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