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This study assessed psychosocial functioning for 2 years after the initiation of gender-affirming hormones in transgender and nonbinary youth. Hormone therapy improved appearance congruence and psychosocial functioning.

Abstract Context The decision whether to treat a child with delayed puberty with sex steroids is primarily based on patient, family, and provider preference. Knowing when children with constitutional delay eventually enter puberty would inform this decision. Objective, Design, Setting, Participants, and Outcome Measures To estimate and compare rates of pubertal entry, we conducted a retrospective cohort study by reviewing medical records of children evaluated for delayed puberty at a large academic medical center between 2000 and 2015, extracting data on pubertal status for all clinical visits, then conducting time-to-event analyses. Results Of 392 girls and 683 boys with delayed puberty, constitutional delay was the most common cause, found in 32% of girls and 70% of boys. In a subcohort of 97 girls and 243 boys who were prepubertal at one or more visits, we observed a broad age range for pubertal entry, up to >16 years for girls and >17 years for boys. The probability of entering puberty within the next year for 12- to 15.5-year-old girls and 13.5- to 16.5-year-old boys with delayed puberty ranged between 38% and 74%. No differences in the rates of pubertal entry were seen between girls and boys after data harmonization. Conclusion The broad range of ages at pubertal entry for children with constitutional delay challenges the concept that constitutional delay is merely an extreme of normal variation. Discussions with patients and families about management should consider the possibility that some children may need to wait years after presentation until puberty starts.

Abstract Context Variation in pubertal timing is associated with a wide range of adult risks and outcomes, but it is unclear whether these associations are causal, and it is largely unknown whether these associations can be modified by treatment. Evidence Acquisition We conducted PubMed searches to identify Mendelian randomization (MR) studies on the influence of pubertal timing on adult health and studies on sex-steroid treatment of the following conditions associated with reduced reproductive endocrine function in adolescence: constitutional delay, Turner syndrome, and Klinefelter syndrome. Evidence Synthesis Results of MR studies suggest that earlier pubertal timing increases body mass index; increases risk for breast, ovarian, endometrial, and prostate cancers; elevates fasting glucose levels and blood pressure; impairs lung capacity and increases risk for asthma; leads to earlier sexual intercourse and first birth; decreases time spent in education; and increases depressive symptoms in adolescence. Later pubertal timing appears to lower bone mineral density (BMD). Although studies of constitutional delay have not shown that sex-steroid treatment alters adult height or BMD, studies of girls with Turner syndrome and boys with Klinefelter syndrome suggest that earlier initiation of sex-steroid treatment improves physical and neurocognitive outcomes. Conclusions Despite having some limitations, MR studies suggest that pubertal timing causally influences many adult conditions and disease risks. Studies of Turner syndrome and Klinefelter syndrome suggest that earlier sex-steroid exposure may have short- and long-term benefits. The mechanisms underlying these findings and the effects of trends and treatments affecting pubertal timing remain to be determined. This article explores how pubertal timing affects adult outcomes by reviewing findings from Mendelian randomization studies and studies of sex-steroid treatment of adolescent hypogonadal conditions.

The American Psychological Association defines gender identity as, “A person’s deeply-felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender (e.g., genderqueer, gender nonconforming, gender neutral) that may or may not correspond to a person’s sex assigned at birth or to a person’s primary or secondary sex characteristics” (American Psychological Association, Am Psychol 70(9):832–864, 2015). Here we review the evidence that gender identity and related socially defined gender constructs are influenced in part by innate factors including genes. Based on the data reviewed, we hypothesize that gender identity is a multifactorial complex trait with a heritable polygenic component. We argue that increasing the awareness of the biological diversity underlying gender identity development is relevant to all domains of social, medical, and neuroscience research and foundational for reducing health disparities and promoting human-rights protections for gender minorities.

The hypothalamic–pituitary–gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic–pituitary–gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development. Male hypogonadism is a disorder associated with low testosterone levels and impaired spermatogenesis. The condition can arise from inherent defects in the testes or abnormalities in the regulation of testosterone secretion at the hypothalamic or pituitary level. This Primer summarizes the conditions that can lead to hypogonadism in boys and men.

Abstract Context The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis. Objective We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay. Design, Setting, and Participants We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty. Intervention and Outcome Measures Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.

This report ascribes ataxia and hypogonadism to mutations affecting two proteins in a ubiquitination pathway, which affects the cellular disposal of specific proteins. In recent years, we have seen great advances in the elucidation of genetic causes of cerebellar ataxia, with newly identified genes regulating a wide spectrum of cellular functions, including intracellular signaling, tau regulation, and mitochondrial function. 1 However, a genetic defect cannot be found in approximately 40% of patients with ataxia, 1 including those in whom ataxia is associated with reproductive endocrine failure, a syndrome first reported by Gordon Holmes in 1908. 2 Most patients with this syndrome have a hypogonadotropic condition, with defective secretion of gonadotropins by the pituitary gland. 3 – 12 Strikingly, genes associated with ataxia have little functional overlap with genes . . .

Abstract Context Polycystic ovary syndrome (PCOS) has historically been conceptualized as a disorder of the reproductive system in women. However, offspring of women with PCOS begin to show metabolic features of PCOS in childhood, suggestive of childhood manifestations. Objective To identify childhood manifestations of genetic risk for PCOS. Methods We calculated a PCOS polygenic risk score (PRS) for 12 350 girls and boys in 4 pediatric cohorts—ALSPAC (UK), COPSAC (Denmark), Project Viva (USA), and The HOLBÆK Study (Denmark). We tested for association of the PRS with PCOS-related phenotypes throughout childhood and with age at pubarche and age at peak height velocity and meta-analyzed effects across cohorts using fixed-effect models. Results Higher PRS for PCOS was associated with higher body mass index in midchildhood (0.05 kg/m2 increase per 1 SD of PRS, 95% CI 0.03, 0.07, P = 3 × 10−5) and higher risk of obesity in early childhood (OR 1.34, 95% CI 1.13, 1.59, P = .0009); both persisted through late adolescence (P all ≤.03). Higher PCOS PRS was associated with earlier age at pubarche (0.85-month decrease per 1 SD of PRS, 95% CI −1.44, −0.26, P = .005) and younger age at peak height velocity (0.64-month decrease per 1 SD of PRS, 95% CI −0.94, −0.33, P = 4 × 10−5). Conclusion Genetic risk factors for PCOS are associated with alterations in metabolic, growth, and developmental traits in childhood. Thus, PCOS may not simply be a condition that affects women of reproductive age but, rather, a possible manifestation of an underlying condition that affects both sexes starting in early life.

Transgender children and adolescents (ie, those who experience incongruence between assigned sex at birth and internal gender identity) are poorly understood and an understudied population in the United States. Since 2008, medical care for transgender youth has generally followed guidelines developed by professional consensus, given the paucity of empirical research, particularly in the US setting. The objective of this research was to provide evidence-based data to inform clinical care for transgender youth. The study aims (1) to evaluate the impact of gonadotropin-releasing hormone agonists administered for puberty suppression on mental health, psychological well-being, and metabolic and physiologic parameters including bone health in a cohort of children and adolescents (Tanner stages 2-4) with gender dysphoria, comparing baseline and follow-up assessments, and (2) to determine the impact of gender-affirming hormones (eg, estradiol and testosterone) administered for phenotypic gender transition on mental health, psychological well-being, and metabolic and physiologic parameters in a cohort of adolescents with gender dysphoria, comparing baseline and follow-up assessments. The study uses a longitudinal observational design to examine the outcomes of existing medical treatment protocols for gender dysphoria in two distinct cohorts: youth initiating puberty suppression and youth pursuing a phenotypic gender transition. Data on routine anthropometric and physiologic parameters are collected through chart abstraction, questionnaires, and research interviews in the 24-month study period. Audio computer-assisted self-interview and individual interview survey instruments are used to collect demographic, mental health, psychosocial, and behavioral data from parents and youth in the blocker cohort and only from youth in the gender-affirming hormone cohort at baseline and 6, 12, 18, and 24 months. Participant recruitment commenced in July 2016, and enrollment was completed in September 2018. A total of 90 participants were enrolled in the blocker cohort and 301 participants were enrolled in the gender-affirming hormone cohort. Findings based on baseline data are expected to be submitted for publication in 2019. This longitudinal, observational study is collecting critical data on the existing models of care for transgender youth that have been used in clinical settings for close to a decade, although with limited empirical research to support them. This research is a direct response to the Institute of Medicine report calling for such studies as well as the needs of clinicians and patients. Results from this study have the potential to significantly impact the medical and mental health services provided to transgender youth by making available rigorous scientific evidence on the impact and safety of early treatment based on the sexual development stage. Ultimately, we aim to understand if early medical intervention reduces the health disparities well known to disproportionately affect transgender individuals across their lifespan. PRR1-10.2196/14434.

BackgroundA constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy.MethodsWhole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort.ResultsFour individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance.ConclusionsThese findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.