Department of Morphological Sciences, Faculty of Veterinary Sciences, National University of Litoral, Esperanza, Santa Fe, Argentina.
Biol Reprod. 2010 Jun;82(6):1065-75. doi: 10.1095/biolreprod.109.082719. Epub 2010 Feb 10.
Prenatal testosterone (T) excess increases ovarian follicular recruitment, follicular persistence, insulin resistance, and compensatory hyperinsulinemia. Considering the importance of insulin in ovarian physiology, in this study, using prenatal T- and dihydrotestosterone (DHT, a nonaromatizable androgen)-treated female sheep, we tested the hypothesis that prenatal androgen excess alters the intraovarian insulin signaling cascade and metabolic mediators that have an impact on insulin signaling. Changes in ovarian insulin receptor (INSRB), insulin receptor substrate 1 (IRS1), mammalian target of rapamycin (MTOR), phosphatidylinositol 3-kinase (PIK3), peroxisome proliferator-activated receptor-gamma (PPARG), and adiponectin proteins were determined at fetal (Days 90 and 140), postpubertal (10 mo), and adult (21 mo) ages by immunohistochemistry. Results indicated that these proteins were expressed in granulosa, theca, and stromal compartments, with INSRB, IRS1, PPARG, and adiponectin increasing in parallel with advanced follicular differentiation. Importantly, prenatal T excess induced age-specific changes in PPARG and adiponectin expression, with increased PPARG expression evident during fetal life and decreased antral follicular adiponectin expression during adult life. Comparison of developmental changes in prenatal T and DHT-treated females found that the effects on PPARG were programmed by androgenic actions of T, whereas the effects on adiponectin were likely by its estrogenic action. These results suggest a role for PPARG in the programming of ovarian disruptions by prenatal T excess, including a decrease in antral follicular adiponectin expression and a contributory role for adiponectin in follicular persistence and ovulatory failure.
产前睾酮 (T) 过多会增加卵巢卵泡募集、卵泡持续存在、胰岛素抵抗和代偿性高胰岛素血症。考虑到胰岛素在卵巢生理中的重要性，本研究使用产前 T 和二氢睾酮 (DHT，一种非芳香化雄激素) 处理的雌性绵羊，检验了以下假说：即产前雄激素过多会改变对胰岛素信号有影响的卵巢内胰岛素信号级联和代谢介质。通过免疫组织化学法，在胎儿 (90 天和 140 天)、产后 (10 个月) 和成年 (21 个月) 时测定卵巢胰岛素受体 (INSRB)、胰岛素受体底物 1 (IRS1)、雷帕霉素靶蛋白 (MTOR)、磷酸肌醇 3-激酶 (PIK3)、过氧化物酶体增殖物激活受体-γ (PPARG) 和脂联素蛋白的变化。结果表明，这些蛋白在颗粒细胞、膜细胞和基质细胞中表达，INSRB、IRS1、PPARG 和脂联素随着卵泡的分化而平行增加。重要的是，产前 T 过多会导致 PPARG 和脂联素表达出现年龄特异性变化，胎儿期 PPARG 表达增加，成年期窦卵泡脂联素表达减少。比较产前 T 和 DHT 处理的雌性动物的发育变化发现，PPARG 的变化是由 T 的雄激素作用编程的，而脂联素的变化可能是由其雌激素作用引起的。这些结果表明，PPARG 在产前 T 过多导致的卵巢功能障碍的编程中发挥作用，包括窦卵泡脂联素表达减少，以及脂联素在卵泡持续存在和排卵障碍中的作用。
