PROJECT 2 - Reproductive Hormonal Alterations in Obesity

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Increasing BMI in women is related to worsening hypothalamic-pituitary-ovarian axis function and impaired reproductive performance. We have observed a reduced amplitude of pulsatile LH secretion, inappropriately low FSH secretion for the estradiol and inhibin milieu, and dramatically reduced progesterone metabolite excretion in morbidly obese women. After surgically induced weight loss, these changes only partially reverse, indicating that either obesity resets the reproductive axis or that weight loss into the normal range is not achievable for most obese individuals, even after surgical measures are taken. Based on our preliminary evidence that hypothalamic, pituitary and ovarian levels are all adversely affected by obesity, we have planned a series of experiments to elucidate the mechanisms underlying obesity-induced reproductive axis dysfunction. The following specific aims are proposed: 1. To test the hypothesis that reduced pituitary sensitivity to GnRH-induced LH and FSH secretion causes the relative hypogonadotropic hypogonadism of obesity, we will administer intravenous GnRH and observe endogenous LH and FSH response and gonadotropin clearance (Aim 1a), and will administer exogenous LH after GnRH antagonist blockade to observe LH clearance (Aim 1b) when identical molecular species are administered; 2. To test the hypothesis that the hypothalamic-pituitary axis is abnormally sensitive to estradiol negative feedback, we will administer letrozole to normal weight and obese women and observe the pituitary (LH pulsatillty, GnRH sensitivity and FSH response, Aim 2a) and ovarian response (estradiol, inhibin A and B and Mullerian Inhibiting Substance- -MIS-Aim 2b); 3. To test the hypothesis that the corpus luteum insufficiency observed in obesity is due to a defect in responsiveness to LH, we will examine progesterone production in response to both endogenous and exogenous LH (Aim 3a), examine corpus luteum gene expression profiles in a unique vervet monkey colony before and after exposure to an obesity-inducing diet (Aim 3b) and examine a novel potential defect in LH receptor mRNA processing via mevalonate kinase.