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Late Gestation Increase in 11ß-Hydroxysteroid Dehydrogenase 1 Expression in Human Fetal Membranes: A Novel Intrauterine Source of Cortisol

Canadian Institutes for Health Research (CIHR), Institute of Human Development, Child and Youth Health, Department of Obstetrics and Gynecology, and Department of Physiology (N.A., W.L., T.M., J.C.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; and CIHR Group in Fetal and Neonatal Health and Development, Department of Obstetrics and Gynecology (K.Y., J.C.), University of Western Ontario, London, Ontario, Canada N6A 5B8

Address all correspondence and requests for reprints to: Dr. Nadia Alfaidy, University of Toronto, Department of Physiology, Medical Sciences Building (MSB) Room 3344, 1 King’s College Circle, Toronto, M5S 1A8, Ontario, Canada. E-mail: n.alfaidy{at}utoronto.ca.

Late human gestation is associated with an increase in the concentration of cortisol (F) in the fetal circulation and amniotic fluid. It had been assumed that most of the F measured in the amniotic fluid came from the fetal adrenal gland. However, local production of F can also occur in human intrauterine tissues from inactive cortisone under the influence of the enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1. Recent studies have shown that 11ß-HSD 1 activity is up-regulated by prostaglandins (PG) E2 and F2, hormones that are produced in the fetal membranes (FM) at term. In the present study, we hypothesized that 11ß-HSD 1 expression would increase in FM during pregnancy and at labor, creating the potential for local increase in F production at term. We examined 11ß-HSD 1 expression in placenta and FM obtained during normal pregnancy from nonlaboring women [26–28 wk (n = 3); 29–30 wk (n = 3); 32–33 wk (n = 3); 35–36 wk (n = 3)] and from uncomplicated term pregnancies after elective cesarean section (n = 6). 11ß-HSD 1 expression was also examined in amnion and chorionic tissues in relation to term labor (n = 12). Immunohistochemistry and Western blot analysis were used to examine 11ß-HSD 1 localization and expression. 11ß-HSD 1 activity was also measured in microsomal fractions prepared from whole fetal membranes. At term, immunoreactive 11ß-HSD 1 expression was localized predominantly to the chorion trophoblast cells, attached decidua, and amnion epithelial cells. 11ß-HSD 1 expression in FM increased with gestational age and reflected increased enzyme reductase activity. No change in 11ß-HSD 1 expression was found in placental tissue from the same patients. There was a significant increase in 11ß-HSD 1 expression in amnion but not in chorion with the onset of labor. We suggest that increases in 11ß-HSD 1 expression/activity by intrauterine membranes during late gestation may result in increased potential for a local increase in F production and that FM should be considered as an extraadrenal source of F during late gestation. This local F production may be involved in different pathways contributing to the regulation of parturition.

This work was supported by the Canadian Institutes for Health Research in Human Development, Child, and Youth Health (MOP 42378 to J.C.).

Abbreviations: E, Inactive cortisone; F, cortisol; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; IHC, immunohistochemical analysis; NADPH, nicotinamide adenosine dinucleotide phosphate; PG, prostaglandin; PGDH, PG dehydrogenase.

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