Endometriosis: Pathogenesis and Treatment 2014 Ed.

10. Sex Steroids and Endometriosis

Jo Kitawaki 


Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 602-8566, Japan

Jo Kitawaki

Email: kitawaki@koto.kpu-m.ac.jp


Endometriosis develops mostly in women of reproductive age and regresses after menopause, suggesting that the growth of lesions is estrogen dependent. Estrogen metabolism differs considerably in women with a normal endometrium compared to those with estrogen-dependent uterine diseases, including endometriosis, adenomyosis, or fibromas. Altered expression patterns of estrogen receptor (ER)-α/ER-β, progesterone receptor (PR)-A/PR-B, and 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1)/type 2 (HSD17B2) in endometriotic tissue may upregulate aromatase and increase local estrogenic activity. Polymorphisms in ESR1ESR2PRHSD17B1, 17α-hydroxylase (CYP17A1), and aromatase (CYP19) genes have been investigated putative associations with endometriosis susceptibility.


EndometriosisEndometriumEstrogenPolymorphismSteroid receptors

10.1 Introduction

Endometriosis, a common gynecological disorder in women of reproductive age, is characterized by the presence of endometrium-like lesions outside the uterine cavity. The main symptoms are pelvic pain, including dysmenorrhea, chronic pelvic pain and deep dyspareunia, and infertility [1]. Endometriosis develops in approximately 10 % of women of reproductive age and regresses after menopause or ovariectomy. The occurrence of endometriosis before menarche has not been reported. The suppression of estrogen levels using a gonadotropin-releasing hormone agonist causes regression of the lesions. The recovery of estrogen levels after discontinuing therapy causes a relapse. Endometriosis may relapse in postmenopausal women who have been treated with estrogen-replacement therapy, suggesting that endometriosis progresses and regresses in an estrogen-dependent fashion.

10.2 Mechanisms of Estrogen-Dependent Growth

Breast cancer, endometrial cancer, endometriosis, adenomyosis, and fibromas are diseases that progress in an estrogen-dependent fashion. These lesions commonly contain ER, PR, and androgen receptors. Interestingly, all of the estrogen-dependent diseases of the breast and uterus contain not only ER but also aromatase, an enzyme that catalyzes the conversion of androgens to estrogens. Together with the circulating estrogen, local estrogen production increases the estrogen concentration and stimulates the growth of tissue mediated by the ER. Immunohistochemical studies have shown that ER and PR are localized to the nucleus of both glandular and stromal cells [29], whereas aromatase is exclusively localized to the cytoplasm of epithelial glandular cells [9].

Expression patterns of steroid-related molecules, including steroid receptors and enzymes involved in estrogen metabolism, differ between endometriotic tissues and eutopic endometria. Electron microscopic analysis has shown that one-third of endometriotic implants are out of phase with the menstrual cycle [10], and a light microscopic study showed that only 13 % of endometriotic implants were synchronous with the corresponding eutopic endometria [11].

10.2.1 Steroid Receptors

ER-β levels are higher and ER-α levels are lower in women with endometriosis than in those with a normal endometrium. Higher ER-β levels are caused by hypomethylation of a CpG island at the promoter region of this gene. In endometriotic cells, the excess expression of ER-β is responsible for the estrogen-dependent responses, and this expression inhibits ER-α action [12].

The single PR gene is translated into one of two isoforms (PR-A or PR-B) by activating the corresponding promoters. PR-A is a truncated form of PR-B that lacks the N-terminal 164 amino acids; PR-A acts as a repressor of PR-B function. In endometriotic tissue, PR-B is undetectable [13] due to hypermethylation of the PR gene and PR-A is markedly reduced [14]. Furthermore, excess ER-β occupies the estrogen responsive element at PR promoter region and blocks transcription of PR that is normally activated by ER-α [15].

10.2.2 Estrogen Metabolism Aromatase

Steroidogenic factor 1 (SF1), an orphan nuclear receptor, is expressed at a 12,000 times higher concentration in women with endometriosis than in those with a normal endometrium. SF1 is involved in the prostaglandin E2(PGE2)-stimulated increase in aromatase expression [15]. In endometrial cells, a CpG island at the SF1 promoter is highly methylated and binds to a silencer-type transcription factor, whereas in endometriotic cells, SF1 promoter is unmethylated and binds to a coactivator.

A positive feedback cycle indicates that aromatase and cyclooxygenase-2 (COX-2), a PGE2 synthase, are responsible for the continuous local formation of estrogen and PGE2 in endometriotic stromal cells [16]. PGE2 is a major mediator of endometriosis-associated pain. Aromatase expression might be induced by PGE2 in endometriotic cells. Aromatase produces estradiol, which consequently promotes PGE2 production by inducing COX-2 expression [17]. Danazol and dienogest, a fourth-generation progestin, which is used for relieving endometriosis-associated pelvic pain, downregulate expression of aromatase and COX-2 in endometriotic cells [18].

In the normal endometrium of women, aromatase is not expressed, but it is expressed in the endometrium of women with estrogen-dependent uterine diseases such as endometriosis, adenomyosis, or fibromas [91920]. In endometriotic cells, the increased expression of SF1 activates aromatase transcription [21]. Immunohistochemical detection of aromatase P450 protein in endometrial biopsies can be used as a screening test for endometriosis [22]. However, detection of aromatase mRNA is less specific for screening of endometriosis [23]. 17β-Hydroxysteroid Dehydrogenase Type 1 and Type 2

In endometriotic tissues, HSD17B1, an enzyme that converts estrone to the more potent estradiol, predominates, whereas expression of HSD17B2, an enzyme responsible for weakening the activity of estradiol and converting it into less active estrone, is undetectable [24] or at a lower level than HSD17B1 [2025]. This is partially responsible for raising the local estrogen activity level.

In contrast in the endometrium, an oxidative reaction that weakens the activity of estradiol to estrone by HSD17B2 predominates and the expression of HSD17B1 is undetectable [26] or extremely low [25]. During the proliferative phase, the expression level and activity of HSD17B2 are comparable in endometria of women with estrogen-dependent diseases and women without disease. However, during the secretory phase, while the expression and activity of HSD17B2 increase four- to sixfold in diseased endometria, there is no cyclical change in normal endometrium [2027]. Although it is not possible to distinguish histologically between normal and diseased endometria, estrogen metabolism is different between the two states. Furthermore, in endometriotic tissues, progesterone does not stimulate HSD17B2 because there is no PR-B [13], whereas endometrium of women with endometriosis acquires ability to stimulate HSD17B2 by progesterone.

10.3 Polymorphisms in Genes Involved in Steroid Metabolism

Both environmental and genetic factors have been implicated in the pathogenesis of endometriosis. Family and twin studies have indicated that there is a two- to ninefold increase in the risk of developing endometriosis in first-degree relatives of women with endometriosis, suggesting it is a genetic disorder with polygenic or multifactorial inheritance [2830]. Studies have revealed associations between the polymorphisms of many genes, including the genes involved in steroid metabolism and endometriosis susceptibility.

10.3.1 ESR1

Polymorphisms in the gene coding for ER-α (ESR1) have been investigated in European and Asian women. Single-nucleotide polymorphisms in intron 1 of the ESR1 gene have been assessed in PvuII (−398 T/C) and XbaI (−351A/G) restriction fragment length polymorphisms. Several studies found statistically significant differences between the cases and controls in the distribution of PvuII alleles [3134], but other studies found no association with PvuII polymorphisms [3538]. One study found an association with an XbaI polymorphism [34], and three studies found an association with the TA dinucleotide repeat polymorphism [31363940].

10.3.2 ESR2

One study in Japanese women showed association with the gene coding for ER-β (ESR2AluI polymorphism [35], but other studies found no association [3341]. One study showed that shorter CA dinucleotide repeats in the ESR2 gene were linked to endometriosis in women without infertility [40].

10.3.3 PR

Several studies in Austria, Italy, and Brazil showed association between the 306-bp insertion polymorphism in intron G of the PR gene (PROGINS) and the risk of endometriosis risk [4244].

10.3.4 HSD17B1

Several studies showed that, in an A/G polymorphism of the HSD17B1 gene, the A allele was found to be associated with a significantly increased risk of endometriosis [4045].

10.3.5 CYP17

One study showed a possible association of endometriosis in Taiwanese women with a MspA1 (T/C) polymorphism in the CYP17A1 gene [39], whereas other studies found no association between any CYP17A1 gene polymorphisms and endometriosis risk [4648].

10.3.6 CYP19

In intron 4 of the CYP19 gene, there is a TTTA repeat microsatellite polymorphism, and 50-bp upstream of the TTTA polymorphism, a 3-base pair (CTT) insertion/deletion polymorphism. A study in Japanese women showed an association between this 3-base pair insertion/deletion polymorphism and endometriosis risk [46]. The TTTA repeat polymorphism was found to increase endometriosis risk in Greek women [49]. A study in Italian women showed a significant association of AA and CC genotypes in Val80 and C1558T polymorphisms with endometriosis risk [50]. However, two other studies showed no association between CYP19 gene polymorphisms and endometriosis susceptibility [4045].

10.4 Conclusions

Altered expression patterns of a range of receptors and enzymes involved in steroid metabolism (ER-α/ER-β, PR-A/PR-B, and HSD17B1/HSD17B2) in endometriotic tissue may upregulate aromatase and increase local estrogenic activity, thus stimulating the growth of lesions. Substantial differences in estrogen metabolism exist between normal endometrium and the endometrium in women with uterine diseases, including endometriosis, adenomyosis, or fibromas. Polymorphisms in ESR1ESR2PRHSD17B1CYP17A1, and CYP19 genes have all been investigated with varying success. Further investigations to distinguish pathologic from normal endometria and genetic polymorphism associations will contribute to a better understanding of endometriosis and help develop novel therapeutic strategies for this disease.



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