title: Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-β3.
abstract: BACKGROUND
  Uterine leiomyomas occur in 30-70% of reproductive-age women. Leiomyoma reduce implantation, increase miscarriage risk, and increase menstrual bleeding. We hypothesized that endometrial defects induced by leiomyoma result in menorrhagia and reproductive dysfunction.
  
  
  OBJECTIVE
  We evaluated the effect of leiomyoma on endometrial gene expression essential for implantation and hemostasis both in vivo and in primary endometrial stromal cells (ESC).
  
  
  METHODS
  We conducted a case control and in vitro study at a university medical center.
  
  
  METHODS
  The study included 24 subjects with or without leiomyoma. INTERVENTION/MAIN OUTCOME MEASURED: Endometrium, myometrium, leiomyoma, and ESC were obtained. Immunohistochemistry was used to evaluate TGF-β3, bone morphogenetic protein (BMP) receptors (BMPRs), plasminogen activator inhibitor 1 (PAI-1), and thrombomodulin in vivo. BMP-2 secretion was assessed by ELISA. ESC were treated with recombinant human (rh) BMP-2 or rhTGF-β3. Expression of HOXA10, LIF, BMPRs, antithrombin III (ATIII), thrombomodulin, and PAI-1 was assessed by quantitative RT-PCR.
  
  
  RESULTS
  ESC from controls secreted more BMP-2 than those from women with leiomyoma. HOXA10 and LIF expression increased after rhBMP-2 treatment of normal but not leiomyoma-associated ESC. In vivo leiomyoma-associated endometrium expressed lower levels of BMPR 1A, 1B, and 2 than controls. Leiomyoma expressed high levels of TGF-β3; TGF-β3 treatment of ESC reduced expression of BMPRs. Similarly, leiomyoma-associated endometrium expressed less PAI-1 and thrombomodulin in vivo. In ESC, TGF-β3 reduced expression of PAI-1, ATIII, and thrombomodulin.
  
  
  CONCLUSIONS
  Leiomyoma-secreted TGF-β3 induces BMP-2 resistance in endometrium by down-regulation of BMPR-2, likely causing defective endometrial decidualization. TGF-β3 also reduces expression of PAI-1, ATIII, and thrombomodulin in endometrium, likely contributing to menorrhagia. A single molecular signal targeting endometrium may mediate both leiomyoma-induced infertility and bleeding.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
authors.forename: Donna C
authors.initials: DC
authors.lastname: Sinclair
authors.forename: Alex
authors.initials: A
authors.lastname: Mastroyannis
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000990:Antithrombin III / Q000502:physiology; D001777:Blood Coagulation / Q000235:genetics*; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis* / Q000502:physiology*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003656:Decidua / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007247:Infertility, Female / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007889:Leiomyoma / Q000150:complications / Q000235:genetics / Q000473:pathology*; D008595:Menorrhagia / Q000209:etiology / Q000473:pathology; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000502:physiology; D018180:Thrombomodulin / Q000502:physiology; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000502:physiology*; D014594:Uterine Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology*
chemical_list: D055396:Bone Morphogenetic Protein 2; D018076:DNA, Complementary; D017395:Plasminogen Activator Inhibitor 1; D018180:Thrombomodulin; D053782:Transforming Growth Factor beta3; D012313:RNA; D000990:Antithrombin III