Activin-A and myostatin response and steroid regulation in human myometrium: Disruption of their signalling in uterine fibroid

Abstract CONTEXT: Investigation of activin-A (A) and myostatin (M) in human myometrium (HM) and leiomyoma (HL) will explain their involvement in human myometrial pathophysiology. OBJECTIVE: We aimed to investigate A and M response and steroid regulation in HM. We also evaluated A and M expression and response in HL. DESIGN: Tissues were analyzed and cultured. PATIENTS: Patients included fertile (in proliferative phase) and menopausal women undergoing hysterectomy. INTERVENTIONS: HM explant cultures were treated with A and M (for Smad-7 mRNA quantification) or estrogen and progesterone (for A and M mRNA quantification). A and M expression levels were also evaluated in menopausal (physiological absence of steroids) HM specimens. A and M and their receptors were evaluated in HL (n = 8, diameter 5-8 cm) compared with their matched HM. HL explants cultures were treated with A and M (for Smad7 mRNA quantification), and, to explain the absence of response, the levels of follistatin, follistatin-related gene (FLRG), and Cripto were evaluated. RESULTS: A and M increased Smad7 expression in HM explants. A and M mRNAs were both reduced after estradiol treatment, unchanged after progesterone treatment, but were higher in menopausal than fertile (in proliferative phase) specimens. A, M, and FLRG were expressed at higher levels in HL compared with adjacent HM, whereas the receptors, follistatin, and Smad7 mRNAs resulted unchanged. Cripto mRNA was expressed only in HL. CONCLUSIONS: A and M act on human HM and are regulated by steroids. In HL there is an increase of A, M, FLRG, and Cripto expressio