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Hormonal Treatment in Young Denise Chew, BBmed,​a Jemma Anderson, MBBS,b​ Katrina Williams, MBBS, MSc, PhD, FRACP, FAFPHM,​a,​c,​d PeopleTamara May, BA, BSc, GDipPsych,With PGDipPsych, PhD,a,​ ​c,​d,​e Kenneth Dysphoria: Pang, MBBS, BMedSc, FRACP, PhD a,​c,​d,f,​ ​g A Systematic Review CONTEXT: abstract Hormonal interventions are being increasingly used to treat young people with , but their effects in this population have not been systematically reviewed OBJECTIVE: before. To review evidence for the physical, psychosocial, and cognitive effects of -releasing analogs (GnRHa), gender-affirming , DATA SOURCES: , and progestins on adolescents. We searched Medline, Embase, and PubMed databases from January 1, 1946, to STUDY SELECTION: June 10, 2017. We selected primary studies in which researchers examined the hormonal treatment of transgender adolescents and assessed their psychosocial, cognitive, and/or DATA EXTRACTION: physical effects. Two authors independently screened studies for inclusion and extracted data RESULTS: from eligible articles using a standardized recording form. n n n n Thirteen studies met our inclusionn criteria, in which researchers examined GnRHas ( = 9), ( = 3), ( = 5), ( acetate) ( = 1), and progestin () ( = 1). Most treatments successfully achieved their intended physical effects, with GnRHas and suppressing sex hormones and estrogen or testosterone causing or masculinization of secondary sex characteristics. GnRHa treatment was associated with improvement across multiple measures of psychological functioning but not gender dysphoria itself, whereas the psychosocial effects of gender-affirming hormones in have not yet been LIMITATIONS: adequately assessed. CONCLUSIONS: There are few studies in this field and they have all been observational. Low-quality evidence suggests that hormonal treatments for transgender adolescents can achieve their intended physical effects, but evidence regarding their psychosocial and cognitive impact are generally lacking. Future research to address these knowledge gaps and improve understanding of the long-term effects of these treatments is required.

Departments of aPediatrics and fPsychiatry, Melbourne Medical School, University of Melbourne, Parkville, Australia; bDiscipline of Paediatrics, Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, Australia; cMurdoch Children’s Research Institute, Parkville, Australia; dThe Royal Children’s Hospital, Melbourne, Australia; eSchool of Psychology, Deakin University, Burwood, Australia; and gInflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

To cite: Chew D, Anderson J, Williams K, et al. Hormonal Treatment in Young People With Gender Dysphoria: A Systematic Review. Pediatrics. 2018;141(4):e20173742

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10 12 Transgender is a term used to pulmonary embolism). ‍ Studies of Diagnosticas transgender and Statisticalor diagnosed Manual with describe an individual whose antiandrogens in transfemale adults ofGD Mental and/or Disorders, GID according Fourth to Edition the inner differs from have revealed that cyproterone Diagnostic and Statistical Manual of their sex assigned at birth. This acetate is able to reduce levels of Mental Disorders, Fifth Edition ; mismatch can cause distress and testosterone, whereas International Classification of Diseases functional impairment, resulting in has a synergistic effect with estrogen ; or “ gender dysphoria (GD) or what was in improving both physical and ” 13 previously termed1,2​ gender identity hormonal outcomes. criteria. This age range was selected disorder (GID). ‍ to be consistent with the definition In contrast, studies of different Lancet of adolescence used by the recent Several hormonal treatment hormonal treatments in young Commission on Adolescent options are available for GD, the people with GD are scarce, meaning 16 Health. Studies were excluded if the appropriateness of which depends on that clinicians have often had to effects of hormonal could not developmental stage. For instance, extrapolate from adult studies. This be separated from gender-affirming can frequently exacerbate is problematic for several reasons. surgery, which could cause potential GD because of the development Firstly, adolescence is a period of issues related to interpretation of of unwanted secondary sexual rapid development across multiple 3 14 results. We included all published characteristics,​ which can be domains,​ and studies of hormonal study designs in any language, but reversibly suppressed by using treatments in adults with GD may conference abstracts or studies in gonadotropin-releasing hormone not readily translate to adolescents. 4,5​ which researchers failed to report analogs (GnRHas). ‍ In comparison, Secondly, some hormone treatments results at the group level with at least gender-affirming hormones (GAHs; used in young people with GD (eg, 10 individuals were excluded. also known as cross-sex hormonal GnRHas and progestins) are either Study Identification therapy) allow individuals to not commonly used in adults with actively masculinize or feminize GD or are used in adults for different their physical appearance to be reasons (eg, GnRHas for 15 The Medline (Ovid) and Embase more consistent with their gender cancer). Finally, hormonal dosing (Ovid) databases were searched for identity. As GAHs are only partially regimens in adolescents with GD are references from January 1, 1946, to reversible, they are generally used frequently different from those used June 10, 2017, by using thesauri and/or only once an individual reaches in adults, which is likely to affect keywords. PubMed was searched the legal age of medical consent, outcomes. 5 by using keywords to retrieve which varies across countries. In Our purpose in this systematic electronic publications and items addition, antiandrogens, such as review is, therefore, to evaluate not indexed in Medline. The Medline spironolactone and cyproterone the currently available evidence search strategy was adapted for use acetate, can be used to counter the about the physical, psychosocial, in Embase and PubMed with the effects of testosterone in birth- “ 6,7​ and cognitive effects of different main search terms as follows: (GD or assigned male individuals,​ ‍ whereas ” hormonal in transgender transsexualism or sexual and gender progestins, such as youth. By doing so, we can directly disorders or transgender persons and , are inform clinical practice involving this or gender identity), ( therapy often employed to suppress menses population and highlight existing or therapeutic use or [hormonal in younger birth-assigned knowledge gaps. or hormone*] or * or exp individuals. METHODS gestagen or exp antiandrogen), Authors of multiple studies have and (adolescen* or pediatric* or investigated the physical and Eligibility Criteria pediatric* or youth* or teen or psychosocial effects of different teens or teenage*). Detailed search hormonal interventions in adults histories are available on request. with GD. GAHs have been examined Studies were considered eligible if Additional items were identified by most extensively, with authors of participants were given hormonal manually searching reference lists systematic reviews indicating that treatment (GnRHas, GAHs, of relevant retrieved articles. Two

GAHs improve multiple aspects8,9​ of antiandrogens, or progestins) reviewers independently assessed psychosocial functioning,​ ‍ although and if analysis of psychosocial, all study titles and abstracts to they also increase serum triglycerides cognitive, and/or physical effects determine inclusion, with the full and risk of cardiovascular disease of these hormones were included. text being subsequently retrieved for (including , Participants had to be younger potentially eligible studies to assess stroke, myocardial infarction, and than 25 years of age and described final suitability. Any disagreements Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 CHEW et al 19,21,​ 29​ were resolved with discussion and conducted because individual and testosterone ‍ ‍ levels, consensus was reached for final outcome effect sizes were available although 1 study only revealed a Dataarticles. Extraction for a maximum of 2 studies. significant decrease in transfemale RESULTS adolescents (birth-assigned male individuals identifying as Study Selection 19 Two reviewers, working female individuals). There was independently and in duplicate, decreased testicular volume19,21,​ 29​in used a standardized form transfemale adolescents ‍ ‍ and The study selection process is to extract methodological, cessation of menses in transmale depicted in Fig 1. Eighty-three demographic, and outcome data. – – adolescents (birth-assigned female potentially relevant studies19 27,29​ were32 Data extracted included reported individuals identifying21 as male retrieved, of which 13 ‍ ‍ ‍ ‍ youth characteristics (number of individuals),​ although the latter met the inclusion criteria and participants pre- and posttreatment, often occurred after a withdrawal were systematically analyzed. In participant age range, diagnosis bleed in postmenarchal individuals. Table 1, we summarize the main of GD, birth-assigned sex, and Furthermore, GnRHas were shown to characteristics of these 13 studies, gender identity), hormonal therapy decrease (LH) and their key physical, psychosocial, features (type, dose, route, duration and follicle-stimulating19,21​ hormone and cognitive findings are outlined of treatment), study design, and (FSH).Progestin‍ in Tables 2, 3 and 4, respectively. outcomes of interest (length of Because research from the same follow-up duration, follow-up cohort was26,27​ described in 2 of the outcome measures, and treatment Researchers in 1 study examined the30 studies,​ they were considered as Qualityeffect on Assessment outcome measures). effects of the progestin lynestrenol Quality1 study. Appraisal in transmale adolescents. Although there was no report of the Risk of bias in studies was assessed of lynestrenol in stopping menses, In all studies, there was a medium there were significant reductions by 2 authors working independently to high risk of bias (Table 5). In using a modified version of the in levels of serum sex-hormone most studies, there were only binding globulin (SHBG) and LH, in Quality in Prognosis Studies17 (QUIPS) small sample sizes (minimum of tool from a previous study. The addition to a significant increase in 18 21 and maximum of 201), with <50 free testosterone (fT). FSH, estradiol, original QUIPS tool was modified participants in 38.5% of the studies. testosterone, and anti-Mullerian because confounders or prognostic There were controls in only 2 studies, hormone had nonsignificant factors were not analyzed in this 30 and all studies were conducted in Antiandrogendecreases. Reviewreview andProtocol thus did not apply. clinical populations. There was often significant loss to follow-up, attributed partially to most studies In one study, researchers studied A detailed protocol is available being retrospective with missing the effects of the antiandrogen at PROSPERO (identifier data. Overall, the tools used to cyproterone acetate alone in 42017056670). 22 Statistical Analysis measure the specific outcomes were transfemale adolescents. It was valid and reliable, although there was effective in significantly suppressing – no blinding or randomization in any endogenous sex hormones with of the studies. Effect sizes were calculated for19 results27 significant reductions in testosterone PHYSICAL EFFECTS with reported means and SDs,28​ ‍‍ and in according to a previous study. addition to nonsignificant decreases Unadjusted effect sizes using the in and fT after 12 months, posttest SD were calculated for the All relevant results are shown in with no significant changes in LH, majority of studies, with an adjusted Table‍Sex Hormones 2. and Secondary Sexual FSH, and SHBG. Cyproterone acetate ∼ effect size using the experimental Characteristics was associated with a marked SD calculated only for 1 study24 with GnRHas increase in of 2.5-fold comparisonMeta-analysis between groups. that exceeded the normal reference range after 6 months but returned GnRHas were successful in to the normal range after 12 months. Meta-analysis was planned for suppressing No clinical consequences, including outcomes examined by 3 or more with significant decreases29 galactorrhea, were reported. studies but was unable to be in gonadotropin,​ estradiol, Furthermore, 55.6% of participants Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 4, April 2018 3 FIGURE 1 Flow diagram of study selection.

Testosterone also reported decreased22 facial treated in late puberty (Tanner shavingEstrogen frequency. stages B4 and B5), although these Testosterone resulted in , 29 decreased in frequency over time. including lower voice, clitoral No other short-term side effects, enlargement, and growth 29 including local reactions, were Estrogen was successful in feminizing22,29​ in a masculinized pattern. Menses Progestinreported. physical sex characteristics. ‍ ceased in most transmale adolescents In 1 study, 66.7% of participants within 6 months, with an average20 reached Tanner B3 stage (increase time to cessation of 2.9 months. Lynestrenol was evaluated as in and areola size), and 9.5% Testosterone resulted in increased 20,30,​ 32​ relatively safe, with the most reached Tanner B4 (secondary total testosterone and fT,​ ‍ with common side effects being initial mound created by areola and most participants reaching levels metrorrhagia (48.7%), papilla) after treatment with within the normal male range after 20,30​ (12.1%), hot flashes (9.8%), and cyproterone acetate and22 estrogen 6 months,​ ‍ as well as significant 30 (which increased from 14.6% to for at least 6 months. However, decreases in LH and FSH. This 30 was found 28.6%)Antiandrogens. was accompanied by a decline in20, 30,​ 32​ to be objectively dissatisfactory estradiol levels after 6 months,​ ‍ and subjectively less in size22 than which was20, statistically30​ significant in expected for the majority. There 2 studies ‍ but nonsignificant in 1 Treatment with cyproterone acetate 32 was evaluated to be relatively safe, was a significant increase in serum Sidestudy Effects. estradiol after 6 months that reached with the most common22 the female reference range, whereas GnRHas beingEstrogen (37%). total testosterone decreased after 1 to 3 months to be22, outside32​ of the male reference range.22 ‍ Prolactin was Hot flashes were a common side Side effects reported with combined unchanged. effect in transmale adolescents estrogen and cyproterone acetate Downloaded from www.aappublications.org/news by guest on September 27, 2021 4 CHEW et al Outcomes Examined psychosocial functioning sexual characteristics, BMD, growth, body composition, and other physical effects sexual characteristics, safety profile, BMD, growth, and body composition sexual characteristics, body composition, and other physical effects GD-related discomfort, global Sex hormones and secondary Psychological functioning, GD Treatment, y Treatment, eligible for GnRHa: average: 0.75 ± 0.59 transfemale adolescents: average: 1.3, range: 0.5 – 3.8; transmale adolescents: average: 1.5, range: 0.25 – 5.2; GAH: transfemale adolescents: average: 5.8, range: 3 – 8; transmale adolescents: average: 5.4, range: 2.8 – 7.8 1.88 ± 1.05, range: 0.42 – 5.06 Immediately GnRHa: 2 y or longer Sex hormones and secondary GnRHa: average: Not mentioned Sex hormones and secondary ) 26 l Treatment Duration of assessed in de Vries et a treatment studied), GAH testosterone) Effects Analyzed Psychosocial GnRHa Psychosocial GnRHa, GAH (not b a 0 Physical GnRHa 3 Physical GAH (only % Variable Physical GnRHa (only Variable: 0 – 65 Variable: 18 – 42 Loss to Follow-up, 18.7 ± 2.6 Age, y ± SD start of GnRHa: 16.48 ± 1.26 transfemale adolescents: 14.9 ± 1.9, transmale adolescents: 5.0 ± 2.0; at start of GAH: transfemale adolescents: 16.6 ± 1.4, transmale adolescents: median of 16.4 and range interquartile of 2.3 at start of GnRHa: 14.75 ± 1.92, at start of GAH: 16.64 ± 1.90 Baseline: 15.52 ± 1.41, At start of GnRHa: Not mentioned Baseline: 13.65 ± 1.85, reatments in Transgender Youth reatments in Transgender adolescents with GID, 77 transfemale adolescents with GID adolescents with GID, 19 transmale adolescents with GID transgender adolescents adolescents with GID, 10 transfemale adolescents with GID adolescents with GID, 33 (22) transfemale adolescents with GID Gender Identity 34 15 transfemale 36 36 transmale 21 11 transmale ( N ) 201 124 transmale 70 (55) 37 (33) transmale longitudinal longitudinal longitudinal longitudinal longitudinal Type of Study Sample Retrospective, Prospective, Prospective, Prospective, Prospective,

27 l 29 25 20 l l 19 s a l )  Characteristics of 13 Studies on Hormonal T

26 l (de Vries et a de Waal and Cohen- Ketteni Olson et a de Vries et a Study Klink et a Costa et a Delemarre-van TABLE 1

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 4, April 2018 5 Outcomes Examined sexual characteristics, growth, body composition, and other physical effects sexual characteristics, safety profile, body composition, and other physical effects Executive functioning Mental rotation Sex hormones and secondary Treatment, y Treatment, 1.6 ± 1.0 range: 0.17 – 4; testosterone: average: 0.83, range: 0.5 – 1.25 for lynestrenol, average of 0.95 for lynestrenol and testosterone GnRHa: average: At least 0.25 Sex hormones and secondary GnRHa: average: 2, Average of 10.5 Not mentioned BMD, and growth Bone turnover, Treatment Duration of (testosterone) progestin (lynestrenol), combination of androgenic progestin (lynestrenol) and GAH (testosterone) (testosterone and estrogen) Effects Analyzed 9 Physical GnRHa % 26 Cognitive GnRHa 16 Physical Androgenic 20 Physical GnRHa, GAH 8.1 Cognitive GnRHa, GAH Loss to Follow-up, ± Age, y ± SD adolescents: 15.8 ± 1.9, transfemale adolescents: 15.1 ± 2.4, male 14.9 : adolescents 1.5, female adolescents: 14.4 ± 1.8 adolescents: 14.2, transfemale adolescents: 13.6 adolescents: 16.1 ± 0.8, control male subjects: 15.9 ± 0.6, control female subjects: 16.3 ± 1.0 treatment of treatment: transmale adolescents: 15.1, transfemale adolescents: 13.5; GAH at start of treatment: transmale adolescents: 16.3, transfemale adolescents: 16.0 Transmale Transmale Transmale Transmale Transmale 15.8 at start of GnRHa at start adolescents with GID, 18 transfemale adolescents with GID, 21 male control subjects, 24 female control subjects adolescents with GID, 49 transfemale adolescents with GID adolescents with GD, 20 male control subjects, 21 female control subjects adolescents with GID adolescents with GID, 28 transfemale adolescents with GID Gender Identity 45 38 transmale 70 42 transmale ( N ) 128 67 transmale longitudinal longitudinal longitudinal Type of Study Sample Cross-sectional 116 22 transmale Prospective, fMRI 62 21 transmale Prospective, Retrospective, Retrospective, 21 l 23 l 30 Continued l 31 l

24 l et a Burke et a Tack et a Schagen et a Vlot et a Study Staphorsius TABLE 1

Downloaded from www.aappublications.org/news by guest on September 27, 2021 6 CHEW et al Outcomes Examined sexual characteristics, body composition, and other physical effects sexual characteristics, safety profile, growth, body composition, and other physical effects Sex hormones and secondary Treatment, y Treatment, minimum of 0.5 (mean of 1.0), combination of antiandrogen and GAH: minimum of 0.5 (mean of 1.3) Not mentioned Sex hormones and secondary Antiandrogen: in which researchers examined a smaller subset of the cohort subsequently ​ 26 Treatment Duration of and estrogen treatment) (cyproterone acetate), combination of antiandrogen (cyproterone acetate) and GAH (estrogen treatment) Effects Analyzed % Variable Physical GAH (testosterone 22.2 (variable) Physical Antiandrogen Loss to Follow-up, Age, y ± SD adolescents: average of 16 (range of 13 – 22) at start of treatment, Transfemale adolescents: average of 18 (range of 14 – 25) at start of treatment start of treatment, combination of antiandrogen and GAH: 17.6 at start of treatment Transmale Transmale Antiandrogen: 16.5 at adolescents with GD, 44 transfemale adolescents with GD adolescents with GD Gender Identity 27 27 transfemale ( N ) 116 72 transmale longitudinal longitudinal Type of Study Sample 27 . Retrospective, Retrospective, 32 l 22 Continued l

Tack et a Study Jarin et a Variable loss to follow-up depending on test. These 2 studies involved the same cohort and were therefore considered as 1 study. The values in parenthesis are used to indicate the results of earlier study, examined in de Vries et al TABLE 1 Note that transmale adolescents are birth-assigned whereas transfemale adolescents are birth-assigned female individuals who identify as male individuals, male individuals who identify as female individuals. a b

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 4, April 2018 7 in b — — — in diastolic BP, in diastolic BP, in AST c c in Hb (but not b to clinically significant levels), increase systolic BP and ALT (but not to clinically significant levels), decrease increase Increase — — — Safety Profile Other Physical Effects transmale adolescents (when treated in late pubertal stages) Frequent hot flashes in

c

b a in wt for in BMI, decrease in fat mass a b b Body Composition transfemale adolescents and transmale adolescents, increase in BMI actual score for transfemale adolescents and transmale adolescents, nonsignificant changes in BMI SDSs for transfemale adolescents and transmale adolescents in total percentage, decrease glucose, , cholesterol, HDL, and LDL levels in percentage Increase No effect on fasting Increase

Outcome c in z score in z score in actual and in actual and c c b c — in standardized BMD a in bone density a decrease decrease z scores z scores in actual score and decrease significant changes in actual score and decrease Femoral nondominant: Femoral nondominant: Lumbar spine: decrease (actual and z scores) score ( z score) actual values but decrease Lumbar spine: no

adolescents Transmale Transfemale adolescentsTransfemale Increase Increase No change in bone density

a in height in height b c — in height in height in height a a b Measurements Anthropometric actual values, decrease standardized values for transfemale adolescents, decrease standardized values for transmale adolescents velocity, decrease (growth spurt) with substitution therapy in height SDSs youth who still have growth potential (related to bone age) Increase Decrease Increase

b c

b in in LH and FSH in testicular a b b in estradiol, in gonadotropin in total and a b b decrease testosterone in transfemale adolescents with no change in transmale adolescents, decrease fT levels, decrease in normal and serum estradiol levels in testicular volume in transfemale adolescents, decrease and sex hormone levels, decrease volume in transfemale adolescents in , decrease adolescents (low voice, facial clitoris enlarged, and body hair growth) and transfemale adolescents (induced breast development) reatments in Transgender Youth reatments in Transgender Testosterone, Estradiol, and Gonadotropin Levels Decrease Virilization of transmale Decrease Treatment and estrogen) treatment studied), GAH GnRHa GAH (testosterone GnRHa (only GAH (testosterone) Increase 29 29 20 l 19 s s l  Physical Effects of Hormonal T

van de Waal and Cohen- Ketteni van de Waal and Cohen- Ketteni Study Delemarre- Olson et a Klink et a Delemarre- TABLE 2

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b in ALT, in ALT, b in ALP in fT4 in thyrotropin, in fT4, no in creatinine, in creatinine, b c b c b b in transmale in mean Hb and in mean Hb and b b b creatinine levels; no significant change in y-glutamyl transferase, and and ALT; AST, decrease Hct, increase significant changes in AST and thyrotropin Hct levels, increase decrease transfemale adolescents and transmale adolescents increase in ALT and AST (but remained within male reference range), increase increase decrease Increase Increase Decrease in acne, a in acne and — a Safety Profile Other Physical Effects reported in first 6 mo, increase menorrhagia most common safety profile of and hot flashes increase Metrorrhagia mainly Few had fatigue;

b in b in lean body in mean HDL, in BMI in mean LDL b b b c in wt scores, in wt and BMI in wt and BMI; b b b Body Composition increase scores, increase during first 6 mo but back to baseline after 12 mo, no significant changes in total cholesterol and triglyceride levels, no significant change in HbA1c and HOMA, decrease no significant changes in total cholesterol, triglyceride levels, HDL and LDL mean levels, HbA1c, glucose levels, insulin levels, or HOMA index mass percentage in transfemale adolescents and transmale adolescents increase BMI SDSs, increase in fat percentage, decrease Increase Increase Increase Outcome — — — BMD

b — in height in height b a Measurements Anthropometric SDSs and increase in height values in transfemale adolescents and transmale adolescents and wt Increase Decrease

c

c in in c c in b in c in SHBG; in LH and in fT c b b in LH; decrease LH; in in LH and b b in FSH, estradiol, testosterone and AMH; decrease increase FSH, decrease testosterone and fT (reaching levels within male reference ranges), increase FSH, and decrease SHBG, increase estradiol gonadotropin, estradiol, and testosterone in testicular volume, decrease menses ceased; Transfemale adolescents: decrease Testosterone, Estradiol, and Gonadotropin Levels Transmale adolescents: Transmale Decrease Decrease Treatment progestin (lynestrenol) androgenic progestin (lynestrenol) and GAH (testosterone) GnRHa Androgenic Combination of 30 30 Continued l l

21 l et a Tack et a Tack et a Study Schagen TABLE 2

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 4, April 2018 9 — — in ALT after c in Hct and Hb; b no significant changes in SUN, creatinine, prolactin, or AST; decrease 4 – 6 mo but returned to baseline Increase — — — Safety Profile Other Physical Effects in HDL — — b in BMI (no results c Body Composition for height and/or wt); no significant changes in LDL, total cholesterol, triglyceride triglycerides, to HDL ratio, and HbA1c; decrease Increase Outcome — in bone density in bone density in bone density in bone density BMD in bone density in bone density b b b b b b in hip for older bone age (actual and z scores) in lumbar spine for older bone age (actual and z scores) in lumbar spine for young bone age ( z scores) in lumbar spine for young bone age ( z scores) in hip and lumbar spine (actual and z scores) in lumbar spine (actual and z scores) bone density in hip Decrease Decrease Decrease Increase No significant changes in Decrease Increase adolescents Transfemale adolescents Transfemale Transmale adolescents Transmale

Transmale adolescents Transmale — in height in height and c a Measurements Anthropometric wt (significance level not reported) and wt Increase Increase in c — — in total c testosterone after 1 – 3 mo, decrease estradiol Testosterone, Estradiol, and Gonadotropin Levels Treatment and estrogen) GnRHa GAH (testosterone GAH (testosterone) Increase 32 l Continued 31 31 l l

Study Vlot et a Vlot et a Jarin et a TABLE 2

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b

b in in Hb b b in creatinine, in Hct after b b in prolactin (no b 1 – 3 mo but return to baseline; increase clinical galactorrhea); decrease Hb and Hct, but not outside of reference ranges; no significant changes in AST and ALT; no significant change in thyrotropin and fT4 after 4 – 6 mo but return to baseline; no significant changes in SUN, creatinine, prolactin, or HbA1c; decrease AST, prolactin in creatinine after 12 mo, no significant changes in AST and ALT, no significant change in thyrotropin and free thyroxin, decrease in ALT (systolic and diastolic); increase Hb and Hct, increase No significant changes in BP No significant changes in Increase in wt, no — c in BMI after b Safety Profile Other Physical Effects 6 – 12 mo but BMI still less compared with Flemish male peers, increase significant changes in LDL, total cholesterol, HDL, and triglyceride levels emotionality (11.10%), fatigue (36%), hot flashes (3.7%) Breast tenderness (7.4%), Increase in b Body Composition in BMI (no results for height and/or wt), no significant changes in LDL, HDL, total cholesterol, triglycerides, and triglyceride to HDL ratio triglycerides, no significant changes in total cholesterol, HDL, and LDL statistically significant changes in wt and BMI, decrease emotionality (28.60%), hunger (24%), fatigue (14%), hot flashes (14.3%) No significant change No clinically important or Breast tenderness (57.1%), Outcome — — — BMD in height in height b b — in height, in height, b b Measurements Anthropometric decrease decrease compared with male peers compared with male peers Increase Increase

c

c in b

b in in in b b b in b in estradiol c in LH, decrease in estradiol b b levels, decrease SHBG, increase estradiol, decrease dehydroepiandrosterone, decreased facial shaving frequency (55.60%). Breast development: Tanner B2 (14.8%) and B3 (14.8%) testosterone levels in testosterone, nonsignificant decrease testosterone and fT, no testosterone and fT, significant change in dehydroepiandrosterone, decreased shaving need (71.40%). Breast development: Tanner B3 (66.7%) and B4 (9.50%) and fT, decrease and fT, in FSH, increase in SHBG, decrease LH and FSH, decrease Testosterone, Estradiol, and Gonadotropin Levels No significant changes in Decrease Treatment (cyproterone acetate) antiandrogen (cyproterone acetate) and GAH (estrogen treatment) GAH (estrogen) Increase Antiandrogen Combination of 32 l 22 22 Continued l l

Tack et a Tack et a Study Jarin et a Indicates significant change ( P < .05). Indicates that a P value was not calculated. Indicates nonsignificant change ( P > .05). TABLE 2 Note that transmale adolescents are birth-assigned female individuals who identify as male individuals, whereas transfemale adolescents are birth-assigned male individuals who identify as female individuals. AMH, anti-Mullerian hormone; SUN, serum urea nitrogen; — , not applicable. a b c

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 4, April 2018 11 TABLE 3 Psychosocial Effects of Hormonal Treatments in Transgender Youth Study Treatment Outcome Global Anger and Behavioral and Emotional Problems GD and Body Functioning Anxiety Image de Vries et al27 GnRHa, GAH (not Increaseb Decreaseb Decreasec CBCL: decreaseb in total YSR: decreaseb No significant (de Vries assessed) (increasec) and internalizing in total and effectd et al26)a scores, decreaseb internalizing (decreasec) in scores, externalizing scores decreaseb (decreasec) in externalizing scores Costa et al25 GnRHa Increasee — — — — — Although influential articles in this field, Cohen-Kettenis and Van Goozen33 and Smith et al34 were unable to be included in our study because of their focus on patients after . CBCL, Child Behavior Checklist; YSR, Youth Self Report; —, not applicable. a These 2 studies involved the same cohort and were therefore considered as 1 study. Parentheses are used to indicate the results of the earlier study26 in which researchers examined a smaller subset of the cohort subsequently examined in the previous study.27 b Indicates significant change (P < .05). c Indicates nonsignificant change (P > .05). d It is important to note that the Utrecht Gender Dysphoria Scale that was used to measure GD in this study has various limitations, especially in relation to individuals who have already undergone social transition. Thus, the reported lack of improvement in GD here may reflect a lack of sensitivity in detecting psychological benefits. For example, it has been indicated in clinical experience that GnRHas help to satisfy the desire to prevent development of unwanted secondary sex characteristics (which is a criterion for GD under the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition in young adolescents), but the Utrecht Gender Dysphoria Scale does not have any items that address this issue. e Indicates that a P value was not calculated.

TABLE 4 Cognitive Effects of Hormonal Treatments in Transgender Youth Study Treatment Outcome included breast tenderness (57.1%), Executive Functioning Mental Rotation emotionality (28.6%), hunger Staphorsius GnRHa No significant effect on Tower of — (23.8%), fatigue 22(14.3%), and hot et al24 London performance scores flashesTestosterone (14.3%). except for decreasea in accuracy in suppressed transfemale adolescents (but this was thought to be chance finding Few side effects were reported because of small sample size), with testosterone treatment, with 20 no significant change in overall localized injection30 reactions (5.6%) global functioning, exaggerated and fatigue (8%) all relatively sex-typical activation of regions of interest uncommon. However, acne (37.5%) 23 Burke et al GnRHa, GAH — Inferred effect of GnRHa and menorrhagia (25%)30 were (testosterone (transmale adolescents) Bonecommon Mineral complaints Density. treatment) At baseline, showed masculinized mental GnRHas in Transfemale Adolescents rotation–associated brain activation z Testosterone treatment Lumbar spine bone mineral (transmale adolescents) density (BMD) scores decreased Increaseb in performance in after treatment19, with29,​ 31​ GnRHa mental rotation tasks, monotherapy,​ ‍ ‍ and this similar to control reduction29,31​ was statistically19 significant girls; increasea in in all but 1 studyz . When results bilateral parietal and were stratified by bone age, the left frontal activation mean reduction in score was only Note that transmale adolescents are birth-assigned female individuals who identify as male individuals, whereas significant (1.32) for individuals with transfemale adolescents are birth-assigned male individuals who identify as female individuals. —, not applicable. 31 a Indicates significant change (P < .05). a bone age <15 years. Absolute b Indicates that a P value was not calculated. zlumbar spine BMD did not change over time, and thus the decrease in scores after GnRHas likely reflects a failure to accrue BMD compared with age-matched peers. In 2 studies, researchers also examined BMD at the hip and femoral regions, which Downloaded from www.aappublications.org/news by guest on September 27, 2021 12 CHEW et al TABLE 5 Risk of Bias for Studies of Effects of Hormonal Treatments in Transgender Youth Study Study Participation Study Attrition (Overall) Outcome Measures (Overall) (Overall) standard deviation21,29​ scores (SDSs) after treatment. ‍ One study Delemarre-van de Waal High High Medium and Cohen-Kettenis29 revealed significantly lower height 26,27​ de Vries et al ‍ High High Medium standardized values19 for transfemale Klink et al19 Medium High Medium adolescents only. No researchers Olson et al20 Medium High Medium have examined whether individuals 25 Costa et al Medium Medium Medium given GnRHas achieved their Staphorsius et al24 Medium High Medium Burke et al23 Medium Medium Medium predicted final height after GAHs. Schagen et al21 High High Medium After 1 year on GnRHas, individuals Tack et al30 High High Medium had a significant29 increase19,21​ in body fat Vlot et al31 Medium High Medium percentage and BMI,​ ‍ which was Jarin et al32 High High Medium accompanied by a decrease in lean Tack et al22 Medium High Medium 29 bodyProgestins mass. A modified version of the QUIPS tool was used to assess risk of bias according to 3 domains of bias, with each domain having 3 potential ratings of low, medium, or high.18 These domains of bias included study participation (study sample adequately represents population of interest), study attrition (available study data adequately represents the study sample), and outcome measurement (outcomes of interest are measured in a similar way for all participants). Use of the Lynestrenol resulted in significant QUIPS tool has been described previously.17 z increases in weight and BMI absolute and scores during the first 6 months

with a return to baseline30 after 12 z monthsAntiandrogens of treatment. revealed nonsignificant decreases19,31​ in years of estrogen were still belowz absolute and scores for BMD. ‍ that of age- and birth-assigned sex- 31 − However, the duration of treatment matched norms. Specifically, − varied significantly in these studies, scores in the spine were 1.10 and Cyproterone acetate resulted in 31 ≥ a decrease in growth velocity 22 being unknown19 in 1 study29 and at least 0.66 in those with younger (<15 1GnRHas year in and Transmale 2 years Adolescents in the others. years) and older ( 15 years) bone compared with age-matched peers,​ Testosteroneages, respectively. with a final height after 12 months of treatment also being significantly − lower than age-matched peers with a There was a greater reduction in mean standardized score of 0.309. Testosterone monotherapy led to a BMD in transmale adolescents z There were no clinically significant significant increase in both absolute treated with GnRHas than changes in body weight and BMI after BMD and scores in the lumbar transfemale adolescents.z Two studies 29,31​ 31 12Estrogen months. revealed a significant decrease in spine ‍ and hip of transmale z adolescents, who had previously absolute and19, 31​ scores for lumbar been on GnRHas. However, their spine BMD,z ​ ‍ whereas another It is unclear whether differences in scores did not that of age- and study revealed a29 significant reduction z the pubertal stage and bone age at birth-assigned sex-matched controls, in only z scores. In 1 study, which estrogen was commenced aside from the scores in the hip of researchers quantified the reduction z contributed to the variable outcomes individuals with older bone ages. in BMD scores as being 0.79 for − − found because these data were not Specifically, scores in the spine 29 individuals with a bone age <14 collected. Estrogen in combination ≥ and hip were 0.15 and 0.37, years and 0.56 for individuals31 with − with cyproterone acetate resulted in respectively, in those with younger bone ages 14 yearsz . Two studies reduced growth compared with age- (<15 years old) bone ages and 0.06 22 also revealed statistically significant ≥ matched peers in 1 study,​ whereas and 0.02, respectively, in those with reductions in BMD scores at the another study revealed no change olderGrowth ( and15 years Body old)Composition bone ages. 29 hip and femoral19,31​ regions in transmale in growth velocity after estrogen. adolescents.Estrogen ‍ GnRHas Total BMI was significantly22, 32​ increased after estrogen in 1 study,​

although another revealed that total32 Testosterone Estrogen monotherapy wasz Growth velocity decreased29 during BMI did not change after 6 months. associated with significant increases treatment with GnRHas in all in both absolute BMD29, 31​and scores transgender youth compared 21 in the31 lumbar spine,​ ‍ but not the with pubertal-matched peers. Testosterone monotherapy resulted hip,​ of transfemalez adolescents In particular, younger individuals, in increased growth velocity previously treated with GnRHas. who had greater growth potential, compared 29with age-matched peers Furthermore, their scores after 2 had significantly lower height in 1 study,​ but the impact on final Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 4, April 2018 13 Antiandrogens height (nor the age and pubertal Serum creatinine increased after stage at commencement) was not 6 months of testosterone with no Cyproterone acetate was associated specified. Testosterone was also subsequent change thereafter and 30 with a significant reduction in only associated with weight gain,​ was thought to reflect an increase triglycerides, but total cholesterol, 30 20 30 resulting in a significantly raised in muscle mass. Hb and Hct 20,30​ LDL cholesterol, HDL cholesterol, absolute BMI ‍ from an average were increased after 6 months but HbA1c, glucose, insulin, and HOMA baseline of 20.7 to 22.4 within 22 remained stable during the next 20 index were unaffected. There 6 months. This increase in BMI was 6 months within the male reference was no change in or 20,30​ less than that of age-matched male 22 ranges,​ ‍ whereas another study 32 thyrotropin. There was a slight adolescents. revealed no significant change in decrease in Hb and Hct after 12 32 Other Physical Effects these parameters at any stage. months, but this was not clinically 22 Systolic BP was elevated in treated GnRHas Estrogensignificant. individuals, with an average20 rise of 5 mm Hg after 6 months. PSYCHOSOCIAL EFFECTS Apart from 1 study in which a After 1 year of GnRHa, there were significant decrease in HDL32 after 4 to no changes in carbohydrate or lipid 6 months was observed,​ estrogen All relevant results are shown in as measured by fasting had no effect on carbohydrate and 22,29,​ 32​ GnRHasTable‍ 3. glucose, insulin, cholesterol, low- lipid metabolism. ‍ ‍ Similarly, no density lipoprotein (LDL), and high- 29 significant22, changes32​ in liver density lipoprotein (HDL) levels. enzymes,​ ‍ thyrotropin,22 or free In 1 study, researchers observed thyroxine (fT4) were noted with GnRHa treatment was associated that alkaline phosphatase (ALP) estrogen treatment. A significant with significant improvements– in was decreased as a likely secondary increase in serum creatinine was multiple psychological measures,25 27 result of decreased bone turnover, seen after 12 months with combined including global26,27​ functioning,​ ‍ ‍ whereas all other liver enzymes were depression,​ and overall 21 estrogen and22 cyproterone acetate unchanged. In this same study, treatment. Hb was found to be behavioral26, and/or27​ emotional researchers also reported lower problems. ‍ The effects of GnRHas significantly32 elevated after 4 to 6 levels of creatinine and hypothesized months,​ with a corresponding on anger and anxiety remain 26,27​ that this might be due to reduced increase in Hct in 1 to 3 months. unclear with conflicting results. ‍ muscle mass but found that there However, when estrogen was used in Moreover, GnRHa treatment had no significant effect on symptoms of was no correlation between change21 combination with a progestin, Hb and 26,27​ in muscle mass and creatinine. Hct levels did not change any further GD,​ ‍ with researchers in 1 study Progestin 22 after 12 months. observing a nonsignificant increase26 Progestin,in GD and body Antiandrogens, image difficulties Estrogen,. (BP) was unchanged32 after 6 months ofTestosterone estrogen. and Testosterone Progestins were associated with an adverse lipid profile, with Critically, no researchers have a significant decrease in HDL Testosterone had no significant examined the psychosocial effects cholesterol by an average of 0.46 effect on carbohydrate and lipid 29,30,​ 32​ of these hormonal therapy types in mmol/L and an elevation of LDL metabolism. ‍ ‍ Although in transgender youth. cholesterol30 by 0.37 mmol/L after 1 study researchers observed 1 year. There were no significant raised liver enzymes (aspartate COGNITIVE EFFECTS changes in hemoglobin A1c aminotransferase30 [AST] and ALT) (HbA1c), glucose levels, insulin after a year,​ another study revealed All relevant results are shown in levels, or homeostasis model30 no significant change in AST and GnRHasTable‍ 4. assessment (HOMA) index. Alanine a decrease32 in ALT after 4 to 6 aminotransferase (ALT) increased months. Testosterone treatment after 12 months, but this30 was decreased thyrotropin and fT4 to not clinically significant. Mean be outside of the normal reference In one study, researchers examined hemoglobin (Hb) and hematocrit ranges, although these changes were the effect of GnRHas on executive (Hct) levels increased in the first not clinically relevant because there functioning using the Tower of

6 months30 and subsequently remained was no clinical or biochemical hypo-30 London test, which is used to 24 stable. or in participants. assess mental planning ability. Downloaded from www.aappublications.org/news by guest on September 27, 2021 14 CHEW et al After GnRHa treatment, there was by the recent Endocrine Society– clinical practice is their potential significantly reduced accuracy24 in Clinical Practice Guidelines, focused8 11,15​ effects on BMD accrual; their use transfemale adolescents. There on the use of GAHs in adults. ‍ ‍ was associated with19, 29,​a significant31​ was also exaggerated regional brain reduction in BMD,​ ‍ ‍ GnRHas successfully suppressed activation typical of birth-assigned which appeared to be worse for endogenous puberty, consistent 19,31​ sex on functional magnetic resonance transmale adolescents and is 24 with the primary objective of imaging (fMRI). However, given the consistent with previous studies this treatment, although there 39,40​ small sample size (8 participants), of nontransgender youth ‍ and was only a single study in which 41 these results should be interpreted adults who received GnRHas. researchers actually recorded these cautiously. 29 However, given the relatively short data. GnRHas were observed follow-up duration of the studies In another study, researchers to be associated with significant – reviewed here, it will be important examined the effect of GnRHa improvements in global 25 27 26,27​ for future researchers to better treatment on mental rotation in functioning,​ ‍ ‍ depression,​ ‍ and 23 establish if this reduction in bone transmale adolescents,​ exploring overall behavioral and/or emotional 26,27​ density is long-lasting or transient, whether rotated pairs of three- problems ‍ but had no significant as observed in nontransgender dimensional shapes were identical effect on symptoms of GD. The latter 39,40​ 35,36​ youth after GnRHa cessation. It images of each other. ‍ Because is probably not surprising, because is notable that BMD increased after men significantly perform better on GnRHas cannot be expected to lessen estrogen and testosterone, which this task compared with women, the dislike of existing physical sex ’ suggests potential compensation this result has also previously been characteristics associated with by GAHs. However, for estrogen suggested as evidence for the classic an individual s birth-assigned treatment, the BMD of those who theory of the organizational and sex nor satisfy their desire for the had previously received GnRHas activational effects of sex hormones physical sex characteristics of their 37,38​ still remained lower than age- on the brain. Interestingly, GnRHa preferred gender. Like GnRHas, the matched peers 2 years after estrogen suppression in transmale adolescents antiandrogen cyproterone acetate 31 treatment,​ so compensation may was associated with male brain effectively suppressed testosterone 22 only be partial. Furthermore, there activation patterns, with reduced in transfemale adolescents,​ but 23 is a lack of reporting of pubertal Progestin,activity in the Antiandrogens, right frontal area and. its potential psychosocial benefits stage at treatment commencement, Estrogen remain unclear. Meanwhile, GAHs which makes interpretation of some increased estrogen and testosterone changes difficult, especially BMD. levels and thus induced feminization No researchers have examined the and masculinization, respectively, of 22,29​ Clinically, patients who receive Testosteronecognitive effects of these treatments. secondary sex characteristics. ‍ GnRHas and still have significant However, in the case of breast growth potential are counseled development, the outcomes were about the risk of the treatment subjectively less in size than expected In the same study, researchers also 22 affecting their final height. Although in the majority of recipients,​ and examined the effects of testosterone researchers in 2 studies have the potential psychosocial benefits in transmale adolescents on now examined growth and height of GAHs remain unknown. Finally, mental rotation tasks, in which characteristics in transgender youth although the use of the progestin 21,29​ ≤ they observed moderate to strong receiving GnRHas,​ ‍ their relatively (lynestrenol) has been 30studied in improvements23 in accuracy and short follow-up times ( 3 years) transmale adolescents,​ its effects reaction time. Similar to control precluded determination of the were predominantly examined in boys, treated transmale adolescents effects of GnRHas on final height, and the context of potential adverse also demonstrated increased future researchers should address effects, so the therapeutic impact of activation of brain regions implicated23 this knowledge gap. Another clinical progestins for menses suppression in mental rotation on fMRI. concern in the use of GnRHas is and psychosocial outcomes cannot DISCUSSION the induction of menopausal-like be understood from the current symptoms due to the withdrawal literature. of sex steroids, especially in This is the first systematic review of Overall, hormonal treatments for postpubertal individuals. GnRHas the effects of hormonal treatment transgender youth were observed were commonly observed to cause in transgender youth; authors of to be relatively safe but not without hot flashes in transmale adolescents previous systematic reviews in this potential adverse effects. For in late puberty, but these29 decreased field, including those commissioned GnRHas, a significant concern in in frequency over time. For Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 4, April 2018 15 CONCLUSIONS potentially similar reasons, one of the long-term follow-up. In this regard, main complaints after cyproterone although randomized controlled Looking ahead, it will be essential acetate administration in transmale trials are often considered gold for future researchers to reassess adolescents was fatigue. standard evidence for judging clinical and expand on the findings of the interventions, it should be noted that, Hormonal treatment of transgender existing studies. Large, prospective in the context of GD in which current adults is known to be associated with longitudinal studies, such as have – guidelines highlight the important 44 various metabolic and cardiovascular 15 been recently initiated,​ with 10 12 role of hormonal treatments,​ effects. ‍‍ GnRHas significantly sufficient follow-up time and 29 conducting such trials would raise increased both statistical power and the inclusion 19,21​ significant ethical and feasibility and BMI ‍ while decreasing lean of well-matched controls will be 29 concerns. Fourthly, authors of body mass. Similarly, testosterone important, as will the inclusion existing studies have neglected significantly increased both of outcome measures that 20,29​ several key outcomes. These body fat and BMI. ‍ Although investigate beyond the physical include the following: psychological lynestrenol also increased BMI, this manifestations. symptoms related to GD, which is was transient, with BMI returning 30 a critical knowledge gap given the ABBREVIATIONS to baseline after 12 months. high rates of mental health problems Cyproterone acetate was not 22 observed in transgender youth and associated with any changes in BMI. justification of these treatments ALT: alanine aminotransferase In terms of lipid metabolism, neither 42 as treating GD ; the impact of AST: aspartate aminotransferase testosterone nor estrogen had any hormonal treatments on , BMD: bone mineral density observable impact, but lynestrenol which is an integral part of the BP: blood pressure was associated with lower HDL and 30 counseling recommended by current fMRI: functional magnetic higher LDL cholesterol after 1 year,​ 15 guidelines ; and potential adverse resonance imaging whereas cyproterone acetate 22 effects such as arterial hypertension, FSH: follicle-stimulating significantly reduced triglycerides. hormone which was reported in a recent case43 fT: free testosterone The findings from this review are series in association with GnRHas. fT4: free thyroxine subject to limitations. Firstly, the Finally, there are no known studies GAH: gender-affirming hormone current literature has a limited to date in which researchers have GD: gender dysphoria number of studies in which the reported the rates and circumstances GID: gender identity disorder different hormonal treatments in under which transgender youth GnRHa: gonadotropin-releasing transgender youth is examined. cease their hormonal therapy in an hormone analog Secondly, for any given class unplanned manner or the risk of Hb: hemoglobin of hormonal treatments, there subsequent regret, which would be of HbA1c: hemoglobin A1c is a variety of different agents, great clinical utility. Hct: hematocrit formulations, and administration Notwithstanding these limitations, HDL: high-density lipoprotein routes that are being used clinically collectively, the studies reviewed HOMA: homeostasis model in transgender youth. For example, provide qualified support for the assessment the physical effects of 1 antiandrogen use of GnRHas, GAHs, cyproterone LDL: low-density lipoprotein and 1 progestin have been studied acetate and, to a lesser extent, LH: luteinizing hormone in only 1 study each, with no lynestrenol in transgender youth. QUIPS: Quality in Prognosis confirmation of results or further Overall, these hormonal treatments Studies exploration. Thirdly, in existing appear to provide some therapeutic SDS: standard deviation score studies there is a medium to high benefits in terms of physical effects SHBG: sex-hormone binding risk of bias, given small sample sizes, and are generally well-tolerated on globulin retrospective nature, and lack of the basis of current evidence. Ms Chew screened studies for inclusion and exclusion, conducted the data extraction, conducted the analyses, drafted the initial manuscript, and revised the manuscript; Dr May screened studies for inclusion and exclusion, conceptualized and designed the study, and reviewed and revised the manuscript; Dr Anderson conducted the data extraction, conducted the analyses, and revised the manuscript; Prof Williams reviewed and revised the protocol and manuscript; Dr Pang conceptualized and designed the study and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. DOI: https://​doi.​org/​10.​1542/​peds.​2017-​3742 Accepted for publication Jan 12, 2018

Downloaded from www.aappublications.org/news by guest on September 27, 2021 16 CHEW et al Address correspondence to Kenneth Pang, Murdoch Children’s Research Institute, 50 Flemington Rd, Parkville, VIC 3052, Australia. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by the Royal Children’s Hospital Foundation, the Melbourne Children’s Clinician Scientist Fellowship Scheme (Dr Pang), the Apex Foundation for Research into , and the William Collie Trust at the University of Melbourne (Prof Williams). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 18 CHEW et al Hormonal Treatment in Young People With Gender Dysphoria: A Systematic Review Denise Chew, Jemma Anderson, Katrina Williams, Tamara May and Kenneth Pang Pediatrics originally published online March 7, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2018/03/05/peds.2 017-3742 References This article cites 38 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2018/03/05/peds.2 017-3742#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Endocrinology http://www.aappublications.org/cgi/collection/endocrinology_sub Adolescent Health/Medicine http://www.aappublications.org/cgi/collection/adolescent_health:med icine_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 27, 2021 Hormonal Treatment in Young People With Gender Dysphoria: A Systematic Review Denise Chew, Jemma Anderson, Katrina Williams, Tamara May and Kenneth Pang Pediatrics originally published online March 7, 2018;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2018/03/05/peds.2017-3742

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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