Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells.
BACKGROUND
Near term, the human fetal adrenal increases the production of cortisol and dehydroepiandrosterone sulfate (DHEAS). DHEAS, which acts as substrate for placental estrogen production, induces key changes involved in parturition.


OBJECTIVE
The objective of this study was to determine quantitatively the effect of CRH on mRNA levels of enzymes needed for DHEAS production (steroidogenic acute regulatory protein, CYP11A, CYP17, and SULT2A1), to determine the CRH receptor (CRH-R) subtype(s) responsible for CRH action, and to determine the effect of CRH on CRH-R mRNA expression in human adrenal fetal zone (FZ) cells.


METHODS
Human adrenal FZ cells were treated with CRH, ACTH, urocortin (Unc), and CRH antagonists, and RNA was analyzed by microarray and real-time RT-PCR.


METHODS
This study was performed at an academic research laboratory.


METHODS
The main outcome measure was the expression of steroidogenic enzymes and CRH-R.


RESULTS
Microarray analysis of human FZ cells treated for 24 h with CRH or ACTH showed increased mRNA expression levels of the genes needed for DHEAS production. Real-time RT-PCR analysis confirmed these data. Induction was lost in the presence of CRH-R1 antagonists, but not CRH-R2 antagonists. Stimulation was reproduced by Unc. The CRH-R1alpha mRNA splice variant was the only type 1 receptor isoform expressed in the fetal adrenal, and treatment with CRH up-regulates its mRNA levels.


CONCLUSIONS
CRH, Unc, and ACTH stimulate all elements of the DHEAS synthetic pathway and activate CRH-R1 as well. The resulting increased DHEAS levels can be used for placental estrogen synthesis and contribute to the process leading to parturition in humans.
Sirianni
Rosa
R
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Mayhew
Bobbie A
BA
Carr
Bruce R
BR
Parker
C Richard
CR
Rainey
William E
WE
D000311:Adrenal Glands / Q000196:embryology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism*; D004798:Enzymes / Q000378:metabolism; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D013256:Steroids / Q000378:metabolism; D015854:Up-Regulation; D054832:Urocortins; D000099052:CRF Receptor, Type 1
D004798:Enzymes; D020033:Protein Isoforms; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D013256:Steroids; D054832:Urocortins; D019314:Dehydroepiandrosterone Sulfate; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone