Leiomyoma Simultaneously Impair Endometrial BMP-2-mediated Decidualization and Anticoagulant Expression Through Secretion of TGF-β3

Context: 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.

Objectives: 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).

Design And Setting: We conducted a case control and in vitro study at a university medical center.

Patients: 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.