Cyclic Decidualization of the Human Endometrium in Reproductive Health and Failure

Abstract

Decidualization denotes the transformation of endometrial stromal fibroblasts into specialized secretory decidual cells that provide a nutritive and immunoprivileged matrix essential for embryo implantation and placental development. In contrast to most mammals, decidualization of the human endometrium does not require embryo implantation. Instead, this process is driven by the postovulatory rise in progesterone levels and increasing local cAMP production. In response to falling progesterone levels, spontaneous decidualization causes menstrual shedding and cyclic regeneration of the endometrium. A growing body of evidence indicates that the shift from embryonic to maternal control of the decidual process represents a pivotal evolutionary adaptation to the challenge posed by invasive and chromosomally diverse human embryos. This concept is predicated on the ability of decidualizing stromal cells to respond to individual embryos in a manner that either promotes implantation and further development or facilitates early rejection. Furthermore, menstruation and cyclic regeneration involves stem cell recruitment and renders the endometrium intrinsically capable of adapting its decidual response to maximize reproductive success. Here we review the endocrine, paracrine, and autocrine cues that tightly govern this differentiation process. In response to activation of various signaling pathways and genome-wide chromatin remodeling, evolutionarily conserved transcriptional factors gain access to the decidua-specific regulatory circuitry. Once initiated, the decidual process is poised to transit through distinct phenotypic phases that underpin endometrial receptivity, embryo selection, and, ultimately, resolution of pregnancy. We discuss how disorders that subvert the programming, initiation, or progression of decidualization compromise reproductive health and predispose for pregnancy failure.

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

“…As decidualization progresses, Notch1 is down-regulated (10,11), and this down-regulation is necessary to permit differentiation into the decidual phenotype, which was shown in a previous study (11) and is also shown in this study. Decidualization is dependent on cAMP stimulation, sustained PKA activity, and cAMP response elementbinding protein (CREB) activation (38,39), and N1ICD sequesters nuclear CREB and inhibits cAMP/PKA-mediated signaling (40). When N1ICD is overexpressed, cAMP/PKA-mediated signaling is inhibited.…”

Regulation of androgen action during establishment of pregnancy

“…Decidualisation is the differentiation and proliferation of ESC that is initiated in the secretory phase of the menstrual cycle in response to rising levels of progesterone (reviewed in (Gellersen & Brosens 2014)). Decidualisation is accompanied by increased angiogenesis and leukocyte infiltration (Plaisier 2011) and is unique to species that undergo haemochorial placentation (Vogiagis & Salamonsen 1999).…”

Update of Wnt signaling in implantation and decidualization

“…Stabilized b-catenin induces endometrial glandular hyperplasia and formation, whereas aberrant activation of b-catenin leads to squamous cell metaplasia of the luminal epithelium, uncovering that b-catenin signaling is linked to normal uterine function as well as in tumorigenesis [67]. Conditional deletion of b-catenin in embryonic Müllerian duct mesenchyme resulted in FRT developmental abnormalities: underdeveloped oviducts in the knock-out embryo, stunted FRT development at birth with a decrease in proliferation in the mesenchyme and epithelium, as well as fewer uterine glands and a dramatic defect in the smooth muscle of uterine myometrium in adulthood [68,69]. The similar phenotypes of uncoiled oviducts between Wnt7a knock-out mice and b-catenin mutants raised the possibility that Wnt7a might mediate oviduct coiling in the anterior Müllerian duct through bcatenin-dependent signaling [69].…”

“…Conditional deletion of b-catenin in embryonic Müllerian duct mesenchyme resulted in FRT developmental abnormalities: underdeveloped oviducts in the knock-out embryo, stunted FRT development at birth with a decrease in proliferation in the mesenchyme and epithelium, as well as fewer uterine glands and a dramatic defect in the smooth muscle of uterine myometrium in adulthood [68,69]. The similar phenotypes of uncoiled oviducts between Wnt7a knock-out mice and b-catenin mutants raised the possibility that Wnt7a might mediate oviduct coiling in the anterior Müllerian duct through bcatenin-dependent signaling [69]. Mice with conditional ablation of b-catenin in uteri suffered uterine developmental defects including a reduced overall weight and an impaired glandular formation [67].…”

“…Mice with conditional ablation of b-catenin in uteri suffered uterine developmental defects including a reduced overall weight and an impaired glandular formation [67]. In short, these Wnt ligands perform their momentous functions for uterine development and specifically for glands formation via either b-catenin-dependent or -independent pathway in FRT development and function [69].…”