GnRH secretion is critical for normal human reproduction and defects in GnRH secretion contribute to many common reproductive pathologies, including amenorrhea, polycystic ovarian syndrome (PCOS), and infertility associated with anorexia nervosa. Despite the long-standing recognition of the importance and functions of the GnRH neuroendocrine system, a detailed knowledge of the pathways by which the feedback actions of endogenous gonadal steroid hormones are conveyed to GnRH neurons during the ovarian cycle remains elusive. Understanding of the neural substrates responsible for GnRH secretion has been revolutionized in the last few years by identification of two key neuropeptides that are essential for fertility in humans: kisspeptin and neurokinin B (NKB). Work in many laboratories over the last decade has provided a wealth of information on the role of kisspeptin, but it remains unclear whether NKB is also important for either the negative or positive feedback effects of estradiol and progesterone. There is also only rudimentary information on the pathways by which NKB acts to control GnRH secretion. In the current proposal, we will use a combination of physiological, pharmacological, molecular and neuroanatomical approaches to determine if NKB contributes to the control of GnRH secretion by ovarian steroids and to begin identification of the pathways involved. First, we will test the role of NKB in negative feedback by determining which ovarian steroid inhibits NKB expression and the effects of disrupting NKB synthesis or action on episodic LH secretion. Experiments in Aim 2 are based on recent data that NKB actions in the retrochiasmatic area (RCh) contribute to the estrogen-induced LH surge and are mediated by kisspeptin neurons in the arcuate nucleus; they will further test this hypothesis and identify the phenotype of these neurons and the location of the NKB neurons projecting to them. Finally, we will assess the possibility that sexually-dimorphic aspects of NKB input to, or action in, the RCh contribute to the inability of estrogen to induce an LH surge in rams. These questions will be addressed using male and female sheep, an animal model that possesses several unique advantages including the ability to administer reagents to local anatomical areas in the hypothalamus, and an ovarian cycle whose neuroendocrine control closely resembles that of the human menstrual cycle. The proposed studies will provide new information on the physiological roles of NKB in control of LH secretion that may lay the foundation for the development of better treatments for pathological disruptions of reproductive function, and the design of novel contraceptive techniques.

Public Health Relevance

Abnormalities in pulsatile GnRH/LH secretion occur in a number of common reproductive disorders, including amenorrhea, polycystic ovarian syndrome (PCOS), and infertility associated with anorexia nervosa. Disruption of neurokinin B (NKB) signaling leads to infertility in humans, but the precise mechanisms by which NKB controls reproduction are not known. These studies will provide new information on the role of NKB in the negative and positive feedback actions of ovarian steroids and identify neural pathways by which NKB influences GnRH secretion. They may thus lay the foundation for the development of better treatments for pathological disruptions of reproductive function, and may provide the basis for the design of novel contraceptive techniques.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Ravindranath, Neelakanta
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West Virginia University
Schools of Medicine
United States
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