Androgen receptor signaling is crucial for normal female reproduction and hyperandrogenemia is a fundamental aspect of the reproductive disruption seen in Polycystic Ovary Syndrome (PCOS). Either lack of androgen receptor or androgen excess disrupts normal ovulation and neuroendocrine control of female reproduction, but the mechanisms for these effects are unknown. Our overall hypotheses are: 1) androgens acting in the brain and pituitary play an important role in regulating normal female fertility, and2) excess androgens, acting through androgen receptor in the hypothalamus and pituitary, are responsible for the neuroendocrine hallmarks of PCOS: high LH, low FSH, and progesterone (P4) resistance. We will test these hypotheses in a series of three independent but interrelated Aims that focus on the role of physiological androgen signaling and androgen excess in the hypothalamus and pituitary, using a combination of genetic and androgen-excess mouse models. Approaches will utilize genetic manipulation of androgen and P4 signaling in specific cell types in normal female mice and in a novel mouse model of obese PCOS.
Aim 1 will focus on the brain by assessing whether androgen receptor (AR) is required specifically in neurons for normal female reproduction and for the deleterious effects of androgen excess. Using Cre-loxP technology, AR will be selectively deleted from brain neurons, and subsequently specifically from kisspeptin neurons. Females lacking AR in these neurons will be investigated for resistance to the effects of androgen excess in the new PCOS mouse model.
Aim 2 will focus on the pituitary, with the hypothesis that excess androgens act directly at the gonadotrope to dysregulate LH? and FSH? and gonadotropin secretion in females. Female mice lacking AR selectively in the gonadotrope will be studied for altered reproductive function and gonadotropin secretion and in response to excess androgens in the PCOS mouse model. We will use primary pituitary cells in an innovative GnRH pulse system to directly test the actions of androgens on basal and GnRH-induced pulses of LH and FSH and gonadotropin gene expression.
Aim 3 will test whether androgen excess interferes with P4 feedback at the hypothalamus and pituitary, as one attribute of PCOS women is impaired P4 feedback. We will determine if progesterone receptor (PR) is regulated by androgen excess in neuroendocrine tissues and whether P4 feedback is impaired by the actions of excess androgens. We will then remove PR selectively from brain neurons, kisspeptin neurons, or pituitary gonadotropes to investigate which cells mediate P4 negative feedback and the alterations caused by androgen excess. Together, these Aims will elucidate the role of AR and PR in the neuroendocrine system in normal female reproduction and illuminate the role of excess androgens in the dysregulation of neuroendocrine control of reproduction.

Public Health Relevance

Though androgens are often thought of as male hormones, they have important roles in normal female reproduction and in the pathophysiology of Polycystic Ovary Syndrome. The goal of this project is to understand the mechanisms that govern normal and abnormal function of the female hypothalamic-pituitary- ovarian axis utilizing sophisticated genetic mouse models and a mouse model of Polycystic Ovary Syndrome. These studies will delineate the role of androgen and progesterone receptors in neuroendocrine control of normal female reproduction and in conditions of androgen excess causing impaired progesterone negative feedback to establish the role of androgens in female reproductive physiology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ravindranath, Neelakanta
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University of California, San Diego
Obstetrics & Gynecology
Schools of Medicine
La Jolla
United States
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