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.
The fetomaternal interface, consisting of the maternal decidua and the invading fetal trophoblast, critically regulates placental function and the growth and development of the conceptus. In its broadest sense, decidualization could be viewed as the postovulatory process of endometrial remodeling in preparation for pregnancy, which includes secretory transformation of the uterine glands, influx of specialized uterine natural killer cells, and vascular remodeling. A more restricted definition of the decidual process denotes the morphological and biochemical reprogramming of the endometrial stromal compartment. This differentiation process is dependent entirely on the convergence of the cyclic adenosine monophosphate and progesterone signaling pathways that drives integrated changes at both the transcriptome and the proteome level. As a consequence, decidualizing stromal cells acquire the unique ability to regulate trophoblast invasion, to resist inflammatory and oxidative insults, and to dampen local maternal immune responses. In humans, decidualization of the stromal compartment occurs in the mid-luteal phase of the menstrual cycle, independently of pregnancy. This raises the possibility that biochemical analysis of timed endometrial biopsy samples taken in a nonconception cycle could be informative of subsequent pregnancy outcome.
During the menstrual cycle, the ovarian hormones oestradiol and progesterone control the ordered growth and differentiation of uterine cells. This remodelling process is critical for implantation of the developing embryo, the formation of the placenta, and maintenance of pregnancy. Failure of uterine tissues to respond appropriately to ovarian hormone signalling results in defective placentation, associated with a spectrum of pregnancy disorders such as recurrent miscarriages and preeclampsia. These obstetrical disorders are a major cause of maternal and perinatal morbidity and mortality. Progesterone exerts its action on target cells, at least in part, through binding to the progesterone receptor (PR), a member of the steroid/ thyroid hormone receptor superfamily of ligand-activated transcription factors. The mechanism by which progesterone controls the differentiation of human endometrial stromal cells, a process termed decidualization, in the secretory phase of the menstrual cycle is not well understood. Emerging evidence indicates that locally expressed factors and activation of the cAMP second messenger pathway integrate hormonal inputs and confer cellular specificity to progesterone action through the induction of diverse transcription factors capable of modulating PR function.
During the menstrual cycle, ovarian estradiol and progesterone stimulate the ordered growth and differentiation of endometrial tissue compartments. In the human, this includes synchronous growth and coiling of the spiral arteries, secretory transformation of glandular epithelium, migration of bone marrow-derived cells, and decidualization of the stroma, which is thought to be essential for blastocyst implantation and subsequent formation of a hemochorial placenta. Decidualization of human endometrial stromal (ES)
Identification of the mechanisms and receptors that relay rapid progesterone signalling is an area of research fraught with difficulties and controversy. More in-depth characterization of the putative receptors is required before the non-genomic progesterone pathway in normal and pathological reproductive function can be targeted for pharmacological intervention.
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