Endometrial decidualization: of mice and men

Among the clinical diseases of the uterus, endometriosis is a major public health concern for women of reproductive age 58 , 59 . It is a reproductive tract disorder in which endometrial tissue is transported by retrograde menstruation and implants ectopically at abnormal sites outside the uterine cavity. Endometriosis is associated with pelvic pain and infertility. Initial attachment of the menstrual tissue, containing both glandular epithelial and stromal elements, at extrauterine sites, such as the pelvic peritoneum and ovarian surface, establishes small early lesions. These lesions proliferate, and invade the underlying tissue, leading to inflammation, and more progressive disease. The origin of the disease and its association with infertility are not well understood. However, ample evidence now exists in support of biochemical abnormalities present in the endometrium (eutopic) of women with endometriosis 60 – 63 . It is thought that this inherently abnormal endometrial tissue predisposes to lesions at ectopic sites. Alterations in the molecular pathways in the eutopic endometrium during implantation are likely to contribute to the infertility in these subjects. Indeed, a number of recent studies revealed dysregulated gene expression in eutopic endometrium of subjects with endometriosis within the window of implantation and indicated impaired differentiation of endometriotic stromal cells in response to P 64 , 65 . Some of the potential mechanisms by which the molecular pathways underlying decidualization are altered in endometriosis are summarized below. Defects in steroid hormone signaling in eutopic and ectopic endometriotic tissues have been described. Reduced expression of the PR-B isoform and P target genes, e.g., 17β-hydroxysteroid dehydrogenase-2 and glycodelin, in endometriotic tissue was also reported 61 , 62 , 66 . Similarly, other gene products that are important for endometrial stromal decidualization such as Hoxa-10 and Hoxa-11 are downregulated in endometriotic tissue 65 . Based on these findings, a hypothesis was forwarded that endometriosis is associated with altered regulation of P-responsive genes, presumably due to an aberrant PR signaling that creates a condition of P resistance in the endometriotic implants. There is also a growing body of evidence indicating that endometriosis is also an E-dependent disease 67 . The expression of aromatase, an enzyme that catalyzes the conversion of testosterone to E, is markedly enhanced in the endometriotic tissue 68 . Recent studies described increased expression of the steroidogenic factor-1 (SF-1), an orphan nuclear receptor that stimulates transcription of aromatase gene, in endometriotic lesions 69 , 70 . Additionally, the promoter region of SF-1 was found to undergo epigenetic changes, including selective DNA demethylation, in endometriotic stromal cells, allowing this factor to be overexpressed and leading to enhanced aromatase expression. It was further suggested that the increased local production of E sustains the growth of endometriotic lesions. Reduced P sensitivity coupled with the increased presence of local E implies that several steroid hormone-regulated molecular pathways might be in a state of imbalance in endometriosis.

In mammals, the onset of pregnancy is heralded by the implantation of an embryo into the uterus, initiating a complex and reciprocal relationship between the mother and the fetus. This maternal-fetal dialogue involves an intimate interaction between the specialized trophectodermal cells of the embryo and the receptive uterine lining of the mother. The steroid hormones estrogen (E) and progesterone (P) play a pivotal role in directing early uterine events during pregnancy. These hormones orchestrate the changes in the uterine epithelium that makes it competent to attach to the blastocyst and initiate the process of implantation 1 , 2 . Subsequently, E and P regulate a series of complex interactions at the interface between the developing embryo and the cells in the stromal compartment, leading to the formation of a differentiated maternal tissue, known as the “ decidua ,” which supports embryo growth and maintains early pregnancy. Although the details of these events vary in different species, the central roles played by E and P in controlling various phases of early pregnancy are common to many mammals 3 . Ultimately, the timely and ordered regulation of the cellular and genetic changes in the endometrial tissue surrounding the implanting embryo is critical for the establishment of early pregnancy. In humans, infertility is one of the most common disturbances of reproductive health, with 10–15% of couples finding it difficult or impossible to conceive. Despite significant advances in assisted reproductive technologies (ART), many couples experience infertility as a result of failed implantation of the fertilized embryos into the uterus and subsequent loss of these embryos. The implantation rates in ART remain low, even with high-quality embryos, pointing to the importance of uterine deficiency during implantation as a major cause of pregnancy failure and infertility 4 . Therefore, it is imperative to gain a clear understanding of the cellular and genetic mechanisms underlying embryo implantation in order to better address clinical approaches to infertility. In this review, we will focus on studies conducted in the mouse, which has served as an important animal model to investigate the regulation of uterine functions by E and P. We will discuss relevant studies conducted in endometrial cultures obtained from human biopsies. We will summarize the biological sequence of events taking place during the process of decidualization following embryo implantation, describe selected steroid hormone-controlled signaling pathways involved in this transformation and discuss how improper decidualization may lead to endometriosis, a clinical condition of endometrial dysfunction.

Infertility in women due to impaired uterine functions is a critical health concern that requires further exploration. The involvement of steroid hormones E and P acting through their cognate receptors is critical to the precise and timely regulation of the endometrial events required for pregnancy. Beginning with embryo attachment, stromal decidualization and eventually vascularization of the endometrium require the appropriate participation of a host of genes that are regulated by E and P ( Figure 1 , Table 1 ). This review has focused on the theme of decidualization as a biological event that is both unique and essential to pregnancy in mice and humans. The use of powerful mouse genetics and manipulation of hESC culture systems, combined with informative gene expression profiling strategies in both mouse and human samples, has made it feasible to pinpoint specific molecular cues to decidualization. These and future studies will serve to illuminate the mechanisms by which E and P regulate uterine function and will serve as a framework in which to explore new therapeutic approaches to human endometrial diseases, particularly those associated with aberrant steroid hormone signaling such as excessive E action or reduced P sensitivity.