Present address: Department of Obstetrics and Gynecology, Sapporo Medical University, South 1 West 16, Sapporo, Hokkaido, 060-8543, Japan.
Sapporo ART Clinic, 1-4 North 7 West 4, Sapporo, Hokkaido, 060-0807, Japan.
J Ovarian Res. 2019 Aug 31;12(1):82. doi: 10.1186/s13048-019-0556-7.
Polycystic ovary syndrome (PCOS) is an endocrine disease that is common in women in their reproductive period. Patients with this disease suffer from anovulation and hyperandrogenism. Ovulation induction with exogenous gonadotropin often causes ovarian hyperstimulation syndrome because many small antral follicles pause in their growth. Treatment with insulin sensitizers is reportedly effective for both anovulation associated with PCOS, and suppression of excessive follicular growth; however, the underlying mechanism of action remains unknown. Although pioglitazone is known as an insulin sensitizer, it also has a potent modulator of cell growth and apoptosis irrespective of insulin resistance. To clarify the effect of pioglitazone on follicular growth, we performed in vitro culture of murine preantral follicles. Secondary follicles (100-160 μm in diameter) isolated from 6-week-old ICR mice were individually cultured for 13 days. Culture conditions were as follows: 1) follicle-stimulating hormone (FSH; 33 mIU/mL; control), 2) FSH plus dihydrotestosterone (DHT; 500 ng/mL), 3) FSH plus pioglitazone (5 ng/mL), and 4) FSH plus DHT/pioglitazone. Survival rate and follicle diameter were evaluated, and concentrations of estradiol (E2) and vascular endothelial growth factor (VEGF) in culture media were measured. mRNA expression of various growth-promoting factors and Vegf within follicles were also assessed. Although no significant differences were observed with regard to survival rate, follicle diameters on day 13 were significantly different.Compared with the control group, the DHT group showed enhanced growth, while groups administered pioglitazone showed stagnation of the accelerated growth induced by DHT. Although DHT treatment enhanced the expression of bone morphogenetic protein 2 (Bmp2) mRNA, pioglitazone exposure suppressed induction of Bmp2 mRNA by DHT. Vegf mRNA and protein expression were also significantly reduced when pioglitazone was added to culture media containing DHT.Administration of pioglitazone negatively affected follicular growth and VEGF levels, which may suppress excessive follicular growth and prevent ovarian hyperstimulation syndrome.
多囊卵巢综合征（PCOS）是一种常见于育龄期妇女的内分泌疾病。患有这种疾病的患者会出现排卵障碍和高雄激素血症。使用外源性促性腺激素诱导排卵常导致卵巢过度刺激综合征，因为许多小窦卵泡停止生长。据报道，胰岛素增敏剂治疗对 PCOS 相关的排卵障碍和抑制过多卵泡生长均有效；然而，其作用机制尚不清楚。虽然吡格列酮是一种胰岛素增敏剂，但它也具有很强的细胞生长和凋亡调节剂作用，而与胰岛素抵抗无关。为了阐明吡格列酮对卵泡生长的影响，我们进行了小鼠窦前卵泡的体外培养。从 6 周龄 ICR 小鼠中分离出的二级卵泡（直径 100-160μm）单独培养 13 天。培养条件如下：1）卵泡刺激素（FSH；33 mIU/mL；对照）、2）FSH 加二氢睾酮（DHT；500ng/mL）、3）FSH 加吡格列酮（5ng/mL）和 4）FSH 加 DHT/吡格列酮。评估卵泡存活率和卵泡直径，并测量培养物中雌二醇（E2）和血管内皮生长因子（VEGF）的浓度。还评估了卵泡内各种生长促进因子和 Vegf 的 mRNA 表达。尽管存活率无显著差异，但第 13 天的卵泡直径有显著差异。与对照组相比，DHT 组的生长增强，而给予吡格列酮的组的生长则停滞，表明 DHT 诱导的加速生长受到抑制。虽然 DHT 处理增强了骨形态发生蛋白 2（Bmp2）mRNA 的表达，但吡格列酮暴露抑制了 DHT 诱导的 Bmp2 mRNA 的诱导。当添加 DHT 的培养基中添加吡格列酮时，Vegf mRNA 和蛋白表达也显著降低。吡格列酮给药对卵泡生长和 VEGF 水平有负面影响，这可能抑制过多的卵泡生长并预防卵巢过度刺激综合征。
