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This study describes some of the differences between endometriosis lesions and tissue from the uterus (endometrium). It describes the resistance to hormonal treatments, possibly due to the difference in the hormonal receptors on endometriosis lesions versus normal endometrium. While estrogen causes endometriosis lesions to grow and persist, it also affects the inflammation and pain associated with endometriosis. Endometriosis lesions can produce their own estrogen. In addition to that, there are higher numbers of ERβ receptors on endometriosis lesions, which can cause higher prostaglandin production (leading to pain). The authors conclude that “lower ERα-to-ERβ ratio in endometriotic stromal cells may cause a shift from estradiol stimulation to inhibition of PR expression in endometriotic stromal cells”. The authors also note a lower number of progesterone receptors in endometriosis lesions.
“Endometriosis-related pain has conventionally been treated with endocrine agents such as synthetic progestins, oral contraceptives, or gonadotropin-releasing hormone analogs.1 These treatments, which interrupt ovulation and ovarian estrogen production, are successful in only half of the patients treated, however.9–11 Treatment with aromatase inhibitors in combination with an ovulation suppressor has successfully been used in cases refractory to these conventional measures of pain management.12 Patients often develop resistance to repeated treatments with the same agent over a period of 6 months to 3 years….
“Endometriotic tissue in ectopic locations, such as the peritoneum or ovary, is fundamentally different from eutopic endometrium within the uterus in terms of the production of cytokines and prostaglandins, estrogen biosynthesis and metabolism, and clinical response to progestins.11,22,23 There are substantial molecular differences with regard to progesterone response between normal endometrium and eutopic and ectopic tissues from women with endometriosis.17,24,25… Circumstantial and laboratory evidence strongly support the notion that estradiol is a key hormone for the growth and persistence of endometriotic tissue as well as inflammation and pain associated with it. Estradiol, which reaches endometriosis by circulation or is produced locally in endometriotic tissue, acts as a steroid hormone to regulate growth of endometriotic tissue. Estradiol enters cells and binds to the ER in estrogen-responsive cells. ER subtypes α and β are proteins with high affinity for estradiol and are encoded by separate genes….
“Despite its sensitivity to estrogen, endometriosis appears to contain a unique complement of steroid hormone receptors compared with that of its normal tissue counterpart, the eutopic endometrium. For example, several investigators reported markedly higher levels of ERβ and lower levels of ERα in human endometriotic tissues and primary stromal cells compared with eutopic endometrial tissues and cells.31,32 The levels of both isoforms of PR, particularly PR-B, are significantly lower in endometriosis compared with eutopic endometrium.6,33 The estradiol-receptor complex acts as a transcription factor that becomes associated with the promoters of estradiol-responsive genes via direct DNA binding or binding to other docking transcription factors at basal promoter regions.34 This interaction brings about ER-specific initiation of gene transcription, which promotes the synthesis of specific mRNAs and proteins.34 PR is one of many estradiol-responsive genes, and estradiol acts in eutopic endometrial tissues and stromal cells to promote endometrial responsiveness to progesterone.35 In contrast, PR mRNA and protein levels are not elevated in biopsied endometriotic tissues exposed to high estradiol levels during late proliferative phase or in endometriotic cells treated with estradiol, indicating that estradiol-induction PR expression in endometriosis is markedly blunted.33
“In addition to ERα, ERβ, and PR, the orphan nuclear receptor SF1 is also differentially regulated in endometriosis versus eutopic endometrium (Fig. 2). SF1 is responsible for coordinately activating the full steroidogenic cascade of genes including aromatase. The protein products of this set of steroidogenic genes are capable of converting cholesterol to estradiol locally in endometriotic tissue.36 We recently used real-time polymerase chain reaction (RT-PCR) to compare tissue mRNA levels of these key nuclear receptors in endometriosis and eutopic endometrium (Fig. 2). Ovarian endometriotic tissue SF1 and ERβ mRNA levels were >12,000 times and 142 times higher than in endometrium, respectively. In contrast, ERα, PR, and PR-B levels were remarkably lower in endometriotic tissue (Fig. 2)…. ERα mRNA and protein levels are several fold lower in endometriotic tissue and stromal cells compared with endometrial tissue and stromal cells. ERα deficiency in endometriosis may be responsible for the failure of estradiol to induce PR expression, thus contributing to secondary PR deficiency and progesterone resistance in women with this disease. In vivo observations strongly suggest that estradiol induces ERα expression in mouse uterine tissue.39 It is quite likely that estradiol also plays a key role in regulating ERα expression in human endometrial stromal cells. However, strikingly high quantities of estradiol produced via local aromatase activity in addition to high ERβ levels in stromal cells of endometriosis may perturb this regulation and may suppress ERα expression.26,38…
“Summary: High estrogen production is a consistently observed endocrine feature of endometriosis. Expression of steroid receptors and other nuclear receptors are strikingly different between endometriotic and eutopic endometrial tissues. Among these nuclear receptors, ERβ expression is maybe >100 times higher in endometriotic tissue than in endometrium. Defective DNA methylation and other accompanying epigenetic mechanisms may be responsible for strikingly high ERβ expression in endometriosis. ERβ suppresses ERα expression and results in strikingly high ERβ-to-ERα ratios in endometriotic cells. We speculate that a strikingly lower ERα-to-ERβ ratio in endometriotic stromal cells may cause a shift from estradiol stimulation to inhibition of PR expression in endometriotic stromal cells under in vivo circumstances (Fig. 3). This proposed mechanism may explain severely deficient PR-B in endometriotic stromal cells, which contributes to progesterone resistance in women with endometriosis. ERβ overexpression in endometriosis possibly has other broad effects important in the pathology of endometriosis. It is likely that ERβ simulates prostaglandin production in endometriotic tissues and cells via inducing COX2 expression.”