Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women.
Endometriosis is a disorder that affects 5% of the normal population but is present in up to 40% of women with pelvic pain and/or infertility. Recent evidence suggests that the endometrium of women with endometriosis exhibits progesterone insensitivity. One endometrial protein that fluctuates in response to progesterone is the estrogen receptor-alpha (ER alpha), being down-regulated at the time of peak progesterone secretion during the window of implantation. Here we demonstrate that the biomarker of uterine receptivity, beta 3 integrin subunit, is reduced or absent in some women with endometriosis and that such defects are accompanied by inappropriate over-expression of ER alpha during the mid-secretory phase. Using a well-differentiated endometrial cell line we showed that the beta 3 integrin protein is negatively regulated by estrogen and positively regulated by epidermal growth factor (EGF). By competing against estrogen with various selective estrogen receptor modulators (SERMs) and estrogen receptor agonists and antagonists, inhibition of expression of the beta 3 integrin by estrogen can be mitigated. In conclusion, we hypothesize that certain types of uterine receptivity defects may be caused by the loss of appropriate ER alpha down-regulation in the mid-secretory phase, leading to defects in uterine receptivity. Such changes might be effectively treated by timely administration of the appropriate anti-estrogens to artificially block ER alpha and restore normal patterns of gene expression. Such treatments will require further clinical studies.
Lessey
Bruce A
BA
Division of Reproductive Endocrinology and Infertility, University Medical Group, Department of Obstetrics and Gynecology, Greenville Hospital System, Greenville, SC, USA. blessey@ghs.org
Palomino
Wilder A
WA
Apparao
K B C
KB
Young
Steven L
SL
Lininger
Ruth A
RA
D002478:Cells, Cultured; D004715:Endometriosis / Q000235:genetics* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D011247:Pregnancy; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D014599:Uterus / Q000378:metabolism / Q000503:physiopathology*
D047628:Estrogen Receptor alpha; D039661:Integrin beta3; D020845:Selective Estrogen Receptor Modulators; D000077267:Fulvestrant; D004958:Estradiol