This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator.
SPECIFIC AIMS More than half of all US adults are overweight or obese, and over 5% of US health expenditures are directed at medical costs associated with obesity. We have recently reported, in a cohort of 842 women aged 43-55, dramatic differences in reproductive hormone patterns in ovulatory overweight and obese women, compared to women with a body mass index less than 25 kg/m2. These changes include longer and more irregular cycles, and decreased LH, FSH, and luteal progesterone metabolite excretion in urine over the course of an entire menstrual cycle. We hypothesize that these hormonal alterations are weight related, and that they play a role in the increased morbidity that overweight and obese women experience. We propose herein to perform a study to test the hypothesis that weight loss in obese women will result in normalization of reproductive hormones and to determine potential mechanisms for this salutary effect. We propose the following specific aim: To determine the acute and chronic effects of a large weight reduction (at least 25% from mean starting weight) in 30 morbidly obese women aged 35-50, who are scheduled to undergo gastric bypass surgery, on daily reproductive hormone patterns, folliculogenesis, central neural GnRH drive and adipokines. Hypothesis #1: Acute and chronic reduction in body weight of at least 25% in morbidly obese women will result in overall increases in integrated, whole-cycle pregnanediol (Pdg), LH and FSH from baseline. Outcome: whole cycle reproductive hormone patterns assessed at three time points: i. before gastric bypass surgery, ii. during the 'acute' weight loss phase, and iii. during the 'plateau' phase after surgery. Hypothesis #2: Chronic, but not acute reductions in body weight of at least 25% in morbidly obese women will alter central neural hypothalamic-pituitary drive. Outcome: follicular phase pulsatile LH secretory patterns assessed: i. before gastric bypass surgery, ii. during the 'acute' weight loss phase, and iii. during the 'plateau' phase after surgery. Hypothesis #3: Chronic, but not acute reductions in body weight of at least 25% in morbidly obese women will result in a more appropriate pattern of folliculogenesis and follicle growth. Outcome: serial transvaginal ultrasounds for one cycle or up to 25 days assessed at three time points: i. before gastric bypass surgery, ii. during the 'acute' weight loss phase, and iii. during the 'plateau' phase after surgery. Hypothesis #4: Improved adiponectin profiles and reductions in leptin and TNF-alpha will predict reproductive hormone normalization. Outcome: Adiponectin, leptin, and TNF-alpha will be examined periodically in relation to rate of weight loss and reproductive hormones. Demonstration of the reversibility of obesity related changes on menstrual cyclicity would provide support for the conduct of a larger randomized, clinical trial, and the detailed monitoring of follicle growth and hypothalamic-pituitary-axis function over the course of weight loss can be used to provide important clues to the mechanisms by which the acute and chronic reversal of obesity impacts positively upon female reproduction. Thus, this initial exploration, if successful, would provide the basis for a new line of investigation for the PI into the interactions between reproduction and metabolism.
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