Endometriosis is a disease associated with the presence of implants of endometrium outside the uterine cavity. The disease affects 10% of reproductive-age women and is associated with pelvic pain and infertility, including lowered embryo implantation rates. In advanced endometriosis, extensive pelvic adhesions cause mechanical impedance, resulting in infertility. However, the low implantation rates seen in endometriosis occur independently of disease stage, including patients undergoing treatment for infertility with in vitro fertilization. It is likely that multiple mechanisms in addition to mechanical obstruction may result in infertility associated with the disease. We have identified the aberrant expression of multiple molecular markers of implantation in the endometrium of women with endometriosis and in the ectopic implants.
We identified diminished HOXA10 expression as a potential mechanism of diminished implantation in women with endometriosis. We subsequently identified the endometrial expression of the EMX2 gene (a HOXA10 target gene) and found that low secretory phase endometrial HOXA10 levels were associated with elevated endometrial EMX2 mRNA levels, likely due to a failure of HOXA10-mediated transcriptional repression. To confirm that high endometrial EMX2 expression is due to decreased transcriptional suppression by HOXA10, we tested this regulation in an in vitro model. Using HOXA10 antisense to artificially suppress endogenous HOXA10 protein levels in primary endometrial stromal cells, we created an in vitro model of HOXA10-deficient endometrium as seen in endometriosis. We cotransfected endometrial stromal cells with HOXA10 antisense and the same EMX2-luciferase reporter construct containing HOXA10 binding sites in the EMX2 regulatory region as described above. Cotransfection with HOXA10 antisense resulted in increased EMX2 expression, indicating that endogenous HOXA10 is sufficient to suppress endometrial EMX2; as expected, lowering levels of HOXA10 released EMX2 from transcriptional repression. EMX2 expression was increased in women with endometriosis. Increased EMX2 expression resulted in diminished implantation in a mouse model. Both HOXA10 and EMX2 are essential for optimal implantation and pregnancy.
Additionally, we are determining the expresssion of HOX genes in the ectopic endometrium of women with endometriosis. We have demonstrated that endometriosis expresses HOXA10 in locations outside of the normal HOXA10 expression domain. Nuclear HOXA10 stromal and glandular expression was found in pelvic peritoneal ectopic endometrial tissue, ovarian endometriomas and in lung parencyhmal tissue with endometriosis. HOXA10 expression, even in distant disease outside of its normal expression domain, suggests that HOXA10 is necessary to impart endometrial developmental identity on endometriosis. The diminished expression of HOXA10 in ectopic endometrial implants compared to eutopic endometrium may not allow for normal endometrial development.
Finally we have proposed a new theory for the origin of endometriosis. We have determined that endometrium can arise from bone marrow derived stem cells. Some endometriosis may arise by ectopic transdifferentiation of stem cells, rather than from retrograde menstruation.
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