Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep

Endocrinology. 2008 Nov;149(11):5770-82. doi: 10.1210/en.2008-0581. Epub 2008 Jul 10.


Reproductive activity in sheep is seasonal, being activated by short-day photoperiods and inhibited by long days. During the nonbreeding season, GnRH secretion is reduced by both steroid-independent and steroid-dependent (increased response to estradiol negative feedback) effects of photoperiod. Kisspeptin (also known as metastin) and gonadotropin-inhibitory hormone (GnIH, or RFRP) are two RFamide neuropeptides that appear critical in the regulation of the reproductive neuroendocrine axis. We hypothesized that expression of kisspeptin and/or RFRP underlies the seasonal change in GnRH secretion. We examined kisspeptin and RFRP (protein and mRNA) expression in the brains of ovariectomized (OVX) ewes treated with estradiol (OVX+E) during the nonbreeding and breeding seasons. In OVX+E ewes, greater expression of kisspeptin and Kiss1 mRNA in the arcuate nucleus and lesser expression of RFRP (protein) in the dorsomedial nucleus of the hypothalamus were concurrent with the breeding season. There was also a greater number of kisspeptin terminal contacts onto GnRH neurons and less RFRP-GnRH contacts during the breeding season (compared with the nonbreeding season) in OVX+E ewes. Comparison of OVX and OVX+E ewes in the breeding and nonbreeding season revealed a greater effect of steroid replacement on inhibition of kisspeptin protein and Kiss1 mRNA expression during the nonbreeding season. Overall, we propose that the two RFamide peptides, kisspeptin and RFRP, act in concert, with opposing effects, to regulate the activity of GnRH neurons across the seasons, leading to the annual change in fertility and the cyclical seasonal transition from nonbreeding to breeding season.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / physiology
  • Estradiol / pharmacology
  • Female
  • Gene Expression Regulation
  • Gonadotropin-Releasing Hormone / metabolism*
  • Neurons / metabolism
  • Neuropeptides / genetics*
  • Neuropeptides / metabolism
  • Neuropeptides / physiology
  • Ovariectomy
  • Presynaptic Terminals / metabolism*
  • RNA, Messenger / metabolism
  • Reproduction / drug effects
  • Reproduction / genetics
  • Reproduction / physiology*
  • Seasons
  • Sheep / metabolism
  • Sheep / physiology*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology


  • Neuropeptides
  • RFamide peptide
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Gonadotropin-Releasing Hormone
  • Estradiol