Dual Actions of Mammalian and Piscine Gonadotropin-Inhibitory Hormones, RFamide-Related Peptides and LPXRFamide Peptides, in the Hypothalamic–Pituitary–Gonadal Axis

Abstract

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of gonadotropin-releasing hormone (GnRH) neurons. GnIH is also called RFamide-related peptide in mammals or LPXRFamide peptide in fishes due to its characteristic C-terminal structure. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. Although most of the studies in mammals, birds, and fish have shown the inhibitory action of GnIH in the hypothalamic–pituitary–gonadal (HPG) axis, several in vivo studies in mammals and many in vivo and in vitro studies in fish have shown its stimulatory action. In mouse, although the firing rate of the majority of GnRH neurons is decreased, a small population of GnRH neurons is stimulated by GnIH. In hamsters, GnIH inhibits luteinizing hormone (LH) release in the breeding season when their endogenous LH level is high but stimulates LH release in non-breeding season when their LH level is basal. Besides different effects of GnIH on the HPG axis depending on the reproductive stages in fish, higher concentration or longer duration of GnIH administration can stimulate their HPG axis. These results suggest that GnIH action in the HPG axis is modulated by sex-steroid concentration, the action of neuroestrogen synthesized by the activity of aromatase stimulated by GnIH, estrogen membrane receptor, heteromerization and internalization of GnIH, GnRH, and estrogen membrane receptors. The inhibitory and stimulatory action of GnIH in the HPG axis may have a physiological role to maintain reproductive homeostasis according to developmental and reproductive stages.

Effects of GnRH and the dual regulatory actions of GnIH in the pituitary explants and brain slices of Astyanax altiparanae males

“…GnIH acts on GnRH neurons modulating the GnRH-induced gonadotropin release (Smith et al, 2012;Ubuka et al, 2012). Nevertheless, the effects of GnIH orthologs in fish seems to be conflicting, because GnIH can either exert stimulatory or inhibitory roles on gonadotropin expression and release (Muñoz-Cueto et al, 2017;Ubuka and Parhar, 2018). In our study, zGnIH-3 (LPXRFa-3 or GnIH-3) showed no effects on the basal expression of male A. altiparanae fshb or lhb mRNA levels.…”

“…To determine whether zGnIH-3 might be acting at the central level to modulate the neuroendocrine system of A. altiparanae males, we evaluated gnrh2 and gnrh3 mRNA levels in brain slices treated either with zGnIH-3 or cGnRH-2 or both combined. To date, most of the reported effects of different GnIH orthologs on brain neuroendocrine systems are inhibitory and seems to be dependent of the route of administration (Muñoz-Cueto et al, 2017;Ubuka and Parhar, 2018). For example, intracerebroventricular injection of sea bass GnIH-2 (sbGnIH-2) reduced gnrh2 expression levels, while the intramuscular administration of the same peptide increased gnrh2 mRNA levels in male European sea bass (Paullada-Salmerón et al, 2016).…”

Editorial: Progress in Reproductive Neuroendocrinology in Vertebrates

“…The article introduces the pathway after visual perception of a potential mate and the rapid change in gonadotropin levels via the GnIH neuronal system in male birds. The fifth review article by Di Yorio et al summarizes what are known and unknown about fish GnIH (24,25). The article emphasizes that teleost is characterized by three round whole genome duplication that could be responsible for the great phenotypic complexity and variability in reproductive strategies and sexual behavior.…”

Ontogeny of gonadotrophin‐inhibitory hormone in the cichlid fish Cichlasoma dimerus

“…Most studies focused on the reproductive function of GnIH and reported both stimulatory and inhibitory effects of the hormone . This dual effect has been proposed to depend on the action of sex‐steroids and neuro‐oestrogens and on the abundance of GnIH, GnRH and oestrogen receptors in the plasmatic membrane …”

“…[6][7][8][9][10][11][12] This dual effect has been proposed to depend on the action of sex-steroids and neuro-oestrogens and on the abundance of GnIH, GnRH and oestrogen receptors in the plasmatic membrane. 13 Little is known about spatial-temporal expression patterns and roles of GnIH during development 1,14 because most published work focused on GnIH anatomical distribution and function in adult vertebrates. [2][3][4][5][6] Even though some studies have evaluated GnIH (gene: gnih) expression during embryonic stages in birds and mammals, [15][16][17] the GnIH system has been examined to a greater extent throughout sexual development and the pre-pubertal period.…”