Biol Reprod Keystone Symposia Conference on Frontiers in Reproductive Biology & Regulation of Fertility.
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BOR - Papers in Press, published online ahead of print April 7, 2004.
Biol Reprod 2004, 10.1095/biolreprod.103.025197
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Submitted November 5, 2003
Returned for revision November 28, 2003
Accepted March 30, 2004

Mechanisms of Hormone Action


Differential Actions of Metyrapone on the Fetal Pituitary-Adrenal Axis in the Sheep Fetus in Late Gestation

K. E. Warnes , I. C. McMillen , J. S. Robinson , and C. L. Coulter *

* To whom correspondence should be addressed. E-mail: catherine.coulter{at}adelaide.edu.au.

Abstract
It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of 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 gestation (term = 147 ± 3 d) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH, pituitary pro-opiomelanocortin (POMC) mRNA and expression of ACTH receptor (melanocortin type 2 receptor; MC2-R), steroidogenic acute regulatory protein (StAR), 11 beta hydroxysteroid dehydrogenase type 2 (11{beta}HSD2), cytochrome P450 cholesterol side chain cleavage (CYP11A1), cytochrome P450 17 hydroxylase (CYP17), 3{beta} hydroxysteroid dehydrogenase (3{beta}HSD) and cytochrome P450 21 hydroxylase (CYP21A1) mRNA and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P<0.05), whilst plasma cortisol concentrations were not significantly different in metyrapone compared with vehicle infused fetuses. The ratio of plasma cortisol: ACTH concentrations was higher (P<0.0001), between 136-140d than between 120-135d 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), whilst the levels of mature StAR protein (30 kDa) were higher (P<0.05) in the metyrapone infused fetuses. In addition, adrenal mRNA expression of 11{beta}HSD2, CYP11A1 and CYP17 were higher (P<0.05) in the metyrapone infused fetuses. Thus metyrapone administration may represent a unique model which allows the dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation to be investigated.

Key words: Pregnancy • Adrenal cortex • Adrenocorticotropic hormone receptor • Anterior pituitary • Steroid hormones




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