ReviewEstrogen metabolism and action in endometriosis
Introduction
Endometriosis is a complex disease that is defined as the presence of endometrial glands and stroma outside the uterine cavity (Guidice and Kao, 2004). It is most commonly diagnosed in women of a reproductive age, and affects up to 10% of all premenopausal women. This incidence increases from 35% to 50% in women with infertility, pelvic pain, or both (Eskenazi and Warner, 1997, Guidice and Kao, 2004). Symptoms of endometriosis include several types of severe pain and infertility, which significantly impair the quality of life in these women (Berkley et al., 2005, Hompes and Mijatovic, 2007). The diagnostic methods that are available include ultrasonography and magnetic resonance imaging of the pelvis, while the gold standard for definitive diagnosis still remains surgical assessment by laparoscopy (Olive and Schwartz, 1993, Kennedy et al., 1998, Guidice and Kao, 2004, Carbognin et al., 2006). Ectopic endometrial tissue can be present on the ovaries, the pelvic peritoneum and the rectovaginal septum, and also in other pelvic sites (fallopian tubes, vagina, cervix and uterosacral ligaments). More rarely, extra pelvic sites are involved, such as the pleura and even the brain, thus forming at least three different entities: ovarian endometriosis, peritoneal endometriosis and deep-infiltrative endometriosis (Guidice and Kao, 2004, Nap et al., 2004).
This review aims to present the current theories on the pathogenesis of endometriosis, followed by an overview of the local production of estrogens in peripheral tissues, with the emphasis on the diseased endometrium of endometriosis patients (henceforth referred to as endometriotic or ectopic endometrium). The potential role of aberrant expression of individual estrogen-metabolizing enzymes will be discussed, and a model mechanism for the increased formation of estradiol will be presented separately for all of the three types of endometriosis. The disturbed expression of estrogen receptors in endometriosis will also be detailed, and finally, estrogen biosynthetic enzymes and receptors will be discussed as potential therapeutic targets for treatment of endometriosis.
Section snippets
The pathogenesis of endometriosis
Neither the etiology nor the pathogenesis of endometriosis is fully understood. Endometriosis is a polygenic, heritable disease, and surgically confirmed disease occurs six- to nine-fold more commonly in first-degree relatives of affected women than in those of unaffected women (Kennedy et al., 1998; Hompes and Mijatovic, 2007). The immune system is also involved in the pathogenesis of endometriosis (Guidice and Kao, 2004). Peritoneal fluid in women with endometriosis is marked by increased
Endometriosis is an estrogen-dependent disease
Endometriosis primarily affects women of reproductive age and is occasionally diagnosed in postmenopausal women, usually in those with relatively high estrogen levels, or who are treated with estrogen-replacement therapy. Suppression of estrogen levels using gonadotropin-releasing hormone (GnRH) agonists can provide regression of the lesions. However, the recovery of estrogen levels after the discontinuation of the therapies causes a relapse of the lesions, which suggests that endometriosis
The local production of estrogens
In premenopausal women, estrogens can be synthesized in the ovaries and in peripheral tissues (e.g. adipose tissue, skin) (Labrie, 1991, Fang et al., 2002, Simpson, 2003). In target tissues, estrogens can originate from three main sources: (1) ovarian secretion via an endocrine mechanism; (2) peripheral formation that increases the concentrations of circulating estrone sulfate, which is converted in the target tissue; and (3) local formation in the target tissue (Fang et al., 2002). Locally,
Estrogen metabolism in normal endometrium
All of the enzymes necessary for the local production of estrogens from DHEA-S, DHEA, androstenedione and estrone sulfate are expressed in human endometrium. DHEA sulfatase activity that can convert DHEA-S to DHEA has been detected in human endometrium (Hausknecht et al., 1982; Prost et al., 1983). A small percentage of DHEA can also be converted to androstenedione, demonstrating the presence of 3β-HSD activity (Collins et al., 1969, Hausknecht et al., 1982). Early studies showed that human
Estrogen metabolism in endometriosis
In ectopic endometrium, aberrant expression of several estrogen-metabolizing enzymes has been reported, which can lead to high E2 biosynthesis and low E2 inactivation, and to an excess of local E2, which results in further proliferation of ectopic endometrium (Guidice and Kao, 2004). In addition to the biochemical disturbances seen in eutopic endometrium of endometriosis patients, the local microenvironment of ectopic endometrium might further affect gene expression in a paracrine manner, which
Estrogen receptors and endometriosis
The E2 that is formed in the endometrium exerts its actions through the estrogen receptors (ERs), of which there are two distinct isoforms: ERα and ERβ⋅ Both of these ERs are members of the steroid receptor superfamily, and they act as ligand-dependent transcription factors. The ERs classically bind to the estrogen response elements (EREs) in the promoter regions of their target genes; however, the ER can also regulate genes that lack an ERE, via protein–protein interactions with other
Putative estrogen actions in endometriosis
Based on published data, a hypothesis as to estrogen actions and the crosstalk between inflammation and proliferation in endometriosis can be proposed (Fig. 3). Ectopic endometrium induces inflammation within the peritoneal cavity, which results in the formation of cytokines. IL-1β and the VEGF produced by macrophages or endometriotic lesions can induce COX-2 (Tamura et al., 2002a, Tamura et al., 2002b). COX-2 catalyzes the formation of prostaglandin (PG) G2, which is further converted to PGE2 (
Estrogen biosynthetic enzymes and estrogen receptors as targets for treatment
The current therapy of endometriosis is focused on lowering of the endogenous estrogen levels, with surgical therapy to remove endometriotic lesions also widely combined with medical therapy to induce a hypo-estrogenic state in patients (Guidice and Kao, 2004). Suppression of the estrogen levels by GnRH agonists provides regression of the lesions; however, this type of treatment cannot be used for prolonged durations because of the severe side effects. In addition, discontinuation of these
Perspectives and conclusions
Current data on the expression of the estrogen-metabolizing enzymes and the ERs suggest different mechanisms of increased local E2 formation in peritoneal and ovarian endometriosis, and in deep infiltrating endometriosis. This further supports the theory of different diseases with different etiologies and pathogenesis. There is still controversy relating to the expression of certain pre-receptor regulatory enzymes, and therefore there remains the need to examine and re-examine the expression of
Acknowledgements
This work was supported by a J3-9448 grant to T.L.R. from the Slovenian Research Agency. The author thanks Dr. Martina Ribič-Pucelj for helpful discussion regarding the pathogenesis of endometriosis and Dr. Chris Berrie for critical reading of the manuscript.
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2023, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :Therefore, the metabolism of estrogen is closely related to the occurrence of endometriosis. Usually, in tissues, estrogen is mainly derived from three approaches: ovarian secretion, peripheral formation enhancing circulating concentrations of estrone sulfate (E1S), and local formation from adrenal dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), and androstenedione in the target tissue [38]. Local estrogen biosynthesis in ectopic endometrial cells is important for understanding many physiological and pathological phenomena of the endometrium.
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