title: Cortisol inactivation by 11beta-hydroxysteroid dehydrogenase-2 may enhance endometrial angiogenesis via reduced thrombospondin-1 in heavy menstruation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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, 11beta-hydroxysteroid dehydrogenases-1 and -2 (11betaHSD1,2) 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 11betaHSD2 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 11betaHSD2 in endometrium from women with HMB may explain reduced TSP-1 levels and hence endothelial cell dysfunction and abnormal angiogenesis. Inhibition of 11betaHSD2 may be a rational novel therapy for heavy menstrual bleeding.
authors.affiliation: Centre for Reproductive Biology, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Mick
authors.initials: M
authors.lastname: Rae
authors.forename: Amirah
authors.initials: A
authors.lastname: Mohamad
authors.forename: Deborah
authors.initials: D
authors.lastname: Price
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: J Ian
authors.initials: JI
authors.lastname: Mason
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Hillier
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors*; D000328:Adult; D004717:Endometrium / Q000098:blood supply* / Q000201:enzymology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008595:Menorrhagia / Q000188:drug therapy* / Q000473:pathology; D008597:Menstrual Cycle; D008599:Menstruation Disturbances / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D008833:Microcirculation; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D012313:RNA; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006854:Hydrocortisone