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.

Introduction: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50-75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood. Objective: To characterize the clinical and genetic features of a CDGP cohort. Methods: Fiftynine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development. Results: All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior to 18 years of age. The mean clinical follow-up time was 46 ± 28 months. Male predominance (81%), short stature (91%), and family history of delayed puberty (59%) were the main clinical features of this CDGP cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes (IGSF10, GHSR, CHD7, SPRY4, WDR11, SEMA3A, and IL17RD). IGSF10 and GHSR were the most prevalent affected genes in this group. Conclusions: Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in a quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.

Abstract Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD). Here we report thirteen families (twelve autosomal dominant, and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome; KS) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12; and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD; highlight the genetic links between craniofacial patterning and GnRH dysfunction; and begin to assemble the functional network that regulates the development of the GnRH axis.

Testotoxicosis is a rare cause of peripheral precocious puberty in boys caused by constitutively activating mutations of the LHCG receptor. Affected males usually have normal gonadotropin profiles and fertility in their adult life. Here, we described the long-term follow-up of a 24-year-old young man with severe testotoxicosis due to a de novo activating mutation in the third transmembrane helix of the LHCGR (p.Leu457Arg). This patient was treated with different medications, including medroxyprogesterone acetate, ketoconazole, cyproterone acetate and aromatase inhibitor from age 2.5 to 9.5 years. His basal and GnRH-stimulated gonadotropin levels were continually suppressed during and after medical treatment. At adulthood, extremely high serum testosterone levels (>35 nmol/L), undetectable gonadotropin levels (LH < 0.15 IU/L and FSH < 0.6 IU/L) and oligozoospermia were evidenced. Despite his suppressed FSH levels and an unfavorable spermogram, the patient fathered a healthy girl and biological paternity was confirmed through analysis of microsatellites. Spontaneous fertility in a young man with severe testotoxicosis and chronic suppression of FSH levels reinforces the key role of high intratesticular testosterone levels in human spermatogenesis.

Background: The management of youth presenting with delayed puberty is challenging because it can be difficult to predict which children will eventually progress through puberty and which children will not. We have previously shown that exogenous administration of the neuropeptide kisspeptin, which stimulates GnRH release, can be used to probe the integrity of the reproductive endocrine axis. We hypothesized that responses to kisspeptin could predict outcomes for individuals with pubertal delay. Methods: We conducted a longitudinal study of 16 children (3 girls and 13 boys) with delayed or stalled puberty who had undergone stimulation testing with kisspeptin and GnRH. Participants were followed with serial physical examinations and laboratory studies every six months for evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results: “Kisspeptin responders” who had responded to kisspeptin with a rise in LH of 0.8 mIU/mL or greater all subsequently progressed through puberty (n = 8). In contrast, “kisspeptin nonresponders” who had exhibited LH responses to kisspeptin ≤0.4 mIU/mL all reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (p = 0.0002), with sensitivity and specificity of 100% (95% CI 74-100%). Moreover, the kisspeptin-stimulation test outperformed overnight LH measurements, GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion: The kisspeptin-stimulation test can be used to reveal future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty. Trial registration: ClinicalTrials.gov NCT01438034