Kisspeptin and puberty in mammals

Abstract

Since the discovery of the G-protein coupled receptor 54 (kisspeptin receptor) and its ligand, kisspeptin, our understanding of the neurobiological mechanisms that govern the pituitary-gonadal axis has evolved dramatically. In this chapter, we have reviewed progress regarding the relationship between kisspeptin and puberty, and have proposed a novel hypothesis for the role of kisspeptin signaling in the onset of this crucial developmental event. According to this hypothesis, although kisspeptin neurons in the arcuate nucleus (ARC) are critical for puberty, this is simply because these cells are an integral component of the hypothalamic GnRH pulse generating mechanism that drives intermittent release of the decapeptide, as an increase in GnRH is obligatory for the onset of puberty. In our model, ARC kisspeptin neurons play no "regulatory" role in controlling the timing of puberty. Rather, as a component of the neural network responsible for GnRH pulse generation, they subserve upstream regulatory mechanisms that are responsible for the timing of puberty.

Figure 12.1

Developmental increases in kisspeptin-54 (KP-54) release are independent of the presence or absence of the ovary in female monkeys. In vivo KP-54 release from the S-ME of ovarian intact prepubertal (A and B) and pubertal (E and F) monkeys as well as ovariectomized prepubertal (C and D) and pubertal (G and H) monkeys are shown. Samples were obtained during the morning period (A, C, E, and G) and during the evening period (B, D, F and H) as indicated by the open and closed bars, respectively, at the top of each graph. Both pulse frequency and amplitude of KP-54 release in ovarian intact pubertal monkeys (E and F) are higher than those in ovarian intact prepubertal monkeys (A and B). Similarly, pulse frequency and amplitude of KP-54 release in ovariectomized pubertal monkeys (G and H) are higher than those in ovariectomzed prepubertal monkeys (A and B). Importantly, ovariectomy does not cause any change in KP-54 release (A and B vs. C and D) in prepubertal monkeys, whereas ovariectomy increases the pulse amplitude of KP-54 release in pubertal monkeys (E and F vs. G and H). Asterisks indicate peaks as determined by PULSAR. Note that the scale of the y-axis in E, F, G, and H (pubertal monkeys) is 10-fold higher than that in A, B, C, and D (prepubertal monkeys). Modified with permission from 68.

Figure 12.2

A confocal projection illustrating the relationship between kisspeptin neurons (green) in the arcuate nucleus (ARC) and GnRH cell bodies and projections (red) to the median eminence in a coronal section of the mediobasal hypothalamus of a castrated adult male rhesus monkey. VHT, ventral hypothalamic tract; 3V, third ventricle; ME, median eminence. Scale bar, 100 um. Reprinted with permission from 78.

Figure 12.3

A model for the control of the timing of puberty in primates, in which the role of kisspeptin (KP, green) signaling is posited to be a critical component of the neural machinery essential for generation of pulsatile GnRH (red) release in the hypothalamus. In this model, the GnRH pulse generating mechanism resides in the arcuate nucleus (ARC) and the output of this signaling is relayed to GnRH terminals in the median eminence (ME) by KP projections arising from perikarya in the ARC. During infancy (left panel), ARC GnRH pulse generating activity is robust leading to intermittent release of KP in the ME, resulting in a corresponding pattern of GnRH release into the portal circulation. This, in turn, drives pulsatile gonadotropin (LH and FSH) secretion. In the transition from infancy to the juvenile phase of development (middle panel), a neurobiological brake (central inhibition) holds the ARC GnRH pulse generating mechanism in check and pulsatile release of KP in the ME is markedly suppressed. This leads to reduced GnRH release and to a hypogonadotropic state in the juvenile period. Puberty is triggered when the brake is removed and GnRH pulse generation with robust intermittent release of KP in the ME is reactivated (right panel). According to this model, the mystery of primate puberty lies in the nature of the neurobiological brake, i.e., the mechanism that times its application during infancy and its release at the end of the juvenile phase of development. The thickness of the blue (T, testosterone) and gold (E, estradiol) arrows indicating negative feedback by the testis and ovary, respectively, reflect the degree of gonadal steroid inhibition exerted on LH secretion at these three stages of primate development. AC, anterior commissure; AP, anterior pituitary gland, ARC, arcuate nucleus; OC, optic chiasm; ME, median eminence; MMB, mamillary body.

Figure 12.4

A. GABA_A antagonist bicuculline (BM) stimulates KP-54 release in prepubertal female monkeys (but not pubertal monkeys, data not shown). An example showing that bicuculline infusion the S-ME (dark shaded bar) for 10 min induces an increase KP-54 release, whereas vehicle (light shaded bar) infusion does not. B. Blockade of the bicuculline-induced GnRH release by the kisspeptin receptor antagonist, peptide 234 (P234), in a prepubertal monkey. The stimulated GnRH release by bicuculline infusion in the S-ME (dark shaded bars) are not seen in the presence of P234 (light shaded bar). Modified with permission from 91.