Daniel Klink

Bone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria.

CONTEXT Sex steroids are important for bone mass accrual. Adolescents with gender dysphoria (GD) treated with gonadotropin-releasing hormone analog (GnRHa) therapy are temporarily sex-steroid deprived until the addition of cross-sex hormones (CSH). The effect of this treatment on bone mineral density (BMD) in later life is not known. OBJECTIVE This study aimed to assess BMD development during GnRHa therapy and at age 22 years in young adults with GD who started sex reassignment (SR) during adolescence. DESIGN AND SETTING This was a longitudinal observational study at a tertiary referral center. PATIENTS Young adults diagnosed with gender identity disorder of adolescence (DSM IV-TR) who started SR in puberty and had undergone gonadectomy between June 1998 and August 2012 were included. In 34 subjects BMD development until the age of 22 years was analyzed. INTERVENTION GnRHa monotherapy (median duration in natal boys with GD [transwomen] and natal girls with GD [transmen] 1.3 and 1.5 y, respectively) followed by CSH (median duration in transwomen and transmen, 5.8 and 5.4 y, respectively) with discontinuation of GnRHa after gonadectomy. MAJOR OUTCOME MEASURES How BMD develops during SR until the age of 22 years. RESULTS AND CONCLUSION Between the start of GnRHa and age 22 years the lumbar areal BMD z score (for natal sex) in transwomen decreased significantly from -0.8 to -1.4 and in transmen there was a trend for decrease from 0.2 to -0.3. This suggests that the BMD was below their pretreatment potential and either attainment of peak bone mass has been delayed or peak bone mass itself is attenuated.

Hypothalamic Response to the Chemo-Signal Androstadienone in Gender Dysphoric Children and Adolescents

The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone, we measured the hypothalamic responsiveness to this chemo-signal in 39 pre-pubertal and 41 adolescent boys and girls by means of functional magnetic resonance imaging. We then investigated whether 36 pre-pubertal children and 38 adolescents diagnosed with gender dysphoria (GD; DSM-5) exhibited sex-atypical (in accordance with their experienced gender), rather than sex-typical (in accordance with their natal sex) hypothalamic activations during olfactory stimulation with androstadienone. We found that the sex difference in responsiveness to androstadienone was already present in pre-pubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, pre-pubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and pre-pubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical. We present here a unique data set of boys and girls diagnosed with GD at two different developmental stages, showing that these children possess certain sex-atypical functional brain characteristics and may have undergone atypical sexual differentiation of the brain.

Adolescents with gender dysphoria

Young people with gender dysphoria are increasingly seen by pediatric endocrinologists. Mental health child specialists assess the adolescent and give advice about psychological or medical treatment. Provided they fulfill eligibility and readiness criteria, adolescents may receive pubertal suspension, consisting of using gonadotrophin-releasing hormone analogs, later followed by cross-sex hormones (sex steroids of the experienced gender). If they fulfill additional criteria, they may have various types of gender affirming surgery. Current issues involve safety aspects. Although generally considered safe in the short-term, the long-term effects regarding bone health and cardiovascular risks are still unknown. Therefore, vigilance is warranted during and long after completion of the last gender affirming surgeries. The timing of the various treatment steps is also under debate: instead of fixed age limits, the cognitive and emotional maturation, along with the physical development, are now often considered as more relevant.

Effect of pubertal suppression and cross-sex hormone therapy on bone turnover markers and bone mineral apparent density (BMAD) in transgender adolescents

Puberty is highly important for the accumulation of bone mass. Bone turnover and bone mineral density (BMD) can be affected in transgender adolescents when puberty is suppressed by gonadotropin-releasing hormone analogues (GnRHa), followed by treatment with cross-sex hormone therapy (CSHT). We aimed to investigate the effect of GnRHa and CSHT on bone turnover markers (BTMs) and bone mineral apparent density (BMAD) in transgender adolescents. Gender dysphoria was diagnosed based on diagnostic criteria according to the DSM-IV (TR). Thirty four female-to-male persons (transmen) and 22 male-to-female persons (transwomen)were included. Patients were allocated to a young (bone age of <15years in transwomen or <14 in transmen) or old group (bone age of ≥15years in transwomen or ≥14years in transmen). All were treated with GnRHa triptorelin and CSHT was added in incremental doses from the age of 16years. Transmen received testosterone esters (Sustanon, MSD) and transwomen received 17-β estradiol. P1NP, osteocalcin, ICTP and BMD of lumbar spine (LS) and femoral neck (FN) were measured at three time points. In addition, BMAD and Z-scores were calculated. We found a decrease of P1NP and 1CTP during GnRHa treatment, indicating decreased bone turnover (young transmen 95% CI -74 to -50%, p=0.02, young transwomen 95% CI -73 to -43, p=0.008). The decrease in bone turnover upon GnRHa treatment was accompanied by an unchanged BMAD of FN and LS, whereas BMAD Z-scores of predominantly the LS decreased especially in the young transwomen. Twenty-four months after CSHT the BTMs P1NP and ICTP were even more decreased in all groups except for the old transmen. During CSHT BMAD increased and Z-scores returned towards normal, especially of the LS (young transwomen CI 95% 0.1 to 0.6, p=0.01, old transwomen 95% CI 0.3 to 0.8, p=0.04). To conclude, suppressing puberty by GnRHa leads to a decrease of BTMs in both transwomen and transmen transgender adolescents. The increase of BMAD and BMAD Z-scores predominantly in the LS as a result of treatment with CSHT is accompanied by decreasing BTM concentrations after 24months of CSHT. Therefore, the added value of evaluating BTMs seems to be limited and DXA-scans remain important in follow-up of bone health of transgender adolescents.

Salivary testosterone in female-to-male transgender adolescents during treatment with intra-muscular injectable testosterone esters.

INTRODUCTION In our hospital, female-to-male (FtM) transgender adolescents from the age of 16 are treated with two- or four-weekly intra-muscular injections of testosterone-esters. Some patients treated with four-weekly injections have complaints of fatigue and experience mood swings towards the end of the inter-injection period, which calls for an evaluation of the time-course of testosterone levels between injections. Evaluation of salivary testosterone is a practical approach for sequential measurements. Since only ∼2% of total serum testosterone is present in saliva, a sensitive assay is necessary. The objective was to develop an isotope dilution-liquid chromatography-tandem mass spectrometry method (ID-LC-MS/MS) for salivary testosterone measurements and to evaluate the testosterone profiles after testosterone-ester mixture injections in FtM-adolescents. EXPERIMENTAL FtM treated with 125 mg/2 weeks or with 250 mg/4 weeks depots of testosterone-ester mixture collected saliva at different time intervals. Salivary testosterone was measured by a thoroughly validated ID-LC-MS/MS assay. RESULTS An ID-LC-MS/MS method for measuring salivary testosterone was developed with adequate accuracy and specificity. The reference range was established at 135-400 pmol/L. Testosterone levels peaked supra-physiologically immediately post-injection, and decreased to levels within the male reference range after nine days in all patients. 250 mg/4 weeks depots resulted in values below the reference range at the end of the 4 weeks. DISCUSSION The development of an adequate ID-LC-MS/MS method for measuring salivary testosterone allowed us to investigate the testosterone profile in FtM-adolescents after testosterone-esters mixture injections. These injections lead to extreme concentrations which may affect the wellbeing of the patients.

Click-Evoked Otoacoustic Emissions in Children and Adolescents with Gender Identity Disorder

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds that are produced by the inner ear in response to click-stimuli. CEOAEs generally have a higher amplitude in women compared to men and neonates already show a similar sex difference in CEOAEs. Weaker responses in males are proposed to originate from elevated levels of testosterone during perinatal sexual differentiation. Therefore, CEOAEs may be used as a retrospective indicator of someone’s perinatal androgen environment. Individuals diagnosed with Gender Identity Disorder (GID), according to DSM-IV-TR, are characterized by a strong identification with the other gender and discomfort about their natal sex. Although the etiology of GID is far from established, it is hypothesized that atypical levels of sex steroids during a critical period of sexual differentiation of the brain might play a role. In the present study, we compared CEOAEs in treatment-naïve children and adolescents with early-onset GID (24 natal boys, 23 natal girls) and control subjects (65 boys, 62 girls). We replicated the sex difference in CEOAE response amplitude in the control group. This sex difference, however, was not present in the GID groups. Boys with GID showed stronger, more female-typical CEOAEs whereas girls with GID did not differ in emission strength compared to control girls. Based on the assumption that CEOAE amplitude can be seen as an index of relative androgen exposure, our results provide some evidence for the idea that boys with GID may have been exposed to lower amounts of androgen during early development in comparison to control boys.

What the Primary Care Pediatrician Needs to Know About Gender Incongruence and Gender Dysphoria in Children and Adolescents

The recognition and acknowledgment that gender identity and birth-assigned sex may be incongruent in children and adolescents have evolved in recent decades. Transgender care for children and adolescents has developed and is now more widely available. Controversies exist, however, around clinical management of gender dysphoria and gender incongruence in children and adolescents. Clinical guidelines are consensus based and research evidence is limited. Puberty suppression as part of clinical management has become a valuable element of adolescent transgender care, but long-term evidence of success is limited. These uncertainties should be weighed against the risk of harming a transgender adolescent when medical intervention is denied.

Genetic Aspects of Gender Identity Development and Gender Dysphoria

The development of gender identity, its variance, and gender dysphoria is thought to be a complex process involving biological and psychosocial factors. Heritability studies have demonstrated a genetic factor for the development of gender dysphoria. The brain is regarded as the anatomical substrate of gender identity, and sex differences of the brain are studied to elucidate the process of gender identity development. Many sex differences have been attributed to hormonal action, and the first genetic studies in transsexuals were focused on sex-steroid-related genes. To this day, a convincing candidate gene has not been identified, and it is now known that sex chromosomes have a direct effect on sex differentiation and that they may play a role in gender identity development. For future studies of the genetic base of gender dysphoria, new techniques, such as genome-wide studies, have become available. In addition, epigenetic studies may provide for a different association perspective of the genetics of gender dysphoria.

Bone mineral density in late adolescence of transsexuals treated with GnRH-analogues in their teens

Fig 1. Longitudinal BMD (g/cm2) development of the lumbar spine and hip from start medical treatment to the age of 22 in male-tofemale (MtF) and female-to-male (FtM) transsexuals (± SEM). • Early treatment of young transsexuals is controversial and concerns have raised about peak bone mass. • These first data supports the safety of the treatment protocol. • The study population was heterogeneous regarding factors that may influence BMD such as age and pubertal stage at start of treatment and duration of GnRHa treatment but group size did not allow for correction.