Insulin Reduces Reaction of Follicular Granulosa Cells to FSH Stimulation in Women With Obesity-Related Infertility During IVF

作者：Pei Xu, Baoyi Huang, Jia-Hui Zhan, Man-Ting Liu, Yang Fu, You‐Qiang Su, Qing‐Yuan Sun, Wei‐Hua Wang, Dunjin Chen, Jianqiao Liu · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2018 · DOI：10.1210/jc.2018-00686 · 被引用次数：55 · 研究领域：Ovarian function and disorders、Hypothalamic control of reproductive hormones、Reproductive Biology and Fertility

CONTEXT: Women with obesity usually need larger doses of FSH for ovarian stimulation, resulting in poor outcomes; however, the mechanism is still unclear. OBJECTIVE: To investigate the molecular regulation of FSH receptor (FSHR) expression associated with obesity. DESIGN: Case-control study to improve in vitro fertilization (IVF) outcomes. PATIENTS: Women with obesity (82) and women who were overweight (457) undergoing IVF and 1790 age-matched controls with normal weight from our reproductive medicine center. MAIN OUTCOME MEASURES: FSHR expression was decreased in parallel with body mass index (BMI), whereas the estradiol (E2) level on the human chorionic gonadotropin (hCG) trigger day was significantly lower. RESULTS: FSHR expression in human granulosa cells (hGCs), both mRNA (P = 0.02) and protein (P = 0.001) levels, was decreased in women who were overweight or obese. Both insulin (P < 0.001) and glucose (P = 0.0017) levels were positively correlated with BMI in fasting blood and follicle fluids (FFs) but not with FFs leptin level. We treated human granulosa-like tumor cells (KGN) cells with insulin; E2 production was compromised; the level of phosphorylated (p)-protein kinase B (p-Akt2) decreased, whereas p-glycogen synthase kinase 3 (GSK3) increased; and there were similar changes in hGCs from women with obesity. Stimulated hGCs from women with obesity with compound 21 (CP21), an inhibitor of GSK3β, resulted in upregulated β-catenin activation and increased FSHR expressi...