikas, Florian D Zepf*, Ashleigh Lin*

The World Professional Association for Transgender Health’s standards of care recommend suspending puberty, preferably with the use of gonadotropin-releasing hormone agonists, in certain gender non-conforming minors (aged under 18 years) who have undergone a psychiatric assessment and have reached at least Tanner stage II of puberty. This approach seeks to lessen the discordance between assigned natal sex and gender identity by temporarily halting the development of secondary sexual characteristics, essentially widening the temporal window for gender clarification. Despite promising preliminary evidence on the clinical utility of this approach, there is a dearth of research to inform evidence-based practice. In view of these challenges, we review the available empirical evidence on the cognitive, physical, and surgical implications of puberty suppression in gender-incongruent children and adolescents. We also explore the historical underpinnings and clinical impetus for suspending puberty in this population, and propose key research priorities.

Introduction Puberty suppression as a treatment for genderincongruent minors (aged under 18 years) has been the subject of prolific debate and ethical discussion,1–3 at times generating a schism among specialists. Puberty suppression is used to lessen the discordance between body and gender identity, and to extend the temporal window for gender clarification.4 Because the use of this intervention for extreme gender incongruence is a fairly recent innovation (this intervention has been used for less than 20 years5), very few empirical studies have been done to examine the clinical utility of pubertysuppression treatments in this group, although there is some promising preliminary evidence. Although reversible,6 concerns have been expressed that these treatments can affect physical development and interfere with the natural trajectory of gender expression. In this Review, we examine the scientific literature on the use of puberty-suppression treatment in transgender minors. We start by providing an overview of child and adolescent gender incongruence and gender dysphoria, and the developmental course of gender-discordant behaviour. We then discuss the historical underpinnings and clinical impetus for delaying puberty in this population, provide a summary of the hypothalamic–pituitary– gonadal axis and puberty-suppression treatment, and examine the available empirical evidence for the ability of these treatments to alleviate the distress common in children and adolescents with a transgender identity. We also consider the implications on cognitive and physical development, and surgical outcome, drawing on evidence from recent studies. In recognition of the rapid increase in referrals to child and adolescent gender clinics worldwide,7–9 with patients presenting at increasingly younger ages,10 we intend this Review to be a timely synthesis of the available evidence. There is substantial debate about the classification of gender identity diagnoses,11–14 including those of childhood, in the upcoming revision of the International Classification of Diseases (ICD)-11 and in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5; terminology defined in the appendix).15 The

Working Group on Sexual Disorders and Sexual Health was convened by WHO in 2012 to recommend necessary changes to the ICD-10 regarding diagnoses related to sexuality and gender. Notable propositions include reconceptualising the current adult or adolescent diagnosis of “transsexualism” to “gender incongruence of adolescence/adulthood”, and changing the current childhood diagnosis of “gender identity disorder of childhood” to “gender incongruence of childhood”.16 With this revised term, although it can be present, clinically significant distress is not a necessary diagnostic criterion, as with gender dysphoria as in the DSM-5 definition.15 This stance is complemented by the Working Group’s recommendation to remove the proposed ICD-11 diagnoses of “gender incongruence of adolescence/adulthood” and “gender incongruence of childhood” from the chapter on Mental and Behavioural Disorders.16 The proportion of children who experience gender incongruence during childhood that will continue to experience gender incongruence into adolescence and adulthood is unclear. Investigators of very early studies17 concluded that gender discordance did not persist into adolescence in most children. Perhaps partly for this reason, medical intervention by means of puberty suppression was not conceptualised as a plausible treatment option for minors until 1998.5 In a retrospective study18 of 77 patients who had been referred to a specialist gender clinic as children (mean age 8·4 years), only 21 (39%) of the 54 children who were able to be reassessed in adolescence had a persistent transgender identity. In another study,19 three (12%) of 25 patients assigned a female gender at birth had a persistent transgender identity in adolescence or young adulthood (mean age, 23·24 years), although such estimates do not account for the trajectory of the patients lost to follow-up (n=12). Drawing from followup interviews in the qualitative literature,20 when gender incongruence is exacerbated by the onset of puberty it seems rarely to subside. However, little empirical evidence exists to support this association. Gender incongruence can also emerge for the first time during pubertal development,21 with no history of gender-

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Lancet Diabetes Endocrinol 2017 Published Online May 22, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30099-2 *These authors contributed equally and share senior authorship Centre and Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, School of Medicine, Faculty of Health and Medical Sciences (S Mahfouda BA, J K Moore FRANZCP, Prof F D Zepf MD), and Telethon Kids Institute, (S Mahfouda, A Siafarikas MD, A Lin PhD, Prof F D Zepf), University of Western Australia, Perth, WA, Australia; Gender Diversity Service, Acute Child and Adolescent Mental Health Service, Child and Adolescent Health Service, Perth, WA, Australia (J K Moore); Department of Endocrinology and Diabetes, Princess Margaret Hospital, Perth, WA, Australia (A Siafarikas); Division of Paediatrics and Child Health, School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia (A Siafarikas); Institute for Health Research, University of Notre Dame, Fremantle, WA, Australia (A Siafarikas); and Specialised Child and Adolescent Mental Health Services, Department of Health in Western Australia, Perth, WA, Australia (Prof F D Zepf) Correspondence to: Prof Florian D Zepf, Centre and Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, WA 6009, Australia [email protected] See Online for appendix

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Panel 1: Puberty suppression—the global picture Transgenderism in minors is a well documented global phenomenon that transcends cultural, religious, and socioeconomic boundaries. For patients in whom there is a longstanding history of gender incongruence and related distress that has worsened with the onset of puberty, the World Professional Association for Transgender Health (WPATH)6 and the Endocrine Society25 recommend suppressing puberty with gonadotropin-releasing hormone agonists. Despite these recommendations, specialist child and adolescent gender services offering these treatments are not only scarce and often expensive or difficult to access, but are also located exclusively in high-income countries . Private gender-affirming providers operate in several countries, including Argentina, India, Turkey, and Thailand,26 but most of these specialists do not seem to provide medical treatment to children and adolescents. There are several reasons for the poor accessibility of these services; these include the sociocultural context, legal system, and poor awareness of child and adolescent transgender care. As evidence expands, and children and their families become more aware of puberty suppression as an option for gender incongruence, the demand for these services is likely to increase globally.

discordant behaviours or feelings reported in childhood or pre­pubertal adolescence.

Historical underpinnings and clinical impetus The argument for puberty-suppressing treatment for gender-incongruent minors developed in response to two clinical observations made at the Amsterdam Gender Identity Clinic (now the Centre of Expertise on Gender Dysphoria, VU University Medical Centre, Amsterdam, Netherlands) in the late 1980s. The first observation was that gender dysphoria in children and adolescents did not abate despite extensive psychotherapy. The second was that psychiatric comorbidities and peer-related problems seemed to result from gender incongruence and the stigma attached to identifying as transgender, rather than psychiatric and psychosocial problems (such as anxiety, depression, and difficulties with their peers) causing subsequent gender incongruence.22 Some clinicians argued that puberty suppression could allow adolescents with severe gender dysphoria the opportunity to safely explore their gender expression without the anticipatory burden of developing into a body that did not align with their identity.10 Several other important points were raised.10,22 For example, inhibiting puberty in the early Tanner stages of puberty also allowed patients wishing to pursue cross-sex hormone (CSH) therapy a better chance of presenting a typical physical appearance of the identified gender—a necessary outcome for many. For individuals wishing to pursue gender-affirming surgery, it rendered some cosmetic procedures redundant or less invasive—eg, bilateral mastectomy and chest 2

recontouring in female-to–male transgender people, or facial feminisation in male-to-female transgender people.23 Previous evidence had also suggested that cosmetic factors, such as breast scarring, and the need for extra surgery were associated with poor postoperative psychopathology in transgender adults.24 In 1998, clinicians from the Amsterdam Gender Identity Clinic published the first case report5 detailing the use of a gonadotropin-releasing hormone (GnRH) agonist (monthly intramuscular triptorelin, 3·75 mg) in a genetically female patient with severe childhoodonset gender dysphoria (age 13·7 years at treatment initiation, Tanner stage III). Following virilisation with testosterone (age 18·6 years) and an ovariectomy and subcutaneous mastectomy (age 20·0 years), the patient reported no gender dysphoria. The investigators concluded that pubertal suppression might be a beneficial diagnostic aid for patients with gender dysphoria who have extreme and persistent presen­ tations, although it is not possible to conclude whether this positive finding was a result of early puberty suppression, virilisation, surgical intervention, or a combination of these interventions. The clinic has since revised several protocols for GnRH agonist treatment in minors with gender dysphoria, each stipulating stringent eligibility criteria for potential candidates.10 These guidelines had a prominent role in shaping the World Professional Association for Transgender Health (WPATH) standards of care (version 7, 2012)6 and the Endocrine Society clinical practice guidelines (2009; panels 1, 2).25 Notably, although many clinics worldwide have adapted this protocol,10,27–32 such specialist clinical treatment is not readily available.

Clinical suspension of puberty When puberty begins, GnRH is secreted in a pulsatile manner by neuroendocrine cells in the hypothalamus and released into the hypophyseal portal system.33 GnRH binds to specialised cell plasma membrane receptors on the surface of the anterior pituitary gland, stimulating the release of luteinising hormone (LH) and follicle stimulating hormone (FSH). Notably, this pathway is identical in male and female individuals. These hormones, in turn, prompt the appropriate gonads to synthesise and secrete the steroids (testosterone in male individuals and oestrogen and progesterone in female individuals) that lead to the development and maintenance of sexual characteristics and function.33 Oestrogen and testosterone are then circulated back to the hypothalamus and the pituitary gland, and regulate further LH and FSH secretion.34 One clinical approach in the management of gender incongruence is watchful waiting, usually until at least Tanner stage II of puberty.10 Physiologically, this stage corresponds with a growth spurt, and breast bud formation and widening of the areolae in girls, or testicular enlargement to at least 4 mL in boys (mean age

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10·70 years [SD 1·00] in white female individuals,35 and 11·47 years [1·62] in white male individuals36). If these secondary sexual developments are associated with an increasing aversion to bodily changes and a deterioration in psychological wellbeing or social functioning, this clinical observation could represent additional diagnostic evidence that the adolescent will continue to maintain a transgender identity in the long term.7 Before considering any form of physical intervention in minors with gender incongruence, including suppression of pubertal development, a thorough diagnostic exploration of psychosocial and familial factors should be done. Since puberty occurs over a finite period, however, there is a limited margin of time in which to intervene; when breasts develop under the influence of oestrogen, or facial hair, masculinised facial bone structure, laryngeal growth, and voice mutation develop in response to testosterone, these changes are not reversible with pharmacological intervention.35 Additionally, these features increase the complexity and invasiveness of many gender-affirming procedures (eg, mastectomy, laryngeal surgery, facial feminisation surgery, and hair-removal procedures), which patients might choose to undergo. If the decision is made to suppress puberty (the first phase of gender-affirming treatment), this treatment forms part of an extended diagnostic phase, essentially widening the temporal window for gender clarification.10 GnRH agonists are the most potent method of suspending puberty,25 and have been studied extensively in the clinical treatment of children with central precocious puberty37–40 and, more recently, transgender adolescents.41 These drugs are synthetic pep­tides that work by paradoxically stimulating gonadotropin release, which ultimately desensitises the gonadotropin receptors in patients who receive them.33 Over several weeks, the production and secretion of sex steroids recedes. Progression of sexual development ultimately ceases, and can even regress somewhat if started early enough in puberty.42 Discontinuation of the medication results in reactivation of the hypothalamic– pituitary–gonadal axis, leading to continuation of pubertal development in line with gonadal sex and the reversal of changes.10,38 For example, in a study of 46 girls who had received GnRH agonist treatment of at least 2 years duration for central precocious puberty, patients went on to have normal menstrual and ovulation cycles, and full-term pregnancies.38 Progestins are another method for suspending puberty, although these are not as effective as GnRH agonists, and can suppress adrenal activity.43 These treatments—either antiandrogenic progestins for male-to-female patients or proandrogenic progestins for female-to-male patients— serve several purposes in the clinical treatment of transgender adolescents. For example, they provide a cheaper alternative to costly GnRH agonists, particularly when GnRH agonists are not reimbursable by health insurance schemes. Proandrogenic progestins can induce

Panel 2: Minimum eligibility criteria for puberty-suppression treatment According to the World Professional Association for Transgender Health standards of care,6 potential candidates must fulfil each of the following minimum criteria to be considered eligible for puberty-suppression treatment. Optimally, assessments and decisions should rely on the clinical expertise of an experienced multidisciplinary team. • The adolescent has shown a pervasive and intense pattern of gender non-conformity or gender dysphoria. • The gender dysphoria emerged or worsened at the onset of puberty. • Any co-existing psychological, medical, or social problems that could interfere with treatment have been addressed, such that the adolescent’s situation and functioning are stable enough to start treatment. • The adolescent has given informed consent and, particularly when the adolescent has not reached the age of medical consent, the parents or other caretakers have consented to the treatment and are involved in supporting the adolescent through the treatment process.

amenorrhoea in female-to-male candidates with advanced puberty.44 To induce natural breast development and lessen masculinisation in male-to-female patients, antiandrogenic progestins such as cyproterone acetate and spironolactone are important for lessening the effects of testosterone.45 Spironolactone, which works via androgen receptor blockade to subdue androgendependent hair growth, has been offered to male-tofemale patients who choose not to take GnRH agonists.9,46 Although the terminal hair follicles do not regress, its use can reduce the frequency of shaving or future hair removal treatments. Consistent with the staged approach of genderaffirming intervention endorsed by international consensus guidelines,25 CSH therapy (the second phase of treatment) can subsequently be offered, if appropriate, when the adolescent meets an additional set of criteria. The age at which CSH therapy is offered depends on the country, but is usually age 16 years. For a male-to-female transition, feminising puberty with CSH therapy is achieved using oestrogen, usually in the form of tablets or transdermal patches.47 Intramuscular oestradiol valerate or cypionate can also be used,48 although these injections must be given more frequently (weekly to fortnightly) than other forms of oestrogen, and concentrations can be difficult to monitor.49 Testosterone, usually administered via a transdermal gel or long-acting depot injection, is used for a female-to-male transition.47 Since hormone concentrations are initially not high enough to suppress LH and FSH, gonadal suppression is recommended to be continued during CSH treatment. GnRH agonist treatment is usually stopped should the patient decide

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to undergo gonadectomy (bilateral orchiectomy in male-to-female patients and bilateral salpingooophorectomy in female-to-male patients). However, there is some evidence that prolonged testosterone use (of at least 2 years duration) can suppress puberty in female-to-male adolescents, without the need for simultaneous GnRH agonist therapy.48–50 CSH treatment for transgender adolescents is usually initiated after 16 years of age, corresponding to the age at which many countries consider minors to be legal adults with respect to medical decision making.25 In Australia, this process requires approval from the Family Court.51 The purpose of this procedure is to ensure that the child under review is either competent to consent to the treatment, or that the treatment is in the best interests of the child when competency cannot be shown.51 By contrast, some institutions have been studying the effect of adding CSH therapy to puberty-suppression treatment at age 14 years.3,52 This approach is based on the premise that keeping adolescents in a prepubertal state until age 16 years might not only compromise bone health, but also further isolate these adolescents developmentally from their peers.52 Similarly, in Japan, CSH therapy can be started at age 15 years.30

Psychiatric and psychosocial comorbidities Some researchers have argued that gender-affirming treatments, such as puberty suppression, can reduce subsequent mental health problems and improve general functioning and quality of life.53 Psychiatric comorbidities are more prevalent in transgender children and adolescents than in the general population.54,55 These comorbidities include depression;56,57 anxiety disorders, including social phobia and separation anxiety;58 and illicit substance use.53 Suicidality is of particular concern and has been heavily documented in this group.56,59–61 In a cross-sectional study21 of 218 children and adolescents with gender incongruence, peripubertal development was identified as an especially vulnerable time, corresponding with increased levels of self-harm (n=84), suicidal ideation (n=76), and suicide attempts (n=29) in the cohort examined. Although the precise mechanisms linking gender incongruence and comorbid psycho­ pathology are not clearly understood, a novel retrospective field study62 of transgender adults in Mexico (n=250) has shed some light in this regard. The investigators reported that psychological distress and functional impairment were better explained by experiences of social rejection and violence than by factors related to gender incongruence. Experiences of gender-related bullying in a sample of gender dysphoric adolescents (n=56) were significantly associated with self-reported emotional and behavioural problems,63 suggesting that these issues might be a partial consequence of the stigma attached to a transgender identity. Although there are genuine cases of comorbid gender incongruence and psychiatric disorder, the clinical opinion of the specialists treating 4

these children and adolescents is that such comorbidities, particularly mood disorders, tend to decrease in intensity after medical intervention.27

Puberty suppression to alleviate distress In 2011, a patient who was female at birth and who had been treated with a GnRH agonist at age 13 years at the Amsterdam Gender Identity Clinic was re-assessed after 22 years, culminating in the publication of the first long-term retrospective case-report in the medical literature.23 The female-to-male transgender patient had since undergone gonadectomy, metoidioplasty, and prosthetic testes implantation and was functioning fairly well psychologically, socially, and intellectually. Anthropomorphic, endocrine, and bone mineral density (BMD) variables were all within the normal range. The patient reported no regret and was described as having a “very masculine” appearance by the authors. This appearance would have reduced the possibility of transphobic discrimination, a factor that has been associated with both poor mental health and substantial detriments in other crucial areas of functioning.21,64

Current evidence for treatment Few studies have examined the ability of pubertysuppression treatments to alleviate the distress that might have been experienced by children and adolescents with a transgender identity. Similarly, very few studies have assessed physical and cognitive function during treatment. This dearth in the scientific literature is compounded by several factors. Because the prevalence of gender incongruence is fairly low, convenience samples are often used, and participant numbers tend to be small. Much of the research is longitudinal in design, and sample sizes are often further reduced by attrition. Because of ethical considerations, few opportunities exist for randomised controlled trials. The available evidence from experimental studies that have assessed the effect of pubertysuppression treatment in adolescents with gender incongruence are summarised in the appendix; notably, most of this research was done in the Netherlands. In a prospective follow-up study53 of the first 70 eligible candidates for puberty suppression and CSH therapy at the VU University Medical Centre in Amsterdam, psychological and general functioning was assessed at baseline, and again after an average of 2 years of GnRH agonist treatment (at initiation of CSH therapy). Neither the gender dysphoria nor the dissatisfaction with primary or secondary sexual characteristics had subsided at followup. This outcome might have been because the misalignment between body and gender identity had not yet been rectified, a finding that was consistent with those of several earlier studies.65–67 By contrast, the investigators noted significant reductions in symptoms of depression, as assessed by the Beck Depression Inventory,68 from a mean of 8·31 (SD 7·12) to 4·95 (6·72; p=0·004). Global functioning, as assessed by the Children’s Global

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Assessment Scale (CGAS),69 had also significantly improved from a mean of 70·24 (10·12) to 73·90 (9·63; p=0·005). Additionally, the proportion of adolescents scoring in the clinical range on the internalising and externalising subscales of the Child Behaviour Checklist70 decreased substantially (from 44% to 22%), although measures of anxiety and anger remained unchanged. The assurance that sexual development would not continue to unfold in line with gonadal sex and the guarantee that sequential phases of gender-affirming treatment would be explored were probably helpful for the study participants. These patients had also received regular appointments with a clinical psychologist or psychiatrist; it is therefore unclear to what extent these benefits could be specifically attributed to puberty suppression. In a more recent report,71 55 patients from the same cohort were assessed on the same test battery at an additional timepoint, 1 year after gender-reassignment surgery. The investigators noted that the gender dysphoria and dissatisfaction with primary and secondary sexual characteristics had remitted, and no regret was reported. Compared with baseline data (at which mean age was 13·6 years), the proportion of adolescents (at a mean age of 16·7 years) with clinically significant psychological morbidity was also substantially reduced (from 30% to 7%). Furthermore, subjective wellbeing, including quality of life, satisfaction with life, and subjective happiness, was also similar to age-matched peers in the general population.72–74 Notably, improvements in psychological functioning and satisfaction with secondary sexual characteristics were more prominent in male-to-female than in female-to-male transgender individuals, probably because none from the female-tomale transgender group had yet undergone phalloplasty. However, timely suppression of puberty had ensured that the patients were easily recognised as their identified gender. Hence, although pubertal suspension had not directly ameliorated the anatomical incongruence per se, the findings from these studies suggest that puberty suppression might be a necessary platform for a more favourable long-term outcome, both physically and psychologically. However, as cautioned by the investigators,71 early medical treatment in isolation is unlikely to be the sole factor for these successes; extensive evaluations from the experienced multidisciplinary clinical team and social support probably also contributed to the beneficial outcomes. Employing a longitudinal design, Costa and colleagues32 examined psychosocial functioning in adolescent patients who had been referred for gender dysphoria at the Gender Identity Development Service in London, UK (n=201). Psychosocial scores, as measured by the CGAS,69 were collected at baseline and every 6 months over an 18-month period, for a total of four assessments. Following an initial diagnosis at baseline (T0), all patients received 6 months of psychological support, standardised in accordance with WPATH guidelines.6 Eligibility for puberty suppression was then assessed, and the sample was divided into two

groups based on whether they were considered immediately eligible (n=100) or delayed eligible (n=101) for GnRH agonist treatment. The delayed eligible group required additional time, such that psychiatric comorbidities or psychological difficulties could be sufficiently addressed by a mental health professional. Within each group, a preliminary comparison of baseline psychosocial scores with scores from the second assessment (T1) indicated a significant improvement in the delayed eligible group only, from a mean of 56·63 (SD 12·80) to 60·29 (12·81; p=0·05). For the remaining 12 months of the study, the delayed eligible group continued to receive psychological support only, although the immediately eligible group also received GnRH agonist therapy in addition to psycho­logical support. No additional improvements were seen within the delayed eligible group at either the third or fourth 6-monthly assessments, reflecting 12 months (T2) and 18 months (T3) of psychological support, respectively. By contrast, the immediately eligible group exhibited substantially higher levels of psychosocial functioning at the fourth assessment (T3, after 18 months of psychological support and 12 months of GnRH agonist therapy) compared with the second assessment (T1, after 6 months of psychological support only), from a mean of 60·89 (12·17) to 67·40 (13·93; p=0·001). The findings within each group might result from several factors, including a general improvement over time, or a placebo effect. However, one plausible explanation is that psychological support could exert a clinical benefit, particularly when psychiatric comorbidities are indicated. Where coexisting issues have been addressed, suspending puberty might confer an added advantage over psychological support alone.

Cognitive development with GnRH agonist treatment In a novel functional MRI (fMRI) study, Staphorsius and colleagues75 investigated executive function in six groups: two GnRH agonist-treated groups (male-to-female trans­ gender, n=8; female-to-male transgender, n=12), two untreated groups (male-to-female transgender, n=10; female-to-male transgender, n=10), a control male group (n=21), and a control female group (n=24). The inclusion of an age-matched untreated gender dysphoric group allowed for the experimenters to discern whether any differences were due to GnRH agonist treatment specifically, rather than due to gender dysphoria. At the time of investigation, the treated groups were receiving 3·75 mg triptorelin, given either subcutaneously or intramuscularly every 4 weeks. Executive function, specifically cognitive planning, was assessed with the Tower of London (ToL) task. On the basis of previous evidence of sex-specific neural activation in the ToL task,76 the dorsolateral and rostrolateral prefrontal cortices and the precuneus were chosen as the regions of interest. No effect of GnRH agonist therapy on ToL performance scores (reaction time or accuracy) was noted in either male-to-

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female or female-to-male transgender adolescents, suggesting that pubertal suppression with GnRH agonists is not associated with a detrimental effect on this higherorder cognitive process.77 Concomitant fMRI analyses showed that activation of the dorsolateral and rostrolateral prefrontal cortices in the treated groups, as compared with activation in the baseline condition, did not align with the profile of their expressed gender. Rather, this activation was more characteristic of natal assigned sex. Consequently, these findings do not support the conjecture that treatment with GnRH agonists intensifies gender incongruence towards the direction of the experienced gender. In a 2016 study78 of female patients with idiopathic central precocious puberty (n=15), investigators sought to examine whether treatment with a GnRH agonist affected cognitive, emotional, and psychosocial func­ tioning. At the time of the study, patients were receiving slow-release triptorelin acetate, at doses of either 11·25 mg every tenth week or 3·75 mg every fourth week. Performance on a comprehensive battery of tasks was measured against typically developing controls matched for age and gender (n=15). Results between the two groups were similar in almost all of the domains examined, including auditory and visual memory, response inhibition, spatial ability, behavioural problems, and social competence. During an emotional flanker task,79 a computerised assessment instructed participants to determine whether a series of building pairs were identical (match condition) or different (mismatch condition) as quickly as possible. A pair of faces was presented simultaneously in the periphery of each slide, but were irrelevant for task solution. It is of note that the patients with central precocious puberty reacted significantly faster than controls in the presence of fearful faces in the “mismatch” condition. These findings suggest that patients with central precocious puberty who have been given GnRH agonists might process emotional stimuli differently from their age-matched peers, possibly attributable to the direct effects of GnRH agonist treatment or deprivation of sexual steroids. Several alternate explanations are possible, including the effects of previous androgen exposure, or of negative social experiences secondary to precocious puberty; these possibilities cannot be excluded in the absence of an untreated clinical group.

Bone development during treatment Adolescence is the period of peak bone mass accrual, a process that can affect an individual’s risk of getting osteoporosis later in life.80 Changes in oestrogen and testosterone during adolescence can affect peak bone mass accretion,80,81 but it is currently unknown whether transgender adults who received puberty-suppression treatment in adolescence are at an increased risk of fracture in adulthood. Studies of BMD in children with central precocious puberty treated with GnRH agonist therapy for at least 3 years did not suggest any bone density loss compared with typically developing children 6

matched for chronological age and skeletal maturation.33 GnRH agonist use in children with central precocious puberty serves as an invaluable clinical model, but there might be consequences of suspending puberty that are unique to individuals who identify as transgender. Importantly, much of the published research on GnRH agonist use in precocious puberty has been undertaken in girls,82–85 since the condition is rare in boys. Concerns about possible long-term effects of puberty suppression were identified as a salient theme by transgender youth in a small qualitative study,86 although most of the adolescents reported that the lack of data would not deter them from seeking treatment. A summary of documented side-effects experienced by gender incongruent adolescents during puberty suppression is discussed in panel 3. Preliminary results of the first 21 patients (n=11, female-to-male transgender patients) with gender identity disorder to be given GnRH agonist treatment (triptorelin, 3·75 mg given subcutaneously or intramuscularly every 4 weeks) showed a significant decrease in bone accretion during puberty suppression, although bone accretion normalised during CSH treatment.41 Klink and colleagues89 retrospectively assessed BMD in a cohort of patients with gender identity disorder (n=34) who had received triptorelin mono­therapy during adolescence, followed by CSH therapy in combination with triptorelin, and then surgical gonadectomy and CSH therapy as adults. BMD of the lumbar spine and femoral region was assessed three times via dual-energy X-ray absorptiometry (DXA): before commencing each phase of pharmaco­logical treatment, and at age 22 years (after surgery). Interpretation of BMD Z scores, matched for age, ethnic origin, and natal assigned sex, as opposed to absolute values, were the most appropriate for comparison in this context. Although areal BMD Z scores in the lumbar spine were significantly lower at age 22 years compared with pretreatment levels, these values were not associated with the duration of triptorelin monotherapy. In female-to-male patients, areal BMD Z scores of both the lumbar spine and femoral region significantly decreased with triptorelin monotherapy, although these scores improved substantially with CSH treatment. The researchers surmised that this improvement was probably due to the rapid increase in dose increments of testosterone.89 By contrast, BMD Z scores did not significantly decrease during triptorelin monotherapy in male-to-female patients, although a rise in these scores was not seen following low-dose oestrogen administration. Similar results have led to the proposition that higher doses of oestrogen might be warranted in male-to-female patients.25 In an examination of bone turnover markers in transgender adolescents,90 gonadal suppression with triptorelin was associated with a significant reduction in the bone turnover markers serum procollagen type 1 N-terminal propeptide and cross-linked carboxy-terminal telopeptide of type 1 collagen in both male-to-female

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(n=28) and female-to-male patients (n=42). These reductions also coincided with reductions in bone mineral apparent density Z scores of the lumbar spine, particularly in young male-to-female patients (bone age <14 years, n=15). DXA scans remain important for following bone development in patients receiving puberty-suppression treatment, but these data suggest that there is little added clinical utility in monitoring bone turnover metabolism, although further research is needed. In view of the small number of specialist gender clinics and patients treated worldwide, long-term multicentre studies exploring the independent effect of pubertysuppression treatments on bone development are unfeasible. Therefore, regular monitoring of BMD in transgender patients receiving medical treatment is recommended, in accordance with Endocrine Society guidelines.25 This recommended monitoring includes an examination of BMD before treatment initiation. Encouraging young transgender patients to maintain optimal bone health with adequate calcium intake, vitamin D supplementation (if indicated), and weightbearing exercise is also important.

Clinical and biochemical effects of GnRH agonists In a prospective analysis,91 researchers in the Netherlands explored the safety profile of GnRH agonist monotherapy in a fairly large cohort (n=116) of adolescents with gender dysphoria who had attended the VU University Medical Centre between 1998 and 2009 and had received treatment for a minimum of 3 months. Body composition and biochemical parameters were examined at baseline, and at regular intervals thereafter during 1 year of treatment. An increase in fat percentage and a decrease in lean body mass were noted, although no control group was included to ascertain to what extent these changes were associated with GnRH agonist therapy. Biochemical measurements obtained during the course of GnRH agonist treatment suggested neither renal abnormalities nor clinically significant increases in concentrations of liver enzymes (γ glutamyl­ transferase, aspartate transaminase, and alanine transaminase). Alkaline phosphatase had decreased, which probably reflected a decrease in bone fraction (but not liver fraction) of this enzyme and bone mineral accrual, in view of the absence of hepatic abnormalities. None of the patients ceased treatment because of adverse effects, consistent with the evidence from the treatment of central precocious puberty, which suggests that GnRH agonists are well tolerated in children and adolescents.92 In view of these findings, the investigators proposed that the stringent routine monitoring of renal function and liver enzymes during GnRH agonist treatment, as stipulated in the current Endocrine Society guidelines,25 is not necessary.91 Notably, very few the patients in this study were in early puberty when treatment commenced (female-to-male patients in Tanner stage II, n=4), with most male-to-

Panel 3: Reported side-effects of puberty-suppression treatment in transgender adolescents A retrospective chart review by the British Columbia Transgender Clinical Care Group9 identified 27 patients with gender dysphoria prescribed gonadotrophin-releasing hormone (GnRH) agonist therapy between 1998 and 2011. From this sample, one female-to-male patient reported mood swings and emotional lability, resulting in treatment discontinuation. One female-to-male patient developed sterile abscesses while receiving leuprolide acetate and treatment was changed to triptorelin, which was well tolerated. Leg pain and headache were reported in one female-to-male patient, which resolved without discontinuation of treatment. One patient (unspecified male-to-female or female-to-male) gained 19 kg within the first 9 months of treatment, although bodyweight was greater than the 85th percentile before treatment. Within this cohort, spironolactone was offered to female-to-male patients who had not been prescribed a GnRH agonist (n=25), and this treatment was not associated with abnormalities in electrolyte and urea or creatinine concentrations in any patient (assessed at full dose titration). In a study of lynestrenol monotherapy,44 reported side-effects included headache and fatigue. Hot flushes were also reported, and treatment was discontinued in four of 41 patients because of this side-effect. Metrorrhagia was documented in 19 (48·7%) patients, but this decreased significantly after 6 months of treatment (p=0·004). In several cases, this symptom was controlled by doubling the dose of lynestrenol to 10 mg for 10 days, and then returning to the initial 5 mg dose. Additionally, three case reports of arterial hypertension in female-born patients with gender dysphoria on triptorelin treatment have been documented.87 Papilloedema and increased intracranial pressure was also noted in one of these cases (aged 11·8 years at treatment initiation). GnRH agonist treatment was therefore stopped at 16 months in this individual, and acetazolamide was given to alleviate the intracranial hypertension. After blood pressure normalised at 3 months, GnRH agonist therapy was reinitiated with conservative monitoring. Although no increase in intracranial pressure was seen, hypertension recurred, which was treated with nifedipine and labetalol. In the second case (aged 18 years at treatment initiation), triptorelin was discontinued after arterial hypertension 3 months into treatment. Lynestrenol was prescribed to suppress menses. Although blood pressure normalised after 1 month, the patient had reached sexual maturation and therefore GnRH agonist therapy was not reinitiated. In the third case (aged 12·5 years at treatment initiation), hypertension was noted 3 months into GnRH agonist treatment. This patient was treated with calcium antagonists, without discontinuation of the triptorelin. These cases suggest that oestrogen loss (secondary to suppressing puberty) plays an important part in the pathogenesis of hypertension, particularly as blood pressure normalised when treatment was stopped (cases one and two), but reoccurred when GnRH agonist treatment was reinitiated (case one). Hormone-replacement therapy with oestrogen has been shown to significantly increase the passive diameter of arteries in female rats on triptorelin treatment.88 Therefore, since all three cases were natally assigned female and had evidence of some sexual maturation, the researchers surmised that these cases of hypertension were probably due to depletion of oestrogen with its vasoprotective properties.

female and female-to-male patients in Tanner stage IV or V. Hence, the extent to which these findings translate to early pubertal patients is questionable and, in our opinion, comprehensive safety monitoring should continue in this group until more data are available. Thus far, there is only one study44 that has examined the efficacy and safety profile of progestin monotherapy in gender-incongruent adolescents. In addition to being substantially cheaper than GnRH agonists, lynestrenol exerts an uterotropic effect, and is therefore suitable

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Panel 4: Research priorities • How can treatment be accessed by adolescents in localities where specialist gender clinics are non-existent, particularly in low-income and middle-income countries that do not impose legal barriers? How can general health-care practitioners and specialists in these localities receive education on the benefits of this treatment option? • What legal, socioeconomic, and sociocultural developments need be made to increase the global accessibility of this treatment? • Since existing research publications are from a very small number of treatment centres, are outcomes similar elsewhere? To what extent are mental health outcomes mediated by the sociocultural context? • How can we ensure concordance of research efforts and standardise data collection in clinical settings?96 • Are benefits, or regret, more pronounced in certain gender dysphoric groups—eg, in individuals with childhood-onset presentations, or those with autism spectrum disorders? • What are the physical, metabolic, cognitive, and psychological outcomes of treatment in patients with late-onset presentations, in those treated in the early Tanner stages of puberty (Tanner stage II or III), and in patients with autism spectrum disorders? • Is there an association between the length of pubertal suspension in adolescence, and physical and cognitive outcomes, both in the short term and long term? • How can the current treatment paradigm support individuals with gender dysphoria who identify as gender non-binary or as agender? • What are some of the complex clinical cases that have been encountered, and what lessons can be learned? • What is the long-term risk of osteopenia, osteoporosis, and fracture following treatment in adolescence, particularly in male-to-female transgender individuals? • Does progestin use in male-to-female transgender adolescents confer an increased risk of polycystic ovarian syndrome or thromboembolic disease, and does it limit the opportunity for successful ovarian cryopreservation? • What are the needs of transgender youth with respect to fertility preservation, what is the risk of later distress from reduced fertility, and how can we ensure that candidates and their families receive comprehensive fertility counselling? • What is the optimal developmental stage for transgender adolescents to consent to puberty-suppression treatment? • What is the safe balance between thorough, extended assessment of adolescents for treatment eligibility, and prompt access to treatment to prevent the harm of progressive pubertal changes? • How can clinicians help early adolescents and families to weigh benefits and risks of treatment timing, balancing advantages of early treatment (preventing secondary sexual characteristics) with advantages of later treatment (optimal genital development for successful surgical outcome)?

Search strategy and selection criteria We searched MEDLINE and Embase (from inception until Jan 4, 2017), without language restrictions, using the following search terms: “gender dysphori*” or “gender identity” or “gender incongruen*” or transgender*, and pubert* or adolescen*, and GnRH* or “gonadotropin-releasing hormone” or “pubert* block*” or “suppression treatment” or progestin* or spironolactone or cyproterone acetate. We identified eight relevant papers that looked directly at puberty suppression treatments in transgender adolescents: three longitudinal studies assessing psychiatric and psychosocial outcomes, one cross-sectional study assessing executive function, and four longitudinal studies assessing physical and metabolic parameters. Guidelines by the World Professional Association for Transgender Health and the Endocrine Society were also reviewed. Relevant articles cited within these references were also incorporated.

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for inducing amenorrhoea in female-to-male patients in later puberty (at least Tanner stage IV of breast development). Anthropometric and biochemical data from female-to-male patients who had received lyn­estrenol monotherapy for at least 6 months between 2010 and 2015 at Ghent University Hospital (n=43) were analysed before treatment initiation, and at 6-monthly intervals for 1 year. Bodyweight and BMI significantly increased after 6 months of medication, but had returned to baseline by 12 months of treatment. Concentrations of creatinine, free thyroxine, and mean haemoglobin and haematocrit were increased at 6 months and 12 months compared with baseline values. In these cases, according to the investigators, these changes were not clinically relevant, and did not result in treatment discontinuation. At these timepoints, the lipid profile was unfavourable, showing increased concentrations of LDL and decreased concentrations of HDL. A significant increase in average alanine transaminase was noted at 12 months, with values transiently surpassing the male reference range of 57 U/L in one individual, although the concentration normalised with the addition of testosterone esters. Glucose metabolism did not change, complementing findings from 2014 that progestins do not affect these values in healthy, young natal-assigned women.93

Surgical outcome and fertility after treatment Where the decision is made to suspend puberty, issues pertaining to surgical outcome and fertility warrant careful consideration and discussion. For example, puberty suppression at an early Tanner stage hinders the opportunity for gamete cryopreservation in transgender adolescents. Fertility counselling before treatment initiation is therefore very important. Some candidates might want to postpone treatment to a later date, after fertility preservation procedures have been done. Surgical interventions, including gonadectomy, are the third phase of gender-affirming treatment. These procedures are usually done in adulthood, although they have been documented in adolescent patients.66 Vaginectomy in a female-to-male transgender patient, which requires surgical reconstruction of the vaginal mucosa and labia, is a procedure associated with a high risk of postoperative bleeding and urological complications.93 Oestrogen plays an important part in the structural integrity of vaginal tissue and proliferation of the epithelium, posing challenges for female-to-male patients who have had little exposure to oestrogen because of puberty suppression in adolescence. Furthermore, to perform penile inversion vaginoplasty, the most researched surgical technique for creating a neovagina in male-to-female patients,94 sufficient phallic and scrotal development is necessary. This development corresponds to at least Tanner stage IV of genital development in natal-assigned male adolescents, which exceeds the optimal timeframe for preventing secondary sexual characteristics with

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puberty-suppressing treatment (maximum Tanner stage III of genital development). Laparoscopic intestinal vaginoplasty with the sigmoid or ileal segment was found to be a possible surgical alternative in a study of 31 young, healthy adult male-to-female candidates with penoscrotal hypoplasia.95 Notably, 26 (84%) of the patients examined in this survey study had received puberty-suppressing treatment in adolescence for childhood-onset gender dysphoria. Patient-reported postoperative aesthetic and functional outcome of the neovagina was graded a median score of 8 out of 10, and was associated with a better quality of life on three scales (the Satisfaction with Life Scale, the Subjective Happiness Scale, and a single-item indicator from Cantril’s Ladder of Life Scale, for satisfaction with neovaginal aesthetics and neovaginal function).

Conclusions Gender incongruence in children and adolescents is complex, and medical treatment raises several ethical considerations. Clinical decision making has been fostered by research efforts, but there are still substantial knowledge gaps that warrant examination to inform best clinical practice (panel 4). The limited available evidence suggests that puberty suppression, when clearly indicated, is reasonably safe. The few studies that have examined the psychological effects of suppressing puberty, as the first stage before possible future commencement of CSH therapy, have shown benefits. Further research is needed to help identify which patients benefit most, and which are at higher risk of regret, changed wishes, or poorer quality-of-life outcomes. The most appropriate time to start treatment remains to be clarified. Contributors SM contributed to the conceptualisation and primary writing of the Review, including panels, under the supervision and guidance of AL and FDZ. All coauthors contributed to the editing of the Review, appraisal of evidence, and addressing of the peer-review comments. Recommendations and analyses on the basis of specialist clinical expertise in child and adolescent transgender care were provided by JKM (psychiatry) and AS (endocrinology). Declaration of interests FDZ has received an unrestricted award donated by the American Psychiatric Association, the American Psychiatric Institute for Research and Education, and AstraZeneca (Young Minds in Psychiatry Award); has received research support from the German Federal Ministry for Economics and Technology, the European Union, the German Society for Social Paediatrics and Adolescent Medicine, the Paul and Ursula Klein Foundation, the Dr August Scheidel Foundation, the IZKF fund of the University Hospital of RWTH Aachen University, and a travel stipend donated by the GlaxoSmithKline Foundation; has received an unrestricted educational grant, travel support, and speaker honoraria from Shire Pharmaceuticals, Germany; and has received support from the Raine Foundation for Medical Research (Raine Visiting Professorship) and editorial fees from Co-Action Publishing (Sweden). All other authors declare no competing interests. Acknowledgments SM is funded by a University Postgraduate Award and Safety Net Top-Up Scholarship from the University of Western Australia. AL is funded by an Australian National Health and Medical Research Council Early Career Fellowship (#1072593).

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