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11ß-Hydroxysteroid Dehydrogenase Type II in the Human Endometrium: Localization and Activity during the Menstrual Cycle¹

Laboratories of Molecular Hypertension (R.E.S., K.X.Z.L., Z.K.) and Molecular Physiology (P.A.K., K.M.M.) Baker Medical Research Institute, Prahran; Prince Henry’s Institute of Medical Research, Clayton (L.A.S.); and the Department of Obstetrics and Gynecology, Monash University (M.L.), Melbourne, Australia

Address all correspondence and requests for reprints to: Dr. Z. Krozowski, Molecular Hypertension Laboratory, Baker Medical Research Institute, P.O. Box 348, Prahran 3181, Australia. E-mail: zygmunt.krozowski{at}baker.edu.au

The 11ß-hydroxysteroid dehydrogenase type II enzyme (11ßHSD2) is a potent inactivator of glucocorticoids and is present in high amounts in the placental syncytiotrophoblast and sodium-transporting epithelia. Placental 11ßHSD2 is thought to protect the fetus from high circulating levels of maternal glucocorticoids, whereas the renal enzyme is important in conferring aldosterone specificity on the mineralocorticoid receptor. An isoform of 11ßHSD (11ßHSD1) is also present in a wide range of tissues, but usually acts as an oxoreductase, converting the biologically inactive cortisone to cortisol. In the present study we have used an immunopurified antibody to the carboxy-terminus of human 11ßHSD2 (HUH23) to demonstrate localization of the enzyme in luminal and glandular epithelia of human endometrium. In some specimens staining was uniformly distributed, but in others there was clear evidence of heterogeneity both between and within epithelia. Although 11ßHSD2 was found mainly in the cytoplasm, some cells showed evidence of nuclear staining only. Western blot analysis showed a band at 41 kDa in endometrium and myometrium, confirming the presence of 11ßHSD2. Measurement of activity throughout the menstrual cycle showed that mean levels (±SEM) of activity were 156 ± 17 and 6.1 ± 1.1 pmol product/min·g homogenate protein for 11ßHSD2 and 11ßHSD1, respectively. Patients taking combined estrogen/progesterone contraceptives had significantly lower activities of both enzymes (76 ± 19 and 1.9 ± 0.4; both P < 0.01) compared with the control group. 11ßHSD2 activity was significantly higher in the secretory than in the proliferative phase of the cycle in controls (193 ± 22 vs. 120 ± 23; P < 0.05). All groups contained outliers with elevated enzyme activities, with some patients displaying 11ßHSD2 levels comparable to those observed in human kidney (>1000 pmol/min·g). Further analysis showed that there was a statistically significant correlation (r = 0.43; P < 0.001) between the levels of 11ßHSD1 and 11ßHSD2. There was no detectable mineralocorticoid receptor binding in endometrial cytosols prepared from patients with a range of 11ßHSD2 activities. It remains to be determined whether elevated or suppressed levels of either isoform are associated with fertility or endometrial pathology.

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