Reduced Transforming Growth Factor-β Activity in the Endometrium of Women With Heavy Menstrual Bleeding

CONTEXT: Heavy menstrual bleeding (HMB) is common and incapacitating. Aberrant menstrual endometrial repair may result in HMB. The transforming growth factor (TGF)-β superfamily contributes to tissue repair, but its role in HMB is unknown. OBJECTIVE: We hypothesized that TGF-β1 is important for endometrial repair, and women with HMB have aberrant TGF-β1 activity at menses. PARTICIPANTS/SETTING: Endometrial biopsies were collected from women, and menstrual blood loss objectively measured [HMB >80 mL/cycle; normal menstrual bleeding (NMB) <80 mL]. DESIGN: Immunohistochemistry and reverse transcription polymerase chain reaction examined endometrial TGF-β1 ligand, receptors, and downstream SMADs in women with NMB and HMB. The function and regulation of TGF-β1 were examined using cell culture. RESULTS: TGFB1 mRNA was maximal immediately prior to menses, but no differences detected between women with NMB and HMB at any cycle stage. Histoscoring of TGFB1 revealed reduced staining in the stroma during menses in women with HMB (P < 0.05). There were no significant differences in TGFBR1/2 or TGFBR1/2 immunostaining. Cortisol increased activation of TGFB1 in the supernatant of human endometrial stromal cells (HES; P < 0.05) via thrombospondin-1. Endometrial SMAD2 and SMAD3 were lower in women with HMB during menstruation (P < 0.05), and decreased phosphorylated SMAD2/3 immunostaining was seen in glandular epithelial cells during the late secretory phase (P < 0.05). Wound scratch assays revealed increased repair in HES cells treated with TGF-β1 versus control (P < 0.05). CONCLUSIONS: Women with HMB had decreased TGF-β1 and SMADs perimenstrually. Cortisol activated latent TGF-β1 to enhance endometrial stromal cell repair. Decreased TGF-β1 activity may hinder repair of the denuded menstrual endometrium, resulting in HMB.