Kisspeptin Synchronizes Preovulatory Surges in Cyclical Ewes and Causes Ovulation in Seasonally Acyclic Ewes

Abstract

We determined whether kisspeptin could be used to manipulate the gonadotropin axis and ovulation in sheep. First, a series of experiments was performed to determine the gonadotropic responses to different modes and doses of kisspeptin administration during the anestrous season using estradiol-treated ovariectomized ewes. We found that: 1) injections (iv) of doses as low as 6 nmol human C-terminal Kiss1 decapeptide elevate plasma LH and FSH levels, 2) murine C-terminal Kiss1 decapeptide was equipotent to human C-terminal Kiss1 decapeptide in terms of the release of LH or FSH, and 3) constant iv infusion of kisspeptin induced a sustained release of LH and FSH over a number of hours. During the breeding season and in progesterone-synchronized cyclical ewes, constant iv infusion of murine C-terminal Kiss1 decapeptide-10 (0.48 mumol/h over 8 h) was administered 30 h after withdrawal of a progesterone priming period, and surge responses in LH occurred within 2 h. Thus, the treatment synchronized preovulatory LH surges, whereas the surges in vehicle-infused controls were later and more widely dispersed. During the anestrous season, we conducted experiments to determine whether kisspeptin treatment could cause ovulation. Infusion (iv) of 12.4 nmol/h kisspeptin for either 30 or 48 h caused ovulation in more than 80% of kisspeptin-treated animals, whereas less than 20% of control animals ovulated. Our results indicate that systemic delivery of kisspeptin provides new strategies for the manipulation of the gonadotropin secretion and can cause ovulation in noncyclical females.

Exogenous kisspeptin does not alter photoperiod-induced gonadal regression in Siberian hamsters (Phodopus sungorus)

“…A recent report in sheep indicates that continuous infusion of kisspeptin over 30-48 h stimulates ovulation in the majority of seasonally anestrous sheep (80-86% ovulation) (Caraty et al, 2007). Interestingly though, continuous infusion was unable to maintain elevated levels of LH, dropping after 24 h in kisspeptin infused sheep and displaying similar LH levels as vehicle infused animals after 48 h (Caraty et al, 2007).…”

“…Kisspeptin has been localized to the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (Arc) of mammals (Smith and Clarke, 2007), and seasonal breeders display significantly different kisspeptin expression patterns (as measured by immunohistochemistry and in situ hybridization) in one or both of these nuclei in response to photoperiod or season (Siberian hamster: (Greives et al, 2007;Mason et al, 2007); Syrian hamster: (Revel et al, 2006); Sheep: . Interestingly, although marked photoperiod-induced changes in kisspeptin staining in the hypothalamus are observed, short-term administration of kisspeptin to both reproductive and non-reproductive hamsters and sheep elicits robust elevations in circulating levels of LH (Caraty et al, 2007;Greives et al, 2007), suggesting reproductive regression results from reductions in kisspeptin rather than sensitivity of GnRH neurons to this peptide.…”

“…In a recent study in anestrous sheep, intravenous (i.v.) infusion of kisspeptin transiently elevated circulating LH levels, inducing ovulation, before returning to baseline, (Caraty et al, 2007), and in Syrian hamsters, chronic intracerebroventricular (i.c.v.) exposure to kisspeptin across four weeks via osmotic mini-pump significantly increased gonadal mass in short-day housed, reproductively regressed animals, suggesting that kisspeptin is able to reverse reproductive status in these animals (Revel et al, 2006).…”

Recent advances in reproductive neuroendocrinology: a role for RFamide peptides in seasonal reproduction?

“…Additionally, acute administration of exogenous kisspeptin stimulates the HPG axis in all seasonally breeding mammals studied to date (Messager et al 2005;Revel et al 2006;Caraty et al 2007;Greives et al 2007;Mason et al 2007b); however the effect of prolonged kisspeptin treatment on the HPG axis appears inconsistent. In Siberian hamsters, six weeks of daily kisspeptin injections were unable to alter gonadal state (Greives et al 2008), and continuous kisspeptin (i.e.…”

“…Additionally, kisspeptin infusion initially activates the HPG axis in female acyclic sheep, inducing ovulation; however, exposure to kisspeptin in these sheep over a prolonged period downregulates the HPG axis (i.e. LH levels return to baseline; Caraty et al 2007). The role GnIH plays in short-day breeders has not yet been investigated.…”