Seasonal variation in the gonadotropin-releasing hormone response to kisspeptin in sheep: Possible kisspeptin regulation of the kisspeptin receptor

Kisspeptin signaling in the hypothalamus appears critical for the onset of puberty and driving the reproductive axis. In sheep, reproduction is seasonal, being activated by short days and inhibited by long days. During the non-breeding (anestrous) season, gonadotropin-releasing hormone (GnRH) and gonadotropin secretion is reduced, as is the expression of Kiss1 mRNA in the brain. Conversely, the luteinizing hormone response to kisspeptin during this time is greater. To determine whether the GnRH response to kisspeptin is increased during anestrus, we utilized hypophysial portal blood sampling. In anestrus ewes, the GnRH and LH responses to kisspeptin were greater compared to the breeding season (luteal phase). To ascertain whether this difference reflects a change in Kiss1r, we measured its expression on GnRH neurons using in situ hybridization. The level of Kiss1r was greater during the non-breeding season compared to the breeding season. To further examine the mechanism underlying this change in Kiss1r, we examined Kiss1r/GnRH expression in ovariectomized ewes (controlling for sex steroids) during the breeding and non-breeding seasons, and also ovariectomized non-breeding season ewes with or without estradiol replacement. In both experiments, Kiss1r expression on GnRH neurons was unchanged. Finally, we examined the effect of kisspeptin treatment on Kiss1r. Kiss1r expression on GnRH neurons was reduced by kisspeptin infusion. These studies indicate the kisspeptin response is indeed greater during the non-breeding season and this may be due in part to increased Kiss1r expression on GnRH neurons. We also show that kisspeptin may regulate the expression of its own receptor.