CORTICOTROPIN-RELEASING HORMONE DIRECTLY AND PREFERENTIALLY STIMULATES DEHYDROEPIANDROSTERONE-SULFATE SECRETION BY HUMAN FETAL ADRENAL-CORTICAL CELLS

Estrogens produced by the placenta play a pivotal role in the endocrin e control of pregnancy and induce many of the key changes involved in parturition. The placentae of humans and higher primates use the C-19 androgen dehydroepiandrosterone sulfate (DHEA-S) supplied by the fetal adrenals as the principal substrate for estrogen synthesis. Thus, sec retion of androgens by the fetal adrenals may be central to the proces s of primate parturition. The timing of human parturition also is corr elated with placental CRH concentrations in the maternal circulation. Because the mechanisms that regulate DHEA-S production by the fetal ad renals are incompletely understood, we examined whether there is a fun ctional relationship between CRH and steroid production by human fetal adrenal cortical cells. Using Northern blot analysis, we detected mes senger RNA transcripts (2.7 kb) encoding the type-1 CRH receptor in to tal RNA extracted from midgestation human fetal adrenals, suggesting t hat the fetal adrenal cortex may be directly responsive to CRH. To tes t this, primary cultures of human fetal adrenal cortical cells were ex posed to human CRH. Human CRH increased DHEA-S production by cultured human fetal adrenal cortical cells in a dose-dependent fashion, with a n ED50 of 10-100 pmol/L. Human CRH was as effective as ACTH at stimula ting DHEA-S production; however, it was 70% less potent than ACTH at s timulating cortisol production, indicating that its actions were prefe rentially directed toward increasing DHEA-S synthesis. Consistent with this thesis, we found that CRH increased abundance of messenger RNA e ncoding cytochrome P450 cholesterol bide-chain cleavage and 17 alpha-h ydroxylase/17,20 lyase but not 3 beta-hydroxysteroid dehydrogenase in adrenal cells. CRH did not alter cell number, indicating that it is no t mitogenic for fetal adrenal cortical cells. These data demonstrate a direct functional interaction between CRH and the fetal adrenal. Ther efore, placental CRH production, which rises exponentially during huma n pregnancy, may play a key role in promoting DHEA-S production by the fetal adrenals, which could lead to increasing placental estrogen syn thesis and contribute to the process of parturition in humans.