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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, 11 beta-hydroxysteroid dehydrogenases-1 and -2 (11 beta HSD1,2) 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 11 beta HSD2 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 11 beta HSD2 in endometrium from women with HMB may explain reduced TSP-1 levels and hence endothelial cell dysfunction and abnormal angiogenesis. Inhibition of 11 beta HSD2 may be a rational novel therapy for heavy menstrual bleeding.
- Young Adult
- Thrombospondin 1
- Menstrual Cycle
- RNA, Small Interfering
- Reverse Transcriptase Polymerase Chain Reaction
- 11-beta-Hydroxysteroid Dehydrogenase Type 2
- Menstruation Disturbances
- Middle Aged
- Neovascularization, Pathologic