Systematic Review: Puberty suppression with GnRH analogues in adolescents with gender incongruity.

CONTEXT: Gender incongruence is defined as disharmony between assigned gender and gender identity. Several interventions are liable in this case including genital affirming surgery among other surgical interventions such as harmonization, and also the use of gonadotropin-releasing hormone agonists (GnRHa) for gonadal shielding. This aids in preventing the development of secondary sexual characteristics related to the genetic sex. OBJECTIVE: Systematically review the treatment of gender incongruity with GnRHa analogues. DATA SOURCES: The data source of this research is from Pubmed-Medline and Embase. STUDY SELECTION: Articles published between 2009 and 2019 which studied transgender adolescents treated with GnRHa were carefully selected. DATA EXTRACTION: Were extracted: design, sample size, study context, targeted subjects of intervention, outcome measures, and results. RESULTS: Eleven studies were included. The use of GnRHa seems to be well tolerated by the studied population. When started in pubertal transition, it was associated with a more distinct resemblance to body shape than to the affirmed sex. In addition to preventing the irreversible phenotypic changes that occur in cross-hormonal therapy, the use of GnRHa can equally contribute to the mental health of these adolescents. LIMITATION: There are few consistent studies on the use of GnRHa for gender incongruence. CONCLUSION: As the population of transgender children and adolescents grows, they acquire knowledge and greater access to the various forms and stages of treatment for sex reassignment. The medical community needs to be adequately prepared to better serve this population and offer the safest resources available.

Gender Dysphoria, Eating Disorders and Body Image: An Overview.

BACKGROUND: Gender dysphoria is a clinical condition in which a state of inner suffering, stress and anxiety is detected when biological sex and a person's gender identity do not coincide. People who identify themselves as transgender people are more vulnerable and may have higher rates of dissatisfaction with their bodies which are often associated with a disorderly diet in an attempt to change the bodily characteristics of the genus of birth and, conversely, to accentuate the characteristics of the desired sexual identity. AIM: The purpose of this work is to examine the association between dissatisfaction with one's own body and eating and weight disorders in people with gender dysphoria. RESULTS: Gender dysphoria and eating disorders are characterized by a serious discomfort to the body and the body suffers in both conditions. The results of our study suggest that rates of pathological eating behaviors and symptoms related to a disordered diet are high in patients with gender dysphoria and that standard screening for these symptoms must be considered in both populations at the time of evaluation and during the course of the treatment. CONCLUSION: In light of this evidence, clinicians should always investigate issues related to sexuality and gender identity in patients with eating disorders, to develop more effective prevention measures and better strategies for therapeutic intervention.

The effect of GnRH analogue treatment on bone mineral density in young adolescents with gender dysphoria: findings from a large national cohort.

Background More young people with gender dysphoria (GD) are undergoing hormonal intervention starting with gonadotropin-releasing hormone analogue (GnRHa) treatment. The impact on bone density is not known, with guidelines mentioning that bone mineral density (BMD) should be monitored without suggesting when. This study aimed to examine a cohort of adolescents from a single centre to investigate whether there were any clinically significant changes in BMD and bone mineral apparent density (BMAD) whilst on GnRHa therapy. Methods A retrospective review of 70 subjects aged 12-14 years, referred to a national centre for the management of GD (2011-2016) who had yearly dual energy X-ray absorptiometry (DXA) scans. BMAD scores were calculated from available data. Two analyses were performed, a complete longitudinal analysis (n=31) where patients had scans over a 2-year treatment period, and a larger cohort over the first treatment year (n=70) to extend the observation of rapid changes in lumbar spine BMD when puberty is blocked. Results At baseline transboys had lower BMD measures than transgirls. Although there was a significant fall in hip and lumbar spine BMD and lumbar spine BMAD Z-scores, there was no significant change in the absolute values of hip or spine BMD or lumbar spine BMAD after 1 year on GnRHa and a lower fall in BMD/BMAD Z-scores in the longitudinal group in the second year. Conclusions We suggest that reference ranges may need to be re-defined for this select patient cohort. Long-term BMD recovery studies on sex hormone treatment are needed.

Hormone Therapy in Children and Adolescents.

For children and adolescents with gender dysphoria, an interdisciplinary care team is essential for proper diagnosis and appropriate treatment. For children who present with gender dysphoria, once puberty begins, they can be treated with gonadotropin-releasing hormone analogs to stop pubertal progression. This allows for further gender exploration, relief of dysphoria, and better cosmetic outcomes by avoiding the physical changes associated with puberty of the gender assigned at birth. After pubertal suppression, the individual may opt to proceed with puberty or start treatment with gender-affirming hormones.

Transfeminine Hormone Therapy.

Transgender women often seek hormone therapy to attain feminine physical features congruent with their gender identity. The aim of feminizing hormone therapy (FHT) is to provide suppression of endogenous testosterone and to maintain estradiol levels within the normal female range. Overall, FHT is safe if provided under supervision of an experienced health care provider and has been shown to improve quality of life. Data on care of transgender women are scarce and high-quality evidence-based recommendations are lacking. This article aims to review the published literature on FHT and provide guidance to clinicians caring for transgender women.

Transgender medicine - puberty suppression.

Puberty suppression is the reversible first step of endocrine medical treatment in transgender youth, and allows for two very important aspects of transgender management. Firstly, it buys the patient, family and their medical team time to fully evaluate the presence and persistence of gender dysphoria. Secondly, it successfully prevents the development of cis-gender unwanted secondary sexual characteristics. The latter, when present, almost certainly increase the burden of psychological co-morbidity for any transgender person. This management is modelled from treatment of gonadotropin-dependent precious puberty, with use of GnRH agonists at its core. With the increasing number of transgender youth treated, and the changing demographics of patients seeking medical care, providers are faced with the decision to start puberty blockade at younger ages than previous decades. This article will review the rationale behind puberty blockade for transgender children, the providers' options for achieving this goal, the emerging literature for potential adverse effects on such an approach, as well as identify directions of potential future research.

Molecular basis of Gender Dysphoria: androgen and estrogen receptor interaction.

BACKGROUND: Polymorphisms in sex steroid receptors have been associated with transsexualism. However, published replication studies have yielded inconsistent findings, possibly because of a limited sample size and/or the heterogeneity of the transsexual population with respect to the onset of dysphoria and sexual orientation. We assessed the role of androgen receptor (AR), estrogen receptors alpha (ERα) and beta (ERß), and aromatase (CYP19A1) in two large and homogeneous transsexual male-to-female (MtF) and female-to-male (FtM) populations. METHODS: The association of each polymorphism with transsexualism was studied with a twofold subject-control analysis: in a homogeneous population of 549 early onset androphilic MtF transsexuals versus 728 male controls, and 425 gynephilic FtMs versus 599 female controls. Associations and interactions were investigated using binary logistic regression. RESULTS: Our data show that specific allele and genotype combinations of ERß, ERα and AR are implicated in the genetic basis of transsexualism, and that MtF gender development requires AR, which must be accompanied by ERß. An inverse allele interaction between ERß and AR is characteristic of the MtF population: when either of these polymorphisms is short, the other is long. ERß and ERα are also associated with transsexualism in the FtM population although there was no interaction between the polymorphisms. Our data show that ERß plays a key role in the typical brain differentiation of humans. CONCLUSION: ERß plays a key role in human gender differentiation in males and females.

A gender dimorphism in up-regulation of BACE1 gene expression in schizophrenia.

Schizophrenia has long been considered as a devastating brain disorder in which both genetic and environmental factors are involved. The BACE1 gene is one of the most important susceptibility genes for this disorder. However, the changes in BACE1 expression in schizophrenic patients compared with healthy subjects have not been evaluated yet. In this case-control study, we examined BACE1 expression in a group of 50 patients with schizophrenia and 50 healthy controls. The level of BACE1 gene expression was measured using Real-Time PCR. Substantial increase in gene expression was detected in the patients compared with normal individuals (P = 0.001). Furthermore, a gender dimorphism was observed in BACE1 gene expression in the patients in a way that the male patients manifested a statistically significant higher levels of BACE1 expression (P = 0.002). BACE1 might be implicated in the pathogenesis of schizophrenia. Besides, BACE1 physiology may be gender -based at some levels. Our findings warrant an investigation of BACE1 gene in a larger number of cases and controls.

Effects of sex steroids on the pattern of methylation and expression of the promoter region of estrogen and androgen receptors in people with gender dysphoria under cross-sex hormone treatment.

Cross-sex hormone therapy (CHT) is critical for phenotypical and physiological transition in adults with gender dysphoria (GD). However, the impact of the CHT onto the molecular level/epigenetic regulation has not been comprehensively addressed. We postulate that CHT in GD could drive changes at the androgen receptor (AR), estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), affecting their DNA methylation pattern and mRNA expression that may influence in the phenotypical changes associated to CHT. We carried out a prospective observational study on individuals with a diagnosis of GD. 18 subjects (no previous CHT): 12 female to male (FtoM) and 6 male to female (MtoF). An Epityper Mass array TM method was used to study the DNA methylation and Real-time PCR quantitative reverse transcription PCR (qRT-PCR) was used to quantify the gene expression. The analysis of AR, ESR1 and ESR2 receptor was performed at baseline, 6 and 12 months after CHT. No differences in DNA methylation of ESR were found in MtoF, while DNA methylation was increased in FtoM at 6 and 12 months of CHT. The AR showed a significant increase of methylation in MtoF group after 12 months of estrogenic treatment. Regarding the expression analysis, AR expression was significantly decreased in FtoM upon CHT treatment. AR, ESR1 and ESR2 methylation were correlated with anthropometric, metabolic and hormonal parameters in FtoM and MtoF. Our results support that CHT is associated to epigenetic changes that might affect the response to treatment with sex steroids.

12-months metabolic changes among gender dysphoric individuals under cross-sex hormone treatment: a targeted metabolomics study.

Metabolomic analyses in epidemiological studies have demonstrated a strong sexual dimorphism for most metabolites. Cross-sex hormone treatment (CSH) in transgender individuals enables the study of metabolites in a cross-gender setting. Targeted metabolomic profiling of serum of fasting transmen and transwomen at baseline and following 12 months of CSH (N = 20/group) was performed. Changes in 186 serum metabolites and metabolite ratios were determined by targeted metabolomics analysis based on ESI-LC-MS/MS. RandomForest (RF) analysis was applied to detect metabolites of highest interest for grouping of transwomen and transmen before and after initiation of CSH. Principal component analysis (PCA) was performed to check whether group differentiation was achievable according to these variables and to see if changes in metabolite levels could be explained by a priori gender differences. PCA predicted grouping of individuals-determined by the citrulline/arginine-ratio and the amino acids lysine, alanine and asymmetric dimethylarginine - in addition to the expected grouping due to changes in sex steroids and body composition. The fact that most of the investigated metabolites did, however, not change, indicates that the majority of sex dependent differences in metabolites reported in the literature before may primarily not be attributable to sex hormones but to other gender-differences.

Gender identity disorders and multiple sclerosis risk: A national record-linkage study.

BACKGROUND: An altered balance of gonadal hormones in males with gender identity disorders (GIDs) may increase multiple sclerosis (MS) risk both inherently and secondary to treatment in undergoing male-to-female conversion. OBJECTIVE: We investigated any association between GIDs and MS through analysis of record-linked hospital statistics. METHOD: Analysis of English Hospital Episode Statistics, 1999-2012. RESULTS: The adjusted rate ratio (RR) of MS following GIDs in males was 6.63 (95% confidence interval (95% CI) = 1.81-17.01, p = 0.0002). The RR of MS following GIDs in females was 1.44 (95% CI = 0.47-3.37, p = 0.58). CONCLUSION: We report a strong association between GIDs and MS in male-to-females, supporting a potential role for low testosterone and/or feminising hormones on MS risk in males.

A review of the physical and metabolic effects of cross-sex hormonal therapy in the treatment of gender dysphoria.

This review focuses on the effect that cross-gender sex steroid therapy has on metabolic and hormonal parameters. There is an emphasis on those changes that result in significant clinical effects such as the positive effects of the development of secondary sexual characteristics and negative effects such as haemostatic effects and thromboembolism in transwomen or dyslipidaemia in transmen. There is also a description of the current hormonal regimens used at the largest UK gender identity clinic. The overall safety of these treatments in the context of long-term outcome data is reviewed.