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

Abstract

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.

Overexpression of microRNA‐542‐3p attenuates the differentiating capacity of endometriotic stromal cells

“…In the absence of pregnancy, luteolysis and falling ovarian progesterone levels induce a cascade of events in the endometrium of menstruating species, leading to proteolytic breakdown, shedding of the functional layer, and bleeding. The notion that decidualization in the absence of pregnancy is causally linked to menstruation is supported by several other lines of evidence 21. The behavior of the endometrium in patients with endometriosis could be attributed to the aberrant transport of the decidual phenotype endometrium into the peritoneal cavity.…”

Expression, activation, and role of AKT isoforms in the uterus

“…This reduction has been shown to be responsible for the increased FoxO1 translocation to endometrial stromal cell nuclei. This effect can be explained by the inhibition of AKTdependent phosphorylation of FoxO1 which usually results in its cytoplasmic sequestration (Labied et al 2006. As FoxO1 is of crucial importance in the regulation of progesterone response in endometrial cells , Kajihara et al 2013, it is plausible that the modulation of AKT activity is of crucial importance in the establishment of decidualization.…”

FOXO1 Transcription Factor Inhibits Luteinizing Hormone β Gene Expression in Pituitary Gonadotrope Cells

“…Although disruption of FOXO4 has no overt phenotype, FOXO3 null mice have an age-dependent reduction in fertility caused by defective follicular growth in the ovary similar to premature ovarian failure in women (44). In addition to genetic analyses, mechanistic studies have established a role for FOXOs in reproductive tissues, such as the ovary and uterus (45)(46)(47)(48)(49)(50)(51)(52), but the function of FOXOs in the neuroendocrine control of reproduction remains to be elucidated.…”