Pubertal development in 46,XY patients with NR5A1 mutations

Purpose Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. Methods We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. Results Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. Conclusion Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.

On-Time Maturation in Female Adolescent Ballet Dancers: Learning From Lived Experiences

This study employed semi-structured interviews and Interpretative Phenomenological Analysis to explore experiences of on-time maturation in nine adolescent ballet dancers from across three vocational ballet schools in the United Kingdom. Two themes were identified as central to their experiences: ‘A right and a wrong way to grow’, and fitting in and moving forward. Instead of perceiving themselves as ‘average’ and experiencing a relatively easy pubertal transition, on-time dancers described unique challenges associated with a fluctuation between fitting in and not fitting in within their social context. The implications of on-time maturation in this context are complex and do not appear to follow the same trajectory as early maturing ballet dancers nor on-time non-dancers.

Joint trajectories of life style indicators and their links to psychopathological outcomes in the adolescence

Background Rapid socio-economic development makes China a unique laboratory for examining how lifestyle changes affect adolescent mental health. This study aims to identify joint trajectories of modifiable lifestyle indicators during pubertal transition and its associations with psychopathological outcomes. Methods A cohort of 1974 children aged 7–9 years were recruited in Anhui Province, China during March 2013. The assessment of lifestyle behaviors (screen time, physical activity, sleep duration and beverage intake) and depressive symptoms were conducted from Wave 1 to Wave 4 (2018). Suicide ideation, non-suicidal self-harm (NSSI) and alcohol use were self-reported at Wave 4. Longitudinal trajectories of lifestyle patterns were defined using group-based multi-trajectory models in 2019. Results Four lifestyle trajectories were identified: persistent healthy (39.9%), suboptimal healthy (25.3%), unhealthy mitigation (17.2%), and persistent unhealthy (17.7%). Compared with persistent healthy group, the risk of subsequent suicide ideation [odds ratio (OR): 2.86, 95%CI: 2.15–3.81], depressive symptoms (OR: 2.16, 95%CI: 1.39–3.35), alcohol use (OR: 2.53, 95%CI: 1.78–3.61) and non-suicidal self-harm (OR: 1.35, 95%CI: 1.09–1.67) was significantly higher in persistent unhealthy group. Conclusions This study provided convincing evidence that unhealthy lifestyle trajectory during adolescence is associated with more than two-fold elevated odds for multiple domains of psychopathological outcomes over 5 years.

Immature Follicular Origins and Disrupted Oocyte Growth Pathways Contribute to Decreased Gamete Quality During Reproductive Juvenescence in Mice

Egg quality dictates fertility outcomes, and although there is a well-documented decline with advanced reproductive age, how it changes during puberty is less understood. Such knowledge is critical, since advances in Assisted Reproductive Technologies are enabling pre- and peri-pubertal patients to preserve fertility in the medical setting. Therefore, we investigated egg quality parameters in a mouse model of the pubertal transition or juvenescence (postnatal day; PND 11–40). Animal weight, vaginal opening, serum inhibin B levels, oocyte yield, oocyte diameter, and zona pellucida thickness increased with age. After PND 15, there was an age-associated ability of oocytes to resume meiosis and reach metaphase of meiosis II (MII) following in vitro maturation (IVM). However, eggs from the younger cohort (PND 16–20) had significantly more chromosome configuration abnormalities relative to the older cohorts and many were at telophase I instead of MII, indicative of a cell cycle delay. Oocytes from the youngest mouse cohorts originated from the smallest antral follicles with the fewest cumulus layers per oocyte, suggesting a more developmentally immature state. RNA Seq analysis of oocytes from mice at distinct ages revealed that the genes involved in cellular growth signaling pathways (PI3K, mTOR, and Hippo) were consistently repressed with meiotic competence, whereas genes involved in cellular communication were upregulated in oocytes with age. Taken together, these data demonstrate that gametes harvested during the pubertal transition have low meiotic maturation potential and derive from immature follicular origins.

Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of the role of puberty

Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize the importance of considering multidimensional factors in understanding risk for suicidal thoughts and behaviors (STBs) during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal events that occur during puberty have significant effects on the organization and development of brain systems implicated in the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing, warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more effective, sex-specific, psychiatric interventions for adolescents.

Metabolomic Profiling in Response to an Oral Glucose Tolerance Test Reveals Pathways Associated With Obesity and Insulin Resistance During the Pubertal Transition

Objectives To reveal alterations in metabolic pathways in response to an oral glucose tolerance test (OGTT) underlying the development of insulin resistance during the pubertal transition. Methods Participants were recruited as healthy controls (HC, n = 55, aged 8.3–18.0 years, BMI percentile 5–85%) and overweight and obese individuals (OVOB, n = 228, aged 8.1–17.9 years, BMI percentile ≥ 85%). Participants were grouped based on their peak insulin response to the OGTT, stratified by peak at t30 (Group 1, n = 163), t60 (Group 2, n = 75), and t120 minutes (Group 3, n = 44). Untargeted metabolomics profiled 267 annotated metabolites and > 3000 unannotated features in plasma at t0 and t60 minutes. Regression classified changes in metabolites across the time-course, assessing the influence of BMI and insulin response (FDR < 0.05). The connectivity of the metabolome was determined using differential network enrichment analysis (DNEA), stratified by insulin response group. Results At fasting, 32% of the metabolites differed between HC and OVOB, including elevated kynurenine, leucine/isoleucine, methionine, tyrosine, short-chain acylcarnitines, and diacylglycerols in OVOB. At t60, only 4% of the metabolites differed between HC and OVOB participants, suggesting a “normalization” of the metabolome, with exceptions of acylcarnitines and FA oxidation (FAO) intermediates. Although no metabolites differed significantly between insulin response group, differential subnetworks were observed, including increased connectivity between FA and FAO intermediates in Group 1 at t60, suggesting differential regulation in post-prandial FAs. Conclusions Profiling the metabolome response to an OGTT may highlight metabolic dysfunction prior to type 2 diabetes and will be used in future longitudinal analyses predicting insulin resistance trajectory. Funding Sources The National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institutes of Health

Alternative Splicing Dynamics of the Hypothalamus–Pituitary–Ovary Axis During Pubertal Transition in Gilts

The timing of puberty in mammals marks the point at which reproduction becomes possible. Abnormalities in the timing of puberty may exert a series of negative effects on subsequent health outcomes. Alternative splicing (AS) has not only emerged as a significant factor in the transcription of genes but it is also reported to play a role in the timing of puberty. However, to date, the changes and dynamics of AS during the onset of puberty is extremely seldom explored. In the present study, we used gilts as a research model to investigated the dynamics of AS and differentially expressed AS (DEAS) events within the hypothalamus–pituitary–ovary (HPO) axis across pre-, in-, and post-puberty. We detected 3,390, 6,098, and 9,085 DEAS events in the hypothalamus, pituitary, and ovary when compared across pre-, in-, and post-pubertal stages, respectively. Within the entire HPO axis, we also identified 22,889, 22,857, and 21,055 DEAS events in the pre-, in-, and post-pubertal stages, respectively. Further analysis revealed that the differentially spliced genes (DSGs) associated with staged DEAS events were likely to be enriched in the oxytocin signaling pathway, thyroid hormone signaling pathway, GnRH signaling pathway, and oocyte meiosis signaling pathway. The DSGs associated with DEAS events across the entire HPO axis were enriched in endocytosis signaling pathway, the MAPK signaling pathway, and the Rap1 signaling pathway. Moreover. the ASs of TAC1, TACR3, CYP19A1, ESR1, ESRRA, and FSHR were likely to regulate the functions of the certain HPO tissues during the onset of puberty. Collectively, the AS dynamics and DEAS events were comprehensively profiled in hypothalamus, pituitary, and ovary across the pre-, in-, and post-pubertal stages in pigs. These findings may enhance our knowledge of how puberty is regulated by AS and shed new light on the molecular mechanisms underlying the timing of puberty in mammals.

Resolution of Severe Anorexia Nervosa Associated with Gender Dysphoria (Dysphorexia) by Testosterone Therapy in Two Male Transgender Youth

Anorexia nervosa is a severe and potentially lethal eating disorder. In transgender youth with severe gender dysphoria, a severe eating disorder (proposed name: dysphorexia), coherent with anorexia nervosa may be triggered by the desire to avoid the cisgender pubertal transition. In these patients, gender-affirming hormone therapy can be extremely effective. We report hereby the cases of two female-to-male transsexual patients with severe gender dysphoria whose anorexia nervosa was related to their pubertal development and who promptly recovered when they started gender-affirming hormone therapy with testosterone, after very limited success with standard psychotherapy and pharmacotherapy for anorexia nervosa. Our patients could not access pubertal suppression due to lack of parental consent in one case and failure to express the conflict in the other. We postulate that avoiding the cisgender pubertal transition with GnRH agonist treatment might also be able to prevent the development of dysphorexia.