Ulipristal acetate decreases active TGF-β3 and its canonical signaling in uterine leiomyoma via two novel mechanisms

Objective: To characterize the effect of ulipristal acetate (UPA) treatment on transforming growth factor (TGF) canonical and noncanonical signaling pathways in uterine leiomyoma tissue and cells. UPA decreased extracellular matrix in surgical specimens; we characterize the mechanism in this study. Design: Laboratory study. Setting: University. Intervention(s): Exposure of leiomyoma cell lines to UPA. Main Outcome Measure(s): RNAseq was performed on matched myometrium and leiomyoma surgical specimens of placebo- and UPA-treated patients. Changes in gene expression and protein were measured using quantitative polymerase chain reaction and western immunoblot analysis, respectively. Result(s): In surgical specimen, mRNA for TGF-beta 3 was elevated 3.75-fold and TGFR2 was decreased 0.50-fold in placebo leiomyomas compared with myometrium. Analysis of leiomyomas from UPA-treated women by western blot revealed significant reductions of active TGF-beta 3 (0.64 +/- 0.12-fold), p-TGFR2 (0.56 +/- 0.23-fold), pSmad 2 (0.54 +/- 0.04-fold), and pSmad 3 (0.65 +/- 0.09-fold) compared with untreated leiomyomas. UPA treatment demonstrated statistically significant reduction in collagen 1, fibronectin, and versican proteins. Notably, there was a statistically significant increase of the extracellular matrix protein fibrillin in leiomyoma treated with UPA (1.48 +/- 0.41-fold). Data from in vitro assays with physiologic concentrations of UPA supported the in vivo findings. Conclusion(s): TGF-beta pathway is highly up-regulated in leiomyoma and is directly responsible for development of the fibrotic phenotype. UPAattenuates this pathway by reducingTGF-beta 3 message and protein expression, resulting in a reduction inTGF-beta canonical signaling. In addition, UPA significantly increased fibrillin protein expression, which can serve to bind inactive TGF-beta complexes. Therefore, UPA inhibits leiomyoma fibrosis by decreasing active TGF-beta 3 and diminishing signaling through the canonical pathway. (C) 2019 by American Society for Reproductive Medicine.