Tissue-Specific Messenger Ribonucleic Acid Expression of 11b-Hydroxysteroid Dehydrogenase Types 1 and 2 and the Glucocorticoid Receptor within Rat Placenta Suggests Exquisite Local Control of Glucocorticoid Action*

Placental 11b-hydroxysteroid dehydrogenase (11b-HSD) regulates transplacental passage of maternal glucocorticoids to the fetus and is thus a key determinant of fetal glucocorticoid levels. It has also been proposed that placental 11b-HSD expression may influence local glucocorticoid actions by regulating access of corticosterone to the glucocorticoid receptor (GR) or mineralocorticoid receptor (MR). Therefore, the present study used a rat model to assess whether the GR or MR are coexpressed with the two forms of 11b-HSD (types 1 and 2) in the placental labyrinth zone, the major site of maternal-fetal transfer, and in the basal zone, the primary site of placental hormone synthesis. In situ hybridization analysis was used to assess messenger RNA (mRNA) expression for the GR, MR, 11b-HSD-1, and 11bHSD-2 in the two placental zones on days 16, 19 and 22 of pregnancy (term 5 day 23). Whereas expression of the GR appeared relatively unchanged in both zones at these three stages of pregnancy, that of 11b-HSD-1 clearly increased in the labyrinth zone but fell in basal zone, whereas the opposite pattern of expression was observed for 11b-HSD-2. MR expression was not detected at any stage. The pattern of placental 11b-HSD-2 mRNA expression over days 16, 19, and 22 of pregnancy was paralleled by changes in 11b-HSD-2-specific bioactivity, but despite clear expression of 11b-HSD-1 mRNA, no bioactivity attributable to this enzyme was measurable in either placental zone. To assess the role of fetal adrenal maturation on these changes in 11b-HSD, two experimental models, maternal adrenalectomy and fetectomy, were employed. Maternal adrenalectomy on day 13 advanced maturation of the fetal adrenal cortex but had no effect on 11b-HSD-2 bioactivity in either of the placental zones at day 19. Placental 11b-HSD-2 bioactivity on day 22 was also unaffected by fetectomy 3 or 6 days earlier. In conclusion, the consistent expression of the GR in the two placental zones late in pregnancy suggests that concomitant and marked changes in 11b-HSD-1 and 11b-HSD-2 expression could have a major influence on glucocorticoid action in the placenta at this time. Moreover, the changes in 11b-HSD expression appear to be unrelated to development of the fetal adrenal cortex and are likely to reduce the placental glucocorticoid barrier near the end of pregnancy. (Endocrinology 139: 1517–1523, 1998) G action in several target organs is regulated by local, tissue-specific expression of the two recognized forms of 11b-hydroxysteroid dehydrogenase (11b-HSD) (types 1 and 2) (for reviews see Refs. 1–3). These enzymes catalyze the interconversion of active glucocorticoids (corticosterone or cortisol) and their biologically inert 11-keto forms (11-dehydrocorticosterone and cortisone, respectively). In the placenta, 11b-HSD activity regulates passage of active glucocorticoid from the mother to the fetus, a critical role in view of the deleterious effects of excess glucocorticoid on fetal growth and subsequent development of disease in postnatal life (3–6). Both 11b-HSD-1 and -2 are expressed in the rat placenta and each exhibits marked, zonespecific changes in expression over the last third of pregnancy (7) concomitant with development of the fetal hypothalamic-pituitary-adrenal (HPA) axis (8). In the basal zone, the major site of placental steroid and peptide hormone synthesis, 11b-HSD-1 messenger RNA (mRNA) expression falls between day 16 and 22 (term 5 day 23), whereas that for 11b-HSD-2 increases over the same period. In contrast, the reverse pattern of increasing 11b-HSD-1 and decreasing 11bHSD-2 mRNA expression is evident in the placental labyrinth zone (7), the major site of maternal-fetal exchange. Whereas such variation is likely to have a major impact on transplacental passage of glucocorticoids, it has also been proposed that placental 11b-HSD may be an important determinant of local glucocorticoid action within the placenta by regulating access of glucocorticoids to their intracellular receptors (7, 9). Therefore, the initial objective of the present work was to assess whether the glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) are coexpressed with the two forms of 11b-HSD in the basal and labyrinth zones of the placenta. Secondly, we addressed the possibility that changes in rat placental 11b-HSD expression are linked Received August 4, 1997. Address all correspondence and requests for reprints to: Dr. Brendan J. Waddell, Department of Anatomy and Human Biology, The University of Western Australia, Nedlands, Perth, Western Australia 6907, Australia. E-mail: [email protected]. * We are grateful for a Wellcome Senior Research Fellowship (to J.R.S.), an MRC Clinician-Scientist Fellowship (to R.W.B.) and a Wellcome Advanced Training Fellowship (to R.B.), which supported these studies. 0013-7227/98/$03.00/0 Vol. 139, No. 4 Endocrinology Printed in U.S.A. Copyright © 1998 by The Endocrine Society