A receptive endometrium is characterized by abundant secretory activity (22
). Many genes are expressed during the window of implantation, but their functional roles remain unclear (2
). We evaluated the expression of four proteins known or suspected to be involved in the embryonic implantation process, in women with endometriosis and healthy volunteers.
In women, OPN has been associated with glandular epithelial cells during the secretory phase and in increasing concentrations in uterine secretions during the mid-to-late secretory phase during which implantation would be expected to occur (11
). We found a dramatic decrease of OPN expression in the mid-late secretory phase endometrium from patients with endometriosis. The current report extends previous findings indicating that osteopontin mRNA is reduced in the early secretory phase of women with moderate-to-severe endometriosis (4
). An earlier report of patients with endometriosis suggested reduced OPN binding to the surface epithelium, but only in cases where αv
was decreased (24
). Taken together, these data support the hypothesis that reduced osteopontin production or binding may be involved in subfertility of endometriosis patients.
This study is the first to show decreased expression of LPA3 in the mid- and late secretory phase endometrial epithelium from patients with endometriosis. Low expression of Cox2 in LPA3 null mice results in low production of prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), leading to low vascular permeability and endometrial adhesiveness and delayed implantation. By extrapolation, decreased expression of the receptor in women may reduce fertility.
We found decreased expression of HOXA10 in the mid- and late secretory phase glands and stroma from endometriosis patients. The current study also confirmed previous reports localizing the expression of HOXA10 to both stromal and glandular cells, and also reports showing reduced HOXA10 expression in the mid-secretory phase endometrium of women with endometriosis (16
). In contrast to one previous report, we found decreased HOXA10 expression in the stromal cells as well as the glands. Findings that baboons with endometriosis and decreased HOXA10 expression also have reduced expression of beta3 integrin suggests a possible mechanism by which HOXA10 deficiency might impair fertility (26
). While mice lacking HOXA10 showed decreased litter size due to failure of implantation (14
), decreased HOXA10 expression has been described in women with other disorders associated with infertility, suggesting a role in human receptivity defects (27
Our finding of reduced glycodelin expression in the epithelial endometrium of women with endometriosis confirms previous findings that mRNA expression is reduced in these women (4
). As the major secretory protein of the endometrium, glycodelin has been suspected to have a role in implantation. A previous study of women with unexplained infertility supported this hypothesis by demonstrating that infertile women had a marked decrease in immunohistochemical staining of endometrial glycodelin during the implantation window compared to fertile controls (28
). Others have also noted decreased glycodelin levels in uterine flushings of women with endometriosis (29
It is important to emphasize that the women in these studies were not chosen based on a history of infertility. Thus further studies in women attempting pregnancy or with infertility are need to establish a more causal association of abnormal markers with abnormal endometrial function.
The reduced expression of these putative biomarkers of implantation provides additional evidence for an abnormal endometrium, and in particular, abnormal epithelial function, in women with endometriosis. Most of these women had mild endometriosis, suggesting that endometrial abnormalities are intrinsic to the disorder and are not a late manifestation. The underlying mechanisms for these differences in peptide expression are not clear and the design of this descriptive study did not examine whether message is reduced or whether there is a post-transcriptional abnormality.
Although the markers studied all have a progesterone-responsive element(s) in their promoter region, and the blood progesterone level is reportedly normal in women with endometriosis, we found reduced expression of these genes. This supports previous speculation of progesterone resistance in eutopic endometrium from women with endometriosis (2
). In aggregate, these studies demonstrate an altered mRNA “fingerprint” in the secretory phase endometrium of women with endometriosis, characterized by persistence of proliferative phase transcripts and decreases in progesterone-dependent genes. Thus the expression of many genes is altered in the endometrium of women with endometriosis. Further studies are needed to understand the mechanism of this apparent progesterone resistance, which may be effected by alterations in the progesterone receptors, transcription factors or downstream messengers.
One intriguing mechanism for this was suggested by demonstration of increased methylation in the HOXA10 gene promoter in the endometrium of endometriosis patients (30
). Hypermethylation also has been documented in the progesterone receptor B gene, whose endometrial expression is reduced in these patients (31
). The recent demonstration by the same group of increased expression in women with endometriosis of deoxyribonucleic acid methyltransferases responsible for methylation suggests a plausible mechanism by which multiple genes might be down-regulated in this disorder (26