Leiomyoma-derived transforming growth factor-β impairs bone morphogenetic protein-2-mediated endometrial receptivity

Objective: To determine whether transforming growth factor (TGF)-beta 3 is a paracrine signal secreted by leiomyoma that inhibits bone morphogenetic protein (BMP)-mediated endometrial receptivity and decidualization. Design: Experimental. Setting: Laboratory. Patient(s): Women with symptomatic leiomyomas. Intervention(s): Endometrial stromal cells (ESCs) and leiomyoma cells were isolated from surgical specimens. Leiomyoma-conditioned media (LCM) was applied to cultured ESC. The TGF-beta was blocked by two approaches: TGF-beta pan-specific antibody or transfection with a mutant TGF-beta receptor type II. Cells were then treated with recombinant human BMP-2 to assess BMP responsiveness. Main Outcome Measure(s): Expression of BMP receptor types 1A, 1B, 2, as well as endometrial receptivity mediators HOXA10 and leukemia inhibitory factor (LIF). Result(s): Enzyme-linked immunosorbent assay showed elevated TGF-b levels in LCM. LCM treatment of ESC reduced expression of BMP receptor types 1B and 2 to approximately 60% of pretreatment levels. Preincubation of LCM with TGF-beta neutralizing antibody or mutant TGF receptor, but not respective controls, prevented repression of BMP receptors. HOXA10 and LIF expression was repressed in recombinant human BMP-2 treated, LCM exposed ESC. Pretreatment of LCM with TGF-beta antibody or transfection with mutant TGF receptor prevented HOXA10 and LIF repression. Conclusion(s): Leiomyoma-derived TGF-beta was necessary and sufficient to alter endometrial BMP-2 responsiveness. Blockade of TGF-beta prevents repression of BMP-2 receptors and restores BMP-2-stimulated expression of HOXA10 and LIF. Blockade of TGF signaling is a potential strategy to improve infertility and pregnancy loss associated with uterine leiomyoma. (Fertil Steril (R) 2015; 103: 845-52. (C) 2015 by American Society for Reproductive Medicine.)