Central RFRP-3 Stimulates LH Secretion in Male Mice and Has Cycle Stage–Dependent Inhibitory Effects in Females

Abstract

RFamide-related peptide (RFRP)-3 is a neuropeptide thought to play an inhibitory role in the regulation of reproduction in various mammalian species, although some stimulatory effects have been reported. To date, the effects of RFRP-3 on gonadotropin secretion have been scarcely studied in mice. The aim of the current study was to characterize the effect of RFRP-3 administration on gonadotropin secretion in male and female mice. Adult intact and castrated male mice received acute central injections of 0.5 to 5 nmol of RFRP-3, and luteinizing hormone (LH) concentration was assayed in tail-tip blood samples. RFRP-3 had a dose-dependent stimulatory effect on LH secretion when administered centrally to both intact and castrated mice, and this effect was diminished when RFRP-3 was administered to kisspeptin receptor knockout mice. In female mice, central RFRP-3 had an inhibitory effect on LH secretion when administered at the time of the preovulatory LH surge in intact mice, or of an estradiol-induced LH surge in ovariectomized mice. Conversely, central RFRP-3 administration had no effect on LH levels in intact diestrus or ovariectomized, low-dose estradiol-implanted mice. Finally, peripheral administration of RFRP-3 to intact males and to females at the time of the preovulatory LH surge or during diestrus had no effect on LH secretion. Taken together, these results provide a detailed description of sex- and cycle stage-dependent effects of RFRP-3 on gonadotrophin secretion in mice. Moreover, it appears that the stimulatory effects are mediated in part by the receptor for kisspeptin, a potent stimulator of the reproductive axis.

Gonadotrophin‐inhibitory hormone and its mammalian orthologue RFamide‐related peptide‐3: Discovery and functional implications for reproduction and stress

“…For example, RFRP‐3 inhibits the release of LH in female Syrian hamsters but stimulates LH in males . The stimulatory effect of RFRP‐3 on LH secretion in males was also recently observed in mice . In male Siberian hamsters, RFRP‐3 is inhibitory in LD animals but stimulatory in SD hamsters .…”

“…Across mammals, including humans, RFRP‐3, generally inhibits gonadotrophin synthesis and/or release . However, RFRP‐3 stimulates gonadotrophin secretion in some contexts, dependent on sex, season and/or reproductive status . These disparate effects of RFRP‐3 are a result of the fact that GPR147 can be coupled to either Gα i , Gα s or Gα q proteins, and this coupling may differ by sex and/or reproductive status in some species .…”

“…The suppression of RFRP‐3 at the time of the surge appears to be common across mammalian species. In mice, RFRP‐3 inhibits LH secretion when administered at the time of the preovulatory LH surge in intact mice, or during an oestradiol‐induced LH surge in ovariectomised mice . In rats, Rfrp mRNA is lower during pro‐oestrus than during dioestrus and treatment with RFRP‐3 during pro‐oestrus suppresses GnRH cellular activity .…”

Expression of genes for Kisspeptin ( KISS1 ), Neurokinin B ( TAC3 ), Prodynorphin ( PDYN ), and gonadotropin inhibitory hormone ( RFRP ) across natural puberty in ewes

“…On the other hand, RFRP expression changes with development in rodents, with a postnatal rise, a peak in expression at the time of puberty, and a decline in adulthood in both rats and mice (Iwasa et al, 2012; Poling, Kim, Dhamija, & Kauffman, 2012; Quennell, Rizwan, Relf, & Anderson, 2010). Strangely, RFRP‐3 stimulates LH secretion in male mice but is inhibitory in females (Ancel, Inglis, & Anderson, 2017). How this relates to control of the onset of puberty in either sex is not clear.…”

Time‐of‐day‐dependent sensitivity of the reproductive axis to RFamide‐related peptide‐3 inhibition in female Syrian hamsters

“…If true, then LH concentrations should be inhibited by RFRP‐3 in the morning but not (or to a greater degree than) in the afternoon. However, it is also possible that the GnRH system is maximally responsive to RFRP‐3 in the afternoon, because this is a time during which RFRP‐3 neurones are transiently inactive . If it is the case that maximal responsiveness of the GnRH system occurs in the afternoon, then LH concentrations should be inhibited by RFRP‐3 in the afternoon but not (or to a greater degree than) in the morning.…”