Prednisolone Alters Endometrial Decidual Cells and Affects Decidual-Trophoblast Interactions.

Eliza Grbac,Swati Varshney,Evdokia Dimitriadis,Teresa So,Ellen Menkhorst,Nicholas Williamson

doi:10.3389/fcell.2021.647496

Abstract

Poor pregnancy outcomes such as recurrent pregnancy loss (RPL) and preeclampsia are associated with impaired decidualization and abnormal trophoblast invasion. Emerging evidence suggests that use of corticosteroids, including prednisolone affects fertility by altering uterine function and may be associated with preeclampsia incidence. In this study, using primary and gestational-age appropriate tissue, we aimed to define the effect of prednisolone on human endometrial stromal fibroblast (hESF) decidualization and determine whether hESF decidualization in the presence of prednisolone would alter hESF regulation of trophoblast function. We found that prednisolone treatment reduced hESF cytokine expression (IL6, IL11, IL18, LIF, and LIFR) but had no effect on hESF expression or secretion of the classic markers of decidualization [prolactin (PRL) and IGFBP1]. Using proteomics we determined that prednisolone altered decidualized hESF protein production, enriching hESF proteins associated with acetylation and mitrochondria. Conditioned media from hESF decidualized in the presence of prednisolone significantly enhanced trophoblast outgrowth and trophoblast mRNA expression of cell motility gene PLCG1 and reduced trophoblast production of PGF. Prednisolone treatment during the menstrual cycle and 1st trimester of pregnancy might alter decidual interactions with other cells, including invasive trophoblast.

Highlights

To prepare for embryo implantation and pregnancy, uterine endometrial stromal fibroblast [human(h)ESF] differentiate or “decidualize” in response to progesterone to become decidual cells (Evans et al, 2016)
We determined whether prednisolone could directly regulate genes associated with decidualization: prednisolone had no effect on PRL, insulin-like growth factor binding protein 1 (IGFBP1) (Figure 1C), bone morphogenic protein (BMP) 2, BMP7, homeobox A (HOXA) 10, or inhibinβA (INHBA) production, but significantly inhibited IL11, Leukemia inhibitory factor (LIF; eightfold), and LIF receptor (LIFR; twofold) mRNA expression (Figure 1D)
There was no effect of prednisolone on decidualized human endometrial stromal fibroblast (hESF) glucocorticoid receptor (GR) (Figure 2C), PRL, IGFBP1 (Figure 2D), BMP2, BMP7, HOXA10, IL11, INHBA, LIF, LIFR (Figure 2E), endoglin (ENG), vascular endothelial growth factor receptor (FLT1), or placental-like growth factor (PGF) production (Figure 2F)

Summary

Introduction

To prepare for embryo implantation and pregnancy, uterine endometrial stromal fibroblast [human(h)ESF] differentiate or “decidualize” in response to progesterone to become decidual cells (Evans et al, 2016). During implantation extravillous trophoblast (EVT) invades into the decidualized endometrium (decidua) and upper third of the myometrium (Lunghi et al, 2007). Murine models suggest that prednisolone or other corticosteroid administration during early pregnancy affects fertility and pregnancy outcome via actions on the uterus (Matejevic et al, 1995; Li et al, 2018; Kieffer et al, 2020), the precise impact of these drugs on endometrial cells is unknown

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