Development of Gonadotropin-Releasing Hormone Secretion and Pituitary Response

Abstract

Acquisition of a mature pattern of gonadotropin-releasing hormone (GnRH) secretion from the CNS is a hallmark of the pubertal process. Little is known about GnRH release during sexual maturation, but it is assumed to be minimal before later stages of puberty. We studied spontaneous GnRH secretion in brain slices from male mice during perinatal and postnatal development using fast-scan cyclic voltammetry (FSCV) to detect directly the oxidation of secreted GnRH. There was good correspondence between the frequency of GnRH release detected by FSCV in the median eminence of slices from adults with previous reports of in vivo luteinizing hormone (LH) pulse frequency. The frequency of GnRH release in the late embryonic stage was surprisingly high, reaching a maximum in newborns and remaining elevated in 1-week-old animals despite low LH levels. Early high-frequency GnRH release was similar in wild-type and kisspeptin knock-out mice indicating that this release is independent of kisspeptin-mediated excitation. In vivo treatment with testosterone or in vitro treatment with gonadotropin-inhibitory hormone (GnIH) reduced GnRH release frequency in slices from 1-week-old mice. RF9, a putative GnIH antagonist, restored GnRH release in slices from testosterone-treated mice, suggesting that testosterone inhibition may be GnIH-dependent. At 2-3 weeks, GnRH release is suppressed before attaining adult patterns. Reduction in early life spontaneous GnRH release frequency coincides with the onset of the ability of exogenous GnRH to induce pituitary LH secretion. These findings suggest that lack of pituitary secretory response, not lack of GnRH release, initially blocks downstream activation of the reproductive system.

Molecular, cellular, morphological, physiological and behavioral aspects of gonadotropin-inhibitory hormone

“…These data reveal a central inhibitory effect of RFRP-3 on the hypothalamo-pituitary gonadal axis specifically during the estradiol-induced GnRH/LH surge . In vivo treatment with testosterone or in vitro treatment with GnIH reduced GnRH release frequency in slices from 1-week-old male mice, and RF9 restored GnRH release in slices from testosterone-treated male mice (Glanowska et al, 2014) (Table 1). These results suggest that testosterone inhibition of GnRH release may be GnIH-dependent in male mice (Glanowska et al, 2014).…”

Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats

“…Our data show for the first time the role of kisspeptin antagonist in mediating the effects of RF9 on puberty onset and LH secretion, thus supporting the hypothesis that RF9 actions on reproductive functions are indirectly mediated via kisspeptin/GPR54 signaling in female rats. It has been reported that the GnRH release in response to kisspeptin occurs only in a portion (50%) of brain slices from mice at 1 and 2 weeks of age, whereas RF9 had a consistent effect to increase GnRH release in 100% of preparations tested at 2 weeks of age (Glanowska et al 2014). Therefore, it has been suggested that there is an additional caveat beyond RF9 acting at both GPR147 and GPR74 that is important to consider, and it is possible that RF9 has off-target actions as an agonist on a stimulatory receptor as similarities in C-terminal structure of GnIH with kisspeptin might indicate the kisspeptin receptor as a possible target, which is consistent with our findings.…”

Control of puberty onset and fertility by gonadotropin-releasing hormone neurons

“…For example, the HPG axis can be reactivated during the juvenile hiatus by treatment with neurotransmitters such as glutamate [133][134][135] and kisspeptin 47,136 . Furthermore, when isolated from the rest of the brain and body, in vitro hypothalamic preparations from prepubertal animals can exhibit episodic secretion of GnRH 137,138 .…”