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Objective: High concentrations of dehydroepiandrosterone sulfate (DHEAS) often precede premature puberty and sometimes polycystic ovary syndrome (PCOS). We hypothesized that the underlying mechanisms might involve DNA methylation. As an indicator of the downstream effects of DHEAS, we looked for associations between prepubertal DHEAS concentration, pubertal progression, and DNA methylation at puberty-related genes in blood cells., Design: Blood methylome and DHEAS concentration at 7.5 and 8.5 years, respectively, were analyzed in 91 boys and 82 girls. Pubertal development data were collected between 8.1 and 17 years (all from UK birth cohort, Avon Longitudinal Study of Parents and Children [ALSPAC])., Methods: Correlation between DHEAS and pubertal measurements was assessed by Spearman's correlation. DHEAS association with methylation at individual CpGs or regions was evaluated by linear regression, and nearby genes examined by enrichment analysis and intersection with known puberty-related genes., Results: Boys and girls with higher childhood DHEAS concentrations had more advanced pubic hair growth throughout puberty; girls also had advanced breast development, earlier menarche, and longer menstrual cycles. DHEAS concentration was associated with methylation at individual CpGs near several puberty-related genes. In boys, 14 genes near CpG islands with DHEAS-associated methylation were detected, and in girls, there were 9 which included LHCGR and SRD5A2; FGFR1 and FTO were detected in both sexes., Conclusions: The association between DHEAS and pubertal development, as reported previously, suggests a physiological connection. Our novel findings showing that DHEAS concentration correlates negatively and linearly with DNA methylation levels at regulatory regions of key puberty-related genes, provide a mechanism for such a functional relationship., Competing Interests: Conflict of interest: The authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective,: To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty., Design and Methods: A bootstrap subsampling and genome-wide association study were performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty., Results: A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner (validation group: Cochran-Armitage trend test: P-value < 1.00E-04; wPRS quartile 2 (Q2) (odds ratio (OR) = 5.00, 95% CI: 1.55-16.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.44-55.83))., Conclusions: This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identification of individuals with a potential genetic risk of early puberty.

Objective: The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied., Design and Methods: Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated., Results: During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (s.d.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P < 0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P < 0.01-0.05)., Conclusions: Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

Objective: Pubertal timing is highly heritable. Observational studies were inconclusive concerning a potential sex-specific difference in the parental contribution, while genome-wide association studies highlighted a heterogeneity in the genetic architecture of pubertal timing between sexes. Our objectives were to evaluate the association of timing of pubertal milestones in offspring with parental pubertal timing and to identify the genetic basis of the heterogeneity., Design: (1.) Population-based mixed cross-sectional/longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) comprising 1381 healthy Danish children including their parents. (2.) UK Biobank-based summary statistics of genetic data on timing of menarche (n = 188 644), voice-break (n = 154 459) and facial hair (n = 161 470)., Methods: (1.) Participants underwent clinical examination(s) including blood sampling. Parental pubertal timing was obtained by questionnaire. Timing of milestones were analyzed using SAS-lifereg. (2.) Genetic correlations between pubertal outcomes were estimated using LD Score regression. Genetic heterogeneity was analyzed using METAL., Results: We observed significant associations of relative parental pubertal timing with timing of pubertal milestones in offspring of concordant sex, that is, fathers/sons (e.g. testicular enlargement: P = 0.004, β = 0.34 years per relative category) and mothers/daughters (e.g. thelarche: P < 0.001, β = 0.45 years per relative category). Fewer milestones were associated with relative parental pubertal timing in offspring of discordant sex compared to concordant sex. Large-scale genetic data highlight both moderate to strong genetic correlations between timing of menarche, voice-break and facial hair. Out of 434 lead single-nucleotide polymorphisms significantly associated with at least one outcome, 39 exhibited a significant genetic heterogeneity between sexes (P < 1.15 × 10-4)., Conclusion: Our results highlight a distinct genetic heterogeneity of pubertal timing between sexes.

Context: 3β-hydroxysteroid dehydrogenase deficiency (3βHSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3βHSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk., Objective: To describe the molecular genetics, the steroid biochemistry, the (immuno-)histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation., Methods: Biochemical, genetic and immunohistochemical investigations on human biomaterials., Results: A 46,XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c.687del27 deletion. At pubertal age, he showed some virilization of the external genitalia and some sex steroid metabolites appeared likely through conversion of precursors secreted by the testis and converted by unaffected HSD3B1 in peripheral tissues. However, he also developed enlarged breasts through production of estrogens in the periphery. Testis histology in late puberty revealed primarily a Sertoli-cell-only pattern and only few tubules with arrested spermatogenesis, presence of few Leydig cells in stroma, but no neoplastic changes., Conclusions: The testis with HSD3B2 deficiency due to the c.687del27 deletion does not express the defective protein. This patient is unlikely to be fertile and his risk for gonadal malignancy is low. Further studies are needed to obtain firm knowledge on malignancy risk for gonads harboring defects of androgen biosynthesis., (© 2015 European Society of Endocrinology.)

Objective: DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia., Case Report: The proband was referred for infertility at the age of 32 years. He reported adrenal insufficiency diagnosed at the age of 19 years. Puberty started at the age of 13 years, with spontaneous virilization, growth spurt, and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length, and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic-pituitary-gonadal axis with normal testosterone and inhibin B; basal and GNRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew, and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild HHG, and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia., Conclusion: Long-term preservation of normal hypothalamic-pituitary-gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.

Puberty is a fascinating developmental phase that involves the attainment of reproductive capacity and the completion of sexual and somatic maturation. As a life-changing event, puberty onset is precisely controlled by interconnected regulatory pathways that are sensitive to numerous endogenous signals and environmental cues. The mechanisms of normal puberty and its potential deviations have been thoroughly studied in humans and model species. Yet, characterization of the neurobiological basis of puberty is still incomplete. Progress on this front is not only relevant from a physiological perspective but would also help to unravel the underlying causes for the observed changes in the timing of puberty in humans, with a trend for earlier puberty onset, especially in girls. In this review, we will provide a synoptic overview of some recent developments in the field that have deepened our understanding of the neuroendocrine and molecular basis for the control of puberty onset. These include not only the demonstration of the involvement of the hypothalamic Kiss1 system in the control of puberty and its modulation by metabolic cues but also the identification of the roles of other neuropeptide pathways and molecular mediators in the regulation of puberty. In addition, the potential contribution of novel regulatory mechanisms, such as epigenetics, in the central control of puberty will be briefly discussed. Characterization of these novel players and regulatory mechanisms will improve our understanding of the basis of normal puberty and its eventual alterations in various pathological conditions.

Background: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic-pituitary-gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown., Subjects and Methods: Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected., Results: Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro., Conclusion: Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible.

Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth., Design and Methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9T>A, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)&#95;(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function., Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen., Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

Objective: Premature ovarian failure (POF) encompasses a heterogeneous spectrum of conditions, with phenotypic variability among patients. The etiology of POF remains unknown in most cases. We performed a global phenotyping of POF women with the aim of better orienting attempts at an etiological diagnosis., Design and Methods: We performed a mixed retrospective and prospective study of clinical, biological, histological, morphological, and genetic data relating to 357 consecutive POF patients between 1997 and 2008. The study was conducted at a reproductive endocrinology referral center., Results: Seventy-six percent of the patients presented with normal puberty and secondary amenorrhea. Family history was present in 14% of the patients, clinical and/or biological autoimmunity in 14.3%. Fifty-six women had a fluctuating form of POF. The presence of follicles was suggested at ultrasonography in 50% of the patients, and observed in 29% at histology; the negative predictive value of the presence of follicles at ultrasonography was 77%. Bone mineral density alterations were found in 58% of the women. Eight patients had X chromosomal abnormalities other than Turner's syndrome, eight other patients evidenced FMR1 pre-mutation. Two other patients had autoimmune polyendocrine syndrome type 2 and 1., Conclusion: A genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort. POF etiology remains most often undiscovered. Novel strategies of POF phenotyping are in such content mandatory to improve the rate of POF patients for whom etiology is identified.