Developmental programming: gestational testosterone excess disrupts LH secretion in the female sheep fetus.
Developmental programming: gestational testosterone excess disrupts LH secretion in the female sheep fetus.
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DOI：
10.1186/s12958-020-00667-z
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发表时间：
2020-11-07
期刊：
影响因子：
--
通讯作者：
Cardoso RC
中科院分区：
文献类型：
--
作者：
Landers RSM;Padmanabhan V;Cardoso RC
孕期睾酮(T)过量会导致母羊的生殖和代谢紊乱，这与患有多囊卵巢综合征(PCOS)的妇女的情况非常相似。在神经内分泌水平上，产前用T处理的绵羊表现出对GnRH和随后的促黄体生成素高分泌的敏感性增加。在本研究中，我们研究了妊娠期T处理对雌性绵羊胚胎黄体生成素分泌和脑垂体功能的影响。此外，由于产前T效应可以通过雄激素受体或由于胰岛素稳态的改变而介导，因此对雄激素拮抗剂(氟他胺)或胰岛素增敏剂(罗格列酮)的产前联合治疗进行了测试。妊娠绵羊在妊娠30~90天期间，分别用溶剂(对照组)、丙酸(~ 1.2 mg/kg)、丙酸和氟他胺(15 mg/kg/d)、丙酸和罗格列酮(8 mg/d)处理。在GD90时，测定子宫动脉(母体)和脐动脉(胎儿)的促黄体生成素浓度，并对女性胎儿实施安乐死。采集脑垂体腺称重，测定促黄体生成素分泌的几个关键调节因子的蛋白水平。经产前T处理后，胎儿脑垂体重量明显减轻。氟他胺完全阻止了垂体重量的减轻，而罗格列酮仅部分阻止了这种减轻。产前T显著降低胎儿黄体生成素水平，氟他胺联合治疗使黄体生成素部分恢复到对照水平。孕期促性腺激素释放激素引起促性腺激素释放激素受体和雌激素受体β蛋白水平显著降低，雄激素受体α水平升高。除了雄激素受体，氟他胺联合治疗完全阻止了胎儿脑垂体的这些变化，而罗格列酮在很大程度上未能阻止这些变化。产前T-治疗不改变胰岛素受体-β的蛋白水平和胰岛素信号通路的激活(磷酸化)。这些结果表明，产前T治疗导致胎儿黄体生成素分泌减少，胎儿脑垂体重量减轻，并改变了促性腺激素分泌的几种调节剂的蛋白水平。氟他胺联合治疗阻止了这些变化的观察表明，胎儿发育过程中的编程可能是通过直接的雄激素作用发生的。
Prenatal testosterone (T) excess results in reproductive and metabolic perturbations in female sheep that closely recapitulate those seen in women with polycystic ovary syndrome (PCOS). At the neuroendocrine level, prenatal T-treated sheep manifest increased pituitary sensitivity to GnRH and subsequent LH hypersecretion. In this study, we investigated the early effects of gestational T-treatment on LH secretion and pituitary function in the female sheep fetus. Additionally, because prenatal T effects can be mediated via the androgen receptor or due to changes in insulin homeostasis, prenatal co-treatment with an androgen antagonist (flutamide) or an insulin sensitizer (rosiglitazone) were tested. Pregnant sheep were treated from gestational day (GD) 30 to 90 with either: 1) vehicle (control); 2) T-propionate (~ 1.2 mg/kg); 3) T-propionate and flutamide (15 mg/kg/day); and 4) T-propionate and rosiglitazone (8 mg/day). At GD 90, LH concentrations were determined in the uterine artery (maternal) and umbilical artery (fetal), and female fetuses were euthanized. Pituitary glands were collected, weighed, and protein level of several key regulators of LH secretion was determined. Fetal pituitary weight was significantly reduced by prenatal T-treatment. Flutamide completely prevented the reduction in pituitary weight, while rosiglitazone only partially prevented this reduction. Prenatal T markedly reduced fetal LH concentrations and flutamide co-treatment partially restored LH to control levels. Prenatal T resulted in a marked reduction in LH-β protein level, which was associated with a reduction in GnRH receptor and estrogen receptor-α levels and an increase in androgen receptor. With the exception of androgen receptor, flutamide co-treatment completely prevented these alterations in the fetal pituitary, while rosiglitazone largely failed to prevent these changes. Prenatal T-treatment did not alter the protein levels of insulin receptor-β and activation (phosphorylation) of the insulin signaling pathways. These findings demonstrate that prenatal T-treatment results in reduced fetal LH secretion, reduced fetal pituitary weight, and altered protein levels of several regulators of gonadotropin secretion. The observations that flutamide co-treatment prevented these changes suggest that programming during fetal development likely occurs via direct androgen actions.
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