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)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
United States
Zip Code
Al-Safi, Zain A; Polotsky, Alex; Chosich, Justin et al. (2018) Evidence for disruption of normal circadian cortisol rhythm in women with obesity. Gynecol Endocrinol 34:336-340
Chosich, Justin; Bradford, Andrew P; Allshouse, Amanda A et al. (2017) Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins. Obesity (Silver Spring) 25:553-560
Kuokkanen, Satu; Zhu, Liyin; Pollard, Jeffrey W (2017) Xenografted tissue models for the study of human endometrial biology. Differentiation 98:62-69
Al-Safi, Zain A; Liu, Huayu; Carlson, Nichole E et al. (2016) Omega-3 Fatty Acid Supplementation Lowers Serum FSH in Normal Weight But Not Obese Women. J Clin Endocrinol Metab 101:324-33
Kuokkanen, Satu; Polotsky, Alex J; Chosich, Justin et al. (2016) Corpus luteum as a novel target of weight changes that contribute to impaired female reproductive physiology and function. Syst Biol Reprod Med 62:227-42
Merhi, Zaher; Polotsky, Alex J; Bradford, Andrew P et al. (2015) Adiposity Alters Genes Important in Inflammation and Cell Cycle Division in Human Cumulus Granulosa Cell. Reprod Sci 22:1220-8
Wang, Yuxiang; Zhu, Liyin; Kuokkanen, Satu et al. (2015) Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17? is mediated by a PKC-ERK1/2-mTOR signaling pathway. Proc Natl Acad Sci U S A 112:E1382-91
Wooding, Kerry M; Hankin, Joseph A; Johnson, Chris A et al. (2015) Measurement of estradiol, estrone, and testosterone in postmenopausal human serum by isotope dilution liquid chromatography tandem mass spectrometry without derivatization. Steroids 96:89-94
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
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

Showing the most recent 10 out of 41 publications