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Progestins Regulate the Expression and Activity of the Forkhead Transcription Factor FOXO1 in Differentiating Human Endometrium

Institute of Reproductive and Developmental Biology (S.L., T.K., L.F., M.C.J., J.M.F., G.Z., J.J.B.), Wolfson and Weston Research Centre for Family Health, and Cancer Research-United Kingdom Laboratories and Section of Cancer Cell Biology (P.A.M., R.V., A.E., S.F.d.M., E.W.-F.L.), Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; and Department of Obstetrics and Gynaecology (J.M.H.), Imperial College London, St. Mary’s Hospital, London W2 1PG, United Kingdom

Address all correspondence and requests for reprints to: Jan Brosens, Institute of Reproductive and Developmental Biology, Wolfson & Weston Research Centre for Family Health, Imperial College London, Faculty of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom. E-mail: j.brosens{at}imperial.ac.uk.

Menstruation, or cyclic shedding of nonpregnant endometrial tissue with associated bleeding, occurs only in humans and a few other species. This breakdown of the endometrium in response to falling ovarian progesterone levels is a complex process, characterized by local leukocyte infiltration, expression and activation of matrix metalloproteinases, and apoptosis. Spontaneous decidualization (differentiation) of the stromal compartment precedes the cyclic shedding of the endometrium in various menstruating species but the mechanisms that link these processes are not understood. In this study, we identified FOXO1 as a key transcription factor responsible for mediating apoptosis of decidualized human endometrial stromal cells (HESCs) in response to progesterone withdrawal. We demonstrate that medroxyprogesterone acetate (MPA, a synthetic progestin) enhances the expression of FOXO1 in differentiating HESCs while simultaneously inducing cytoplasmic retention and inactivation of FOXO1. Withdrawal of MPA from decidualized HESCs results in rapid nuclear accumulation of FOXO1, increased BIM expression, a proapoptotic FOXO1 target gene, and cell death. Conversely, silencing of FOXO1 expression completely abolishes cell death induced by MPA withdrawal. In summary, the observation that differentiating HESCs become dependent on progesterone signaling for survival through induction and reversible inactivation of FOXO1 suggests a novel mechanism that links decidualization of the endometrium to menstruation.

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