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

Abstract

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, PGF2alpha, known to act via PKC, induced a sustained response for up to 20 min. The response to CRH was dose dependent, maximal at 1 micromol/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 17alpha-hydroxylase/17,20 lyase (P450c17), but not 3beta-hydroxysteroid dehydrogenase/delta(4-5) isomerase. However, 3betaHSD 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.

Repeating ACTH Stimulation Test Is Necessary to Diagnose ACTH Deficiency in Neonatal Hypopituitarism With Initial False Negative Result

“…After birth, the fetal zone of the adrenal that produces DHEAS during pregnancy undergoes involution. 3,9 Cortisol is produced in the transitional zone, which is believed to give rise to the postnatal zona fasciculate. 10…”

“…2 After birth, the fetal zone of the adrenal that produces DHEAS during pregnancy undergoes involution. 3,9 Cortisol is produced in the transitional zone, which is believed to give rise to the postnatal zona fasciculate. 10 In newborns with congenital hypopituitarism with ACTH deficiency, there is a normal upregulation of fetal steroidogenic enzymes secondary to placental CRH stimulation, leading to fetal adrenal maturation and steroidogenesis, including cortisol production.…”

100th anniversary of the discovery of the human adrenal fetal zone by Stella Starkel and Lesław Węgrzynowski: how far have we come?

“…In cultured fetal adrenocortical cells CRH stimulates all elements of DHEAS synthetic pathway [129][130][131][132][133].…”

The Corticotropin-Releasing Factor (CRF) Family of Neuropeptides in Inflammation: Potential Therapeutic Applications

“…It now appears that several other effects of CRF, including that in Leydig cells, adrenals, placenta, immunocytes, myometrium, and hippocampus, may be mediated by the Gq -phospholipase C-inositol 1,4,5-trisphosphate -PKC pathway [37,38].…”