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

Rae, Mick T; Mohamad, Amirah; Price, Deborah; Hadoke, Patrick W F; Walker, Brian R; Mason, J Ian; Hillier, Stephen G; Critchley, Hilary O D


Amirah Mohamad

Deborah Price

Patrick W F Hadoke

Brian R Walker

J Ian Mason

Stephen G Hillier

Hilary O D Critchley


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


Rae, M. T., Mohamad, A., Price, D., Hadoke, P. W. F., Walker, B. R., Mason, J. I., …Critchley, H. O. D. (2009). Cortisol Inactivation by 11β-Hydroxysteroid dehydrogenase-2 May Enhance Endometrial Angiogenesis via Reduced Thrombospondin-1 in Heavy Menstruation. Journal of Clinical Endocrinology and Metabolism, 94, 1443-1450.

Journal Article Type Article
Acceptance Date Jan 13, 2009
Online Publication Date Jan 21, 2009
Publication Date 2009-04
Deposit Date Mar 27, 2014
Print ISSN 0021-972X
Electronic ISSN 1945-7197
Publisher Endocrine Society
Peer Reviewed Peer Reviewed
Volume 94
Pages 1443-1450
Keywords Heavy menstrual bleeding (HMB; menorrhagia); endothelial cell dysfunction; Inhibition of 11?HSD2; rational novel therapy;
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