The Molecular Basis for Implantation Failure in Endometriosis

Abstract

Endometriosis is a benign gynecologic disorder associated with pelvic pain and infertility, with the latter being due, in part, to failure of embryonic implantation in the maternal endometrium. Adequacy of the endometrium for fertility has been classically investigated by histologic evaluation of a mid-late luteal phase biopsy and, historically, normal histology has been reassuring. However, recent studies demonstrate histologically normal, but biochemically abnormal, endometrium during the window of implantation in some women with endometriosis. In the pregenomic era, a "one-by-one" approach has been adopted to investigate proteins and genes expressed in the window of implantation, and several genes or gene products have been found to be aberrantly expressed in endometrium of women with endometriosis either during the implantation window or at other times of the cycle. Some of these are related to failure of implantation, while others likely contribute to the establishment and growth of endometriotic lesions. The time has come for a genome-wide approach to evaluate uterine endometrium for embryonic implantation. Knowing the biochemical mechanisms underlying normal implantation and the abnormalities in endometriosis will facilitate development of new diagnostic criteria beyond histologic evaluation and will permit identification and validation of molecular targets for future drug discovery. This monograph reviews (a) some of the evidence of compromised fertility in women with endometriosis and treatments targeted to improve their fertility; (b) the concept of the window of implantation; (c) genes/gene products aberrantly expressed in endometrium during the window of implantation or other times of the cycle in women with endometriosis; and (d) the use of microarray technology to investigate endometrial gene expression in human endometrial stromal cells and preliminary data resulting from a collaborative consortium effort of a genome-wide investigation of gene expression in the window of implantation of women with versus without endometriosis.

Expression Profiling of Endometrium from Women with Endometriosis Reveals Candidate Genes for Disease-Based Implantation Failure and Infertility

“…4). In humans, the implantation process begins with attachment of the em-bryo to the endometrial epithelium, intrusion through the epithelium and then invasion into the decidualizing stromal compartment, eventually resulting in anchoring of the conceptus and establishment of the fetal placenta and blood supply (5).…”

DNA Microarray Analysis of Gene Expression in Eutopic Endometrium from Patients with Endometriosis

“…In a study on the molecular mechanism of implantation problem in endometriosis, Giudice et al reported that the products of specific genes were significantly decreased in the endometriosis group compared to the control group in the "window of implantation", which corresponds to the middle period of the secretory stage of the endometrium [8]. These genes were integrin αv and β3, leukemia inhibitory factor (LIF), HOXA-10 and HOXA-11.…”

“…It also added that the expression of other genes in the endometriosis group significantly increased during the embryo implantation and such increased expression may be associated with the onset of endometriosis. Further, there was research reporting that endometriosis patients had aberrant expressions of a certain gene associated with the generation of the disease and impact on the abdominal cavity and other tissues and that such patients' normal uterus linings may look histologically normal but were biochemically abnormal [8] [9] [10]. Based on the above research results, it is inferred that relative over-expression or under-expression of certain genes in endometriosis patients' uterus linings may generate the disease itself or hinder embryo implantation during the implantation period.…”

Fenretinide:A Potential Treatment for Endometriosis

“…Therefore, there is a continued need to study novel pathways involved in disease initiation, maintenance, and progression in order to develop better therapies. 1,[4][5][6] We have recently shown that retinoid uptake, metabolism, and action are deficient in endometriotic cells compared to normal endometrial cells. 7,8 We believe that this decreased expression in genes regulating retinoid uptake and action affects differentiation in endometriotic cells.…”