Functional evidence for two distinct mechanisms of action of progesterone and selective progesterone receptor modulator on uterine leiomyomas.

OBJECTIVE: To study the specific mechanisms through which progesterone and selective progesterone receptor modulators impact the growth and synthesis/accumulation of the extracellular matrix in uterine leiomyomas.

DESIGN: Laboratory study.

SETTING: Academic Research Institutions.

PATIENTS (S): This study involved reproductive-age women diagnosed with infertility-associated uterine leiomyomas, who underwent myomectomy either after selective progesterone receptor modulator ulipristal acetate treatment or without any pharmacological pre-treatment. Control samples included healthy myometrium tissue (n=100). Specimens were obtained from the Department of Reproduction and Gynecological Endocrinology and Biobank, Medical University of Bialystok, Poland.

INTERVENTIONS: Daily 5mg/day ulipristal acetate treated for 2 months (n=100) and untreated (n=150) patients with uterine leiomyomas or normal healthy myometrium (n=100) tissue samples immediately after surgery collected for the transcriptional analysis and assessments.

MAIN OUTCOME MEASURES: Progesterone-induced activation of the signaling pathways related to uterine leiomyomas extracellular matrix synthesis/deposition/growth, as well as the expression profile of progesterone receptors in uterine leiomyomas, were assessed.

RESULTS: The results indicated that progesterone activated the transforming growth factor-β/SMAD3 signaling pathways and promoted proliferation, growth, and extracellular matrix remodeling in uterine leiomyomas by upregulating SMAD3, transforming growth factor-β receptor type 1/II, RhoA, vascular endothelial growth factor or increasing the fibrosis-related gene collagen, type I, alpha 1 and pro-collagen, type I, alpha 1 production. In contrast, ulipristal acetate had inhibitory effects on these processes. The study also showed that both nuclear and membrane progesterone receptors play distinct roles in uterine leiomyomas pathobiology.

CONCLUSIONS: We showed that both nuclear and membrane progesterone receptors were relevant in the treatment of uterine leiomyomas, especially when combined with selective progesterone receptor modulators. Novel therapeutic approaches combining selective progesterone receptor modulators with or without direct/indirect extracellular matrix targeting through selected specific transforming growth factor-β/SMAD3 (SMAD3, transforming growth factor-β receptor type 1/II, RhoA, vascular endothelial growth factor, collagen, type I, alpha 1) signaling pathway could therefore be a treatment option for uterine leiomyomas.