Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis.
Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)beta promoter resulting in pathologic overexpression of ERbeta in endometriotic stromal cells. We speculate that alterations in the relative levels of ERbeta and ERalpha in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERalpha-tauomicron-ERbeta ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERbeta and ERalpha leading to PR loss and progesterone resistance in endometriosis.
Bulun
Serdar E
SE
Division of Reproductive Biology Research, Department Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. s-bulun@northwestern.edu
Cheng
You-Hong
YH
Pavone
Mary Ellen
ME
Xue
Qing
Q
Attar
Erkut
E
Trukhacheva
Elena
E
Tokunaga
Hideki
H
Utsunomiya
Hiroki
H
Yin
Ping
P
Luo
Xia
X
Lin
Zhihong
Z
Imir
Gonca
G
Thung
Stephen
S
Su
Emily J
EJ
Kim
J Julie
JJ
D018899:CpG Islands; D019175:DNA Methylation; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism*; D004717:Endometrium / Q000378:metabolism; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011374:Progesterone / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011980:Receptors, Progesterone; D011374:Progesterone