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Corticotropin-Releasing Hormone Stimulates P450 17-Hydroxylase/17,20-Lyase in Human Fetal Adrenal Cells via Protein Kinase C¹

San Francisco Reproductive Endocrinology Center, University of California, San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Robert B. Jaffe, M.D., Reproductive Endocrinology Center, University of California, San Francisco, San Francisco, California 94143-0556. E-mail: robert_jaffe{at}quickmail.ucsf.edu

CRH directly stimulates dehydroepiandrosterone sulfate (DHEAS) production in human fetal adrenal cells. In the human fetal and adult pituitary, CRH acts via protein kinase A (PKA). We determined the CRH signal transduction pathway in fetal adrenal cells, i.e. whether CRH modulates human fetal adrenal steroidogenesis via PKA and/or protein kinase C (PKC).

In primary cultures, CRH increased inositol trisphosphate. After CRH treatment, inositol tris-, bis-, and monophosphates increased within 1 min, reaching maximal levels at 5 min. In contrast, PGF₂, known to act via PKC, induced a sustained response for up to 20 min. The response to CRH was dose dependent, maximal at 1 µmol/L at both 1 and 5 min. CRH increased DHEAS production, with a much lesser effect on cortisol. CRH did not stimulate inositol phospholipid in adult adrenal glands, suggesting that this pathway is unique to the fetal adrenal. CRH increased messenger ribonucleic acid encoding 17-hydroxylase/17,20 lyase (P450c17), but not 3ß-hydroxysteroid dehydrogenase/^4–5 isomerase. However, 3ßHSD expression was stimulated by ACTH. PKC, but not PKA, inhibitors blocked CRH-stimulated P450c17 induction, whereas PKA inhibitors blocked ACTH-stimulated cortisol. Thus, CRH is coupled to the phospholipase C-inositol phosphate second messenger system and preferentially induces the expression of P450c17 and DHEAS, suggesting a unique role of CRH regulating human fetal adrenal function via PKC.

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