Effects of disease induced inflammation on reproductive neuroendocrinology in domestic ruminants

Successful reproduction is dependent on the pulsatile release of gonadotropin releasing hormone (GnRH), the final common output from the central nervous system that stimulates luteinizing hormone (LH) secretion to control reproduction. While GnRH, and subsequently LH, is released in an episodic pattern, the “GnRH pulse generator” is believed to be a population of neurons in the arcuate nucleus of the hypothalamus that express kisspeptin, named KNDy neurons. Reproductive success is dependent on various internal and external cues that ultimately regulate GnRH/LH secretion; however, the underlying central mechanisms of inflammation induced suppression of reproduction have yet to be fully elucidated. Chapter I is a review of relevant scientific literature that pertains to the relationship between inflammation and GnRH/LH secretion. Therein, the focus is on the hypothalamic-pituitary-gonadal axis, KNDy neurons, immune response and regulation of GnRH/LH secretion through inflammation. Chapter II focuses on an experiment to elucidate the effects of acute endotoxin-induced inflammation on kisspeptin neurons in adult cows. Chapter III focuses on an experiment to determine the role of cyclooxygenase 1 and 2 in the acute endotoxin induced suppression of reproduction in adult ewes. Chapter IV focuses on an experiment to evaluate the effects of chronic endotoxin induced inflammation on kisspeptin neurons in castrated, male sheep. Each chapter provides a succinct introduction of the current understanding on endotoxin induced suppression of LH secretion and the lack of knowledge surrounding this central regulation in domestic ruminants. Methodologies are provided for our collection and analysis of LH secretion, stress and immune system markers, and immunohistochemistry for reproductively relevant proteins. Chapters II through IV are concluded with discussions of the findings with those of other researchers and considerations of follow-up experiments to strengthen the current studies. In Chapter V, the implications of this research are discussed and a current working model is provided for inflammation induced regulation of GnRH/LH secretion. In addition, it is postulated that a greater understanding of these underlying mechanisms will 1) aid to increase productivity and profitability in domestic livestock and 2) identify targets useful for therapeutic strategies to prevent or lower the risk of infertility in humans.