Smith R, Mesiano S, Chan E C, Brown S, Jaffe R B
Maternal Health Research Centre, John Hunter Hospital, Newcastle, NSW, Australia.
J Clin Endocrinol Metab. 1998 Aug;83(8):2916-20. doi: 10.1210/jcem.83.8.5020.
Estrogens produced by the placenta play a pivotal role in the endocrine control of pregnancy and induce many of the key changes involved in parturition. The placentae of humans and higher primates use the C19 androgen dehydroepiandrosterone sulfate (DHEA-S) supplied by the fetal adrenals as the principal substrate for estrogen synthesis. Thus, secretion of androgens by the fetal adrenals may be central to the process of primate parturition. The timing of human parturition also is correlated with placental CRH concentrations in the maternal circulation. Because the mechanisms that regulate DHEA-S production by the fetal adrenals are incompletely understood, we examined whether there is a functional relationship between CRH and steroid production by human fetal adrenal cortical cells. Using Northern blot analysis, we detected messenger RNA transcripts (2.7 kb) encoding the type-1 CRH receptor in total RNA extracted from midgestation human fetal adrenals, suggesting that the fetal adrenal cortex may be directly responsive to CRH. To test this, primary cultures of human fetal adrenal cortical cells were exposed to human CRH. Human CRH increased DHEA-S production by cultured human fetal adrenal cortical cells in a dose-dependent fashion, with an ED50 of 10-100 pmol/L. Human CRH was as effective as ACTH at stimulating DHEA-S production; however, it was 70% less potent than ACTH at stimulating cortisol production, indicating that its actions were preferentially directed toward increasing DHEA-S synthesis. Consistent with this thesis, we found that CRH increased abundance of messenger RNA encoding cytochrome P450 cholesterol side-chain cleavage and 17alpha-hydroxylase/17,20 lyase but not 3beta-hydroxysteroid dehydrogenase in adrenal cells. CRH did not alter cell number, indicating that it is not mitogenic for fetal adrenal cortical cells. These data demonstrate a direct functional interaction between CRH and the fetal adrenal. Therefore, placental CRH production, which rises exponentially during human pregnancy, may play a key role in promoting DHEA-S production by the fetal adrenals, which could lead to increasing placental estrogen synthesis and contribute to the process of parturition in humans.
胎盘产生的雌激素在妊娠的内分泌控制中起关键作用，并引发分娩过程中涉及的许多关键变化。人类和高等灵长类动物的胎盘利用胎儿肾上腺提供的C19雄激素硫酸脱氢表雄酮（DHEA-S）作为雌激素合成的主要底物。因此，胎儿肾上腺雄激素的分泌可能是灵长类动物分娩过程的核心。人类分娩的时间也与母体循环中胎盘促肾上腺皮质激素释放激素（CRH）的浓度相关。由于调节胎儿肾上腺产生DHEA-S的机制尚未完全了解，我们研究了CRH与人类胎儿肾上腺皮质细胞类固醇产生之间是否存在功能关系。使用Northern印迹分析，我们在从妊娠中期人类胎儿肾上腺提取的总RNA中检测到编码1型CRH受体的信使RNA转录本（2.7 kb），这表明胎儿肾上腺皮质可能直接对CRH产生反应。为了验证这一点，将人类胎儿肾上腺皮质细胞的原代培养物暴露于人类CRH。人类CRH以剂量依赖性方式增加培养的人类胎儿肾上腺皮质细胞的DHEA-S产生，半数有效剂量（ED50）为10 - 100 pmol/L。人类CRH在刺激DHEA-S产生方面与促肾上腺皮质激素（ACTH）一样有效；然而，在刺激皮质醇产生方面，它的效力比ACTH低70%，这表明其作用主要是增加DHEA-S的合成。与此论点一致的是，我们发现CRH增加了肾上腺细胞中编码细胞色素P450胆固醇侧链裂解酶和17α-羟化酶/17,20裂解酶的信使RNA丰度，但未增加3β-羟基类固醇脱氢酶的信使RNA丰度。CRH没有改变细胞数量，这表明它对胎儿肾上腺皮质细胞没有促有丝分裂作用。这些数据证明了CRH与胎儿肾上腺之间存在直接的功能相互作用。因此，在人类妊娠期间呈指数上升的胎盘CRH产生可能在促进胎儿肾上腺产生DHEA-S方面起关键作用，这可能导致胎盘雌激素合成增加，并有助于人类的分娩过程。
