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Original Studies |
Maternal Health Research Centre (R.S., E.-C.C.), John Hunter Hospital, Newcastle, NSW 2310, Australia; Reproductive Endocrinology Center (S.M., R.B.J.), Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143; and Department of Endocrinology (S.B.), Prince of Wales Hospital, High Street, Randwick, NSW 2031, Australia
Address all correspondence and requests for reprints to: Professor Roger Smith, Maternal Health Research Centre, Endocrine Unit, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia, or to Sam Messiano, Maternal Health Research Centre, John Hunter Hospital, Newcastle, NSW 2310, Australia.
Estrogens produced by the placenta play a pivotal role in the endocrine
control of pregnancy and induce many of the key changes involved in
parturition. The placentae of humans and higher primates use the
C19 androgen dehydroepiandrosterone sulfate (DHEA-S)
supplied by the fetal adrenals as the principal substrate for estrogen
synthesis. Thus, secretion of androgens by the fetal adrenals may be
central to the process of primate parturition. The timing of human
parturition also is correlated with placental CRH concentrations
in the maternal circulation. Because the mechanisms that regulate
DHEA-S production by the fetal adrenals are incompletely understood, we
examined whether there is a functional relationship between CRH and
steroid production by human fetal adrenal cortical cells. Using
Northern blot analysis, we detected messenger RNA transcripts (2.7 kb)
encoding the type-1 CRH receptor in total RNA extracted from
midgestation human fetal adrenals, suggesting that the fetal adrenal
cortex may be directly responsive to CRH. To test this, primary
cultures of human fetal adrenal cortical cells were exposed to human
CRH. Human CRH increased DHEA-S production by cultured human fetal
adrenal cortical cells in a dose-dependent fashion, with an
ED50 of 10–100 pmol/L. Human CRH was as effective as
ACTH at stimulating DHEA-S production; however, it was 70% less
potent than ACTH at stimulating cortisol production, indicating that
its actions were preferentially directed toward increasing DHEA-S
synthesis. Consistent with this thesis, we found that CRH increased
abundance of messenger RNA encoding cytochrome P450 cholesterol
side-chain cleavage and 17
-hydroxylase/17,20 lyase but not
3ß-hydroxysteroid dehydrogenase in adrenal cells. CRH did not alter
cell number, indicating that it is not mitogenic for fetal adrenal
cortical cells. These data demonstrate a direct functional interaction
between CRH and the fetal adrenal. Therefore, placental CRH production,
which rises exponentially during human pregnancy, may play a key role
in promoting DHEA-S production by the fetal adrenals, which could lead
to increasing placental estrogen synthesis and contribute to the
process of parturition in humans.
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