Laboratorio de Alteraciones Reproductivas y Metabólicas, Centro de Neurobiología y Plasticidad Cerebral (CNPC), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Laboratorio de Neuroquímica y Neurofarmacología, Centro de Neurobiología y Plasticidad Cerebral (CNPC), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
J Endocrinol. 2018 Dec 1;239(3):325-338. doi: 10.1530/JOE-18-0352.
Maternal obesity causes a wide range of impairment in offspring, such as metabolic and reproductive dysfunctions. We previously demonstrated that female offspring of obese rats have increased serum estradiol levels during early postnatal life, probably because of decreased hepatic cytochrome P450 3A2 levels, which could lead to early onset of puberty and polycystic ovary condition in adulthood. Using metformin during pregnancy and nursing to improve the metabolic status of obese mothers could prevent the sequence of events that lead to an increase in postnatal serum estradiol levels in female offspring and, hence, reproductive dysfunction. We found that metformin prevented an increase in serum estradiol levels at postnatal day 14 in female offspring of obese mothers, which was associated with a restoration of hepatic cytochrome P450 3A2 levels to control values. Treatment using metformin could not prevent advanced puberty, but we observed that the number of antral follicles, follicular cysts and multi-oocyte follicles returned to control values in the female offspring of obese mothers treated with metformin. We also observed an increase in the levels of norepinephrine and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol in the ovaries, indicating increased sympathetic activity in female offspring induced by an obesogenic uterine environment. We found that this effect was prevented by metformin administration. From the results of this study, we concluded that metformin administration to obese mothers during pregnancy and nursing partially prevents ovarian dysfunction in female offspring during adulthood.
母体肥胖会导致后代出现广泛的损伤，如代谢和生殖功能障碍。我们之前的研究表明，肥胖大鼠的雌性后代在出生后早期的血清雌二醇水平升高，可能是由于肝脏细胞色素 P450 3A2 水平降低，导致青春期提前和成年多囊卵巢。在怀孕期间和哺乳期使用二甲双胍改善肥胖母亲的代谢状况，可以预防导致雌性后代产后血清雌二醇水平升高的一系列事件，从而预防生殖功能障碍。我们发现，二甲双胍可预防肥胖母亲的雌性后代在产后第 14 天血清雌二醇水平升高，这与肝脏细胞色素 P450 3A2 水平恢复到对照值有关。二甲双胍治疗不能预防青春期提前，但我们观察到，肥胖母亲的雌性后代的窦卵泡、卵泡囊肿和多卵卵泡数量恢复到对照值。我们还观察到卵巢中去甲肾上腺素和去甲肾上腺素代谢物 3-甲氧基-4-羟基苯乙二醇水平升高，这表明肥胖的子宫环境会导致雌性后代的交感神经活动增加。我们发现，二甲双胍的给药可以预防这种作用。从这项研究的结果来看，我们得出结论，在怀孕期间和哺乳期给肥胖母亲服用二甲双胍可以部分预防成年雌性后代的卵巢功能障碍。
