A Critical Role for the Evolutionarily Conserved Gonadotropin-Releasing Hormone II: Mediation of Energy Status and Female Sexual Behavior

GnRH is an evolutionarily conserved neuropeptide, of which there are multiple structural variants; the function of the most widespread variant, GnRH-II, remains undefined. GnRH-II may affect reproductive behavior; GnRH-II administration to female musk shrews reinstates mating behavior previously inhibited by food restriction. To determine whether this action of GnRH-II is universal, we conducted the following studies in mice. Ovariectomized mice were primed with estradiol benzoate and progesterone once a week and tested for sexual behavior. Females showing a lordosis quotient (LQ) of 50 or higher on the fourth trial underwent food deprivation (FD) for either 24 or 48 h before an additional behavior test. FD for 48 h significantly reduced LQ compared with ad libitum-fed females. Next, females were FD for 48 h or maintained on ad libitum feeding and retested for sexual behavior after an intracerebroventricular infusion of either GnRH-I, GnRH-II, or saline. GnRH-II, but not GnRH-I, significantly increased LQ in FD females compared with FD females treated with saline. Lordosis was unaffected by GnRH-II in females maintained on ad libitum feeding. To assess whether the GnRH-I receptor mediates GnRH-II's behavioral effects, underfed females were pretreated with the type 1 GnRH receptor antagonist Antide and retested for sexual behavior. Antide pretreatment did not prevent GnRH-II from promoting mating behavior, suggesting that GnRH-II's behavioral actions are mediated through the type 2 GnRH receptor. We speculate that GnRH-II acts via its own receptor as a regulatory signal in mammals to ensure that reproduction is synchronized with energetically favorable conditions.