Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Reproductive Medicine Center of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
J Clin Endocrinol Metab. 2019 Jul 1;104(7):2547-2560. doi: 10.1210/jc.2018-00686.
Women with obesity usually need larger doses of FSH for ovarian stimulation, resulting in poor outcomes; however, the mechanism is still unclear.
To investigate the molecular regulation of FSH receptor (FSHR) expression associated with obesity.
Case-control study to improve in vitro fertilization (IVF) outcomes.
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.
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.
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.
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.
肥胖女性通常需要更大剂量的 FSH 进行卵巢刺激，导致结局不佳；然而，其机制仍不清楚。
研究与肥胖相关的 FSH 受体（FSHR）表达的分子调控。
为改善体外受精（IVF）结局而进行的病例对照研究。
在我们的生殖医学中心进行 IVF 的肥胖女性（82 例）和超重女性（457 例）以及 1790 名年龄匹配的正常体重对照者。
FSHR 表达与体重指数（BMI）平行下降，而人绒毛膜促性腺激素（hCG）扳机日的雌二醇（E2）水平显著降低。
超重或肥胖女性的人卵巢颗粒细胞（hGC）中 FSHR 的 mRNA（P=0.02）和蛋白（P=0.001）水平均降低。空腹血和卵泡液（FF）中的胰岛素（P<0.001）和葡萄糖（P=0.0017）水平与 BMI 呈正相关，但与 FF 瘦素水平无关。我们用胰岛素处理人卵巢颗粒样肿瘤细胞（KGN），发现 E2 产生受损；磷酸化（p）-蛋白激酶 B（p-Akt2）水平降低，而糖原合酶激酶 3（GSK3）升高；肥胖女性的 hGC 也出现类似变化。用 GSK3β抑制剂 CP21 刺激肥胖女性的 hGC，导致 β-连环蛋白激活和 FSHR 表达上调。CP21 还增加了胰岛素受体底物 1 和磷脂酰肌醇 3-激酶（PI3K）的表达，以及 p-Akt2 的表达。
IVF 中肥胖女性的 FSHR 表达和 E2 产生减少与胰岛素途径功能障碍有关。肥胖女性的 hGC 中 FSHR 表达减少以及胰岛素处理的 KGN 细胞可通过 GSK3β 抑制剂挽救，这可能是改善肥胖女性受损 FSH 刺激反应的潜在靶点。
