Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production.
We examined the regulation of steroid production in fetal zone cells from midgestation (16-21 weeks) human fetal adrenal glands to elucidate the mechanism by which these cells secrete large quantities of dehydroepiandrosterone sulfate (DHAS) and little cortisol in response to ACTH. Our underlying hypothesis is that estrogen and insulin-like to ACTH. Our underlying hypothesis is that estrogen and insulin-like growth factor-II (IGF-II) modulate the steroidogenic response of fetal zone cells to ACTH, driving steroid production toward DHAS rather than cortisol. We also hypothesize that the effects of IGF-II and estrogen on steroidogenesis are achieved by modulating the expression of key enzymes in the steroidogenic pathway. Basal cortisol secretion by cultured fetal zone cells was below the limit of assay sensitivity (< 0.54 pmol/10(5) cells.24 h), whereas basal DHAS secretion was 210.8 +/- 41.0 pmol/10(5) cells.24 h (mean +/- SE). ACTH-(1-24) increased the secretion of cortisol to 228.96 +/- 6.75 pmol/10(5) cells.24 h and that of DHAS to 2039.8 +/- 121.7 pmol/10(5) cells.24 h. Neither IGF-II nor estradiol (E2) affected basal (no added ACTH) steroid secretion by fetal zone cells. IGF-II increased ACTH-stimulated cortisol and DHAS secretion by fetal zone cells in a dose-dependent fashion. In contrast, E2 at high concentrations (1-10 mumol/L) decreased ACTH-stimulated cortisol production to basal levels, but increased ACTH-stimulated DHAS production 1.5- to 2-fold. Combinations of IGF-II (100 ng/mL) and E2 (1 mumol/L) increased ACTH-stimulated cortisol and DHAS secretion by 1.5- to 2-fold compared with control values. However, compared with cultures exposed to IGF-II alone, inclusion of E2 decreased ACTH-stimulated cortisol secretion by about 60% and increased ACTH-stimulated DHAS secretion by about 50%. IGF-II increased the abundance of ACTH-stimulated mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450scc), 17 alpha hydroxylase/17,20 lyase P450 (P450c17), and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD). In addition, IGF-II increased the abundance of mRNA encoding P450c17 under basal conditions, but did not affect the basal expression of P450scc or 3 beta HSD. E2 had no effect on basal expression of these steroidogenic enzymes, but increased the abundance of ACTH-stimulated mRNA encoding P450scc and P450c17. The abundance of mRNA encoding 3 beta HSD was not affected by E2. The effect of IGF-II and E2 in combination on steroidogenic enzyme mRNA abundance was not different from that of IGF-II alone. These data indicate that IGF-II increases ACTH-stimulated steroid production in fetal zone cells by increasing the expression of key steroidogenic enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco 94143.
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Jaffe
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000311:Adrenal Glands / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000096:biosynthesis; D019314:Dehydroepiandrosterone Sulfate; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics
D000305:Adrenal Cortex Hormones; D012333:RNA, Messenger; D003687:Dehydroepiandrosterone; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D007335:Insulin-Like Growth Factor II; D000324:Adrenocorticotropic Hormone; D015096:3-Hydroxysteroid Dehydrogenases; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D006854:Hydrocortisone