{"paper_id":"13321b56-86e0-489d-860f-184129d5fd1b","body_text":"https://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nIntracrine oestrogens and \nendometriosis\nC A Piccinato et al.Journal of Molecular \nEndocrinology\nT253–T270\n61 2:\nTHEMATIC REVIEW\nSULFATION PATHWAYS\nContribution of intracrine oestrogens to the \naetiology of endometriosis\nCarla A Piccinato1, Helena Malvezzi1, Douglas A Gibson2 and Philippa T K Saunders2\n1Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil\n2MRC Centre for Inflammation Research, The University of Edinburgh, Edinburgh, UK\nCorrespondence should be addressed to C A Piccinato: cpiccinato@uwalumni.com\nThis paper is part of a thematic section on Sulfation Pathways. The guest editors for this section were Jonathan Wolf Mueller and Paul Foster.\nAbstract\nEndometriosis is an incurable hormone-dependent inflammatory disease that causes \nchronic pelvic pain and infertility characterized by implantation and growth of endometrial \ntissue outside the uterine cavity. Symptoms have a major impact on the quality of life \nof patients resulting in socioeconomic, physical and psychological burdens. Although \nthe immune system and environmental factors may play a role in the aetiology of \nendometriosis, oestrogen dependency is still considered a hallmark of the disorder. The \nimpact of oestrogens such as oestrone and particularly, oestradiol, on the endometrium or \nendometriotic lesions may be mediated by steroids originating from ovarian steroidogenesis \nor local intra-tissue production (intracrinology) dependent upon the expression and activity \nof enzymes that regulate oestrogen biosynthesis and metabolism. Two key pathways have \nbeen implicated: while there is contradictory data on the participation of the aromatase \nenzyme (encoded by CYP19A1), there is increasing evidence that the steroid sulphatase \npathway plays a role in both the aetiology and pathology of endometriosis. In this review, \nwe consider the evidence related to the pathways leading to oestrogen accumulation in \nendometriotic lesions and how this might inform the development of new therapeutic \nstrategies to treat endometriosis without causing the undesirable side effects of current \nregimes that suppress ovarian hormone production.\nIntroduction\nPrevalence, characteristics and socioeconomic \nimpact of endometriosis\nEndometriosis is characterized by implantation and growth \nof endometrial tissue outside the uterine cavity ( Agarwal \net al.  2005). It is often associated with clinical symptoms \nthat impair quality of life, including dysmenorrhoea, \ndyspareunia, acyclic pelvic pain, infertility and alterations \nof intestinal and urinary habits (Kyama et al.  2003, Bellelis \net al.  2014, Vercellini et al.  2014). Endometriosis lesions can \nform at different sites within the pelvis such as superficial \nperitoneal lesions, ovarian endometriomas (cysts) and \nmay also be detected as deep-infiltrating lesions that can \ncompromise other organs such as rectum and bladder \n(Chapron et  al.  2006 ). The location of the lesion, its \ninvasiveness and the presence and severity of adhesions \nin the peritoneal cavity were all taken into account by \nthe American Society for Reproductive Medicine when \nJournal of Molecular \nEndocrinology  \n(2018) 61, T253–T270\nKey Words\n f pain\n f infertility\n f steroid sulphatase\n f oestrogen\n f inflammation\n-17-0297\n261\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT254\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nthey proposed a characterization of the disorder into four \nstages (I-minimal, II-mild, III-moderate and IV-severe) \n(American Society for Reproductive Medicine 1997).\nEndometriosis is a common disorder that is believed \nto affect 6–10% of women of reproductive age estimated to \nbe ~176 million women worldwide (Bulletti et al.  2010). An \nincreased prevalence is commonly found in women with \ninfertility, pelvic pain or both, with values ranging from \n30 to 50% (Eskenazi & Warner 1997, Giudice & Kao 2004). \nDue to the severity of the symptoms experienced by some \nwomen with endometriosis, it has a high socioeconomic \ncost resulting in women being unable to work or care for \ntheir families and high associated health care costs in part \nbecause of the number of hospital admissions ( Nnoaham \net  al.  2011 , Fuldeore et  al.  2015 ). For all these reasons, \nit has been argued that endometriosis should receive \nfar greater attention and funding than it does currently \n(Signorile & Baldi 2010, Nnoaham et al.  2011, Culley et al.  \n2013, De Graaff et al.  2013, 2015, Vercellini et al.  2014, \nFuldeore et al.  2015, Zubrzycka et al.  2015).\nGenomics, genetics and lack of \npredictive biomarkers\nDefinitive diagnosis of endometriosis is based on the \nidentification of lesions by visual inspection at the time \nof surgery. Importantly, there is poor correlation between \nextent of disease and severity of symptoms, which \nunderlies our poor understanding of disease aetiology \n(Gopalakrishnan Radhika et  al.  2016 ). Currently, there \nare no reliable, non-invasive biomarker tests which, in \npart, explains why diagnosis is often delayed for many \nyears (Gupta et al.  2016, Nisenblat et al.  2016). Surgically \nconfirmed disease occurs six- to nine-fold more commonly \nin first-degree relatives of affected women than in those of \nunaffected women ( Kennedy 1999, Hompes & Mijatovic \n2007), which has led to the classification of endometriosis \nas a polygenic, heritable disease and prompted the search \nfor genetic biomarkers. A recent meta-analysis of 11 \ngenome-wide association case–control data sets, involving \n17,045 endometriosis cases identified five new genetic \nloci (SNPs) significantly associated with endometriosis \nrisk implicating genes involved in sex steroid hormone \npathways that included FN1, CCDC170, ESR1, SYNE1 and \nFSHB genes ( Sapkota et  al.  2017 ). In addition, genomic \nanalysis of eutopic endometrium has reported differential \nexpression of key genes between samples from women \nwith endometriosis and those without ( Aghajanova \net al.  2009, Zelenko et al.  2012) that are associated with \nalterations in functional activities ( Nikoo et  al.  2014 ). \nThese findings offer potential for development of new \ndiagnostic approaches based on genetic or tissue profiling \n(Tamaresis et  al.  2014 ) with the former prompting the \nformation of large multinational consortia to test findings \nusing larger datasets (Montgomery et al.  2008).\nCurrent therapies\nCurrent treatments for endometriosis-associated pelvic \npain and/or infertility include both surgical and medical \napproaches. Due to the high costs and risks associated \nwith surgery, it is frequently considered as a second \nchoice with priority given to medical therapy for mild/\nmoderate disease. For severe disease, particularly, that \ninvolves obstructive urinary/intestinal lesions or large \nendometrioma, surgery is the first choice ( Halpern et al.  \n2015). Surgical removal of lesions can offer some relief \nfrom pain and may improve fertility; however, recurrence \nof symptoms is reported in up to 75% of women within \n5 years of surgery ( Guo 2009). Although the cause(s) of \nendometriosis remain incompletely understood, there \nis intense research activity involving observations on \nprimary samples and fluids (blood, peritoneal), in vitro  \nstudies using cells isolated from patients and controls, \nas well as testing in a range of preclinical animal models \n(see recent review by Greaves et al.  2017) all directed at \ngaining knowledge that might be translated into more \neffective ways to prevent recurrence or treat symptoms.\nIt is widely accepted that inflammatory processes \ncan contribute to the development of endometriosis \nand associated pain symptoms ( Králíčková & Vetvicka \n2015). However, currently, it is the hormone (oestrogen) \ndependence of the disease that has been most effectively \ntargeted by medical therapy. The first-line treatments of \nhormonal therapies work by suppressing ovarian function: \nthis includes use of GnRH agonists and birth control \npills, whereas others utilise inhibitors of the aromatase \nenzyme, which is essential for biosynthesis of oestrogens \nby ovarian follicles ( Lindsay et  al. 2015, Vercellini et  al. \n2016). Some reports suggest these treatments may \nresult in pain reduction up to 80% of endometriosis \npatients, especially when a combination of drugs is used \n(Platteeuw & D’Hooghe 2014, Zhao et al.  2015). However, \ngonadotropin-releasing hormone analogue or aromatase \ninhibitor (AI) therapies are associated with negative side \neffects that mimic a premature menopause (including hot \nflashes symptoms) while birth control pills are not ideal \nfor women wanting to get pregnant. Also, a proportion \nof patients either fail to respond or relapse after relatively \nshort period of time. In the search for new therapies, steroid \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT255\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\nsulphatase (STS) inhibitors originally developed as a new \ndrug for oestrogen-dependent breast cancers are being \nconsidered (Purohit et al.  2008). The suggestion that STS \ninhibitors could be repurposed for treating endometriosis \nhas been supported by reports using murine models \nof endometriosis where a 40% reduction in lesions size \nwas reported following oral treatment with oestradiol-\n3-O-sulfamate, a readily absorbed and transformed STS \ninhibitor (Colette et al.  2011). In the following review, we \nconsider the evidence that endometriosis is an oestrogen-\ndependent disorder, that local oestrogens generated in situ \nare important regulators of disease and how this might \ninform new therapies avoiding undesirable side effects.\nEndometriosis: an oestrogen-dependent  \ndisorder\nSources of endometrial-acting oestrogens\nDuring a woman’s reproductive years, the primary site of \nsynthesis of the bioactive oestrogens, oestrone (E1) and \noestradiol (E2) are the ovaries, particularly the ovarian \nfollicles. Oestrogen biosynthesis by ovarian follicular cell \ntypes has been extensively reviewed ( Lessey et  al. 1989, \nHuhtinen et al . 2012a). In brief, it begins with the transport \nof cellular cholesterol from the cytosol to mitochondria \nmatrix by steroidogenic acute regulatory protein (STAR). \nInside the mitochondria, cholesterol is converted \ninto pregnenolone by cholesterol side-chain cleavage \nenzyme (P450scc, encoded by CYP11A1). Pregnenolone \ncan then be transformed into progesterone by 3 \nβ-hydroxysteroid dehydrogenase type 2 (HSD3B2) ( Attar \net al . 2009). Pregnenolone can also be converted into 17-β \nhydroxypregnenolone, DHEA and then androstenedione \nby steroid 17 α-monooxygenase (17, 20-lyase, P450c17, \nencoded by CYP17A1), which in turn can be reduced \nto testosterone primarily by 17- β-hydroxysteroid \ndehydrogenase 3 (HSD17B3), mainly expressed in testis, \nand AKR1C3 which is expressed in endometrium and \nendometriosis (Catalano et al . 2011, Sinreih et al . 2015). \nAndrostenedione and testosterone are substrates of the \naromatase complex (P450arom, encoded by CYP19A1), \nwhich are converted to E1 and E2, respectively. Finally, \nHSD17B1 can convert E1 into E2, considered to be the \nmore potent bioactive form of oestrogen: both E1 and E2 \ncan bind and activate oestrogen receptors.\nThere is also evidence that oestrogens can be \nsynthesized in extra-ovarian sites including the \nendometrium, endometriosis lesions (discussed \nbelow) and adipose tissue. According to the concept \nof intracrinology ( Labrie et  al.  2000 ), extra-ovarian \ntissues that express the enzymes that regulate oestrogen \nbiosynthesis have the capacity to utilize blood borne \nprecursors including DHEA and the sulphated oestrogens \n(E1S and E2S). One potential extra-ovarian site for E2 \nbiosynthesis is adipose tissue ( Kim et  al. 2014). Adipose \ncells express oestrogen-synthesizing enzymes ( Nelson & \nBulun 2001 ), and in vitro  production of oestrogens has \nbeen described ( Ghosh et al.  2013). It remains unknown \nwhether the oestrogen produced by adipose tissues has any \nimpact on the amount of circulating E1/E2 or if this has \nan impact on the endometrium or endometriosis lesion \ndevelopment. However, as women with endometriosis \nhave a significantly lower body mass index than women \nwithout disease ( Vitonis et al.  2010), it is less likely that \nadipose-derived oestrogens have a prominent role in \nendometriosis development.\nNotably, endometrial tissue homogenates are reported \nto contain two to five times greater concentrations of E2 \ncompared to the serum levels ( Huhtinen et  al.  2012 b) \nconsistent with a potential role for intracrine synthesis. \nOne possible source of E2 is the reduction of E1 present in \nthe blood bathing the tissue to E2 by action of the reductive \nenzyme HSD17B type 1 that has been consistently detected \nin the endometrium and differs between ectopic and \neutopic tissue (Huhtinen et al.  2012b, Delvoux et al.  2014). \nAlthough aromatase expression has not been detected in \nstromal cells isolated from healthy endometrium during \nthe proliferative phase, it is reported to be upregulated \nin response to a decidualization stimulus (progesterone \nand cAMP), suggesting that this enzyme may play a role \nin intracrine production of E2 required for regulation \nof immune and other cells in preparation for embryo \nimplantation ( Gibson et  al.  2013 , 2015, 2016). Clearly, \nfurther studies are needed to fully understand the local \nmechanisms of oestrogen biosynthesis and metabolism \nin the healthy endometrium, taking into account reports \nof an impaired response to progesterone in women with \nendometriosis (termed ‘progesterone resistance’, Burney \net al.  2007).\nExpression of oestrogen receptors and impact of \noestrogen on normal endometrium\nIn humans, two isoforms of oestrogen receptor have \nbeen identified: ERα (NR3A1) and ERβ (NR3A2). These are \nencoded by two separate genes, ESR1 and ESR2, respectively, \nlocated on the human chromosomes 6q25.1 ( ESR1) and \n14q23.3 (ESR2) (Nilsson et al.  2001). The messenger RNAs \nfor both receptors are present in the human endometrium, \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT256\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nand detailed immunohistochemical analysis has revealed \nthat expression of the two receptors are distinct with \nrespect to cell type with changes in the epithelial cells \nbeing regulated according to stage of the cycle ( Critchley \net  al.  2001 ). Studies in mouse models have identified a \nkey role for ER α in both stromal–epithelial interactions \nand the regulation of epithelial cell proliferation ( Hewitt \net  al.  2017 ). Notably, ER β but not ER α is present in the \nvascular endothelium of the human and non-human \nprimate endometrium and appears to regulate the E2 \nresponsiveness of these cells consistent with oestrogen \nregulation of angiogenesis ( Critchley et al.  2001, Greaves \net  al.  2013 ). The impact of E2 on diverse immune cell \npopulations may also be regulated by ER β as the receptor \nhas been detected in the nuclei of uterine natural killer \n(uNK) (Henderson et al.  2003) and mast cells (De Leo et al.  \n2017). Notably, recent studies have demonstrated that \nuNK cells treated with E2 release the chemokine CCL2, \nwhich promotes endometrial endothelial cells to form \nangiogenesis networks ( Gibson et al.  2015). This will, in \nturn, provide a potential mechanism by which local E2 \nmight have an impact on cell types that play a key role in \nestablishment of endometriosis lesions.\nDetection of steroids in endometrium and \nendometriosis lesions\nTraditionally, oestrogens have been measured using \neither gas chromatography/mass spectrometry or \nimmunoassay. The development of highly sensitive liquid \nchromatography coupled with tandem mass spectrometry \n(LC-MS-MS) as a technique for steroid detection offered \nan approach for more precise, accurate detection of E2 \n(Harwood & Handelsman 2009 ). Using LC-MS-MS, it has \nbeen possible to measure E2 and E1 in endometrial tissue \nhomogenates demonstrating that they vary according to \nmenstrual cycle phase and that they do not parallel serum \nlevels (Huhtinen et al.  2012b). In endometriosis lesions, \nE2 was the most abundant oestrogen and concentrations \nwere independent of cycle phase in peritoneal and deep-\ninfiltrating lesions ( Huhtinen et  al.  2012 b). Notably, \nalterations in expression of many of the enzymes \ninvolved in biosynthesis and metabolism of oestrogens in \nendometriosis and endometrial cancer has been reviewed \npreviously ( Rižner 2009 , 2013, Huhtinen et  al.  2012 a) \nwith parallels to reports of local oestrogen biosynthesis \nin endometrial cancer (as reviewed by Rižner et al.  2017) \nwith a pro-oestrogenic environment reported to drive cell \nproliferation in the latter.\nExpression of oestrogen receptors in \nendometriosis lesions\nDifferences in expression of ESR1 and ESR2 in endometriotic \ntissue have been reported by several groups (reviewed by \nRižner 2009 , Huhtinen et  al.  2012 a). The Bulun group \nhas investigated the expression of oestrogen receptors \nin endometriosis lesions (reviewed in Bulun et al.  2012), \nreporting overexpression of ERß and identifying changes \nin promoter methylation as a possible mechanism ( Xue \net al.  2007). Immunohistochemical analysis has localized \nERß to both immune cells and nerves in lesions recovered \nfrom women and animal models ( Greaves et  al.  2015 ). \nRemarkably, as shown in studies using in vitro models, E2 \ncan have an impact on nerves, vascular cells and immune \ncells, and it has been suggested they could be regulated via \nERß. It has also been postulated that E2 may have an impact \non neuroangiogenesis (Greaves et al.  2014) and contribute \nto pain mechanisms ( Liang & Yao 2016 ). Following the \ndevelopment of ERß-selective agonists and antagonists \n(reviewed in Burris et  al.  2013 ), these observations that \nERß was overexpressed in endometriosis lesions prompted \ninvestigations in preclinical models to see if they might \noffer a novel therapeutic option. Although some results \nfrom preclinical tests appeared promising (reviewed by \nHarris 2007) to date, there has been limited transparency \nabout the results of clinical trials ( Guo et  al.  2009 ) and \nsearches do not suggest they are still in active development \nfor treatment of this condition.\nLocal (intracrine) biosynthesis of oestrogens \nin endometriosis\nUntil recently, it has been widely accepted that the \npathway most likely to influence local concentrations of \nE1/E2 in endometriotic lesions is the one that culminates \nin transformation of androgens into oestrogens by the \naromatase enzyme complex (P450arom). However, a \nsecond pathway that depends on the ability of STS to \nconvert conjugated steroids found at high concentration \nin blood such as sulphated oestrogens oestradiol sulphate \n(E2S) and oestrone sulphate (E1S) into bioactive E2 or \nE1, respectively, is also likely to be playing a role. In \nendometriotic lesions, oestrogens can be formed by \nthe following three main pathways: (i) de novo  from \ncholesterol; (ii) from androstenedione or testosterone via \nthe aromatase pathway or (iii) from E1S via the sulphatase \npathway. Evidence for all these pathways operating in the \ncontext of endometriosis is reviewed below.\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT257\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\nPathways utilizing cholesterol to generate \nandrogens or progestins\nTable 1  summarizes articles that study the main enzymes \nthat utilize cholesterol to generate androgens or progestins.\nSteroidogenic acute regulatory protein\nCholesterol is a ubiquitous steroid precursor, and STAR \nregulates the transport of cholesterol from the outer \nmembrane to the inner membrane of mitochondria where \nit can be metabolized into pregnenolone by P450scc \n(Soffientini & Graham 2016). STAR mRNA expression was \nfound to be higher in ectopic endometrium compared to \neutopic and control endometrium ( Tsai et al.  2001, Attar \net  al. 2009, Huhtinen et  al. 2014). Moreover, between eutopic \nand control endometrium, STAR was described as more \npronounced in eutopic endometrium of endometriosis \npatients ( Tsai et  al.  2001 , Sun et  al.  2003 ), showing a \ncorrelation with the severity of the disease ( Tian et  al.  \n2009). Utsunomiya et al . (2008) went further, suggesting \nthat alterations in the amount of the transcription factor \nsteroidogenic factor 1 (SF-1), which promotes expression \nof both STAR and P450arom, was regulated by higher \nexpression of stimulatory factor type 2 (USF2) that was \nuniquely expressed in ectopic stromal endometrium cells. \nThus, dysregulation in stromal endometriotic cells may \nbe causing enhanced expression of SF-1, which in turn \nupregulates STAR mRNA expression ( Shen et  al . 2013 ). \nProstaglandin E2 (PGE2), present in high concentrations \nin inflammatory diseases such as endometriosis, also \nstimulates STAR expression in human endometriotic \nstromal cells (Tsai et al.  2001, Hsu et al.  2008, Attar et al.  \n2009), which could also increase the concentration of \nmitochondrial cholesterol and favour increased oestrogen \nbiosynthesis. Conversely, a lack of difference in STAR \nexpression between eutopic endometrium from women \nwith vs without endometriosis was reported in one study \n(Aghajanova et al.  2009) suggesting further investigations \nare required.\nCholesterol side chain cleavage (CYP11A1)\nThe cholesterol side chain cleavage enzyme (encoded by \nCYP11A1, also referred to as CYP450scc) that is responsible \nfor converting cholesterol into pregnenolone is located \nexclusively within the inner mitochondria membrane \n(Van 2013). An in vivo experiment by Attar et al.  described \nhigher CYP450scc mRNA levels in ectopic lesions \ncompared with control endometrium ( Attar et al.  2009). \nConversely, in other studies, no differences in CYP11A1 \nmRNA expression between eutopic control endometrium \nand ectopic endometrium were recorded ( Tsai et  al.  \n2001, Aghajanova et  al.  2009 ). Interestingly, treatment \nof endometrial epithelial and stromal cell cultures from \nTable 1 mRNA expression of enzymes from pathways utilizing cholesterol to generate androgens or progestagens.\nEnzyme Patient number Sample number Differential expression Reference\nSTAR E = 29; C = 13 EE = 7; CE = 6 EE = CE Aghajanova et al. (2009)\nE = 30; C = 16 EL = 13; OE = 17; CE = 16 ↑ EL/CE Attar et al. (2009)\nE = 23; C = 15 EL = 23; EE = 23; CE = 15 ↑ EL; EE/CE Shen et al. (2013)\n↑ EL/EE\nE = 30; C = 25 EL = 30; CE = 25 ↑ EL/CE Tian et al. (2009)\nE = 35; C = 15 EL = 25; OE = 10; ADM = 4; \nCEL = 10; CE = 1\n↑ EL; OE/ADM; CL; CE Tsai et al. (2001)\nCYP11A1 E = 29; C = 13 EE = 7; CE = 6 EE = CE Aghajanova et al. (2009)\nE = 30; C = 16 EL = 13; OE = 17; CE = 16 ↑ EL/CE Attar et al. (2009)\nE = 38; C = 31 EL = 16; EE = 16; CE = 31 ↑ EL; EE/CE Fouquet et al. (2016)\nE = 60; C = 16 EL = 23; OE = 18; EE = 18; CE = 16↑ OE/CE Huhtinen et al. (2014)\nE = 35; C = 15 EL = 25; OE = 10; ADM = 4; \nCL = 10; CE = 1\n↑ EL; OE = ADM; CL; CE Tsai et al. (2001)\nHSD3B2 E = 29; C = 13 EE = 7; CE = 6 EE = CE Aghajanova et al. (2009)\nE = 30; C = 16 EL = 13; OE = 17; CE = 16 ↑ EL/CE Attar et al. (2009)\nE = 60; C = 16 EL = 23; OE = 18; EE = 18; CE = 16↑ EL; OE/CE Huhtinen et al. (2014)\nE = 35; C = 15 EL = 25; OE = 10; ADM = 4; \nCL = 10; CE = 1\n↑ EL; OE = ADM; CL; CE Tsai et al. (2001)\nP450c17 \n \nE = 30; C = 16 EL = 13; OE = 17; CE = 16 ↑ EL/CE Attar et al. (2009)\nE = 38; C = 31 EL = 16; EE = 16; CE = 31 ↑ EL; EE/CE Fouquet et al. (2016)\nE = 60; C = 16 EL = 23; OE = 18; EE = 18; CE = 16↑ OE/CE Huhtinen et al. (2014)\nADM, adenomyosis myometrium; C, control patients – control patients are considered all women without endometriosis; CE, control endometrium; CEL, \ncontrol endometrium from leiomyoma patients; E, endometriosis patients; EE, eutopic endometrium from endometriosis; EL, endometriosis lesion-\nextraovarian; OE, ovarian endometriosis.\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT258\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nwomen with and without endometriosis with PGE2 \npromoted increased levels of  CYP11A1  gene expression \n(Attar et  al.  2009 , Fouquet et  al.  2016 ), indicating that \ninflammatory mediators may also influence the expression \nof this steroidogenic enzyme.\nHSD3B2\nThe steroidogenic enzyme HSD3B catalyzes the \nconversion of pregnenolone into progesterone, DHEA \ninto androstenedione and also 17-hydroxypregnenolone \ninto 17-hydroxyprogesterone. 3 β-HSD (isoform not \nspecified) are expressed in the ovary ( Simard et al.  2005) \nand endometrium ( Casey et  al.  1994 ). The published \nstudies evaluated difference in HSD3B2 expression in the \nendometriosis patients, Tsai et al.  and Aghajanova et al.  \nobserved no difference in amount of HSD3B2 expression \nbetween normal and ectopic endometrium (Tsai et al.  2001, \nAghajanova et al.  2009). In contrast, other studies, higher \nHSD3B2 mRNA concentrations and enzyme activity were \ndetected in ectopic vs eutopic endometrium ( Attar et al.  \n2009, Huhtinen et  al.  2014 ), suggesting a greater intra-\nlesion synthesis of steroidogenesis precursors. To further \ninvestigate the regulation of HSD3B2 in endometriosis \npatients, Urata and colleagues designed an experiment \nto test the effect of PGE2 and interleukin 4 (IL-4), a \ncytokine known to be present in high levels in women \nwith endometriosis, on stromal cells from endometrioma, \nshowing that both factors enhanced HSD3B2 mRNA \nexpression in a dose-dependent manner ( Urata et  al.  \n2013). Similar findings were described by Attar et  al.  \n(2009). Nevertheless, the treatment with IL-4 or PGE2 \ndid not produce an effect on HSD3B2 mRNA expression \nin stromal cells from eutopic endometrium ( Urata et al.  \n2013).\nCYP17A1\nSteroid 17 α-monooxygenase catalyzes the conversion \nof progestins to androstenedione by firstly \nconverting progesterone and pregnenolone into \n17-hydroxyprogesterone and 17-hydroxypregnenolone, \nrespectively. Afterwards, 17-hydroxyprogesterone is \nfurther metabolized by P450c17 into androstenedione. \nAlternatively, 17-hydroxypregnenolone can either be \nconverted into DHEA or 17-hydroxyprogesterone by \nP450c17 and HSD3B2, respectively. HSD3B2 catalyzes the \nconversion of DHEA into androstenedione ( Simard et al.  \n2005, Tsuchiya et  al.  2005 a). Increasing the expression \nof P450c17 in HEK 293 cells enhances the formation of \nDHEA and diminishes 17-hydroxypregnenolone showing \nthe importance of this enzyme in complex steroidogenesis \npathways (Soucy & Van 2000). In endometriosis, P450c17 \nmRNA expression was found to be higher in ectopic \nlesions (ovarian endometrioma and/or peritoneal tissue) \ncompared with control endometrium ( Borghese et  al.  \n2008, Attar et al.  2009, Huhtinen et al.  2014). The same \nhigher expression was observed in epithelial and stromal \nendometriotic cells ( Attar et al.  2009). As with CYP11A1 \nand HSD3B2 enzymes, the expression of P450c17 in \nstromal endometriotic cell cultures was also enhanced \nby treatment with PGE2 highlighting the potential for \npro-inflammatory factors to have an impact on multiple \nenzymes within the steroidogenic pathways to regulate \nsteroid synthesis in endometriosis ( Tsai et al.  2001, Attar \net  al.  2009 ). Moreover, P450c17 expression in epithelial \nendometriotic cells was also enhanced by human \nchorionic gonadotropin and insulin like-3, both factors \nknown to be involved in cell growth, differentiation, \ninvasion and vascularization, all pathophysiological \nmechanism implicated in the development of the disease \n(Fouquet et  al.  2016 ). On the contrary, others have \nreported no difference in expression of P450c17 between \neutopic endometrium from women with and without \nendometriosis (Aghajanova et al.  2009). The CYP17 gene, \nlocated on chromosome 10q24.3, has been intensively \nstudies to find disease-associated polymorphisms ( Soucy \n& Van 2000): some have been correlated with variations \nin steroid hormone levels, menstrual factors and risk \nof endometrial and breast cancers (Devore & Scott \n2012). However, although several studies have tried to \nrelate polymorphisms in CYP17 with susceptibility to \nendometriosis ( Supplementary Table  1 , see section on \nsupplementary data given at the end of this article), there \nis as yet no clear evidence for a correlation.\nPathways utilizing androgens to \ngenerate oestrogens\nTable 2  summarizes articles that study the main enzymes, \nwhich utilize androgens to generate oestrogens.\nAKR1C3\nAldo–keto reductase family 1 member C3 (AKR1C3; also \nknown as 17 β hydroxysteroid dehydrogenase type 5) is a \nsteroidogenic enzyme with diverse substrate specificities \nand activities. AKR1C3 may contribute to a pro-\noestrogenic state in endometriosis as studies investigating \nthe enzyme kinetics of the recombinant human protein \nsuggest AKR1C3 can promote (i) direct reduction of E1 \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT259\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\nto the more potent E2 and (ii) reduction of progesterone \nto less potent metabolite 20 α-hydroxyprogesterone \n(Penning et  al.  2000 ). In hormone-dependent cancers, \nAKR1C3 is reported to promote activation of oestrogens \nby catalysing the reduction of E1 to E2, which promotes \nproliferation of MCF7 breast cancer cells ( Penning & \nByrns 2009). In addition, AKR1C3 catalyses reduction of \nandrostenedione to testosterone, which may impact on \nandrogen–oestrogen balance in the endometrium.\nAKR1C3 has been detected in the human endometrium \nwith peak expression reported in the early secretory phase \nof the menstrual cycle (Catalano et al.  2011). Expression of \nAKR1C3 mRNA measured by qPCR in endometriosis has \nbeen reported in tissue from peritoneal, ovarian and deep-\ninfiltrating endometriosis, but no significant changes \nin expression were reported across menstrual cycle \nphase or between different tissue types ( Huhtinen et  al. \n2012b). Hevir et al.  reported AKR1C3 mRNA is modestly \nincreased in ovarian endometriomas compared to normal \nendometrium ( Hevir et  al.  2011 ) while the same group \nsubsequently found that expression of AKR1C3 protein \nwas unchanged between endometrioma and control \nendometrium (Sinreih et al.  2015). Recent reports suggest \nAKR1C3 is increased in primary ectopic endometrial cells \nfrom ovarian endometriomas compared to cells isolated \nfrom control endometria, although the cell types isolated \nfrom these tissues were not stated in the study ( Kim et al.  \n2017). Immunohistochemistry analysis of AKR1C3 in \nendometrioma tissues demonstrated expression mainly \ndetected in epithelial and to a lesser extent in stromal \ncells ( Hevir et  al.  2011 ). Analysis of cell lines derived \nfrom peritoneal endometriosis tissues suggest AKR1C3 \nmRNA is increased in peritoneal endometriosis stromal \ncell lines (22-B) compared to control stromal cell lines \n(HIESC) (Sinreih et al.  2015). In contrast, AKR1C3 mRNA \nexpression was decreased in 12-Z epithelial cells derived \nfrom peritoneal endometriosis compared to control \nHIEEC epithelial cell line ( Sinreih et  al.  2015 ). Rakhila \net  al. investigated AKR1C3 mRNA expression in women \nwith stage I–II endometriosis (American Fertility Society \nclassification system ( Practice & Medicine 2012 ) and \nreported increased AKR1C3 in ectopic endometrium \ncompared to control endometrium ( Rakhila et al.  2013). \nNotably, when samples were stratified according to \nmenstrual cycle stage, a significant increase in AKR1C3 \nwas only detected in samples from the proliferative phase \nof the cycle highlighting the complexity of interpreting \nAKR1C3 expression studies ( Rakhila et  al.  2013 ). Taken \ntogether, these studies suggest endometrial AKR1C3 may \ncontribute to an altered steroid environment within \nTable 2 mRNA expression of enzymes from pathways utilizing androgens to generate oestrogens.\nEnzyme Patient number Sample number Differential expression Reference\n AKR1C3 E = 24; C = 10 OE = 24; CE = 10 ↑ OE/CE Šmuc et al. (2009)\nE = 31; C = 37 OE = 31; CE = 28; CEM = 9 ↑ OE/CE; CEM Hevir et al. (2011)\nE = 60; C = 16 EL = 4; OE = 4; EE = 4; CE = 4 EL = OE = EE = CE Huhtinen et al. (2012b)***\nE = 45; C = 29 EL = 21; EE = 45; CE = 29 ↑ EL/CE* Rakhila et al. (2013)\nEL = EE\nCYP19 \n \n \n \n \n \n \n \n \n \n \n \n \n \nE = 14; C = 48 EL = 14; EE = 14; CE = 48 CE^ Dassen et al. (2007)\nE = 30; C = 16 EL = 13; OE = 17; CE = 16 ↑ EL/#CE Attar et al. (2009)\nE = 29; C = 13 EE = 7; CE = 6 ↑ EE/CE Aghajanova et al. (2009)\nE = 14; C = 15 EL = 14; EE = 12; CE = 8; CFE = 7 ↑ EE/#CE; CFE Bukulmez et al. (2008b)\n↑ EL/EE\nE = 38; C = 31 EL = 16; EE = 16; CE = 31 ↑ EL and EE/#CE Fouquet et al. (2016)\nE = 60; C = 16 EL = 23; OE = 18; EE = 18; CE = 15 ↑ OE/#CE Huhtinen et al. (2012b)***\nE = 10; C = 20 EL = 10; EE = 10; ADM = 10; CCE = 10 ↑ EL; EE; ADM/CCE Kitawaki et al. (1997)\nE = 42; C = 21 EE = 42; CCE = 21 ↑ EE/#CCE Kitawaki et al. (1999)\nE = 15; C = 19 EL = 15; EE = 15; CE = 19 ↑ EL/EE; CE Morsch et al. (2009)\nE = 17; C = 7 EL = 17; EE = 11; CE = 7; ENP = 7 ↑ EL; EE/#CE; ENP Noble et al. (1996b)\nE = 23; C = 15 EL = 23; EE = 23; CE = 15 ↑ EL; EE/#CE Shen et al. (2013)\n↑ EL/EE\nE = 16; C = 9 OCE = 16; COC = 9 ↑ OE/#COC Smuc et al. (2007)\nE = 24; C = 10 OE = 24; CE = 10 ↑ OE/CE Šmuc et al. (2009)\n#Absence of mRNA expression; ^mRNA expression near detection limit; *only when comparing patients in the proliferative phase; ***when comparing \npatients in the proliferative vs secretory phase. It was considered significant all mRNA expression with P < 0.005.\nADM, adenomyosis myometrium; C, control patients – control patients are considered all women without endometriosis; CCE, cervical carcinoma \nendometrium; CE, control endometrium; CEM, control endometrium with myoma; CFE, control with fibrosis endometrium; COC, control ovarian cyst; E, \nendometriosis patients; EE, eutopic endometrium from endometriosis women; EL, endometriosis lesion-extraovarian; ENP, endometriosis normal \nperitonium; OCE, ovarian endometriotic cyst from patients with endometriosis; OE, ovarian endometriomas.\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT260\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nendometriosis lesions but further studies are required to \nestablish if this affects growth/persistence of endometriosis \nlesions. Notably, AKR1C3 also catalyses reduction of \nisoprenyl aldehydes as well as retinaldehydes with high \ncatalytic efficiency as compared to other substrates (Endo \net  al.  2011 , Ruiz et  al.  2011 ). In addition, AKR1C3 can \nfunction as a prostaglandin F2 α (PGF2 α) synthase and \nPGF2α concentrations are elevated in the peritoneal fluid \nfrom endometriosis patients compared to healthy women \n(Sinreih et al.  2015). AKR1C3 may therefore have diverse \neffects and influence multiple signalling pathways in \nendometriosis.\nAromatase (CYP19)\nAromatase (P450arom), encoded by CYP19A1, is a \nmember of the cytochrome P450 family. This enzyme \nplays a key role in oestrogen biosynthesis by catalysing \nthe aromatization of the androgens, androstenedione \nand testosterone into E2 and E1, respectively. The \nCYP19A1 gene is located in chromosome 15q21.2 and \nthe association of polymorphism and endometriosis risk \nin different ethnicities has been explored; however, the \nresults are inconsistent and inconclusive, even within the \nsame population (Supplementary Table 2 ) (Yi et al.  2016). \nThere have also been differing results reported related to \nthe presence or absence of P450arom in endometrium \nand ectopic lesions with reports of atypical expression in \npatients with endometriosis ( Bulun et  al.  2004 , Ferrero \net al.  2014, Blakemore & Naftolin 2016 ). Several studies \nreport that protein and mRNA expression of P450arom \ncan be detected in ectopic and/or eutopic endometrium of \nendometriosis patients, but not in normal endometrium \n(Noble et al.  1996a, Kitawaki et al.  1997, 1999, Tsai et al.  \n2001, Dassen et al.  2007, Hudelist et al.  2007, Smuc et al.  \n2007, Bukulmez et al.  2008a, Attar et al.  2009, Šmuc et al.  \n2009, Morsch et  al.  2009 , Huhtinen et  al.  2012 b, 2014, \nShen et  al.  2013 , Suganuma et  al.  2014 , Fouquet et  al.  \n2016) although this is disputed by others who failed to \ndetect expression in either ectopic or eutopic endometrial \ntissue ( Colette et  al.  2009 , Delvoux et  al.  2009 , 2014), \nothers record expression in normal endometrium ( Tseng \n1984, Neulcn et  al.  1987 , Huang et  al.  1989 , Castro \net  al.  2010 ) and in endometrium from women with \nand without endometriosis ( Aghajanova et  al.  2009 ). \nVariations in the location of P450arom have also been \nrecorded with detection in epithelial cells ( Kitawaki et al.  \n1997, Bukulmez et  al.  2008 a, Castro et  al.  2010 ), but \nmostly in stromal cells ( Noble et al.  1996a, Zeitoun et al.  \n1999, Suganuma et  al.  2014 ) ( Supplementary Tables  3  \nand 4). Some of the variations in the reported patterns \nof expression may relate to use of different antibodies, \nrecovery of eutopic endometrium at different stages of the \ncycle, the type of lesion or the status of the inflammatory \nmicroenvironment as discussed below.\nA number of factors that are altered in endometriosis \npatients can induce the expression of P450arom. For \ninstance, the observed increase in concentrations of \nandrostenedione ( Huhtinen et  al.  2014 ) may induce \nP450arom expression in human endometrial stromal cells \nand the human endometrial surface epithelial (HES) cell \nline, as has been previously described ( Bukulmez et  al.  \n2008b). Inflammatory cells or inflammatory mediators \nmay also have an impact. For example, P450arom protein \nand mRNA were enhanced by macrophage activity \nin endometrial stromal and endometrial cells, and \nmacrophage inhibition significantly reduced P450arom \nexpression (Veillat et al.  2012). In different experiments, \ntreatments of stromal cells derived from ovarian \nendometrioma, with PGE-2 or IL-(1, 2, 4, 6, 11, 15) \nstimulated expression of P450arom in a time- and dose-\ndependent manner ( Noble et al.  1997, Urata et al.  2013, \nZeng et  al.  2015 ). Interestingly, in these experiments, \neutopic endometrial cells showed low levels of P450arom \nmRNA expression and not upregulated by PGE-2 or ILs, \nsuggesting there may be different responses in eutopic vs \nectopic tissues.\nAccordingly, in face of these conflicting results, \ncontroversy still exists with regard to the association \nbetween P450arom expression and clinical symptoms \nof endometriosis. Higher CYP17A1 GG genotype was \nlinked to infertility although there were no differences \nbetween patients with endometriosis and patients \nwithout endometriosis ( Szczepańska et  al.  2013 ). In \na study on 62 women with endometriosis, positive \nimmunohistochemical expression for aromatase was \ndetected in the endometriotic tissues from 38 patients \n(61.3%): these patients were more likely to have ovarian \ndisease and moderate-to-severe chronic pelvic pain (Acién \net al.  2007).\nPathways utilizing sulphated steroids\nAlthough the synthesis of E1 and E2 from the sulphated \noestrogens (E1S and E2S, respectively) is usually \nconsidered less important than the aromatase pathway \nin the ovary, for peripheral tissues including the \nendometrium it seems to be an important alternative \npathway that leads to increased bioavailability of local \nactive oestrogens (reviewed by Rižner 2016 ). Thus, due \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT261\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\nto the possible impact that sulphonation pathway could \nhave in oestrogen-dependent diseases, research groups \naround the world investigated the possible involvement \nof sulphated steroids and their respective enzymes in \nendometriosis (Purohit et al.  2008, Delvoux et al.  2014). \nTable 3  summarizes articles that study the main enzymes \nthat utilize sulphated steroids including two forms of \nsulphotransferases (SULTs) not discussed below.\nSteroid sulphatase\nSTS is the enzyme responsible for the hydrolysis of \ndehydroepiandrosterone sulphate, E1S and E2S into their \nunconjugated forms, DHEA, E1 and E2, respectively (Reed \net al.  2005). Although the mRNA expression and activity \nof STS is increased in malignant endometrial tissues \ncompared with nonmalignant tissues according to the \nmajority of studies ( Hevir et al.  2011, 2013), data on STS \nmRNA and protein expression have only recently emerged \nfrom studies on endometriosis. The expression of STS in \nendometriosis has been reviewed by Rižner 2009 , where \ncomparisons of STS expression in eutopic and ectopic \ntissue from the same patients as well as comparison of \nexpression in ectopic tissue vs eutopic tissue of control \npatients were evidenced. Overall, most studies agree that \nthere is a differential STS mRNA expression between \neutopic and ectopic endometrium, in spite of conflicting \nresults in regards of STS expression among endometriotic \nlesions. Data from our group show higher STS mRNA \nexpression in deep-infiltrating and superficial lesions when \ncompared to eutopic and normal endometrium, with \nneither differences between ectopic lesions, nor between \neutopic and normal endometrium (Piccinato et al.  2016a). \nSome authors have reported higher STS mRNA expression \nin ovarian lesions when compared to endometrium from \npatients with myoma (Smuc et al.  2007, Šmuc et al.  2009), \nwhile others have not been able to detect differences \nbetween lesions, compared to the eutopic endometrium \n(Colette et  al.  2013 , Huhtinen et  al.  2014 ). Similarly, in \ndeep-infiltrating lesions, both an unaltered expression \npattern (Dassen et al.  2007) and greater expression of STS \nmRNA expression relative to that in ovarian lesions have \nbeen described (Colette et al.  2013).\nOnly a few researchers have attempted to quantify STS \nprotein expression. Collette et al.  reported no differences \nin protein levels between tissues from endometriosis \npatients and controls ( Colette et al.  2013). In contrast to \nthat, Dassen et al.  reported increased expression levels of \nTable 3 mRNA expression of enzymes from pathways utilizing sulphated steroids.\nEnzyme Patient number Sample number Differential expression Reference\nSTS E = 60; C = 16 EL = 23; OE = 18; EE = 18; CE = 16 OE = CE Huhtinen et al. (2014)\nEE = CE\nEL = CE\nE = 62; C = 16 EL = 34; EE = 24; CE = 25 ↑ EL/EE; CE Piccinato et al. (2016a)\nE = 16; C = 9 OCE = 16; COC = 9 ↑ OE/COC Smuc et al. (2007)\nE = 24; C = 10 OE = 24; CE = 10 ↑ OE/CE Šmuc et al. (2009)\n HSD17B1 E = 29; C = 13 EE = 7; CE = 6 EE = CE Aghajanova et al. (2009)\nE = 29 EL = 23; OE = 6; EE = 29 ↑ EL; OE/EE Delvoux et al. (2014)\nE = 60; C = 16 EL = 23; OE = 18; EE = 18; CE = 15 ↑ OE/CE Huhtinen et al. (2012b)***\nE = 16; C = 9 OCE = 16; COC = 9 ↑ OE/COC Smuc et al. (2007)\nE = 24; C = 10 OE = 24; CE = 10 ↑ OE/CE Šmuc et al. (2009)\nSULT1A1 E = 79; C = 41 EL = 30; OE = 15; EE = 33; CE = 15 EL = OE = EE = CE Colette et al. (2013)\nE = 31; C = 29 OE = 31; CE = 29 OE = CE Hevir et al. (2013)\nE = 24; C = 10 OE = 24; CE = 10 OE = CE Šmuc et al. (2009)\nSULT1E1 E = 79; C = 41 EL = 30; OE = 15; EE = 33; CE = 15 EL = OE = EE = CE Colette et al. (2013)\nE = 14; C = 48 EL = 14; EE = 14; CE = 48 ↑ EL/EE Dassen et al. (2007)\nE = 31; C = 29 OE = 31; CE = 29 OE = CE Hevir et al. (2013)\nE = 62; C = 16 EL = 34; EE = 24; CE = 25 *EL = EE = CE Piccinato et al. (2016a)\nE = 24; C = 10 OE = 24; CE = 10 OE = CE Šmuc et al. (2009)\nSULT2B1\nE = 79; C = 41 EL = 30; OE = 15; EE = 33; CE = 15 EL = OE = EE = CE Colette et al. (2013)\nE = 31; C = 29 OE = 31; CE = 29 ↑ OE/CE Hevir et al. (2013)\nE = 24; C = 10 OE = 24; CE = 10 OE = CE Šmuc et al. (2009)\n*Tendency of reduced expression; ***when comparing patients in the proliferative and secretory phase. It was considered significant all mRNA expression \nwith P < 0.005.\nC, control patients – control patients are considered all women without endometriosis; CE, control endometrium; COC, control ovarian cyst; E, endometriosis \npatients; EE, eutopic endometrium from endometriosis; EL, endometriosis lesion-extraovarian; OCE, ovarian endometriotic cyst endometriosis; OE, ovarian \nendometriomas.\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT262\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nSTS in epithelial cells, but not in stromal cells, of normal \nendometrium when compared to eutopic endometrium \nfrom women with endometriosis, suggesting cell-specific \nenrichment of the enzyme ( Dassen et  al.  2007 ). These \nstudies used immunohistochemical analysis, and no other \nstudies have reported protein expression data, which \nmay reflect problems with antibody quality. Despite the \ncontroversy in protein expression data, STS activity seems \nto be correlated with severity of the disease suggesting \nthat the sulphate pathway might be involved with the \nunderlying mechanisms that contribute to the severity of \nendometriosis ( Purohit et  al.  2008 ). A clear STS activity \nhas been described in endometriosis lesions, with a high \npositive correlation between protein activity and severity \nof the disease ( Dassen et al.  2007). Similarly, STS activity \nin ectopic tissues from minimal-to-mild endometriosis \nwas significantly lower than similar samples collected \nfrom patients affected with a moderate-to-severe form \nof the disease ( Purohit et  al.  2008 ). In the same study, \nhowever, an intriguing overall lower activity in ectopic \nendometrium was detected when compared to eutopic \nendometrium (Purohit et al.  2008) and a lack of differential \nactivity between eutopic and ectopic tissues was also \nreported in another study (Delvoux et al.  2009). Using an \nin vitro approach, endometrial and endometriotic stromal \ncells were incubated with E2S as a STS substrate for 2 h. \nThe result shows E2 concentrations higher in stromal \ncells from deep-infiltrating endometriotic lesions as \ncompared to cells from eutopic endometrium from the \nsame patient (Piccinato et al.  2016a). This finding suggests \na greater efficiency of endometriotic stromal cells in \nmetabolizing oestrogen sulphates, which might explain \nthe ability of lesions to maintain an oestrogenic milieu. \nThe regulation of STS activity and expression seems to \nbe tissue specific ( Dalla Valle et  al.  2006 , Zaichuk et  al.  \n2007). In the endometrium, STS has been shown to be \nregulated by progesterone, according to menstrual cycle \nphases ( Furusawa et  al.  2002 ) with endometrium from \nthe luteal phase of the cycle showing higher mRNA \nSTS expression than that from the follicular phase in \nnormal endometrium: the same observation made in \nendometriosis patients, for both eutopic and ectopic \nendometrium (Piccinato et al.  2016a). In the same study, \nSTS expression was modulated by E2 and progesterone \n(representative steroid hormones from the luteal phase) \nin stromal endometriotic cells. Conversely, Dassen et al.  \nfound that STS mRNA expression was not affected by E2 \nor progesterone in explant endometrial culture ( Dassen \net al.  2007).\nHSD17B subtypes\nThe 17- β-hydroxysteroid-dehydrogenase (HSD17B) \nenzymes play important roles in oestrogen biosynthesis in \nthe sulphatase pathway. It is responsible for catalysing the \noxidation and reduction of steroids, which means they \nactivate and inactivate oestrogens, enabling them to bind \nwith oestrogen receptors ( Marchais-Oberwinkler et  al.  \n2011). There are 15 HSD17B enzymes described today and \nwith the exception of HSD17B5, an aldo–keto reductase \nenzyme, they all belong to short-chain dehydrogenase/\nreductase family and are multimeric enzymes ( He et  al . \n2016). For instance, 17BHSD2 is an oestrogen inactivator \n(E2 to E1) and expression of 17BHSD2 may be decreased \nin endometriosis ( Bulun et al.  2010). Among all HSD17B \nfamily members, HSD17B1 is considered the most \nimportant enzyme for E2 production ( Zhang et al.  2015). \nOf interest, a higher HSD17B1 expression has been \nlinked to endometriosis and the severity of the disease \n(Supplementary Table 5) (Tsuchiya et al.  2005b, Smuc et al.  \n2007, Huhtinen et al.  2012b).\nGene transcripts for HSD17B1 have been found \nupregulated in endometriosis tissues (eutopic and/or \nectopic endometrium) when compared with eutopic \ntissue from healthy women (Dassen et al.  2007, Smuc et al.  \n2007, Šmuc et al.  2009, Huhtinen et al.  2012a, Colette et al.  \n2013, Delvoux et al.  2014), although some reports show \nno detectable mRNA expression for HSD17B1 in normal \nendometrium ( Casey et  al.  1994 ). Results for protein \nexpression appear less consistent, for instance, Dassen \net  al . found higher mRNA expression of HSD17B1, but \nless protein expression in endometriotic tissue compared \nto normal endometrium ( Dassen et  al.  2007 ). Others, \nstudying HDS17B1 protein expression, demonstrated \nhigher HDS17B1 activity in ectopic endometrium \ncompared to eutopic endometrium from the same \npatient (Delvoux et al.  2009). Another group stated that \nthere is no protein expression in normal endometrium \n(Utsunomiya 2001 ). Disparities in findings based on \ndifferent types of endometriosis (ovarian, peritoneal \nand deep-infiltrating) and menstrual phase have also \nbeen reported. In one study when endometriotic sites \nwere compared, no differences were seen in HSD17B1 \ntranscript expression between ovarian, peritoneal and \ndeep-infiltrating endometriosis ( Colette et  al.  2013 ). In \nanother study, a significant increase in HSD17B1 mRNA \nexpression in ovarian endometriosis compared to normal \nendometrium was reported ( Huhtinen et al.  2012b). The \nmenstrual phase did not appear to influence HSD17B1 \nmRNA expression in eutopic tissue from endometriosis \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT263\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\npatients or in non-endometriosis patients ( Colette et  al. \n2013) and protein expression levels were also similar \namong different menstrual phases in both groups of \nwomen with and without endometriosis in other papers \n(Dassen et al.  2007, Colette et al.  2013).\nSulphotransferases\nOestrogen homeostasis is closely controlled by the balance \nbetween desulphonation and sulphation; therefore, \nthe expression and activity of SULTs in a tissue can be \nconsidered as a mechanism that generates a reservoir of \nsulphated steroids that can be readily activated by STS. \nOverall, sulphation pathways include sulphate uptake, \nfollowed by conversion to an active sulphate in the \nform of 3-phospho-adenosine-5-phosphosulphate, and \ntransfer to steroid hydroxyl groups by SULTs (reviewed \nby Mueller et al.  2015). The superfamily of steroid SULTs \ninclude members that have a direct role in oestrogen local \nmetabolism, by catalysing the sulphonation of E1 and \nE2 with high affinity (E1 SULT SULT1E1, also called EST) \nor with low affinity (SULT1A1) ( Adjei & Weinshilboum \n2002); but also members indirectly modulating local \noestrogen concentrations by sulphonating precursors of \noestrogen formation, as for instance SULT2B1 that acts \npreferentially on 3β-hydroxysteroids (Geese & Raftogianis \n2001).\nE1 SULT is expressed in the endometrium and although \nit is not a steroid-synthesizing enzyme, it has been \nincluded in this review due to its impact on intra-tissue \noestrogen concentrations ( Rubin et  al.  1999 ). SULT1E1 \nhas a high affinity for physiological concentrations of E2 \nand E1 (Honma et al.  2002) and is the major SULT isoform \nresponsible for oestrogen sulphation ( Zhang et al.  1998). \nSULT1E1 is, therefore, an important downregulator of \noestrogen activity and can protect cells/tissues from \nadverse effects of excess oestrogens.\nOur own data on SULT1E1 shows tendency of \nincreased expression of the enzyme in ovarian and \nperitoneal endometriotic lesions, as compared to eutopic \nendometrium of endometriosis patients ( Piccinato et  al.  \n2016a). Similar results were obtained by Dassen et  al . \nwho reported increased expression of SULT1E1 mRNA in \nendometriotic lesions (without lesion type classification), \nas compared to that in control endometrium ( Dassen \net  al.  2007 ). However, the same differences were not \ndetected in the samples from 15 patients examined by \nColette et al.  (2013). We and Dassen et al . also reported an \noverexpression of SULT1E1 during the luteal phase of the \nmenstrual cycle samples (lesions and endometrium) from \nwomen with endometriosis, whereas cycle-dependent \nexpression was not detected in endometrium of non-\naffected women (Dassen et al.  2007, Piccinato et al.  2016a). \nOther groups have not detected evidence of menstrual \ncycle phase-dependent regulation in SULT1E1 expression \n(Colette et  al.  2013 , Hevir et  al.  2013 ) or have not \ncontrolled for this variable in their analysis ( Šmuc et al.  \n2009). The only data about SULT1E1 protein expression \ncomes from an immunohistochemical study that shows \nno difference in SULT1E1 expression between eutopic and \nectopic endometrium (Hudelist et al.  2007). However, no \nclear description of type of lesion was provided, suggesting \nthat different kinds of lesions were included in the same \ngroup. Further studies with larger numbers of samples are \nneeded to resolve the differences between these reports.\nIn oestrogen-sensitive tissues, such as the \nendometrium, the activity of SULT1E1 is generally \nlower than that of STS ( Naitoh et  al.  1989 ) promoting \nan increased bioavailability of active oestrogens, which \nmay be further enhanced under pathological conditions. \nAlthough controversy still exists with regard to expression \nin tissue samples from women with endometriosis, reports \nof increased expression of SULT1E1 and co-expression of \nSTS and SULT1E1 (Piccinato et al.  2016a) in endometriosis \nlesions as compared to control endometrium suggest that \nthese enzymes might contribute to local generation of a \nreservoir of sulphated steroids that, upon deconjugation \nby STS, can support growth of lesions or progression of \ndisease.\nOther levels of control of oestrogen accumulation in \nendometriotic lesions\nMetabolizing enzymes  While emphasis is often placed \non the role of the enhancement of E2 biosynthesis path -\nways, there is increasing evidence that enzymes involved \nin the metabolism/inactivation of oestrogens have a role \nin the regulation of local oestrogen homeostasis in lesions. \nThe mechanisms by which altered oestrogen-metabolizing \nenzymes could potentially be involved with the patho -\ngenesis of endometriosis ranges from reduction of local \noestrogen ( Piccinato et  al  2016 a STS) to increase in the \nreactive oxidative species in endometriotic lesions ( Hevir \net al . 2013). Besides SULT1E1, other phase II (conjugative) \nmetabolizing enzymes such as catechol-O-methyltrans -\nferase (COMT) and uridine diphospho-glucuronosyltrans-\nferase (UGT) and even phase I oxidative enzymes (as for \ninstance, CYP1A1 and CYP3A4) can reduce or block oes -\ntrogen availability in endometriotic lesions, representing \nan important regulatory mechanism of oestrogen action. \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT264\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nData from our group (Piccinato et al.  2016a,b,c) and reports \nfrom others (Hevir et al.  2013) show that enzymes classi -\ncally involved in extra-hepatic oestrogen metabolism are \nupregulated in endometriotic lesions. It should be noted \nthat the expression of these metabolizing enzymes may be \ninfluenced by the location of the lesion. For example, it \nhas been reported that expression of CYP1A1 and CYP1B1 \nenzymes is higher in superficial lesions in comparison \nto eutopic endometrium or deep-infiltrating lesions \n(Huhtinen et  al.  2014 , Piccinato et  al.  2016 a). In addi -\ntion, mRNA and protein encoded by UGT1A1 were low \nor absent in eutopic endometrium, whereas it was pos -\nsible to detect the enzyme in almost all types of lesions, \nmost prominently in deep-infiltrating lesions, but also \nin superficial peritoneal and ovarian lesions. It is impor -\ntant to highlight that the metabolism of oestrogens not \nonly alters the intensity of their action but may also alter \nthe profile of their physiological effects in target tissues \n(Tsuchiya et al.  2005a). Although speculative, it appears \nthat the progression of endometriosis can be influenced \nby the expression and activity of enzymes involved in the \nmetabolism of oestrogens.\nCellular transport of sulphated oestrogens Sulphated \nsteroids, such as E1S or E2S are hydrophilic, organic \nanions that need specific active transmembrane transport \nfor cellular influx and efflux (reviewed by Mueller et al.  \n2015). This active cellular transport is regulated by numer-\nous membrane-bound proteins that belong to two super -\nfamilies: solute carrier (SLC) transporters and ATP-binding \ncassette (ABC) transporters ( Roth et al.  2012). Very little \nis known about how E1S is transported into cells in the \nendometrium or lesions ( Plaza-Parrochia et al.  2015). In \ndifferent tissues, it seems that a variety of organic anion \ntransporting polypeptides and SLC21 (all belonging to \nthe SLC family) can carry E1S from the extracellular space \nto the intracellular space (reviewed by Secky et al.  2013). \nThe efflux of E1S is, in turn, actively promoted by ABC \ntransporters, called MRP1 and BCRP. In summary, the \ncombined activity of transmembrane protein transport -\ners, metabolizing enzymes and synthesizing enzymes can \nregulate the amount of sulphated oestrogen and, thus, the \namount of bioactive oestrogen within tissues.\nSummary and future directions\nEndometriosis is an incurable disorder characterized by \ninflammation and hormone dependence. Oestrogens \nacting via oestrogen receptors regulate processes \nincluding proliferation, angiogenesis, inflammation \nand differentiation, which are important in regulation \nof normal endometrium, endometrial pathologies \n(hyperplasia and adenocarcinoma) and have been \nimplicated in the establishment of endometriosis lesions. \nIn vitro  studies using isolated cells have suggested that \npro-inflammatory mediators such as PGE2 can stimulate \nexpression of the steroidogenic enzymes detected \nin lesions providing a mechanism linking these two \nhallmarks of the disease.\nStudies on endometrium and endometriosis lesions \nhave provided compelling evidence that (intracrine) \noestrogen biosynthesis associated with dysregulation \nof enzyme expression occurs in endometriosis. Indeed, \noestrogen accumulation is defined by the balance of \nsynthesis and inactivation/metabolism, and it seems that \nmetabolism might play a previously underappreciated \nrole as several key metabolizing enzymes are upregulated \nin endometriotic tissue. The primary sites of synthesis \nof the bioactive oestrogens (E1, E2) that circulate in the \nbloodstream are the ovarian follicles but expression of \nsteroid-metabolizing enzymes in extraovarian sites can \nhave a significant impact on the local concentrations \nof steroids in the tissue microenvironment. Expression \nof enzymes representing all key steps in the de novo  \nsteroidogenic pathway, including aromatase, has been \ndetected. An alternative source of E1 and E2 are conjugated \nsteroids found in the blood bathing the lesions and \nthe discovery that the STS enzyme which uses E1S and \nE2S as substrate, when appropriate uptake transporters \nare expressed in lesions has opened up an alternative \nmechanism to explain the higher concentrations of E2 \ndetected in lesions using LC/MS-MS.\nTreatments focused on modulation of the enzymes \nthat regulate local (intracrine) actions of oestrogens in \nlesions are being actively explored as these offers the \npromise of capitalizing on the proven success of regimes \nthat suppress ovarian steroid production in reducing \npain symptoms but without acting as contraceptives. AIs \nhave been effective in the treatment of breast cancer and \nsome reports suggest AI can also relieve endometriosis-\nassociated symptoms ( Attar & Bulun 2006 ). Evidence of \nlimitations on the use of AI alone or in combination for \nendometriosis-related chronic pelvic pain and infertility \ntreatment have been reviewed ( Pavone & Bulun 2012 , \nDunselman et al.  2014). Notably, recent data suggest new \nlocal (vaginal) routes of delivery should receive more \nattention and testing ( Buggio et  al.  2017 ). Inhibitors of \nAKR1C3 are an attractive option because the enzyme is \nactive in both the steroid and prostaglandin pathways: \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT265\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\ndrugs have been developed for clinical indications \nincluding castration resistant prostate cancer and breast \ncancer (reviewed in Penning 2017). Bayer has developed \nan AKR1C3 inhibitor (BAY 1128688) for the treatment of \nendometriosis and this is reported in phase I completed \nclinical trial (ClinicalTrials.gov Identifier: NCT02434640) \nthat led to a recently initiated phase II clinical trial. A \nnumber of STS inhibitors have been developed with the \nprimary clinical indication being hormone-dependent \ncancers ( Purohit & Foster 2012 ) and shown to be well \ntolerated in phase I clinical trials for breast cancer (Stanway \net al.  2006). The STS inhibitor EMATE was shown to have \nan impact on lesions in mouse models (Colette et al.  2011), \nand there is a proof-of-principle report regarding the use \nof this STS inhibitor in combination with a progestin to \ntreat women with endometriosis (Pohl et al.  2014) offering \npromising new therapeutic approach worthy of further \ninvestigation. To date, there have not been any studies \nusing drugs targeting SULT1E1 or membrane transporters, \nbut these offer additional novel targets.\nIn summary, there is increasing interest in the \npotential for targeting enzymes involved in generation of \na pro-oestrogenic microenvironment in lesions as a novel \nfertility-sparing therapy for women with endometriosis. \nAs new drugs become available, we can expect to see an \nacceleration and expansion of both basic and clinical \nstudies and trials.\nSupplementary data\nThis is linked to the online version of the paper at https://doi.org/10.1530/\nJME-17-0297.\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be \nperceived as prejudicing the impartiality of this review.\nFunding\nThis work was partially supported by the São Paulo Research Foundation \n(FAPESP: 2010/02412-6). D A G is employed on a grant from the UK Medical \nResearch Council that also supports research activity in the Saunders \nlaboratory (GMR/N024524/1). C A P is a visiting scientist supported by an \ninstitutional grant from Sociedade Beneficiente Israelita Brasileira Albert \nEinstein.\nReferences\nAcién P, Velasco I, Gutiérrez M & Martínez-Beltrán M 2007 Aromatase \nexpression in endometriotic tissues and its relationship to clinical \nand analytical findings. Fertility and Sterility 88 32–38. (https://doi.\norg/10.1016/j.fertnstert.2006.11.188)\nAdjei AA & Weinshilboum RM 2002 Catecholestrogen sulfation: possible \nrole in carcinogenesis. Biochemical and Biophysical Research \nCommunications 292 402–408. (https://doi.org/10.1006/\nbbrc.2002.6658)\nAgarwal A, Gupta S & Sharma RK 2005 Role of oxidative stress in female \nreproduction. Reproductive Biology and Endocrinology  3 28. (https://\ndoi.org/10.1186/1477-7827-3-28)\nAghajanova L, Hamilton A, Kwintkiewicz J, Vo KC & Giudice LC 2009 \nSteroidogenic enzyme and key decidualization marker dysregulation \nin endometrial stromal cells from women with versus without \nendometriosis. Biology of Reproduction 80 105–114. (https://doi.\norg/10.1095/biolreprod.108.070300)\nAmerican Society for Reproductive Medicine 1997 Revised American \nSociety for Reproductive Medicine classification of endometriosis: \n1996. Fertility and Sterility 67 817–821. (https://doi.org/10.15270/43-\n3-276)\nAttar E & Bulun SE 2006 Aromatase inhibitors: the next generation of \ntherapeutics for endometriosis? Fertility and Sterility 85 1307–1318. \n(https://doi.org/10.1016/j.fertnstert.2005.09.064)\nAttar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, \nGurates B, Attar R, Yaegashi N, Hales DB, et al.  2009 Prostaglandin \nE2 via steroidogenic factor-1 coordinately regulates transcription of \nsteroidogenic genes necessary for estrogen synthesis in \nendometriosis. Journal of Clinical Endocrinology and Metabolism  94 \n623–663. (https://doi.org/10.1210/jc.2008-1180)\nBellelis P, Podgaec S & Abrão MS 2014 Fatores ambientais e \nendometriose: um ponto de vista. Revista Brasileira de Ginecologia E \nObstetrícia 36 433–435. (https://doi.org/10.1590/SO100-\n720320140005128)\nBlakemore J & Naftolin F 2016 Aromatase: contributions to physiology \nand disease in women and men. Physiology 31 258–269. (https://doi.\norg/10.1152/physiol.00054.2015)\nBorghese B, Mondon F, Noël J-C, Fayt I, Mignot T-M, Vaiman D & \nChapron C 2008 Gene expression profile for ectopic versus eutopic \nendometrium provides new insights into endometriosis oncogenic \npotential. Molecular Endocrinology 22 2557–2562. (https://doi.\norg/10.1210/me.2008-0322)\nBuggio L, Lazzari C, Monti E, Barbara G, Berlanda N & Vercellini P 2017 \n‘Per vaginam’ topical use of hormonal drugs in women with \nsymptomatic deep endometriosis: a narrative literature review. \nArchives of Gynecology and Obstetrics  296 435–444. (https://doi.\norg/10.1007/s00404-017-4448-z)\nBukulmez O, Hardy DB, Carr BR, Word RA & Mendelson CR 2008 a \nInflammatory status influences aromatase and steroid receptor \nexpression in endometriosis. Endocrinology 149 1190–1204. (https://\ndoi.org/10.1210/en.2007-0665)\nBukulmez O, Hardy DB, Carr BR, Auchus RJ, Toloubeydokhti T, Word RA \n& Mendelson CR 2008 b Androstenedione up-regulation of \nendometrial aromatase expression via local conversion to estrogen: \npotential relevance to the pathogenesis of endometriosis. Journal of \nClinical Endocrinology and Metabolism  93 3471–3477. (https://doi.\norg/10.1210/jc.2008-0248)\nBulletti C, Coccia ME, Battistoni S & Borini A 2010 Endometriosis and \ninfertility. Journal of Assisted Reproduction and Genetics  27 441–447. \n(https://doi.org/10.1007/978-1-4471-4953-8_3)\nBulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, Langoi D, \nAmin S, Yang S & Deb S 2004 Aromatase and endometriosis.  \nSeminars in Reproductive Medicine  22 45–50. (https://doi.\norg/10.1055/s-2004-823026)\nBulun SE, Cheng Y, Pavone ME, Yin P, Imir G, Utsunomiya H, Thung S, \nXue Q, Marsh EE, Tokunaga H, et al.  2010 17Beta-hydroxysteroid \ndehydrogenase-2 deficiency and progesterone resistance in \nendometriosis. Seminars in Reproductive Medicine  28 44–50. (https://\ndoi.org/10.1055/s-0029-1242992.17)\nBulun SE, Monsavais D, Pavone ME, Dyson M, Xue Q, Attar E, \nTokunaga H & Su EJ 2012 Role of estrogen receptor- β in \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT266\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nendometriosis serdar. Seminars in Reproductive Medicine  30 39–45. \n(https://doi.org/10.1055/s-0031-1299596.Role)\nBurney RO, Talbi S, Hamilton AE, Kim CV , Nyegaard M, Nezhat CR, \nLessey BA & Giudice LC 2007 Gene expression analysis of \nendometrium reveals progesterone resistance and candidate \nsusceptibility genes in women with endometriosis. Endocrinology 148 \n3814–3826. (https://doi.org/10.1210/en.2006-1692)\nBurris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, \nLundasen T, Hughes T & Kojetin DJ 2013 Nuclear receptors and their \nselective pharmacologic modulators. Pharmacological Reviews 65  \n710–778. (https://doi.org/10.1124/pr.112.006833)\nCasey ML, MacDonald PC & Andersson S 1994 17 beta-Hydroxysteroid \ndehydrogenase type 2: chromosomal assignment and progestin \nregulation of gene expression in human endometrium. Journal of \nClinical Investigation 94 2135–2141. (https://doi.org/10.1172/\nJCI117569)\nCastro J, Torres M, Sovino H, Fuentes A, Boric MA & Johnson MC 2010 \nP450Arom induction in isolated control endometrial cells by \nperitoneal fluid from women with endometriosis. Fertility and Sterility \n94 2521–2527. (https://doi.org/10.1016/j.fertnstert.2010.03.036)\nCatalano RD, Wilson MR, Boddy SC & Jabbour HN 2011 Comprehensive \nexpression analysis of prostanoid enzymes and receptors in the \nhuman endometrium across the menstrual cycle. Molecular Human \nReproduction 17 182–192. (https://doi.org/10.1093/molehr/gaq094)\nChapron C, Chopin N, Borghese B, Foulot H, Dousset B, Vacher-\nLavenu MC, Vieira M, Hasan W & Bricou A 2006 Deeply infiltrating \nendometriosis: pathogenetic implications of the anatomical \ndistribution. Human Reproduction 21 1839–1845. (https://doi.\norg/10.1093/humrep/del079)\nColette S, Lousse JC, Defrère S, Curaba M, Heilier JF, Van \nLangendonckt A, Mestdagt M, Foidart JM, Loumaye E & Donnez J \n2009 Absence of aromatase protein and mRNA expression in \nendometriosis. Human Reproduction 24 2133–2141. (https://doi.\norg/10.1093/humrep/dep199)\nColette S, Defrère S, Lousse JC, Van Langendonckt A, Gotteland JP, \nLoumaye E & Donnez J 2011 Inhibition of steroid sulfatase decreases \nendometriosis in an in vivo murine model. Human Reproduction 26 \n1362–1370. (https://doi.org/10.1093/humrep/der079)\nColette S, Defrère S, Van Kerk O, Van Langendonckt A, Dolmans MM & \nDonnez J 2013 Differential expression of steroidogenic enzymes \naccording to endometriosis type. Fertility and Sterility 100 1642–1649. \n(https://doi.org/10.1016/j.fertnstert.2013.08.003)\nCritchley HOD, Brenner RM, Teresa A. H, Karin W, Nihar R. N, \nSlayden OD, Millar MR & Saunders PTK 2001 Estrogen receptor beta, \nbut not estrogen receptor alpha, is present in the vascular \nendothelium of the human and nonhuman primate endometrium. \nJournal of Clinical Endocrinology and Metabolism  86 1370–1378. \n(https://doi.org/10.1210/jc.86.3.1370)\nCulley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M & \nRaine-Fenning N 2013 The social and psychological impact of \nendometriosis on women’s lives: a critical narrative review. Human \nReproduction Update 19 625–639. (https://doi.org/10.1093/humupd/\ndmt027)\nDalla Valle L, Toffolo V , Nardi A, Fiore C, Bernante P, Di Liddo R, \nParnigotto PP & Colombo L 2006 Tissue-specific transcriptional \ninitiation and activity of steroid sulfatase complementing \ndehydroepiandrosterone sulfate uptake and intracrine steroid \nactivations in human adipose tissue. Journal of Endocrinology 190 \n129–139. (https://doi.org/10.1677/joe.1.06811)\nDassen H, Punyadeera C, Kamps R, Delvoux B, Van Langendonckt A, \nDonnez J, Husen B, Thole H, Dunselman G & Groothuis P 2007 \nEstrogen metabolizing enzymes in endometrium and endometriosis. \nHuman Reproduction 22 3148–3158. (https://doi.org/10.1093/humrep/\ndem310)\nDe Graaff AA, D’hooghe TM, Dunselman GAJ, Dirksen CD, \nHummelshoj L, Simoens S, Bokor A, Brandes I, Brodszky V , Canis M, \net al.  2013 The significant effect of endometriosis on physical, \nmental and social wellbeing: Results from an international cross-\nsectional survey. Human Reproduction 28 2677–2685. (https://doi.\norg/10.1093/humrep/det284)\nDe Graaff AA, Dirksen CD, Simoens S, De Bie B, Hummelshoj L, \nD’Hooghe TM & Dunselman GAJ 2015 Quality of life outcomes in \nwomen with endometriosis are highly influenced by recruitment \nstrategies. Human Reproduction 30 1331–1341. (https://doi.\norg/10.1093/humrep/dev084)\nDe Leo B, Esnal-Zufiaurre A, Collins F, Critchley HOD & Saunders PTK \n2017 Immunoprofiling of human uterine mast cells identifies three \nphenotypes and expression of ER β and glucocorticoid receptor. \nF1000Research 6 667. (https://doi.org/10.12688/\nf1000research.11432.1)\nDelvoux B, Groothuis P, D’Hooghe T, Kyama C, Dunselman G & \nRomano A 2009 Increased production of 17B-estradiol in \nendometriosis lesions is the result of impaired metabolism. Journal of \nClinical Endocrinology and Metabolism  94 876–883. (https://doi.\norg/10.1210/jc.2008-2218)\nDelvoux B, D’Hooghe T, Kyama C, Koskimies P, Hermans RJJ, \nDunselman GA & Romano A 2014 Inhibition of type 1 \n17β-hydroxysteroid dehydrogenase impairs the synthesis of \n17β-estradiol in endometriosis lesions. Journal of Clinical \nEndocrinology and Metabolism 99 276–284. (https://doi.org/10.1210/\njc.2013-2851)\nDevore NM & Scott EE 2012 Cancer drugs abiraterone and Tok-001. \nNature 482 116–119. (https://doi.org/10.1038/nature10743.\nCYTOCHROME)\nDunselman GAJ, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, \nDe Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A, et al.  2014 \nESHRE guideline: management of women with endometriosis. \nHuman Reproduction 29 400–412. (https://doi.org/10.1093/humrep/\ndet457)\nEndo S, Matsunaga T, Ohta C, Soda M, Kanamori A, Kitade Y, Ohno S, \nTajima K, El-Kabbani O & Hara A 2011 Roles of rat and human aldo-\nketo reductases in metabolism of farnesol and geranylgeraniol. \nChemico-Biological Interactions 191 261–268. (https://doi.\norg/10.1016/j.cbi.2010.12.017)\nEskenazi B & Warner ML 1997 Epidemiology of endometriosis. Obstetrics \nand Gynecology Clinics of North America  24 235-. (https://doi.\norg/10.1136/jech.47.2.84)\nFerrero S, Remorgida V , Maganza C, Venturini PL, Salvatore S, Papaleo E, \nCandiani M & Leone Roberti Maggiore U 2014 Aromatase and \nendometriosis: estrogens play a role.  Annals of the New York Academy \nof Sciences. (https://doi.org/10.1111/nyas.12411)\nFouquet B, Santulli P, Noel JC & Misrahi M 2016 Ovarian-like \ndifferentiation in eutopic and ectopic endometrioses with aberrant \nFSH receptor, INSL3 and GATA4/6 expression. BBA Clinical 6  \n143–152. (https://doi.org/10.1016/j.bbacli.2016.11.002)\nFuldeore M, Yang H, Du EX, Soliman AM, Wu EQ & Winkel C 2015 \nHealthcare utilization and costs in women diagnosed with \nendometriosis before and after diagnosis: a longitudinal analysis of \nclaims databases. Fertility and Sterility 103 163–171. (https://doi.\norg/10.1016/j.fertnstert.2014.10.011)\nFurusawa Y, Matsuoka R, Yanaihara A, Toma Y, Taro Morimoto, Yuasa T, \nTahara R, Saito H & Okai T 2002 Regulation of estrogen activity in \nhuman endometrium: effect of IL-1beta on steroid sulfatase activity \nin human endometrial stromal cells. Showa University Journal of \nMedical Sciences 14 191–197. (https://doi.org/10.15369/\nsujms1989.14.191)\nGeese WJ & Raftogianis RB 2001 Biochemical characterization and tissue \ndistribution of human SULT2B1. Biochemical and Biophysical Research \nCommunications 288 280–289. (https://doi.org/10.1006/\nbbrc.2001.5746)\nGhosh S, Ashcraft K, Jahid MJ, April C, Ghajar CM, Ruan J, Wang H, \nFoster M, Hughes DC, Ramirez AG, et al.  2013 Regulation of adipose \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT267\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\noestrogen output by mechanical stress. Nature Communications 4 \n1821. (https://doi.org/10.1038/ncomms2794)\nGibson DA, McInnes KJ, Critchley HOD & Saunders PTK 2013 \nEndometrial intracrinology – generation of an estrogen-dominated \nmicroenvironment in the secretory phase of women. Journal of \nClinical Endocrinology and Metabolism  98. (https://doi.org/10.1210/\njc.2013-2140)\nGibson DA, Greaves E, Critchley HOD & Saunders PTK 2015 Estrogen-\ndependent regulation of human uterine natural killer cells promotes \nvascular remodelling via secretion of CCL2. Human Reproduction 30 \n1290–1301. (https://doi.org/10.1093/humrep/dev067)\nGibson DA, Simitsidellis I, Cousins FL, Critchley HOD & Saunders PTK \n2016 Intracrine androgens enhance decidualization and modulate \nexpression of human endometrial receptivity genes. Scientific Reports \n6 19970. (https://doi.org/10.1038/srep19970)\nGiudice LC & Kao LC 2004 Endometriosis. Lancet 364 1789–1799. \n(https://doi.org/10.1016/S0140-6736(04)17403-5)\nGopalakrishnan Radhika A, Chawla S, Nanda P, Yadav G & \nRadhakrishnan G 2016 A multivariate analysis of correlation \nbetween severity and duration of symptoms, patient profile and \nstage of endometriosis. Open Journal of Obstetrics and Gynecology  6 \n615–622. (https://doi.org/10.4236/ojog.2016.610077)\nGreaves E, Collins F, Critchley HOD & Saunders PTK 2013 ER β-\ndependent effects on uterine endothelial cells are cell specific and \nmediated via Sp1. Human Reproduction 28 2490–2501. (https://doi.\norg/10.1093/humrep/det235)\nGreaves E, Collins F, Esnal-Zufiaurre A, Giakoumelou S, Horne AW & \nSaunders PTK 2014 Estrogen receptor (ER) agonists differentially \nregulate neuroangiogenesis in peritoneal endometriosis via the \nrepellent factor SLIT3. Endocrinology 155 4015–4026. (https://doi.\norg/10.1210/en.2014-1086)\nGreaves E, Temp J, Esnal-Zufiurre A, Mechsner S, Horne AW & \nSaunders PTK 2015 Estradiol is a critical mediator of macrophage-\nnerve cross talk in peritoneal endometriosis. American Journal of \nPathology 185 2286–2297. (https://doi.org/10.1016/j.\najpath.2015.04.012)\nGreaves E, Critchley HOD, Horne AW & Saunders PTK 2017 Relevant \nhuman tissue resources and laboratory models for use in \nendometriosis research. Acta Obstetricia et Gynecologica Scandinavica  \n96 644–658. (https://doi.org/10.1111/aogs.13119)\nGuo SW 2009 Recurrence of endometriosis and its control. Human \nReproduction Update 15 441–461. (https://doi.org/10.1093/humupd/\ndmp007)\nGuo SW, Hummelshoj L, Olive DL, Bulun SE, D’Hooghe TM & Evers JLH \n2009 A call for more transparency of registered clinical trials on \nendometriosis. Human Reproduction 24 1247–1254. (https://doi.\norg/10.1093/humrep/dep045)\nGupta D, Hull M, Fraser I, Miller L, Bossuyt P, Johnson N & Nisenblat V \n2016 Endometrial biomarkers for the non-invasive diagnosis of \nendometriosis (review). Cochrane Library 1–231. (https://doi.\norg/10.1002/14651858.CD012165)\nHalpern G, Schor E & Kopelman A 2015 Nutritional aspects related to \nendometriosis. Revista Da Associação Médica Brasileira (1992) 61  \n519–523. (https://doi.org/10.1590/1806-9282.61.06.519)\nHarris HA 2007 Preclinical characterization of selective estrogen receptor \nβ agonists: new insights into their therapeutic potential. Tissue-\nSpecific Estrogen Action 149–162.\nHarwood DT & Handelsman DJ 2009 Development and validation of a \nsensitive liquid chromatography-tandem mass spectrometry assay to \nsimultaneously measure androgens and estrogens in serum without \nderivatization. Clinica Chimica Acta 409 78–84. (https://doi.\norg/10.1016/j.cca.2009.09.003)\nHe W, Gauri M, Li T, Wang R & Lin SX 2016 Current knowledge of the \nmultifunctional 17B-hydroxysteroid dehydrogenase type 1 \n(HSD17B1). Gene 588 54–61. (https://doi.org/10.1016/j.\ngene.2016.04.031)\nHenderson TA, Saunders PTK, Moffett-King A, Groome NP & \nCritchley HOD 2003 Steroid receptor expression in uterine natural \nkiller cells. Journal of Clinical Endocrinology and Metabolism  88  \n440–449. (https://doi.org/10.1210/jc.2002-021174)\nHevir N, Vouk K, Šinkovec J, Ribi č-Pucelj M & Lanišnik Rižner T 2011 \nAldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance \nprogesterone metabolism in ovarian endometriosis. Chemico-\nBiological Interactions 191 217–226. (https://doi.org/10.1016/j.\ncbi.2011.01.003)\nHevir N, Ribi č-Pucelj M & Lanišnik Rižner T 2013 Disturbed balance \nbetween phase I and II metabolizing enzymes in ovarian \nendometriosis: a source of excessive hydroxy-estrogens and ROS? \nMolecular and Cellular Endocrinology  367 74–84. (https://doi.\norg/10.1016/j.mce.2012.12.019)\nHewitt SC, Winuthayanon W, Lierz SL, Hamilton KJ, Donoghue LJ, \nRamsey JT, Grimm SA, Arao Y & Korach KS 2017 Role of ER α in \nmediating female uterine transcriptional responses to IGF1. \nEndocrinology 158 2427–2435. (https://doi.org/10.1210/en.2017-00349)\nHompes PGA & Mijatovic V 2007 Endometriosis: the way forward. \nGynecological Endocrinology 23 5–12. (https://doi.\norg/10.1080/09513590601010474)\nHonma S, Shimodaira K, Shimizu Y, Tsuchiya N, Saito H, Yanaihara T & \nOkai T 2002 The influence of inflammatory cytokines on estrogen \nproduction and cell proliferation in human breast cancer cells. \nEndocrine Journal 49 371–377. (https://doi.org/10.1507/\nendocrj.49.371)\nHsu C-C, Lu C-W, Huang B-M, Wu M-H & Tsai S-J 2008 Cyclic \nadenosine 3′,5′-monophosphate response element-binding protein \nand CCAAT/enhancer-binding protein mediate prostaglandin \nE2-induced steroidogenic acute regulatory protein expression in \nendometriotic stromal cells. American Journal of Pathology  173  \n433–441. (https://doi.org/10.2353/ajpath.2008.080199)\nHuang JR, Bellino FL, Osawa Y & Tseng L 1989 Immunologic \nidentification of the aromatase enzyme system in human \nendometrium. Journal of Steroid Biochemistry  33 1043–1047. (https://\ndoi.org/10.1016/0022-4731(89)90407-X)\nHudelist G, Czerwenka K, Keckstein J, Haas C, Fink-Retter A, \nGschwantler-Kaulich D, Kubista E & Singer CF 2007 Expression of \naromatase and estrogen sulfotransferase in eutopic and ectopic \nendometrium: evidence for unbalanced estradiol production in \nendometriosis. Reproductive Sciences 14 798–805. (https://doi.\norg/10.1177/1933719107309120)\nHuhtinen K, Ståhle M, Perheentupa A & Poutanen M 2012 a Estrogen \nbiosynthesis and signaling in endometriosis. Molecular and Cellular \nEndocrinology 358 146–154. (https://doi.org/10.1016/j.\nmce.2011.08.022)\nHuhtinen K, Desai R, Stah ̊le M, Salminen A, Handelsman DJ, \nPerheentupa A & Poutanen M 2012 b Endometrial and endometriotic \nconcentrations of estrone and estradiol are determined by local \nmetabolism rather than circulating levels. Journal of Clinical \nEndocrinology and Metabolism 97 4228–4235. (https://doi.\norg/10.1210/jc.2012-1154)\nHuhtinen K, Saloniemi-Heinonen T, Keski-Rahkonen P, Desai R, \nLaajala D, Stahle M, Hakkinen MR, Awosanya M, Suvitie P, Kujari H, \net al.  2014 Intra-tissue steroid profiling indicates differential \nprogesterone and testosterone metabolism in the endometrium and \nendometriosis lesions. Journal of Clinical Endocrinology and Metabolism  \n99 2188–2197. (https://doi.org/10.1210/jc.2014-1913)\nKennedy S 1999 The genetics of endometriosis. European Journal of \nObstetrics and Gynecology and Reproductive Biology  82 129–133. \n(https://doi.org/10.1111/j.1749-6632.1999.tb07894.x)\nKim JH, Cho HT & Kim YJ 2014 The role of estrogen in adipose tissue \nmetabolism: insights into glucose homeostasis regulation. Endocrine \nJournal 61 1055–1067. (https://doi.org/10.1507/endocrj.EJ14-0262)\nKim LY, Kim MR, Kim JH & Cho HH 2017 Aldo-keto reductase activity \nafter diethylhexyl phthalate exposure in eutopic and ectopic \nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT268\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nendometrial cells. European Journal of Obstetrics and Gynecology and \nReproductive Biology 215 215–219. (https://doi.org/10.1016/j.\nejogrb.2017.05.018)\nKitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Yamamoto T, \nFushiki S, Osawa Y & Honjo H 1997 Expression of aromatase \ncytochrome P450 protein and messenger ribonucleic acid in human \nendometriotic and adenomyotic tissues but not in normal \nendometrium. Biology of Reproduction 57 514–519. (https://doi.\norg/10.1095/biolreprod57.3.514)\nKitawaki J, Kusuki I, Koshiba H, Tsukamoto K & Honjo H 1999 \nDetection of aromatase cytochrome P-450 in endometrial biopsy \nspecimens as a diagnostic test for endometriosis. Fertility and Sterility \n72 1100–1106. (https://doi.org/10.1016/S0015-0282(99)00424-0)\nKrálíčková M & Vetvicka V 2015 Immunological aspects of \nendometriosis: a review. Annals of Translational Medicine 3 153. \n(https://doi.org/10.3978/j.issn.2305-5839.2015.06.08)\nKyama CM, Debrock S, Mwenda JM & D’Hooghe TM 2003 Potential \ninvolvement of the immune system in the development of \nendometriosis. Reproductive Biology and Endocrinology  1 123. (https://\ndoi.org/10.1186/1477-7827-1-123)\nLabrie F, Luu-The V , Lin S-X, Simard J, Labrie C, El-Alfy M, Pelletier G & \nBélanger A 2000 Intracrinology: role of the family of 17 beta-\nhydroxysteroid dehydrogenases in human physiology and disease. \nJournal of Molecular Endocrinology  25 1–16. (https://doi.org/10.1677/\njme.0.0250001)\nLessey BA, Metzger DA, Haney AF & McCarty KS Jr 1989 \nImmunohistochemical analysis of estrogen and progesterone \nreceptors in endometriosis: comparison with normal endometrium \nduring the menstrual cycle and the effect of medical therapy. Fertility \nand Sterility 51 409–415. (https://doi.org/10.1016/S0015-\n0282(16)60545-9)\nLiang Y & Yao S 2016 Potential role of estrogen in maintaining the \nimbalanced sympathetic and sensory innervation in endometriosis. \nMolecular and Cellular Endocrinology  424 42–49. (https://doi.\norg/10.1016/j.mce.2016.01.012)\nLindsay SF, Luciano DE & Luciano AA 2015 Emerging therapy for \nendometriosis. Expert Opinion on Emerging Drugs  8214 1–13. (https://\ndoi.org/10.1517/14728214.2015.1051966)\nMarchais-Oberwinkler S, Henn C, Möller G, Klein T, Negri M, Oster A, \nSpadaro A, Werth R, Wetzel M, Xu K, et al.  2011 17B-Hydroxysteroid \ndehydrogenases (17B-HSDs) as therapeutic targets: protein structures, \nfunctions, and recent progress in inhibitor development. Journal of \nSteroid Biochemistry and Molecular Biology  125 66–82. (https://doi.\norg/10.1016/j.jsbmb.2010.12.013)\nMontgomery GW, Nyholt DR, Zhao ZZ, Treloar SA, Painter JN, \nMissmer SA, Kennedy SH & Zondervan KT 2008 The search for genes \ncontributing to endometriosis risk. Human Reproduction Update 14 \n447–457. (https://doi.org/10.1093/humupd/dmn016)\nMorsch DM, Carneiro MM, Lecke SB, Araújo FC, Camargos AF, Reis FM \n& Spritzer PM 2009 C-fos gene and protein expression in pelvic \nendometriosis: a local marker of estrogen action. Journal of Molecular \nHistology 40 53–58. (https://doi.org/10.1007/s10735-009-9212-7)\nMueller JW, Gilligan LC, Idkowiak J, Arlt W & Foster PA 2015 The \nregulation of steroid action by sulfation and desulfation. Endocrine \nReviews 36 526–563. (https://doi.org/10.1210/er.2015-1036)\nNaitoh K, Honjo H, Yamamoto T, Urabe M, Ogino Y, Yasumura T & \nNambara T 1989 Estrone sulfate and sulfatase activity in human \nbreast cancer and endometrial cancer. Journal of Steroid Biochemistry  \n33 1049–1054. (https://doi.org/10.1016/0022-4731(89)90408-1)\nNelson LR & Bulun SE 2001 Estrogen production and action. Journal of \nthe American Academy of Dermatology  45 116–124. (https://doi.\norg/10.1067/mjd.2001.117432)\nNeulcn J, Hartmann C & Breckwoldt M 1987 Aromatase activity in \nmonolayer cell cultures of human endometrium. Gynecological \nEndocrinology 1 339–343. (https://doi.\norg/10.3109/09513598709082706)\nNikoo S, Ebtekar M, Jeddi-Tehrani M, Shervin A, Bozorgmehr M, \nVafaei S, Kazemnejad S & Zarnani AH 2014 Menstrual blood-derived \nstromal stem cells from women with and without endometriosis \nreveal different phenotypic and functional characteristics. Molecular \nHuman Reproduction 20 905–918. (https://doi.org/10.1093/molehr/\ngau044)\nNilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, \nEnmark E, Pettersson K, Warner M & Gustafsson JA 2001 \nMechanisms of estrogen action. Physiological Reviews 81 1535–1565. \n(https://doi.org/10.1152/physrev.2001.81.4.1535)\nNisenblat V , Bossuyt P, Shaikh R, Farquhar C, Jordan V , Scheffers C, \nMol B & Johnson N 2016 Blood biomarkers for the non-invasive \ndiagnosis of endometriosis. Cochrane Database of Systematic Reviews  \nCD012179. (https://doi.org/10.1002/14651858.CD012179)\nNnoaham KE, Hummelshoj L, Webster P, D’Hooghe T, De Cicco \nNardone F, De Cicco Nardone C, Jenkinson C, Kennedy SH & \nZondervan KT 2011 Impact of endometriosis on quality of life and \nwork productivity: a multicenter study across ten countries. Fertility \nand Sterility 96 366.e8–373.e8. (https://doi.org/10.1016/j.\nfertnstert.2011.05.090)\nNoble S, Simpson R & Bulun E 1996 a Aromatase expression in \nendometriosis. Journal of Clinical Endocrinology and Metabolism  450 \n174–179.\nNoble LS, Simpson ER, Johns A & Bulun SE 1996 b Aromatase expression \nin endometriosis. Journal of Chnical Endocrinology and Metabolism  81 \n174–179.\nNoble LS, Takayama K, Zeitoun KM, Putman JM, Alan D, \nHinshelwood MM, Agarwal VR, Zhao Y, Carr BR & Bulun SE 1997 \nProstaglandin E2 stimulates aromatase expression in endometriosis-\nderived stromal cells. Journal of Clinical Endocrinology and Metabolism  \n82 600–606. (https://doi.org/10.1210/jcem.82.2.3783)\nPavone ME & Bulun SE 2012 Aromatase inhibitors for the treatment of \nendometriosis: a review. Fertility and Sterility 98 1370–1379. (https://\ndoi.org/10.1016/j.fertnstert.2012.08.053)\nPenning TM 2017 Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent \nreview. Expert Opinion on Therapeutic Patents  3776 1–12. (https://doi.\norg/10.1080/13543776.2017.1379503)\nPenning TM & Byrns MC 2009 Steroid hormone transforming aldo-keto \nreductases and cancer. Annals of the New York Academy of Sciences  \n1155 33–34. (https://doi.org/10.1111/j.1749-6632.2009.03700.x)\nPenning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, \nPalackal N & Ratnam K 2000 Human 3alpha-hydroxysteroid \ndehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto \nreductase superfamily: functional plasticity and tissue distribution \nreveals roles in the inactivation and formation of male and female \nsex hormones. Biochemical Journal 351 67–77. (https://doi.\norg/10.1042/0264-6021:3510067)\nPiccinato CA, Neme RM, Torres N, Sanches LR, Derogis PBMC, \nBrudniewski HF, Rosa E Silva JC & Ferriani RA 2016 a Effects of \nsteroid hormone on estrogen sulfotransferase and on steroid \nsulfatase expression in endometriosis tissue and stromal cells. Journal \nof Steroid Biochemistry and Molecular Biology  158 117–126. (https://\ndoi.org/10.1016/j.jsbmb.2015.12.025)\nPiccinato CA, Neme RM, Torres N, Sanches LR, Derogis PBMC, \nBrudniewski HF, Rosa e Silva JC & Ferriani RA 2016 b Increased \nexpression of CYP1A1 and CYP1B1 in ovarian/peritoneal \nendometriotic lesions. Reproduction 151 683–692. (https://doi.\norg/10.1530/REP-15-0581)\nPiccinato CA, Neme RM, Torres N, Silvério R, Pazzini VB, Rosa e Silva JC \n& Ferriani RA 2016 c Is cytochrome P450 3A4 regulated by menstrual \ncycle hormones in control endometrium and endometriosis? \nMolecular and Cellular Biochemistry  1–9. (https://doi.org/10.1007/\ns11010-016-2899-3)\nPlatteeuw L & D’Hooghe T 2014 Novel agents for the medical treatment \nof endometriosis. Current Opinion in Obstetrics and Gynecology  26 \n243–252. (https://doi.org/10.1097/GCO.0000000000000084)\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT269\n61 2:\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis\nJournal of Molecular \nEndocrinology\nPlaza-Parrochia F, Poblete C, Gabler F, Carvajal R, Romero C, \nValladares L & Vega M 2015 Expression of steroid sulfated \ntransporters and 3 β-HSD activity in endometrium of women having \npolycystic ovary syndrome. Steroids 104 189–195. (https://doi.\norg/10.1016/j.steroids.2015.10.001)\nPohl O, Bestel E & Gotteland JP 2014 Synergistic effects of E2MATE and \nnorethindrone acetate on steroid sulfatase inhibition: a randomized \nphase i proof-of-principle clinical study in women of reproductive \nage. Reproductive Sciences 21 1256–1265. (https://doi.\norg/10.1177/1933719114522526)\nPractice T & Medicine R 2012 Endometriosis and infertility: a committee \nopinion. Fertility and Sterility 98 591–598. (https://doi.org/10.1016/j.\nfertnstert.2012.05.031)\nPurohit A & Foster PA 2012 Steroid sulfatase inhibitors for estrogen- and \nandrogen-dependent cancers. Journal of Endocrinology 212 99–110. \n(https://doi.org/10.1530/JOE-11-0266)\nPurohit A, Fusi L, Brosens J, Woo LWL, Potter BVL & Reed MJ 2008 \nInhibition of steroid sulphatase activity in endometriotic implants \nby 667 COUMATE: a potential new therapy. Scientific World Journal 8 \n1325–1327. (https://doi.org/10.1100/tsw.2008.164)\nRakhila H, Carli C, Daris M, Lemyre M, Leboeuf M & Akoum A 2013 \nIdentification of multiple and distinct defects in prostaglandin \nbiosynthetic pathways in eutopic and ectopic endometrium of \nwomen with endometriosis. Fertility and Sterility 100. (https://doi.\norg/10.1016/j.fertnstert.2013.08.016)\nReed MJ, Purohit A, Woo LWL, Newman SP & Potter BVL 2005 Steroid \nsulfatase: molecular biology, regulation, and inhibition. Endocrine \nReviews 26 171–202. (https://doi.org/10.1210/er.2004-0003)\nRižner TL 2009 Estrogen metabolism and action in endometriosis. \nMolecular and Cellular Endocrinology  307 8–18. (https://doi.\norg/10.1016/j.mce.2009.03.022)\nRižner TL 2013 Estrogen biosynthesis, phase I and phase II metabolism, \nand action in endometrial cancer. Molecular and Cellular Endocrinology  \n381 124–139. (https://doi.org/10.1016/j.mce.2013.07.026)\nRižner TL 2016 The important roles of steroid sulfatase and \nsulfotransferases in gynecological diseases. Frontiers in Pharmacology 7 \n1–16. (https://doi.org/10.3389/fphar.2016.00030)\nRižner TL, Thalhammer T & Özvegy-Laczka C 2017 The importance of \nsteroid uptake and intracrine action in endometrial and ovarian \ncancers. Frontiers in Pharmacology 8. (https://doi.org/10.3389/\nfphar.2017.00346)\nRoth M, Obaidat A & Hagenbuch B 2012 OATPs, OATs and OCTs: the \norganic anion and cation transporters of the SLCO and SLC22A gene \nsuperfamilies. British Journal of Pharmacology  165 1260–1287. \n(https://doi.org/10.1111/j.1476-5381.2011.01724.x)\nRubin GL, Harrold AJ, Mills JA, Falany CN & Coughtrie MWH 1999 \nRegulation of sulphotransferase expression in the endometrium \nduring the menstrual cycle, by oral contraceptives and during early \npregnancy. Molecular Human Reproduction 5 995–1002. (https://doi.\norg/10.1093/molehr/5.11.995)\nRuiz FX, Porté S, Gallego O, Moro A, Ardèvol A, Del Río-Espínola A, \nRovira C, Farrés J & Parés X 2011 Retinaldehyde is a substrate for \nhuman aldo–keto reductases of the 1C subfamily. Biochemical Journal \n440 335–347. (https://doi.org/10.1042/BJ20111286)\nSapkota Y, Steinthorsdottir V , Morris AP, Fassbender A, Rahmioglu N, \nDe Vivo I, Buring JE, Zhang F, Edwards TL, Jones S, et al.  2017 \nMeta-analysis identifies five novel loci associated with \nendometriosis highlighting key genes involved in hormone \nmetabolism. Nature Communications  8 15539. (https://doi.\norg/10.1038/ncomms15539)\nSecky L, Svoboda M, Klameth L, Bajna E, Hamilton G, Zeillinger R, \nJäger W & Thalhammer T 2013 The sulfatase pathway for estrogen \nformation: targets for the treatment and diagnosis of hormone-\nassociated tumors. Journal of Drug Delivery  2013 1–13. (https://doi.\norg/10.1155/2013/957605)\nShen L, Yang S, Huang W, Xu W, Wang Q, Song Y & Liu Y 2013 \nMicroRNA23a and MicroRNA23b deregulation derepresses SF-1 and \nupregulates estrogen signaling in ovarian endometriosis. Journal of \nClinical Endocrinology and Metabolism  98 1575–1582. (https://doi.\norg/10.1210/jc.2012-3010)\nSignorile PG & Baldi A 2010 Endometriosis: new concepts in the \npathogenesis. International Journal of Biochemistry and Cell Biology  42 \n778–780. (https://doi.org/10.1016/j.biocel.2010.03.008)\nSimard J, Ricketts ML, Gingras S, Soucy P, Feltus FA & Melner MH 2005 \nMolecular biology of the 3B-hydroxysteroid dehydrogenase/5-4 \nisomerase gene family. Endocrine Reviews 26 525–582. (https://doi.\norg/10.1210/er.2002-0050)\nSinreih M, Anko M, Kene NH, Kocbek V & Rižner TL 2015 Expression of \nAKR1B1, AKR1C3 and other genes of prostaglandin F2 α biosynthesis \nand action in ovarian endometriosis tissue and in model cell lines. \nChemico-Biological Interactions 234 320–331. (https://doi.\norg/10.1016/j.cbi.2014.11.009)\nSmuc T, Pucelj MR, Sinkovec J, Husen B, Thole H & Lanisnik Rizner T \n2007 Expression analysis of the genes involved in estradiol and \nprogesterone action in human ovarian endometriosis. Gynecological \nEndocrinology 23 105–111. (https://doi.\norg/10.1080/09513590601152219)\nŠmuc T, Hevir N, Ribi č-Pucelj M, Husen B, Thole H & Rižner TL 2009 \nDisturbed estrogen and progesterone action in ovarian \nendometriosis. Molecular and Cellular Endocrinology  301 59–64. \n(https://doi.org/10.1016/j.mce.2008.07.020)\nSoffientini U & Graham A 2016 Intracellular cholesterol transport \nproteins: roles in health and disease. Clinical Science 130 1843–1859. \n(https://doi.org/10.1042/CS20160339)\nSoucy P & Van L-T 2000 Conversion of pregnenolone to DHEA by \nhuman. Molecular Endocrinology 3247 3243–3247.\nStanway SJ, Purohit A, Woo LWL, Sufi S, Vigushin D, Ward R, \nWilson RH, Stanczyk FZ, Dobbs N, Kulinskaya E, et al.  2006 Phase \nI study of STX 64 (667 Coumate) in breast cancer  \npatients: The first study of a steroid sulfatase inhibitor. Clinical \nCancer Research  12 1585–1592. (https://doi.org/10.1158/1078-\n0432.CCR-05-1996)\nSuganuma I, Mori T, Ito F, Tanaka Y, Sasaki A, Matsuo S, Kusuki I & \nKitawaki J 2014 Peroxisome proliferator-activated receptor gamma, \ncoactivator 1alfa enhances local estrogen biosynthesis by stimulating \naromatase activity in endometriosis. Journal of Clinical Endocrinology \nand Metabolism 99. (https://doi.org/10.1210/jc.2013-2525)\nSun HS, Hsiao KY, Hsu CC, Wu MH & Tsai SJ 2003 Transactivation of \nsteroidogenic acute regulatory protein in human endometriotic \nstromal cells is mediated by the prostaglandin EP2 receptor. \nEndocrinology 144 3934–3942. (https://doi.org/10.1210/en.2003-\n0289)\nSzczepańska M, Wirstlein P, Skrzypczak J & Jagodzi ński PP 2013 \nPolymorphic variants of CYP17 and CYP19A and risk of infertility in \nendometriosis. Acta Obstetricia et Gynecologica Scandinavica  92  \n1188–1193. (https://doi.org/10.1111/aogs.12210)\nTamaresis JS, Irwin JC, Goldfien GA, Rabban JT, Burney RO, Nezhat C, \nDePaolo L V. & Giudice LC 2014 Molecular classification of \nendometriosis and disease stage using high-dimensional genomic \ndata. Endocrinology 155 4986–4999. (https://doi.org/10.1210/en.2014-\n1490)\nTian Y, Kong B, Zhu W, Su S & Kan Y 2009 Expression of steroidogenic \nfactor 1 (SF-1) and steroidogenic acute regulatory protein (StAR) in \nendometriosis is associated with endometriosis severity. Journal of \nInternational Medical Research 1 1389–1395. (https://doi.\norg/10.1177/147323000903700513)\nTsai S, Wu MH, Lin C, Sun H & Chen H 2001 Regulation of \nsteroidogenic acute regulatory protein expression and progesterone \nproduction in endometriotic stromal cells. Journal of Clinical \nEndocrinology and Metabolism 86 5765–5773.\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0297\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nT270\nC A Piccinato et al. Intracrine oestrogens and \nendometriosis61 2:\nJournal of Molecular \nEndocrinology\nTseng L 1984 Estrogen synthesis in human endometrial epithelial glands \nand stromal cells. Journal of Steroid Biochemistry  20 877–881. (https://\ndoi.org/10.1016/0022-4731(84)90399-6)\nTsuchiya Y, Nakajima M & Yokoi T 2005 a Cytochrome P450-mediated \nmetabolism of estrogens and its regulation in human. Cancer Letters \n227 115–124. (https://doi.org/10.1016/j.canlet.2004.10.007)\nTsuchiya M, Nakao H, Katoh T, Sasaki H, Hiroshima M, Tanaka T, \nMatsunaga T, Hanaoka T, Tsugane S & Ikenoue T 2005 b Association \nbetween endometriosis and genetic polymorphisms of the estradiol-\nsynthesizing enzyme genes HSD17B1 and CYP19. Human \nReproduction 20 974–978. (https://doi.org/10.1093/humrep/deh726)\nUrata Y, Osuga Y, Akiyama I, Nagai M, Izumi G, Takamura M, \nHasegawa A, Harada M, Hirata T, Hirota Y, et al.  2013 Interleukin-4 \nand prostaglandin E2 synergistically up-regulate 3B-hydroxysteroid \ndehydrogenase type 2 in endometrioma stromal cells. Journal of \nClinical Endocrinology and Metabolism  98 1583–1590. (https://doi.\norg/10.1210/jc.2012-3475)\nUtsunomiya H 2001 The analyses of 17-hydroxysteroid dehydrogenase \nisozymes in human endometrial hyperplasia and carcinoma. Journal \nof Clinical Endocrinology and Metabolism  86 3436–3443. (https://doi.\norg/10.1210/jc.86.7.3436)\nUtsunomiya H, Cheng Y-H, Lin Z, Reierstad S, Yin P, Attar E, Xue Q, \nImir G, Thung S, Trukhacheva E, et al.  2008 Upstream stimulatory \nfactor-2 regulates steroidogenic factor-1 expression in endometriosis. \nMolecular Endocrinology 22 904–914. (https://doi.org/10.1210/\nme.2006-0302)\nVan LT 2013 Assessment of steroidogenesis and steroidogenic enzyme \nfunctions. Journal of Steroid Biochemistry and Molecular Biology  137 \n176–182. (https://doi.org/10.1016/j.jsbmb.2013.05.017)\nVeillat V , Sengers V , Metz CN, Roger T, Leboeuf M, Mailloux J & \nAkoum A 2012 Macrophage migration inhibitory factor is involved \nin a positive feedback loop increasing aromatase expression in \nendometriosis. American Journal of Pathology  181 917–927. (https://\ndoi.org/10.1016/j.ajpath.2012.05.018)\nVercellini P, Viganò P, Somigliana E & Fedele L 2014 Endometriosis: \npathogenesis and treatment. Nature Reviews 10 261–275. (https://doi.\norg/10.1038/nrendo.2013.255)\nVercellini P, Buggio L, Berlanda N, Barbara G, Somigliana E & Bosari S \n2016 Estrogen-progestins and progestins for the management of \nendometriosis. Fertility and Sterility 106 1552–1571.e2. (https://doi.\norg/10.1016/j.fertnstert.2016.10.022)\nVitonis AF, Baer HJ, Hankinson SE, Laufer MR & Missmer SA 2010 A \nprospective study of body size during childhood and early adulthood \nand the incidence of endometriosis. Human Reproduction 25  \n1325–1334. (https://doi.org/10.1093/humrep/deq039)\nXue Q, Lin Z, Cheng Y-H, Huang C-C, Marsh E, Yin P, Milad MP, \nConfino E, Reierstad S, Innes J, et al.  2007 Promoter methylation \nregulates estrogen receptor 2 in human endometrium and \nendometriosis. Biology of Reproduction 77 681–687. (https://doi.\norg/10.1095/biolreprod.107.061804)\nYi K, Yang LY, Lan Z & Xi MR 2016 The association between CYP19 \npolymorphism and endometriosis risk: a system review and meta-\nanalysis. European Journal of Obstetrics and Gynecology and Reproductive \nBiology 199 42–48. (https://doi.org/10.1016/j.ejogrb.2016.01.010)\nZaichuk T, Ivancic D, Scholtens D, Schiller C & Khan SA 2007 Tissue-\nspecific transcripts of human steroid sulfatase are under control of \nestrogen signaling pathways in breast carcinoma. Journal of Steroid \nBiochemistry and Molecular Biology  105 76–84. (https://doi.\norg/10.1016/j.jsbmb.2006.12.101)\nZeitoun K, Takayama K, Michael MD & Bulun SE 1999 Stimulation of \naromatase P450 promoter (II) activity in endometriosis and its \ninhibition in endometrium are regulated by competitive binding of \nsteroidogenic factor-1 and chicken ovalbumin upstream promoter \ntranscription factor to the same cis-acting elem. Molecular \nEndocrinology 13 239–253. (https://doi.org/10.1210/me.13.2.239)\nZelenko Z, Aghajanova L, Irwin JC & Giudice LC 2012 Nuclear receptor, \ncoregulator signaling, and chromatin remodeling pathways suggest \ninvolvement of the epigenome in the steroid hormone response of \nendometrium and abnormalities in endometriosis. Reproductive \nSciences 19 152–162. (https://doi.org/10.1177/1933719111415546)\nZeng C, Xu JN, Zhou Y, Yang HX, Zhou YF & Xue Q 2015 C-Jun NH2-\nterminal kinase and p38 inhibition suppresses prostaglandin \nE2-stimulated aromatase and estrogen receptor levels in human \nendometriosis. Journal of Clinical Endocrinology and Metabolism  100 \nE1404–E1414. (https://doi.org/10.1210/jc.2015-2031)\nZhang H, Varmalova O, Vargas FM, Falany CN & Leyh TS 1998 Sulfuryl \ntransfer: the catalytic mechanism of human estrogen \nsulfotransferase. Journal of Biological Chemistry  273 17296. (https://\ndoi.org/10.1074/jbc.273.18.10888)\nZhang CY, Wang WQ, Chen J & Lin SX 2015 Reductive 17beta-\nhydroxysteroid dehydrogenases which synthesize estradiol and \ninactivate dihydrotestosterone constitute major and concerted \nplayers in ER+ breast cancer cells. Journal of Steroid Biochemistry and \nMolecular Biology 150 24–34. (https://doi.org/10.1016/j.\njsbmb.2014.09.017)\nZhao Y, Gong P, Chen Y, Nwachukwu JC, Srinivasan S, Ko C, Bagchi MK, \nTaylor RN, Korach KS, Nettles KW, et al.  2015 Dual suppression of \nestrogenic and inflammatory activities for targeting of endometriosis. \nScience Translational Medicine 7 271ra9. (https://doi.org/10.1126/\nscitranslmed.3010626)\nZubrzycka A, Zubrzycki M, Janecka A & Zubrzycka M 2015 New \nhorizons in the etiopathogenesis and non-invasive diagnosis of \nendometriosis. Current Molecular Medicine 15 697–713. (https://doi.\norg/10.2174/1566524015666150921105218)\nReceived in final form 20 April 2018\nAccepted 3 May 2018\nDownloaded from Bioscientifica.com at 06/12/2026 06:14:45PM\nvia free access","source_license":"CC0","license_restricted":false}