A European Network for the Investigation of Gender Incongruence in adolescents.

BACKGROUND: Knowledge regarding the effects and side effects of gender-affirming hormone therapy (GAHT) in adults is rapidly growing, partly through international research networks such as the European Network for the Investigation of Gender Incongruence (ENIGI). However, data on the effects of puberty suppression (PS) and GAHT in transgender and gender diverse (TGD) youth are limited, although these data are of crucial importance, given the controversies surrounding this treatment. AIM: We sought to present a detailed overview of the design of the ENIGI Adolescents study protocol, including the first baseline data. METHODS: The ENIGI Adolescents study is an ongoing multicenter prospective cohort study. This study protocol was developed by 3 European centers that provide endocrine care for TGD adolescents and were already part of the ENIGI collaboration: Amsterdam, Ghent, and Florence. OUTCOMES: Study outcomes include physical effects and side effects, laboratory parameters, bone mineral density, anthropometric characteristics, attitudes toward fertility and fertility preservation, and psychological well-being, which are measured in the study participants during PS and GAHT, up to 3 years after the start of GAHT. RESULTS: Between November 2021 and May 2023, 172 TGD adolescents were included in the ENIGI Adolescents protocol, of whom 51 were assigned male at birth (AMAB) and 121 were assigned female at birth (AFAB); 3 AFAB participants reported a nonbinary gender identification. A total of 76 participants were included at the start of PS, at a median (IQR) age of 13.7 (12.9-16.5) years in AMAB and 13.5 (12.4-16.1) years in AFAB individuals. The remaining 96 participants were included at start of GAHT, at a median (IQR) age of 15.9 (15.1-17.4) years in AFAB and 16.0 (15.1-16.8) years in AMAB individuals. At the time of this report the study was open for inclusion and follow-up measurements were ongoing. CLINICAL IMPLICATIONS: In response to the rising demand for gender-affirming treatment among TGD youth, this ongoing study is fulfilling the need for prospective data on the effects and safety of PS and GAHT, thus providing a foundation for evidence-based healthcare decisions. STRENGTHS AND LIMITATIONS: This study has a strong multicenter, prospective design that allows for systematic data collection. The use of clinical and self-reported data offers a broad range of outcomes to evaluate. Nevertheless, the burden of additional measurements and questionnaires may lead to withdrawal or lower response rates. Few participants with a non-binary gender identity have been included. CONCLUSION: With the ENIGI Adolescents study we aim to create a comprehensive dataset that we can use for a wide range of studies to address current controversies and uncertainties and to improve healthcare for TGD adolescents.

Spleen function is reduced in individuals with NR5A1 variants with or without a difference of sex development: a cross-sectional study.

OBJECTIVE: NR5A1 is a key regulator of sex differentiation and has been implicated in spleen development through transcription activation of TLX1. Concerns exist about hypo- or asplenism in individuals who have a difference of sex development (DSD) due to an NR5A1 disease-causing variant. We aimed to assess spleen anatomy and function in a clinical cohort of such individuals and in their asymptomatic family member carriers. DESIGN: Cross-sectional assessment in 22 patients with a DSD or primary ovarian insufficiency and 5 asymptomatic carriers from 18 families, harboring 14 different NR5A1 variants. METHODS: Spleen anatomy was assessed by ultrasound, spleen function by peripheral blood cell count, white blood cell differentiation, percentage of nonswitched memory B cells, specific pneumococcal antibody response, % pitted red blood cells, and Howell-Jolly bodies. RESULTS: Patients and asymptomatic heterozygous individuals had significantly decreased nonswitched memory B cells compared to healthy controls, but higher than asplenic patients. Thrombocytosis and spleen hypoplasia were present in 50% of heterozygous individuals. Four out of 5 individuals homozygous for the previously described p.(Arg103Gln) variant had asplenia. CONCLUSIONS: Individuals harboring a heterozygous NR5A1 variant that may cause DSD have a considerable risk for functional hyposplenism, irrespective of their gonadal phenotype. Splenic function should be assessed in these individuals, and if affected or unknown, prophylaxis is recommended to prevent invasive encapsulated bacterial infections. The splenic phenotype associated with NR5A1 variants is more severe in homozygous individuals and is, at least for the p.(Arg103Gln) variant, associated with asplenism.

Time course of body composition changes in transgender adolescents during puberty suppression and sex hormone treatment.

CONTEXT: Transgender adolescents can undergo puberty suppression (PS) and subsequent gender-affirming hormone therapy (GAHT) but little information is available on the expected rate of physical changes. OBJECTIVE: To investigate the time course of body composition changes during PS and GAHT. DESIGN: Retrospective cohort study. SETTING: Gender identity clinic. PARTICIPANTS: 380 trans boys and 168 trans girls treated with PS prior to GAHT. MAIN OUTCOME MEASURES: Total lean- and fat mass Z-scores using birth-assigned sex as reference determined using dual energy X-ray absorptiometry. RESULTS: In trans boys, lean mass Z-scores decreased (-0.32, 95%CI -0.41; -0.23) and fat mass Z-scores increased (0.31, 95%CI 0.21; 0.41) in the first year of PS and remained stable thereafter. Only during the first year of testosterone, lean mass Z-scores increased (0.92, 95%CI 0.81; 1.04) and fat mass Z-scores decreased (-0.43, 95%CI -0.57; -0.29). In trans girls, both lean and fat mass Z-scores gradually changed over three years of PS (respectively -1.13, 95%CI -1.29; -0.98 and 1.06, 95%CI 0.90; 1.23). Only in the first year of GAHT, lean mass Z-scores decreased (-0.19, 95%CI -0.36; -0.03) while fat mass Z-scores remained unchanged after three years (-0.02, 95%CI -0.20; 0.16). CONCLUSIONS: Compared to peers, trans girls experienced ongoing lean mass decrease and fat mass increase during 3 years of PS while in trans boys smaller changes were observed that stabilized after one year. A large increase in lean mass Z-scores occurred only during the first year of testosterone treatment. In trans girls, body composition changed only slightly during GAHT. This information can improve counseling about treatment effects.

Androgen Excess and Deficiency: Analytical and Diagnostic Approaches.

BACKGROUND: Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the different phases of life and regulate important developmental and maturational processes. Androgen excess or deficiency can therefore present at various ages in various ways. CONTENT: The diagnostic approach for atypical genitalia, premature pubarche, delayed pubertal onset or progression, and hirsutism or virilization, including measurement of androgens (testosterone, androstenedione, 17-OHprogesterone, dehydroepiandrosterone, and dihydrotestosterone) is discussed in the current review. Androgens can be measured in serum, saliva, urine, or dried blood spots. Techniques to measure androgens, including immunoassays and LC-MS, have their own advantages and pitfalls. In addition, pre- and postanalytical issues are important when measuring androgens. SUMMARY: During clinical interpretation of androgen measurements, it is important to take preanalytical circumstances, such as time of blood withdrawal, into account. As immunoassays have major drawbacks, especially in samples from women and neonates, concentrations measured using these assays should be interpreted with care. Reference intervals can only be used in relation to the measurement technique and the standardization of the assay. In the near future, new androgens will probably be added to the current repertoire to further improve the diagnosis and follow-up of androgen excess or deficiency.

Bone Mineral Density in Transgender Adolescents Treated With Puberty Suppression and Subsequent Gender-Affirming Hormones.

Importance: Bone mineral density (BMD) z scores in transgender adolescents decrease during puberty suppression with a gonadotropin-releasing hormone (GnRH) agonist. Previous research found that after short-term use of gender-affirming hormones (GAH), pretreatment z scores were not restored. Long-term follow-up studies are lacking. Objective: To assess BMD after long-term GAH treatment in transgender adults who used puberty suppression in adolescence. Design, Setting, and Participants: This single-center cohort study with follow-up duration of 15 years selected participants from a database containing all people visiting a gender identity clinic at an academic hospital in the Netherlands between 1972 and December 31, 2018. Recruitment occurred from March 1, 2020, to August 31, 2021. A total of 75 participants diagnosed with gender dysphoria who had used puberty suppression before age 18 years prior to receiving at least 9 years of long-term GAH were included. Exposures: Puberty suppression with a GnRH agonist followed by GAH treatment. Main Outcomes and Measures: Lumbar spine, total hip, and femoral neck BMD and z scores before the start of puberty suppression, at start of GAH, and at short- and long-term follow-up. Results: Among 75 participants, 25 were assigned male at birth, and 50 were assigned female at birth. At long-term follow-up, the median (IQR) age was 28.2 (27.0-30.8) years in participants assigned male at birth and 28.2 (26.6-30.6) years in participants assigned female at birth. The median (IQR) duration of GAH treatment was 11.6 (10.1-14.7) years among those assigned male at birth and 11.9 (10.2-13.8) years among those assigned female at birth. The z scores decreased during puberty suppression. In individuals assigned male at birth, the mean (SD) z score after long-term GAH use was -1.34 (1.16; change from start of GnRH agonist: -0.87; 95% CI, -1.15 to -0.59) at the lumbar spine, -0.66 (0.75; change from start of GnRH agonist: -0.12; 95% CI, -0.31 to 0.07) at the total hip, and -0.54 (0.84; change from start of GnRH agonist: 0.01; 95% CI, -0.20 to 0.22) at the femoral neck. In individuals assigned female at birth, after long-term GAH use, the mean (SD) z score was 0.20 (1.05; change from start of GnRH agonist: 0.09; 95% CI, -0.09 to 0.27) at the lumbar spine, 0.07 (0.91; change from start of GnRH agonist: 0.10; 95% CI, -0.06 to 0.26) at the total hip, and -0.19 (0.94; change from start of GnRH agonist: -0.20; 95% CI, -0.26 to 0.06) at the femoral neck. Conclusions and Relevance: In this cohort study, after long-term use of GAH, z scores in individuals treated with puberty suppression caught up with pretreatment levels, except for the lumbar spine in participants assigned male at birth, which might have been due to low estradiol concentrations. These findings suggest that treatment with GnRH agonists followed by long-term GAH is safe with regard to bone health in transgender persons receiving testosterone, but bone health in transgender persons receiving estrogen requires extra attention and further study. Estrogen treatment should be optimized and lifestyle counseling provided to maximize bone development in individuals assigned male at birth.

The dose-dependent effect of estrogen on bone mineral density in trans girls.

OBJECTIVE: Treatment in transgender girls can consist of puberty suppression (PS) with a gonadotropin-releasing hormone agonist (GnRHa) followed by gender-affirming hormonal treatment (GAHT) with estrogen. Bone mineral density (BMD) Z-scores decrease during PS and remain relatively low during GAHT, possibly due to insufficient estradiol dosage. Some adolescents receive high-dose estradiol or ethinyl estradiol (EE) to limit growth allowing comparison of BMD outcomes with different dosages. DESIGN: Retrospective study. METHODS: Adolescents treated with GnRHa for ≥1 year prior to GAHT followed by treatment with a regular estradiol dose (gradually increased to 2 mg), 6 mg estradiol or 100-200 µg EE were included to evaluate height-adjusted BMD Z-scores (HAZ scores) on DXA. RESULTS: Eighty-seven adolescents were included. During 2.3 ± 0.7 years PS, lumbar spine HAZ scores decreased by 0.69 [95% confidence interval (CI) -0.82 to -0.56)]. During 2 years HT, lumbar spine HAZ scores hardly increased in the regular group (0.14, 95% CI -0.01 to 0.28, n = 59) vs 0.42 (95% CI 0.13 to 0.72) in the 6 mg group (n = 13), and 0.68 (95% CI 0.20 to 1.15) in the EE group (n = 15). Compared with the regular group, the increase with EE treatment was higher (0.54, 95% CI 0.05 to 1.04). After 2 years HT, HAZ scores approached baseline levels at start of PS in individuals treated with 6 mg or EE (difference in 6 mg group -0.20, 95% CI -0.50 to 0.09; in EE 0.17, 95% CI -0.16 to 0.50) but not in the regular group (-0.64, 95% CI -0.79 to -0.49). CONCLUSION: Higher estrogen dosage is associated with a greater increase in lumbar spine BMD Z-scores. Increasing dosage up to 2 mg estradiol is insufficient to optimize BMD and approximately 4 mg may be required for adequate serum concentrations.

[Children and adolescents with gender questions: dilemmas in the hormonal treatment by multidisciplinary teams]. / Jongeren met genderincongruentie.

In the Netherlands but also in many other countries, there is an increasing social discussion about gender identity and gender diversity, and an increasing number of children and adolescents are seeking medical help because of questions about their gender identity. The cause of this increase is still unknown. Gender questions are diverse and require an individual approach by a multidisciplinary team. A number of adolescents have additional problems such as mood problems, autistiform symptoms and systemic problems. Diagnosis and treatment takes place in accordance with the quality standard for transgender care somatic and psychological. Hormonal treatment can help to reduce gender dysphoria and improve mental health.

Effect of Busulfan and Treosulfan on Gonadal Function after Allogeneic Stem Cell Transplantation in Children and Adolescents with Nonmalignant Diseases Is Not Exposure-Dependent.

With an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant impact on quality of life. In this retrospective study, we evaluated the exposure of busulfan (Bu) and treosulfan (Treo) in relation to gonadal function in pediatric patients who underwent HSCT for a nonmalignant disease between 1997 and 2018. In the Bu group, 56 patients could be evaluated, and gonadal dysfunction was found in 35 (63%). Lower Bu exposure (ie, cumulative area under the curve [AUC] <70 mg*h/L) was not associated with a reduced risk of gonadal dysfunction (odds ratio [OR], .92; 95% confidence interval [CI], .25 to 3.49; P = .90). In the Treo cohort, 32 patients were evaluable and gonadal insufficiency occurred in 9 patients (28%). Lower Treo exposure (AUC <1750 mg*h/L on day 1) was not associated with a reduced risk of gonadal dysfunction (OR, 1.6; 95% CI, .16 to 36.6; P = .71). Our data do not support the premise that reduced-intensity Bu-based conditioning reduces the risk for gonadal toxicity, and it is unlikely that therapeutic drug monitoring-based reduced treosulfan exposure will further limit the risk of gonadal dysfunction.

Undetectable anti-Mullerian hormone and inhibin B do not preclude the presence of germ cell tumours in 45,X/46,XY or 46,XY gonadal dysgenesis.

OBJECTIVE: Individuals with 45,X/46,XY or 46,XY gonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone (AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. DESIGN, PATIENTS AND MEASUREMENTS: Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999-2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. RESULTS: Thirteen males and 16 females were included, 20 with 46,XY and 9 with 45,X/46,XY DSD. Three females had dysgerminoma alongside gonadoblastoma; two gonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. CONCLUSIONS: Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XY or 46,XY gonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.

Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls.

INTRODUCTION: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. METHODS: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. RESULTS: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment. CONCLUSION: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor.

Children and adolescents in the Amsterdam Cohort of Gender Dysphoria: trends in diagnostic- and treatment trajectories during the first 20 years of the Dutch Protocol.

BACKGROUND: Twenty years ago, the Dutch Protocol-consisting of a gonadotropin-releasing hormone agonist (GnRHa) to halt puberty and subsequent gender-affirming hormones (GAHs)-was implemented to treat adolescents with gender dysphoria. AIM: To study trends in trajectories in children and adolescents who were referred for evaluation of gender dysphoria and/or treated following the Dutch Protocol. METHODS: The current study is based on a retrospective cohort of 1766 children and adolescents in the Amsterdam Cohort of Gender Dysphoria. OUTCOMES: Outcomes included trends in number of intakes, ratio of assigned sex at birth, age at intake, age at start of GnRHa and GAH, puberty stage at start of GnRHa, proportions of adolescents starting and stopping GnRHa, reasons for refraining from GnRHa, and proportions of people undergoing gender-affirming surgery. RESULTS: A steep increase in referrals was observed over the years. A change in the AMAB:AFAB ratio (assigned male at birth to assigned female at birth) was seen over time, tipping the balance toward AFAB. Age at intake and at start of GnRHa has increased over time. Of possibly eligible adolescents who had their first visit before age 10 years, nearly half started GnRHa vs around two-thirds who had their first visit at or after age 10 years. The proportion starting GnRHa rose only for those first visiting before age 10. Puberty stage at start of GnRHa fluctuated over time. Absence of gender dysphoria diagnosis was the main reason for not starting GnRHa. Very few stopped GnRHa (1.4%), mostly because of remission of gender dysphoria. Age at start of GAH has increased mainly in the most recent years. When a change in law was made in July 2014 no longer requiring gonadectomy to change legal sex, percentages of people undergoing gonadectomy decreased in AMAB and AFAB. CLINICAL IMPLICATIONS: A substantial number of adolescents did not start medical treatment. In the ones who did, risk for retransitioning was very low, providing ongoing support for medical interventions in comprehensively assessed gender diverse adolescents. STRENGTHS AND LIMITATIONS: Important topics on transgender health care for children and adolescents were studied in a large cohort over an unprecedented time span, limited by the retrospective design. CONCLUSION: Trajectories in diagnostic evaluation and medical treatment in children and adolescents referred for gender dysphoria are diverse. Initiating medical treatment and need for surgical procedures depends on not only personal characteristics but societal and legal factors as well.

Prenatal ultrasound finding of atypical genitalia: Counseling, genetic testing and outcomes.

OBJECTIVE: To report uptake of genetic counseling (GC) and prenatal genetic testing after the finding of atypical genitalia on prenatal ultrasound (US) and the clinical and genetic findings of these pregnancies. METHODS: A retrospective cohort study (2017-2019) of atypical fetal genitalia in a large expert center for disorders/differences of sex development. We describe counseling aspects, invasive prenatal testing, genetic and clinical outcome of fetuses apparently without [group 1, n = 22 (38%)] or with [group 2, n = 36 (62%)] additional anomalies on US. RESULTS: In group 1, 86% of parents opted for GC versus 72% in group 2, and respectively 58% and 15% of these parents refrained from invasive testing. Atypical genitalia were postnatally confirmed in 91% (group 1) and 64% (group 2), indicating a high rate of false positive US diagnosis of ambiguous genitalia. Four genetic diagnoses were established in group 1 (18%) and 10 in group 2 (28%). The total genetic diagnostic yield was 24%. No terminations of pregnancy occurred in group 1. CONCLUSIONS: For optimal care, referral for an expert fetal US scan, GC and invasive diagnostics including broad testing should be offered after prenatal detection of isolated atypical genitalia.

Medical decision-making competence regarding puberty suppression: perceptions of transgender adolescents, their parents and clinicians.

According to international transgender care guidelines, transgender adolescents should have medical decision-making competence (MDC) to start puberty suppression (PS) and halt endogenous pubertal development. However, MDC is a debated concept in adolescent transgender care and little is known about the transgender adolescents', their parents', and clinicians' perspectives on this. Increasing our understanding of these perspectives can improve transgender adolescent care. A qualitative interview study with adolescents attending two Dutch gender identity clinics (eight transgender adolescents who proceeded to gender-affirming hormones after PS, and six adolescents who discontinued PS) and 12 of their parents, and focus groups with ten clinicians was conducted. From thematic analysis, three themes emerged regarding transgender adolescents' MDC to start PS: (1) challenges when assessing MDC, (2) aspects that are considered when assessing MDC, and (3) MDC's relevance. The four criteria one needs to fulfill to have MDC-understanding, appreciating, reasoning, communicating a choice-were all, to a greater or lesser extent, mentioned by most participants, just as MDC being relative to a specific decision and context. Interestingly, most adolescents, parents and clinicians find understanding and appreciating PS and its consequences important for MDC. Nevertheless, most state that the adolescents did not fully understand and appreciate PS and its consequences, but were nonetheless able to decide about PS. Parents' support of their child was considered essential in the decision-making process. Clinicians find MDC difficult to assess and put into practice in a uniform way. Dissemination of knowledge about MDC to start PS would help to adequately support adolescents, parents and clinicians in the decision-making process.

Just as Tall on Testosterone; a Neutral to Positive Effect on Adult Height of GnRHa and Testosterone in Trans Boys.

CONTEXT: Growth is an important topic for many transgender boys. However, few studies have investigated the impact of puberty suppression (PS) and gender-affirming hormone treatment (GAHT) on growth and adult height. OBJECTIVE: To evaluate the effect of PS and GAHT on growth and adult height. DESIGN: Retrospective cohort study. SETTING: Specialized gender identity clinic. PARTICIPANTS: A total of 146 transgender boys treated with GnRH analogues and testosterone who reached adult height. MAIN OUTCOME MEASURES: Growth, bone age (BA), adult height, and difference between adult height and predicted adult height (PAH) and midparental height. RESULTS: In those with BA ≤14 years at start (n = 61), a decrease in growth velocity and bone maturation during PS was followed by an increase during GAHT. Adult height was 172.0 ± 6.9 cm; height SD score was similar to baseline (0.1; 95% CI, -0.2 to 0.4). Adult height was 3.9 ± 6.0 cm above midparental height and 3.0 ± 3.6 cm above PAH at start of PS. A younger BA at start PS was associated with an adult height significantly further above PAH. CONCLUSION: During PS, growth decelerated followed by an acceleration during GAHT. Although adult height SD score was similar to baseline, adult height was taller than predicted based on BA at baseline, especially in those who started treatment at a younger BA. It is reassuring that PS and GAHT do not have a negative impact on adult height in transgender boys and might even lead to a slightly taller adult height, especially in those who start at a younger age.

Perceptions on the function of puberty suppression of transgender adolescents who continued or discontinued treatment, their parents, and clinicians.

Purpose: Treatment of transgender adolescents with puberty suppression (PS) was developed to provide time for exploration before pursuing gender affirming medical treatment (GAMT) with irreversible effects. It may also result in a more satisfactory physical outcome for those who continue with GAMT. Despite being the current first choice treatment, little research has examined the function of PS from the perspectives of transgender adolescents, their parents, and clinicians. Insight into the perceived functions of PS will help to adequately support adolescents in their decision-making process and give them the care they need. Methods: Qualitative study using interviews with eight transgender adolescents who proceeded with GAMT after PS ("continuers"), six adolescents who discontinued PS ("discontinuers") and 12 parents, and focus groups with ten clinicians. Results: All informants considered inhibition of development of secondary sex characteristics an important function of PS. Most continuers saw PS as the first step of GAMT. Nevertheless, some were glad that the effects were reversible even if they didn't expect to change their minds. Some discontinuers did experience PS as an expanded diagnostic phase. One continuer used the time on PS to get used to living in the affirmed gender role, and several parents found the time helpful to adapt to their child's new gender role. PS provided clinicians more time for diagnostic assessment. Conclusions: Adolescents, parents and clinicians do not all report the same functions of PS. Although international guidelines emphasize providing time for exploration of gender identity as an important reason for PS, many adolescents nowadays seem to have clear ideas about their gender identity and treatment wishes, and experience PS as the first step of GAMT. For some discontinuers however, PS offered a valued period of exploration. Guidelines could be modified to provide more customized care, taking adolescents' and parents' ideas about the functions of PS into account.

Mobile Phone Applications Voice Tools and Voice Pitch Analyzer Validated With LingWAVES to Measure Voice Frequency.

OBJECTIVES: Voice frequency can be measured to assess the voice change in transgender men and women during treatment. There are many applications that can analyze voice frequency. This validation study aimed to compare the ability to measure voice frequency of the mobile phone applications "Voice Tools" and "Voice Pitch Analyzer" with the registration program LingWAVES as the gold standard. STUDY DESIGN: Prospective validation study. METHODS: A total of 45 participants of whom 20 transgender individuals were included. They were asked to read "The North Wind and the Sun" twice. The first measurement compared voice frequency measured by Voice Tools with LingWAVES while the second measurement compared Voice Pitch Analyzer with LingWAVES. The two applications that were being compared simultaneously measured the voice frequency. Pearson's regression correlations were performed to test for correlation between the mobile phone applications and LingWAVES. RESULTS: Significant correlations were demonstrated between the measurements of Voice Tools and LingWAVES (P < 0.001) and between Voice Pitch Analyzer and LingWAVES (P < 0.001). Voice Tools overestimated voice frequency with a median deviation of 2Hz (range -4 to 20). The overestimation was more pronounced in the high ranges. Voice Pitch Analyzer showed underestimation of voice frequency in high ranges. Median deviation was -2Hz (range -16 to 14). CONCLUSIONS: This validation study shows that voice frequency can be reliably measured with the mobile phone applications "Voice Tools" and "Voice Pitch Analyzer". Combined with the ease of use, these applications can be used to measure voice frequency in clinical practice and for research purposes.

Continuation of gender-affirming hormones in transgender people starting puberty suppression in adolescence: a cohort study in the Netherlands.

BACKGROUND: In the Netherlands, treatment with puberty suppression is available to transgender adolescents younger than age 18 years. When gender dysphoria persists testosterone or oestradiol can be added as gender-affirming hormones in young people who go on to transition. We investigated the proportion of people who continued gender-affirming hormone treatment at follow-up after having started puberty suppression and gender-affirming hormone treatment in adolescence. METHODS: In this cohort study, we used data from the Amsterdam Cohort of Gender dysphoria (ACOG), which included people who visited the gender identity clinic of the Amsterdam UMC, location Vrije Universiteit Medisch Centrum, Netherlands, for gender dysphoria. People with disorders of sex development were not included in the ACOG. We included people who started medical treatment in adolescence with a gonadotropin-releasing hormone agonist (GnRHa) to suppress puberty before the age of 18 years and used GnRHa for a minimum duration of 3 months before addition of gender-affirming hormones. We linked this data to a nationwide prescription registry supplied by Statistics Netherlands (Centraal Bureau voor de Statistiek) to check for a prescription for gender-affirming hormones at follow-up. The main outcome of this study was a prescription for gender-affirming hormones at the end of data collection (Dec 31, 2018). Data were analysed using Cox regression to identify possible determinants associated with a higher risk of stopping gender-affirming hormone treatment. FINDINGS: 720 people were included, of whom 220 (31%) were assigned male at birth and 500 (69%) were assigned female at birth. At the start of GnRHa treatment, the median age was 14·1 (IQR 13·0-16·3) years for people assigned male at birth and 16·0 (14·1-16·9) years for people assigned female at birth. Median age at end of data collection was 20·2 (17·9-24·8) years for people assigned male at birth and 19·2 (17·8-22·0) years for those assigned female at birth. 704 (98%) people who had started gender-affirming medical treatment in adolescence continued to use gender-affirming hormones at follow-up. Age at first visit, year of first visit, age and puberty stage at start of GnRHa treatment, age at start of gender-affirming hormone treatment, year of start of gender-affirming hormone treatment, and gonadectomy were not associated with discontinuing gender-affirming hormones. INTERPRETATION: Most participants who started gender-affirming hormones in adolescence continued this treatment into adulthood. The continuation of treatment is reassuring considering the worries that people who started treatment in adolescence might discontinue gender-affirming treatment. FUNDING: None.