Insulin reduces reaction of follicular granulosa cells to FSH stimulation in women with obesity-related infertility during IVF.

Journal:J Clin Endocrinol Metab

Place of Publication:USA

Abstract: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 expression. CP21 also increased the expression of insulin receptor substrate 1 and phosphatidylinositol 3-kinase (PI3K), as well as p-Akt2.Conclusions: Women with obesity in IVF were associated with reduced FSHR expression and E2 production caused by a dysfunctional insulin pathway. Decreased FSHR expression in hGCs from women with obesity and insulin-treated KGN cells could be rescued by an inhibitor of GSK3β, which might be a potential target for the improvement of the impaired FSH-stimulation response in women with obesity.

All the Authors:Bao-Yi Huang , Jia-Hui Zhan , Man-Ting Liu , Yang Fu , You-Qiang Su , Qing-Yuan Sun , Wei-Hua Wang , Dun-Jin Chen

First Author:Pei Xu

Indexed by:Research Article

Correspondence Author:Jian-Qiao Liu

Document Code:10.1210/jc.2018-00686

Volume:104

Issue:7

Page Number:2547-2560

ISSN No.:1945-7197

Translation or Not:no

Date of Publication:2019-07-01

Date of Publication:2019-07-01