Endometriosis: Pathogenesis and Treatment 2014 Ed.

10. Sex Steroids and Endometriosis

Jo Kitawaki 

(1)

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

Abstract

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.

Keywords

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

10.2.2.1 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].

10.2.2.2 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.

References

1.

Vercellini P, Somigliana E, Viganò P, Abbiati A, Barbara G, Fedele L. Chronic pelvic pain in women: etiology, pathogenesis and diagnostic approach. Gynecol Endocrinol. 2009;25:149–58.PubMedCrossRef

2.

Lessey BA, Metzger DA, Haney AF, McCarty Jr KS. Immunohistochemical analysis of estrogen and progesterone receptors in endometriosis: comparison with normal endometrium during the menstrual cycle and the effect of medical therapy. Fertil Steril. 1989;51:409–15.PubMed

3.

Prentice A, Randall BJ, Weddell A, McGill A, Henry L, Horne CH, Thomas EJ. Ovarian steroid receptor expression in endometriosis and in two potential parent epithelia: endometrium and peritoneal mesothelium. Hum Reprod. 1992;7:1318–25.PubMed

4.

Bergqvist A, Ljungberg O, Skoog L. Immunohistochemical analysis of oestrogen and progesterone receptors in endometriotic tissue and endometrium. Hum Reprod. 1993;8:1915–22.PubMed

5.

Jones RK, Bulmer JN, Searle RF. Immunohistochemical characterization of proliferation, oestrogen receptor and progesterone receptor expression in endometriosis: comparison of eutopic and ectopic endometrium with normal cycling endometrium. Hum Reprod. 1995;10:3272–9.PubMed

6.

Howell RJ, Dowsett M, Edmonds DK. Oestrogen and progesterone receptors in endometriosis: heterogeneity of different sites. Hum Reprod. 1994;9:1752–8.PubMed

7.

Nisolle M, Casanas-Roux F, Wyns C, de Menten Y, Mathieu PE, Donnez J. Immunohistochemical analysis of estrogen and progesterone receptors in endometrium and peritoneal endometriosis: a new quantitative method. Fertil Steril. 1994;62:751–9.PubMed

8.

Fujishita A, Nakane PK, Koji T, Masuzaki H, Chavez RO, Yamabe T, Ishimaru T. Expression of estrogen and progesterone receptors in endometrium and peritoneal endometriosis: an immunohistochemical and in situ hybridization study. Fertil Steril. 1997;67:856–64.PubMedCrossRef

9.

Kitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Yamamoto T, Fushiki S, Osawa Y, Honjo H. Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol Reprod. 1997;57:514–9.PubMedCrossRef

10.

Schweppe KW, Wynn RM. Ultrastructural changes in endometriotic implants during the menstrual cycle. Obstet Gynecol. 1981;58:465–73.PubMed

11.

Metzger DA, Olive DL, Haney AF. Limited hormonal responsiveness of ectopic endometrium: histologic correlation with intrauterine endometrium. Hum Pathol. 1988;19:1417–24.PubMedCrossRef

12.

Xue Q, Lin Z, Cheng YH, Huang CC, Marsh E, Yin P, Milad MP, Confino E, Reierstad S, Innes J, Bulun SE. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod. 2007;77:681–7.PubMedCrossRef

13.

Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab. 2000;85:2897–902.PubMed

14.

Wu Y, Strawn E, Basir Z, Halverson G, Guo SW. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics. 2006;1:106–11.PubMedCrossRef

15.

Xue Q, Lin Z, Yin P, Milad MP, Cheng YH, Confino E, Reierstad S, Bulun SE. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis. J Clin Endocrinol Metab. 2007;92:3261–7.PubMedCrossRef

16.

Bulun SE. Endometriosis. N Engl J Med. 2009;360:268–79.PubMedCrossRef

17.

Bulun SE, Zeitoun K, Takayama K, Noble L, Michael D, Simpson E, Johns A, Putman M, Sasano H. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer. 1999;6:293–301.PubMedCrossRef

18.

Yamanaka K, Xu B, Suganuma I, Kusuki I, Mita S, Shimizu Y, Mizuguchi K, Kitawaki J. Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic stromal cells in spheroid culture. Fertil Steril. 2012;97:477–82.PubMedCrossRef

19.

Noble LS, Simpson ER, Johns A, Bulun SE. Aromatase expression in endometriosis. J Clin Endocrinol Metab. 1996;81:174–9.PubMed

20.

Matsuzaki S, Canis M, Pouly JL, Déchelotte PJ, Mage G. Analysis of aromatase and 17β-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection. Fertil Steril. 2006;85:308–13.PubMedCrossRef

21.

Zeitoun K, Takayama K, Michael MD, Bulun SE. Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element. Mol Endocrinol. 1999;13:239–53.PubMedCrossRef

22.

Kitawaki J, Kusuki I, Koshiba H, Tsukamoto K, Fushiki S, Honjo H. Detection of aromatase cytochrome P-450 in endometrial biopsy specimens as a diagnostic test for endometriosis. Fertil Steril. 1999;72:1100–6.PubMedCrossRef

23.

Dheenadayalu K, Mak I, Gordts S, Campo R, Higham J, Puttemans P, White J, Christian M, Fusi L, Brosens J. Aromatase P450 messenger RNA expression in eutopic endometrium is not a specific marker for pelvic endometriosis. Fertil Steril. 2002;78:825–9.PubMedCrossRef

24.

Zeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE. Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17β-estradiol. J Clin Endocrinol Metab. 1998;83:4474–80.PubMed

25.

Dassen H, Punyadeera C, Kamps R, Delvoux B, Van Langendonckt A, Donnez J, Husen B, Thole H, Dunselman G, Groothuis P. Estrogen metabolizing enzymes in endometrium and endometriosis. Hum Reprod. 2007;22:3148–58.PubMedCrossRef

26.

Utsunomiya H, Suzuki T, Kaneko C, Takeyama J, Nakamura J, Kimura K, Yoshihama M, Harada N, Ito K, Konno R, Sato S, Okamura K, Sasano H. The analyses of 17β-hydroxysteroid dehydrogenase isozymes in human endometrial hyperplasia and carcinoma. J Clin Endocrinol Metab. 2001;86:3436–43.PubMed

27.

Kitawaki J, Koshiba H, Ishihara H, Kusuki I, Tsukamoto K, Honjo H. Progesterone induction of 17β-hydroxysteroid dehydrogenase type 2 during the secretory phase occurs in the endometrium of estrogen-dependent benign diseases but not in normal endometrium. J Clin Endocrinol Metab. 2000;85:3292–6.PubMed

28.

Moen MH, Magnus P. The familial risk of endometriosis. Acta Obstet Gynecol Scand. 1993;72:560–4.PubMedCrossRef

29.

Kennedy S, Mardon H, Barlow D. Familial endometriosis. J Assist Reprod Genet. 1995;12:32–4.PubMedCrossRef

30.

Treloar SA, O’Connor DT, O’Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. Fertil Steril. 1999;71:701–10.PubMedCrossRef

31.

Georgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M, Navrozoglou I, Lolis D. Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril. 1999;72:164–6.PubMedCrossRef

32.

Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Kado N, Tsukamoto K, Hasegawa G, Nakamura N, Honjo H. Oestrogen receptor-α gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Hum Reprod. 2001;16:51–5.PubMedCrossRef

33.

Luisi S, Galleri L, Marini F, Ambrosini G, Brandi ML, Petraglia F. Estrogen receptor gene polymorphisms are associated with recurrence of endometriosis. Fertil Steril. 2006;85:764–6.PubMedCrossRef

34.

Hsieh YY, Wang YK, Chang CC, Lin CS. Estrogen receptor α-351 XbaI*G and −397 PvuII*C-related genotypes and alleles are associated with higher susceptibilities of endometriosis and leiomyoma. Mol Hum Reprod. 2007;13:117–22.PubMedCrossRef

35.

Wang Z, Yoshida S, Negoro K, Kennedy S, Barlow D, Maruo T. Polymorphisms in the estrogen receptor β gene but not estrogen receptor α gene affect the risk of developing endometriosis in a Japanese population. Fertil Steril. 2004;81:1650–6.PubMedCrossRef

36.

Kim SH, Choi YM, Jun JK, Kim SH, Kim JG, Moon SY. Estrogen receptor dinucleotide repeat polymorphism is associated with minimal or mild endometriosis. Fertil Steril. 2005;84:774–7.PubMedCrossRef

37.

Renner SP, Strick R, Oppelt P, Fasching PA, Engel S, Baumann R, Beckmann MW, Strissel PL. Evaluation of clinical parameters and estrogen receptor α gene polymorphisms for patients with endometriosis. Reproduction. 2006;131:153–61.PubMedCrossRef

38.

Xie J, Wang S, He B, Pan Y, Li Y, Zeng Q, Jiang H, Chen J. Association of estrogen receptor α and interleukin-10 gene polymorphisms with endometriosis in a Chinese population. Fertil Steril. 2009;92:54–60.PubMedCrossRef

39.

Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tsai CH. Estrogen receptor α dinucleotide repeat and cytochrome P450c17α gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril. 2005;83:567–72.PubMedCrossRef

40.

Lamp M, Peters M, Reinmaa E, Haller-Kikkatalo K, Kaart T, Kadastik U, Karro H, Metspalu A, Salumets A. Polymorphisms in ESR1, ESR2 and HSD17B1 genes are associated with fertility status in endometriosis. Gynecol Endocrinol. 2011;27:425–33.PubMedCrossRef

41.

Lee GH, Kim SH, Choi YM, Suh CS, Kim JG, Moon SY. Estrogen receptor β gene +1730 G/A polymorphism in women with endometriosis. Fertil Steril. 2007;88:785–8.PubMedCrossRef

42.

Wieser F, Schneeberger C, Tong D, Tempfer C, Huber JC, Wenzl R. PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril. 2002;77:309–12.PubMedCrossRef

43.

Lattuada D, Somigliana E, Vigano P, Candiani M, Pardi G, Di Blasio AM. Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS? Clin Endocrinol. 2004;61:190–4.CrossRef

44.

De Carvalho CV, Nogueira-De-Souza NC, Costa AM, Baracat EC, Girão MJ, D’Amora P, Schor E, da Silva ID. Genetic polymorphisms of cytochrome P450c17α (CYP17) and progesterone receptor genes (PROGINS) in the assessment of endometriosis risk. Gynecol Endocrinol. 2007;23:29–33.PubMedCrossRef

45.

Tsuchiya M, Nakao H, Katoh T, Sasaki H, Hiroshima M, Tanaka T, Matsunaga T, Hanaoka T, Tsugane S, Ikenoue T. Association between endometriosis and genetic polymorphisms of the estradiol-synthesizing enzyme genes HSD17B1 and CYP19. Hum Reprod. 2005;20:974–8.PubMedCrossRef

46.

Kado N, Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Tsukamoto K, Hasegawa G, Nakamura N, Yoshikawa T, Honjo H. Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in Japanese women. Hum Reprod. 2002;17:897–902.PubMedCrossRef

47.

Asghar T, Yoshida S, Nakago S, Morizane M, Ohara N, Motoyama S, Kennedy S, Barlow D, Maruo T. Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations. Gynecol Endocrinol. 2005;20:59–63.PubMedCrossRef

48.

Juo SH, Wang TN, Lee JN, Wu MT, Long CY, Tsai EM. CYP17, CYP1A1 and COMT polymorphisms and the risk of adenomyosis and endometriosis in Taiwanese women. Hum Reprod. 2006;21:1498–502.PubMedCrossRef

49.

Arvanitis DA, Koumantakis GE, Goumenou AG, Matalliotakis IM, Koumantakis EE, Spandidos DA. CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis. Fertil Steril. 2003;79 Suppl 1:702–9.PubMedCrossRef

50.

Vietri MT, Cioffi M, Sessa M, Simeone S, Bontempo P, Trabucco E, Ardovino M, Colacurci N, Molinari AM, Cobellis L. CYP17 and CYP19 gene polymorphisms in women affected with endometriosis. Fertil Steril. 2009;92:1532–5.PubMedCrossRef