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Corticotropin-Releasing Hormone Directly Stimulates Cortisol and the Cortisol Biosynthetic Pathway in Human Fetal Adrenal Cells

Department of Obstetrics and Gynecology (R.S., K.S.R., B.R.C., W.E.R.), Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Obstetrics and Gynecology (C.R.P.), University of Alabama at Birmingham, Birmingham, Alabama 35233

Address all correspondence and requests for reprints to: William E. Rainey, Ph.D., Professor, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room J6.114, Dallas, Texas 75390-9032. E-mail: william.rainey{at}utsouthwestern.edu.

Near term the human fetal adrenals (HFAs) initiate production of cortisol, which promotes organ maturation and acts to increase placental CRH biosynthesis. The objective of the present study was to determine whether CRH directly stimulates both cortisol production and expression of the steroidogenic enzymes in HFA-definitive zone cells. CRH stimulated the production of cortisol in a time- and dose-dependent manner, with an effective concentration of as low as 0.01 nM. In real-time RT-PCR experiments, CRH treatment increased the mRNA levels of steroidogenic acute regulatory protein and each of the enzymes needed to produce cortisol. CRH induced 3ß-hydroxysteroid dehydrogenase type II (HSD3B2) by 34-fold, 21-hydroxylase (CYP21) by 55-fold, and 11ß-hydroxylase by 41-fold. Induction of steroidogenic acute regulatory protein, cholesterol side chain cleavage (CYP11A), and 17-hydroxylase (CYP17) mRNA by CRH was 6-, 4-, and 6-fold, respectively. We also demonstrated that submaximal concentrations of CRH (30 pM) and ACTH (30 pM) that are seen in fetal circulation were additive on cortisol biosynthesis and 3ß-hydroxysteroid dehydrogenase type II mRNA induction. We suggest that CRH may play an important role in the late gestational rise in cortisol secretion from the HFAs, which may serve to augment placental CRH production and therefore participate in the endocrine cascade that is involved in fetal organ maturation and potentially in the timing of human parturition.

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