Differential actions of metyrapone on the fetal pituitary-adrenal axis in the sheep fetus in late gestation.
It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.
Warnes
K E
KE
Department of Physiology, University of Adelaide, Adelaide, South Australia 5000, Australia.
McMillen
I C
IC
Robinson
J S
JS
Coulter
C L
CL
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000311:Adrenal Glands / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D003350:Cortodoxone / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005865:Gestational Age; D006854:Hydrocortisone / Q000097:blood; D008797:Metyrapone / Q000494:pharmacology*; D009929:Organ Size; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000196:embryology* / Q000502:physiology; D011247:Pregnancy; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D012756:Sheep; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D000098682:Steroidogenic Acute Regulatory Protein
D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D012333:RNA, Messenger; D044103:Receptor, Melanocortin, Type 2; D000098682:Steroidogenic Acute Regulatory Protein; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D015096:3-Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C477269:3 beta-hydroxy-delta 5-steroid dehydrogenase, rat; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D003350:Cortodoxone; D006854:Hydrocortisone; D008797:Metyrapone