Advanced vaginal opening and precocious activation of the reproductive axis by KiSS‐1 peptide, the endogenous ligand of GPR54

Abstract

The awakening of the gonadotrophic axis at puberty is the end-point of a complex cascade of sex developmental events that leads to the attainment of reproductive capacity. Recently, loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been linked to hypogonadotrophic hypogonadism, both in rodents and humans. However, the actual role of the KiSS-1/GPR54 system in the timing of puberty onset remains unexplored. We report herein that chronic central administration of KiSS-1 peptide to immature female rats induced the precocious activation of the gonadotrophic axis, as estimated by advanced vaginal opening, elevated uterus weight, and increased serum levels of luteinizing hormone (LH) and oestrogen. The central effect of KiSS-1 upon LH release appeared to be mediated via the hypothalamic LH-releasing hormone. In contrast, despite the well-documented permissive role of body fat stores and the adipocyte-derived hormone leptin in puberty maturation, acute activation of the gonadotrophic axis by KiSS-1 was persistently observed in pubertal animals under food deprivation, after central immunoneutralization of leptin, and in a model of leptin resistance. Overall, the present results, together with our recent data on maximum expression of KiSS-1 and GPR54 genes in the hypothalamus at puberty, provide novel evidence for a role of the KiSS-1 system as a downstream element in the hypothalamic network triggering the onset of puberty.

Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons

“…Ablation of the GPR54 (12, 13) or the Kiss1 (13, 14) gene renders mice of either sex hypogonadotropic and infertile. Kisspeptin is a powerful GnRH secretagogue (15,16), and kisspeptin administration advances puberty onset (17,18), whereas GPR54 antagonists delay puberty onset (19). These data provide compelling support for the idea that activation of kisspeptin neurons precipitates the pubertal stimulation of GnRH neurosecretion.…”

Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling

“…Matsui et al (2004) demonstrated that peripheral administration of kisspeptin to prepubertal, 25-day-old female rats stimulates LH secretion and induces ovulation in the rat. Shortly thereafter, Navarro et al (2004aNavarro et al ( , 2004b demonstrated a similar effect of kisspeptin on LH secretion in prepubertal male rats and showed that kisspeptins could advance the timing of vaginal opening in females. If kisspeptins trigger puberty onset, one would expect to see an increase in KiSS-1 mRNA and/or GPR54 mRNA expression during this time.…”

Role of leptin in female reproduction

“…However, GnRH neurons in the preoptic area do not express LEPR-b, indicating that leptin indirectly regulates these cells by acting on interneurons upstream of GnRH neurons. In fact, GnRH cell bodies are not affected by leptin directly [31] and other neuropeptides (target for leptin), such as NPY [32,33] and kisspeptin [30,[34][35][36] and proopiomelanocortin (POMC) [35] could mediate the action of leptin. In addition to the stimulatory effect on the HPG axis at the hypothalamic level, leptin has direct effects on the anterior pituitary as well [37].…”