Induction of 11β-HSD 1 and Activation of Distinct Mineralocorticoid Receptor- and Glucocorticoid Receptor-Dependent Gene Networks in Decidualizing Human Endometrial Stromal Cells

Abstract

The actions of glucocorticoids at the feto-maternal interface are not well understood. Here, we show that decidualization of human endometrial stromal cells (HESCs) in response to progesterone and cAMP signaling is associated with a strong induction of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) expression and enzyme activity. Decidualization also triggered a gradual decrease in glucocorticoid receptor (GR) expression and reciprocal increase in mineralocorticoid receptor (MR) levels. Gene expression profiling of differentiating HESCs after small interfering RNA (siRNA)-mediated knockdown of either GR or MR identified 239 and 167 significantly regulated genes, respectively. Interestingly, GR-repressed genes were enriched for Krüppel-associated box domain containing zinc-finger proteins, transcriptional repressors involved in heterochromatin formation. In agreement, GR knockdown was sufficient to enhance trimethylated H3K9 levels in decidualizing cells. Conversely, we identified several MR-dependent genes implicated in lipid droplet biogenesis and retinoid metabolism. For example, the induction in differentiating HESCs of DHRS3, encoding a highly conserved enzyme that catalyzes the oxidation/reduction of retinoids and steroids, was enhanced by aldosterone, attenuated in response to MR knockdown, and abolished upon treatment with the MR antagonist RU26752. Furthermore, we demonstrate that decidualization is associated with dynamic changes in the abundance and distribution of cytoplasmic lipid droplets, the formation of which was blocked by RU26752. In summary, progesterone drives local cortisol biosynthesis by decidual cells through induction of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), leading to transcriptional regulation of distinct GR and MR gene networks involved in epigenetic programming and lipid and retinoid metabolism, respectively.

Decidualization is Impaired in Endometrial Stromal Cells from Uterine Rudiments in Mayer-Rokitansky-Küster-Hauser Syndrome

“…PGR knockout female mice exhibited similar deficiencies accompanied by implantation defects and the absence of ESC decidualization after progesterone stimulation [32, 36]. Moreover, whether other steroid hormones such as testosterone, mineralocorticoids or glucocorticoids are involved, is warranted given its role in decidualization [37, 38]. …”

Physiological and pathological implications of retinoid action in the endometrium

“…Perturbed or inadequate decidualization leads to embryo miscarriage and early pregnancy failure (Kommagani et al 2013). Accompanied by typical morphological changes, differentiating stromal cells express biochemical decidual markers, such as prolactin (PRL), insulin-like growth factor-binding protein-1 (IGFBP1) (Irwin et al 1994, Brar et al 1997) and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) (Brosens et al 1999, Kuroda et al 2013. Data from Ozaki et al (2017) showed that RARs, as well as CRABP2 and FABP5, which are responsible for binding and delivering RA to nuclear receptors RARs and PPARβ/δ respectively, decreased in decidualizing human endometrial stromal cells despite an increase in PPARβ/δ.…”

“…RA plays fundamental roles in the normal maintenance of endometrial physiology (Zheng et al 2000, Sidell et al 2002, Ding et al 2003, Kuroda et al 2013, and aberrant RA metabolism might be a predisposing factor for the development of endometriosis (Pavone et al 2011, Wieser et al 2012, Pierzchalski et al 2014, Yamagata et al 2015. However, a comprehensive and systematic analysis and understanding of RA pathway in endometrial physiology and pathology remain lacking.…”

Is adenomyosis a problem in reproduction and fertility?

“…Nevertheless, the activity of steroid hormones in the uterus is primarily mediated by the uterine microenvironment. Stromal and immune cells present in the uterine milieu regulate angiogenesis and vascular remodeling (Kuroda et al 2013). Many pro-angiogenic and anti-angiogenic modulators are expressed in the endometrium (Becker et al 2006, Saǧsöz andSaruhan 2011).…”