11β-hydroxysteroid dehydrogenase type II in the human endometrium: Localization and activity during the menstrual cycle

The 11β-hydroxysteroid dehydrogenase type II enzyme (11βHSD2) is a potent inactivator of glucocorticoids and is present in high amounts in the placental syncytiotrophoblast and sodium-transporting epithelia. Placental 11βHSD2 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 11βHSD (11βHSD1) 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 carboxyterminus of human 11βHSD2 (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 11βHSD2 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 11βHSD2. 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 11βHSD2 and 11βHSD1, 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. 11βHSD2 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 11βHSD2 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 11βHSD1 and 11βHSD2. There was no detectable mineralocorticoid receptor binding in endometrial cytosols prepared from patients with a range of 11βHSD2 activities. It remains to be determined whether elevated or suppressed levels of either isoform are associated with fertility or endometrial pathology.