Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women

Context: Obesity is associated with a pro-inflammatory state and relative hypogonadotropic hypogonadism. Estrogen (E2) is a potential link between these phenomena because it exhibits negative feedback on gonadotropin secretion and also inhibits production of pro-inflammatory cytokines. Objective: We sought to examine the effect of estrogen priming on the hypothalamic-pituitary-ovarian axis in obesity. Design, Setting, and Participants: This was an interventional study at an academic center of 11 obese and 10 normal-weight (NW) women. Intervention: A frequent blood-sampling study and one month of daily urinary collection were performed before and after administration of transdermal estradiol 0.1 mg/d for one entire menstrual cycle. Main Outcome Measures: Serum LH and FSH before and after GnRH stimulation, and urinary estrogen and progesterone metabolites were measured. Results: E2 increased LH pulse amplitude and FSH response to GnRH (P = .048, and P < .03, respectively) in obese but not NW women. After E2 priming, ovulatory obese but not NW women had a 25% increase in luteal progesterone (P = .01). Obese women had significantly higher baseline IL-6, IL-10, TGF-beta, and IL-12 compared with NW (all P < .05); these levels were reduced after E2 (-6% for IL-1 beta, -21% for IL-8, -5% for TGF-beta, -5% for IL-12; all P < .05) in obese but not in NW women. Conclusions: E2 priming seems to improve hypothalamic-pituitary-ovarian axis function and systemic inflammation in ovulatory, obese women. Reducing chronic inflammation at the pituitary level may decrease the burden of obesity on fertility.