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Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.

ABSTRACT: Context:Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders. Case Description:A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone. Conclusion:This case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone-induced luteinizing hormone secretion than does adolescent puberty.

SUBMITTER: Shahab M

PROVIDER: S-EPMC6276658 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.

Shahab Muhammad M Lippincott Margaret M Chan Yee-Ming YM Davies Addie A Merino Paulina M PM Plummer Lacey L Mericq Veronica V Seminara Stephanie S

The Journal of clinical endocrinology and metabolism 20180401 4

<h4>Context</h4>Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders.<h4>Case description</h4>A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented ...[more]

PMID: 29452377

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Project description:BACKGROUND:The neuropeptide kisspeptin stimulates luteinizing hormone (LH) secretion in healthy adults but not in adults with idiopathic hypogonadotropic hypogonadism. We hypothesized that, in children presenting with delayed or stalled puberty, kisspeptin would elicit LH secretion in those children found on detailed nighttime neuroendocrine profiling to have evidence of emerging reproductive endocrine function. METHODS:Eleven boys and four girls were admitted overnight to assess LH secretion at baseline, after a single intravenous bolus of kisspeptin, and after a single intravenous bolus of gonadotropin-releasing hormone (GnRH). Subjects then received exogenous pulsatile GnRH for 6 days and returned for a second visit to measure responses to kisspeptin and GnRH after this pituitary "priming." Responses to kisspeptin and GnRH were also measured in 5 healthy men. RESULTS:Of the 15 children with delayed/stalled puberty, 6 exhibited at least one spontaneous LH pulse overnight; all of these subjects had clear responses to kisspeptin, as did one additional subject. Seven subjects had no response to kisspeptin, and one subject exhibited an intermediate response. In the children who responded to kisspeptin, the responses had features comparable to those of adult men. CONCLUSION:In this first report of kisspeptin administration to pediatric subjects to our knowledge, children with delayed/stalled puberty showed a wide range of responses, with some showing a robust response and others showing little to no response. Further follow-up will determine whether responses to kisspeptin predict future pubertal entry for children with delayed puberty. TRIAL REGISTRATION:ClinicalTrials.gov NCT01438034 and NCT01952782. FUNDING:NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD043341, R01 HD090071, P50 HD028138), NIH National Center for Advancing Translational (UL1 TR001102), NIH National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007028), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery, Harvard Catalyst, Doris Duke Charitable Foundation (award 2013110), Charles H. Hood Foundation, Robert and Laura Reynolds MGH Research Scholar Program, and Harvard University. These funding sources had no role in the design of this study and did not have any role in conducting the study, analyses, interpretation of the data, or the decision to submit results.

Project description:ObjectivePuberty is a key developmental phenomenon highly sensitive to metabolic modulation. Worrying trends of changes in the timing of puberty have been reported in humans. These might be linked to the escalating prevalence of childhood obesity and could have deleterious impacts on later (cardio-metabolic) health, but their underlying mechanisms remain unsolved. The neuropeptide α-MSH, made by POMC neurons, plays a key role in energy homeostasis by mediating the actions of leptin and likely participates in the control of reproduction. However, its role in the metabolic regulation of puberty and interplay with kisspeptin, an essential puberty-regulating neuropeptide encoded by Kiss1, remain largely unknown. We aim here to unveil the potential contribution of central α-MSH signaling in the metabolic control of puberty by addressing its role in mediating the pubertal effects of leptin and its potential interaction with kisspeptin.MethodsUsing wild type and genetically modified rodent models, we implemented pharmacological studies, expression analyses, electrophysiological recordings, and virogenetic approaches involving DREADD technology to selectively inhibit Kiss1 neurons, in order to interrogate the physiological role of a putative leptin→α-MSH→kisspeptin pathway in the metabolic control of puberty.ResultsStimulation of central α-MSH signaling robustly activated the reproductive axis in pubertal rats, whereas chronic inhibition of melanocortin receptors MC3/4R, delayed puberty, and prevented the permissive effect of leptin on puberty onset. Central blockade of MC3/4R or genetic elimination of kisspeptin receptors from POMC neurons did not affect kisspeptin effects. Conversely, congenital ablation of kisspeptin receptors or inducible, DREADD-mediated inhibition of arcuate nucleus (ARC) Kiss1 neurons resulted in markedly attenuated gonadotropic responses to MC3/4R activation. Furthermore, close appositions were observed between POMC fibers and ARC Kiss1 neurons while blockade of α-MSH signaling suppressed Kiss1 expression in the ARC of pubertal rats.ConclusionsOur physiological, virogenetic, and functional genomic studies document a novel α-MSH→kisspeptin→GnRH neuronal signaling pathway involved in transmitting the permissive effects of leptin on pubertal maturation, which is relevant for the metabolic (and, eventually, pharmacological) regulation of puberty onset.

Dataset Information

Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.

Publications

Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.

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