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Cortisol Inactivation by 11β-Hydroxysteroid dehydrogenase-2 May Enhance Endometrial Angiogenesis via Reduced Thrombospondin-1 in Heavy Menstruation

Centre for Reproductive Biology (M.R., A.M., D.P., J.I.M., S.G.H., H.O.D.C.) and Centre for Cardiovascular Science (P.W.F.H., B.R.W.), University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom

Address all correspondence and requests for reprints to: Professor Hilary Critchley, Division of Reproductive and Developmental Sciences, Centre for Reproductive Biology, University of Edinburgh, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ,

Context: Heavy menstrual bleeding (HMB; menorrhagia) impairs quality of life for women and requires medication or surgery. Because glucocorticoids inhibit angiogenesis in other organs, we hypothesized that endometrium of women with HMB is subject to decreased local glucocorticoid exposure and enhanced angiogenesis, thereby increasing menstrual bleeding.

Design: Endometrium was collected from 29 women with menstrual complaints. Menstrual blood loss was measured by alkaline-hematin assay (n = 12, > 80 ml (HMB); n = 17, < 80 ml). Quantitative RT-PCR for thrombospondin-1 (TSP-1) and glucocorticoid-metabolizing enzymes, 11β-hydroxysteroid dehydrogenases-1 and -2 (11βHSD1,2) was performed. Glucocorticoid effects on endometrial stromal cells and uterine endothelial cells (UECs) were determined. RNA interference studies in UECs examined the effect of TSP-1 ablation on cortisol action.

Results: Secretory phase endometrium mRNA levels for the cortisol inactivating enzyme 11βHSD2 were higher [3.78 ± 1.29 vs. 1.40 ± 0.6 (arbitrary units), P < 0.05], whereas TSP-1 mRNA was lower [0.40 ± 0.13 vs. 1.66 ± 1.02 (arbitrary units), P < 0.05] in women with HMB. In cultured endometrial stromal cells and UECs, cortisol increased TSP-1 expression. Both cortisol and TSP-1 inhibited new vessel formation in endometrial explants embedded in Matrigel. In UECs cortisol inhibition of tube-like structure formation was blocked by small interfering RNA (siRNA) against TSP-1 (25 ± 2.5% cortisol inhibition with scrambled siRNA vs. 0% cortisol inhibition with TSP-1 siRNA inactivation, P<0.01).

Conclusions: Enhanced inactivation of cortisol by 11βHSD2 in endometrium from women with HMB may explain reduced TSP-1 levels and hence endothelial cell dysfunction and abnormal angiogenesis. Inhibition of 11βHSD2 may be a rational novel therapy for heavy menstrual bleeding.