Abstract
Mucosal integrity in the endometrium is essential for immune protection. Since breaches or injury to the epithelial barrier exposes underlying tissue and is hypothesized to increase infection risk, we determined whether endogenous progesterone or three exogenous progestins (medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG)) used by women as contraceptives interfere with wound closure of endometrial epithelial cells and fibroblasts in vitro. Progesterone and LNG had no inhibitory effect on wound closure by either epithelial cells or fibroblasts. MPA significantly impaired wound closure in both cell types and delayed the reestablishment of transepithelial resistance by epithelial cells. In contrast to MPA, NET selectively decreased wound closure by stromal fibroblasts but not epithelial cells. Following epithelial injury, MPA but not LNG or NET, blocked the injury-induced upregulation of HBD2, a broad-spectrum antimicrobial implicated in wound healing, but had no effect on the secretion of RANTES, CCL20 and SDF-1α. This study demonstrates that, unlike progesterone and LNG, MPA and NET may interfere with wound closure following injury in the endometrium, potentially conferring a higher risk of pathogen transmission. Our findings highlight the importance of evaluating progestins for their impact on wound repair at mucosal surfaces.
Highlights
Mucosal integrity in the endometrium is essential for immune protection
Since progestins are used by millions of women worldwide[10], and may be detrimental for barrier integrity[25], we investigated whether in vitro wound closure of monolayers of endometrial epithelial cells and stromal fibroblasts is modulated by exposure to progestins
We demonstrate that medroxyprogesterone acetate (MPA) transiently inhibits wound closure by endometrial epithelial cells, while both MPA and NET inhibit wound closure by stromal fibroblasts in vitro
Summary
Mucosal integrity in the endometrium is essential for immune protection. Since breaches or injury to the epithelial barrier exposes underlying tissue and is hypothesized to increase infection risk, we determined whether endogenous progesterone or three exogenous progestins (medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG)) used by women as contraceptives interfere with wound closure of endometrial epithelial cells and fibroblasts in vitro. Rapid recovery of the upper FRT mucosal surface from these disruptions is necessary for reproductive health and survival Synthetic progestins such as medroxyprogesterone acetate (MPA), norethindrone (NET) and levonorgestrel (LNG) are administered to millions of women for multiple reasons including contraception, menopausal hormone replacement therapy, endometriosis, and cancer[7,8,9]. NET selectively inhibits wound closure by fibroblasts but not epithelial cells while progesterone and LNG have no effect on either cell type This suggests that specific progestins, unlike endogenous progesterone, can selectively compromise wound closure and recovery of mucosal barrier function following injury in the upper FRT, increasing the potential for pathogens to enter the underlying stromal tissue and compromise reproductive health.
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