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.

Public Health Relevance

These studies are expected to elucidate mechanisms by which obesity, a highly prevalent and difficult-totreat problem in the USA, contributes to involuntary infertility-another highly prevalent problem. By highlighting the chronic hormone changes linked to a high BMI in women, these studies may also help explain how hormones contribute to other serous disease associated with obesity, such as breast and endometrial cancer.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Albert Einstein College of Medicine
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Roth, Lauren W; Allshouse, Amanda A; Bradshaw-Pierce, Erica L et al. (2014) Luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight women. Clin Endocrinol (Oxf) 81:418-25
Neal-Perry, Genevieve; Yao, Dachun; Shu, Jun et al. (2014) Insulin-like growth factor-I regulates LH release by modulation of kisspeptin and NMDA-mediated neurotransmission in young and middle-aged female rats. Endocrinology 155:1827-37
Ross, Lauren A; Polotsky, Alex J; Kucherov, Alexander et al. (2014) Profound reduction of ovarian estrogen by aromatase inhibition in obese women. Obesity (Silver Spring) 22:1464-9
Roth, Lauren W; Bradshaw-Pierce, Erica L; Allshouse, Amanda A et al. (2014) Evidence of GnRH antagonist escape in obese women. J Clin Endocrinol Metab 99:E871-5
Meek, Thomas H; Matsen, Miles E; Damian, Vincent et al. (2014) Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology 155:4157-67
Kauffman, Alexander S; Sun, Yan; Kim, Joshua et al. (2014) Vasoactive intestinal peptide modulation of the steroid-induced LH surge involves kisspeptin signaling in young but not in middle-aged female rats. Endocrinology 155:2222-32
Stephens, Sahar M; Pau, Francis K Y; Yalcinkaya, Tamer M et al. (2013) Assessing the pulsatility of luteinizing hormone in female vervet monkeys (Chlorocebus aethiops sabaeus). Comp Med 63:432-8
Kundu, Mila C; May, Margaret C; Chosich, Justin et al. (2013) Assessment of luteal function in the vervet monkey as a means to develop a model for obesity-related reproductive phenotype. Syst Biol Reprod Med 59:74-81
Kulak, D; Polotsky, A J (2013) Should the ketogenic diet be considered for enhancing fertility? Maturitas 74:10-3
Wooding, Kerry M; Barkley, Robert M; Hankin, Joseph A et al. (2013) Mechanism of formation of the major estradiol product ions following collisional activation of the molecular anion in a tandem quadrupole mass spectrometer. J Am Soc Mass Spectrom 24:1451-5

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