Age-related changes in murine myometrial transcript profile are mediated by exposure to the female sex hormones

Abstract

In humans, the risk of operative first delivery increases linearly with maternal age. We previously hypothesized that prolonged, cyclical, pre-pregnancy exposure to estrogen and progesterone contributes to uterine aging. Here we test this hypothesis. Myometrium was obtained from four groups of virgin mice: (1) 10-12 week and 28-30 week old; (2) 10-12 week and 38-40 week old; (3) 38 week old mice that had an ovariectomy or sham operation early in life; (4) 38 week old mice that had been treated with progesterone or vehicle containing implants from 8-36 weeks. Transcript profiling was carried out using Affymetrix Gene ST 1.1 arrays and data were normalized. We identified 60 differentially regulated transcripts associated with advancing age (group 1). We validated these changes in group 2 (P for overlap = 5.8x10-46). Early ovariectomy prevented the age-related changes in myometrial transcript profile. Similarly, progesterone mediated long-term ovarian suppression prevented the age-related changes in myometrial transcript profile. Interferon regulatory factor 7 (Irf7) mRNA was regulated by age and hormonal exposure, and was identified as a predicted regulator of the other differentially expressed transcripts by both promoter sequence and canonical pathway activation analysis (P= 8.47x10-5 and P<10-10, respectively). Immunohistochemistry demonstrated IRF7 in both mouse and human myometrium. We conclude: (1) Myometrial aging in mice is associated with reproducible changes in transcript profile; (2) These changes can be prevented by interventions which inhibit cyclical changes in the female sex hormones; (3) IRF7 may be an important regulator of myometrial function and aging.