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

• Published in: The journal of clinical endocrinology and metabolism 2015-11, Vol.100 (11), p.4372-4381
• Main Authors: Al-Safi, Zain A, Liu, Huayu, Carlson, Nichole E, Chosich, Justin, Lesh, Jennifer, Robledo, Celeste, Bradford, Andrew P, Gee, Nancy A, Phang, Tzu, Santoro, Nanette, Kohrt, Wendy, Polotsky, Alex J
• Format: Article
• Language: English
• Subjects: Absorptiometry, Photon; Administration, Cutaneous; Adolescent; Adult; Cytokines - metabolism; Estradiol - administration & dosage; Estradiol - pharmacology; Estrogens - urine; Female; Follicle Stimulating Hormone - blood; Gonadotropin-Releasing Hormone - metabolism; Gonadotropins - physiology; Humans; Hypogonadism - metabolism; Hypogonadism - physiopathology; Hypothalamo-Hypophyseal System - drug effects; Luteinizing Hormone - blood; Obesity - metabolism; Obesity - physiopathology; Original; Progesterone - urine; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2015-1946

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-β, and IL-12 compared with NW (all P < .05); these levels were reduced after E2 (−6% for IL-1β, −21% for IL-8, −5% for TGF-β, −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.