{"paper_id":"c8749d87-5a68-497a-a402-90e533b992d4","body_text":"https://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nJournal of \nEndocrinology\n246:3\nR75–R93D A Gibson et al. Androgens, oestrogens and \nendometrium\n-20-0106\nREVIEW\nAndrogens, oestrogens and endometrium: a fine \nbalance between perfection and pathology\nDouglas A Gibson , Ioannis Simitsidellis, Frances Collins and Philippa T K Saunders\nCentre for Inflammation Research, The University of Edinburgh, Edinburgh Bioquarter, Edinburgh, UK\nCorrespondence should be addressed to P T K Saunders: p.saunders@ed.ac.uk\nAbstract\nThe endometrium is a complex multicellular tissue that is exquisitely sensitive to the \nactions of sex steroids synthesised in the ovary (endocrine system). Recent studies \nhave highlighted a previously under-appreciated role for local (intracrine) metabolism \nin fine-tuning tissue function in both health and disease. In this review we have focused \non the impact of oestrogens and androgens on endometrial function summarising \ndata from studies on normal endometrial physiology and disorders including infertility, \nendometriosis and cancer. We consider the evidence that expression of enzymes \nincluding aromatase, sulphatase and AKR1C3 by endometrial cells plays an important \nrole in tissue function and malfunction and discuss results from studies using drugs \ntargeting intracrine pathways to treat endometrial disorders. We summarise studies \nexploring the spatial and temporal expression of oestrogen receptors (ERalpha/ESR1, \nERbeta/ESR2 and GPER) and their role in mediating the impact of endogenous and \nsynthetic ligands on cross-talk between vascular, immune, epithelial and stromal cells. \nThere is a single androgen receptor gene and androgens play a key role in stromal-\nepithelial cross-talk, scar-free healing of endometrium during menstruation and \nregulation of cell proliferation. The development of new receptor-selective drugs (SERMs, \nSARMs, SARDs) has reinvigorated interest in targeting receptor subtypes in treatment of \ndisorders including endometriosis and endometrial cancer and some show promise as \nnovel therapies. In summary, understanding the mechanisms regulated by sex steroids \nprovides the platform for improved personalised treatment of endometrial disorders as \nwell as novel insights into the impact of steroids on processes such as tissue repair  \nand regeneration.\nIntroduction\nIn women, the endometrium is divided into an inner/\nluminal functional layer (‘functionalis’) and a basal \nlayer (‘basalis’). On its inner (luminal) aspect, columnar \nepithelial cells form a boundary between the fluid-filled \nuterine lumen and endometrial tissue containing glands, \na well-developed vasculature, stromal mesenchyme \n(fibroblasts, perivascular cells) and a diverse population \nof immune cells. Between menarche and menopause,  \nthe endometrium responds to fluctuating levels of \nblood borne ovarian sex-steroid hormones (primarily \n17β-oestradiol (E2) and progesterone (P)), with cyclical \nproliferation and differentiation ready to support a \nprospective pregnancy. In a non-pregnant cycle, the \nfunctional layer is shed during menstruation, but within a \nfew days the luminal surface is healed and tissue integrity \nrestored ready to resume the next cycle (Garry et al. 2009).\n3\nKey Words\n f oestrogen receptor\n f androgen receptor\n f aromatase\n f endometriosis\n f intracrinology\nJournal of Endocrinology  \n(2020) 246, R75–R93\n246\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR76\nAndrogens, oestrogens and \nendometrium\nD A Gibson et al.246:3\nJournal of \nEndocrinology\nWhile sex-steroid hormones are essential for the \nmaintenance of normal uterine function and fertility, \nthey may also contribute to the development of hormone-\ndependent endometrial disorders that affect millions of \nwomen (Table 1). In this review we have focused on the \nimpact of oestrogens and androgens on the function and \nmalfunction of the endometrium, considering evidence \nfor expression of receptors that can mediate their function \nas well as enzymes that modulate local bioavailability of \nsteroids. The emergence of new classes of drugs that target \nreceptors or enzymes and offer some potential as novel \ntreatments for endometrial disorders is summarised. \nOestrogen and androgen receptors and their \nexpression in endometrial tissues\nOverview of changes in tissue function during the \nmenstrual cycle\nBased on evaluation of 8000 endometrial biopsies, Noyes \net al. (1975) published a classification of the different stages \nof the menstrual cycle which is still considered the gold \nstandard for histological staging. Although cycle length \ncan vary between individuals, staging is typically based \non an average menstrual cycle of 28 days: menstruation \n(day 1), proliferative phase (day 4 to 14) and secretory \nphase (days 16 to 28). Histologically, the functional layer \nthickens from about 2 mm recorded immediately after the \nmenstrual phase to 14 mm prior to ovulation on day 14. \nFollowing ovulation and formation of the corpus luteum \n(CL), there is a rapid rise in circulating concentrations \nof P, which stimulates functional transformation of the \nstromal fibroblasts (decidualisation) resulting in shape \nchange and reprogramming of gene expression leading to \nsecretion of factors that regulate immune cell recruitment \nand receptivity (see comprehensive review by Gellersen \net  al. 2007 ). In the absence of a healthy blastocyst, the \nregression of the CL results in a rapid decrease in the \ncirculating concentrations of ovarian-derived steroid \nhormones (progesterone withdrawal) and triggers a \ncascade of changes in endometrial tissue that results in \ntissue breakdown, piecemeal shedding and synchronous \nhealing during menstruation (Garry et al. 2009).\nStructural and functional features of oestrogen  \nand androgen receptors: genomic and non-genomic \nsignalling\nChanges in expression of oestrogen- and androgen-\ndependent genes are orchestrated by interaction of \ntheir receptors with DNA-binding domains within gene \npromoters/enhancers as well as non-genomic signalling \nTable 1 Hormone-dependent endometrial pathologies in women.\nEndometrial pathology Incidence Features References\nImplantation failure, \nrecurrent pregnancy \nloss\nOne in six couples have infertile \nrates of implantation failure \ndifficult to determine other than \nin IVF, RPL 1–2%\nPoor/out-of-phase decidual response. \nChanges in immune cell cohorts (uNK). \nStromal cell senescence with age?\n(Quenby et al. 2009, \nLucas et al. 2020)\nHeavy menstrual \nbleeding (HMB)\n20–30% of women; may be worse \nduring perimenopause; \nassociated with fibroids\nAcute or chronic; FIGO classification of \ncauses (Palm-Coen) \n(Whitaker & Critchley \n2016)\nEndometriosis ~10% women of reproductive age; \nmay be asymptomatic.\n40% of infertile patients may have \nendometriosis\nThree subtypes – aetiology may be different. \nNeuroinflammation and chronic pain. \nChanges in peritoneal environment.\n(Horne et al. 2017, \nHorne & Saunders \n2019) \nAdenomyosis ~20% in women in gynaecology \nclinics (higher in older women)\nGrowth of endometrial fragments within \nmyometrial wall.\nMyometrial thickening on ultrasound. \nAssociation with endometriosis.\n(Naftalin et al. 2012)\nAsherman’s syndrome Estimates of incidence vary widely: \n3–45% in infertile population?\nAdhesions within uterine cavity; risk \nincreased by endometrial ablation/surgery\n(Dreisler & Kjer 2019)\nEndometrial \nhyperplasia\nIncrease in gland to stroma ratio when \ncompared with proliferative endometrium. \nSome types may progress to endoCa\n(Sanderson  \net al. 2017)\nEndometrial cancer Fourth most common cancer in UK \nwomen; rates rising \nRisk increased by high BMI and Lynch \nsyndrome. Classifications based on \nhistology or genetics with ‘unopposed’ \noestrogen key risk factor for some \nsubtypes.\n(Sanderson et al. 2017, \nRyan et al. 2019) \n \nFor each pathology, an estimate of incidence, hallmark features and one or two key references are summarised.\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR77\nReview\nD A Gibson et al. Androgens, oestrogens and \nendometrium\n246:3\nJournal of \nEndocrinology\npathways initiated at the membrane. Steroid receptors \ncontain three key structure-function domains: a variable \namino-terminal domain, a highly conserved DNA-binding \ndomain (DBD), and a less conserved carboxyl-terminal \nligand binding domain (LBD). Differences in the sequence \nof amino acids located within a C-terminal ligand binding \npocket play a critical role in ligand selectivity (Shiau et al. \n1998, Nadal et al. 2017). A linker region situated between \nthe DBD and the LBD functions as a flexible hinge with \na nuclear localization signal: the proteins also contain \nmultiple sites for phosphorylation (Lannigan 2003). There \nare two oestrogen receptors (alpha and beta) encoded by \nseparate genes, ESR1 and ESR2, respectively: the full-length \nWT proteins they encode (hER α and hER β1 respectively) \nbind a range of oestrogenic ligands with high affinity and \nspecificity. Notably, analysis of natural ligand reported \nthat, while 17 β-oestradiol (E2) bound both receptors \nwith high and equal affinity, oestrone (E1) had higher \naffinity for WT ER β(1) (Zhu et al. 2006). Multiple splice \nisoforms of both genes have been identified (reviewed in \nGibson & Saunders 2012). ER46 was the first splice variant \nof human ESR1 described (initially designated hER α-46;  \nFlouriot et  al. 2000 ). ESR2 splice variants including  \nERβ2/bcx and ER β5 are co-expressed in multiple \nreproductive tissues and reproductive cancers ( Critchley \net  al. 2002 , Saunders et  al. 2002 , Shaaban et  al. 2008 , \nCollins et al. 2009). In addition to ESR1 and ESR2, a family \nof closely related genes have been identified as encoding \n‘estrogen receptor related’ proteins (ESRR1, ESRR2, ESRR3) \nwhich do not bind directly to E1 or E2 as they lack a \nproper binding pocket at their C-terminus but which \nmay be activated by co-factors or other lipids (reviewed in \nHorard & Vanacker 2003, Gibson & Saunders 2012).\nThere is a single androgen receptor gene ( AR) located \non the X chromosome. Elegant studies, including those \nusing surface plasmon resonance, have revealed that \nthe long AR N-terminal domain (NTD) is structurally \nimportant for receptor-dependent gene expression \n(Lavery & McEwan 2008 ) and is a promising drug target \n(Ponnusamy et al. 2019). Several splice variant isoforms \nof AR have been identified with particular attention \npaid to their role in ligand-independent gene activation \nin advanced prostate cancers ( Dehm & Tindall 2011 ). \nExpression of AR variants including AR-V7 (exons 1/2/3/\nCE3) has also been reported in primary breast cancers and \nbreast cancer cell lines (Hickey et al. 2015), but a literature \nsearch did not identify any data related to their expression \nin endometrium or endometrial disorders.\nThere have been extensive studies on the functional \nconsequences of steroid ligand binding to ERs and AR that \nhave been well-reviewed elsewhere (McKenna et al. 1999, \nGronemeyer et al. 2004). Briefly, ligand binding induces \na conformational change in the ligand binding domain, \ndimerization and recruitment of co-regulators that play a \ncritical role in regulating the hormonal response. Ligand-\nactivated receptors bind directly to DNA sequences within \nregulatory regions of genes: sequences that are recognised \nby oestrogen (ERE – oestrogen response elements) or \nandrogen (ARE – androgen response elements) receptors \nhave been described ( Brodie & McEwan 2005 , Carroll \net al. 2006). Binding studies have also identified a number \nof so called ‘pioneer’ factors such as FOXA1 and GATA2 \nthat can enhance direct binding of ER or AR to DNA \n(Carroll et  al. 2005 , He et  al. 2014 ). ERs also regulate \ngene expression through protein-protein interactions \nwith other transcription factors already bound on DNA \n(‘tethering’) – examples of tethering mechanisms include \nbinding to the transcription factor Sp1 which has been \nimplicated in regulation of the progesterone receptor \ngene ( Petz et  al. 2004 ) and ER β-dependent induction of \ngene expression in human endometrial endothelial cells \n(Greaves et al. 2013). \nOestrogens and androgens can also induce changes in \ncell function following binding to ERs or ARs localised in the \ncell membrane. These ‘non-genomic’ signalling cascades \ncan be initiated through the membrane localization \nof the classical receptors following palmitoylation and \ninteraction with scaffolding proteins or by hormone-\nresponsive G protein-coupled transmembrane receptors \n(GPCRs) ( Hammes & Levin 2007 ). One of the most \nextensively investigated GPCRs is GPER (originally named \nGPR 30, also known as GPER1), which was cloned from \nbreast cancer cells in 1997 and binds oestrogens with \nnanomolar affinity (Carmeci et al. 1997). Information on \nGPCRs that bind to androgens is less comprehensive, but \nseveral candidates including GPRC6A have been identified \nin cancer cells (Ye et al. 2019).\nA recent review provided a useful summary of the wide \nrange of different non-genomic signalling pathways and \nhow the different genomic and non-genomic pathways \nmay interact (Wilkenfeld et al. 2018).\nExpression and functional impact of oestrogen \nreceptors during the menstrual cycle\nWe, and others, have used highly specific antibodies to \nexplore temporal and cell-specific patterns of expression \nof ER α, ER β, ERRs and AR in endometrium during \nthe normal cycle ( Critchley & Saunders 2009 , Young \n2013). We have documented cell-specific and temporal \nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR78\nAndrogens, oestrogens and \nendometrium\nD A Gibson et al.246:3\nJournal of \nEndocrinology\nimmunoexpression of full-length ER α (ER66) in both \nnormal endometrium and in endometrial pathologies \nincluding cancer ( Critchley et  al. 2002 , Collins et  al. \n2009). In full-thickness sections of endometrium ( Fig. 1),  \nimmunoexpression of ER α is intense in the epithelial \nglands and in the stroma of both the functional and basal \nlayers: endothelial cells lining the blood vessels appear \nimmuno-negative ( Critchley et  al. 2001 ). Expression is \ndownregulated in the functional layer during the secretory \nphase in response to the rising levels of progesterone  \n(Fig. 1) (Lessey et al. 1988, Young 2013). We have recently \nexplored expression of ER46 in the endometrium \nusing a combination of immunohistochemistry and \nWestern blotting ( Gibson et  al. 2020 ). Notably, the \nvariant protein was co-localised with ER66 in cell nuclei \nduring the proliferative phase with striking expression \nin a population of uterine natural killer cells (uNK)  \nimplicated in vascular remodelling ( Quenby et al. 2009, \nGibson et al. 2015).\nStudies in mice suggest a complex role for ER α in \nepithelial and stromal compartments of the endometrium. \nFor example, the role of epithelial ER α was studied using \na conditional knockout mouse which was ovariectomised \nand then treated with a single intraperitoneal injection of \n0.25 μg 17β-estradiol (E2) in 100 μL sesame oil. Analysis of \nsamples recovered 2, 24 or 72 h after E2 injection revealed \nthat epithelial ER α was dispensable for the proliferative \nresponse observed at 2 h but essential for responses at 24 \nand 72 h (Winuthayanon et al. 2014). Similar studies also \nrevealed a critical role for ER α in paracrine regulation of \nstromal decidualization in this species (Pawar et al. 2015). \nThe pattern of expression of ER β is distinct from that of \nERα, with highest concentrations of mRNA encoding full-\nlength ERβ1 in the secretory phase and immunoexpression \nin epithelial, stromal, endothelial cells and immune cells \n(Critchley et al. 2001): ERβ1 is not downregulated in the \nfunctional layer during the secretory phase (Bombail et al. \n2008). Studies in mice with Esr2 knockout have suggested \na less striking phenotype than in the Esr1 knockout, \nalthough a re-evaluation of the evidence by Hapangama \net  al. (2015)  concluded that sustained E2 stimulation \nof endometrial epithelial cells via ER β might induce \napoptosis. There has been some disagreement about the \ncyclical expression (or otherwise) of ER β in endometrial \nendothelial cells (Critchley et al. 2001, Lecce et al. 2001). \nOur own study using endothelial cells from different \nvascular beds demonstrated those originally isolated \nfrom endometrium or myometrium were ER β+/ERα−  and \nrevealed cell-specific impacts of an ERβ-selective agonist on \ngene expression (Greaves et al. 2013). In contrast, studies \nusing isolated human uNK cells suggest their response to \noestrogens may be complex involving rapid membrane-\ninitiated signalling via ER46 ( Gibson et al. 2020) and/or \nbinding to ERβ (Gibson et al. 2015). Treatment of isolated \nuNK cells with either oestrone (E1) or E2 promotes cell \nmigration and secretion of chemokine (C-C motif) ligand \n2 (CCL2) (Gibson et al. 2015). These studies highlight the \nimportance of endogenous oestrogens in the dynamic \ninterplay between different endometrial cell types that \nplay a critical role in preparation for pregnancy. \nFigure 1\nExpression of oestrogen receptor alpha (ERα) and androgen receptor (AR) \nin full-thickness samples from the human uterus. The tissue is divided \ninto functional and basal layers supported on the myometrium below and \nbounded on upper surface by the luminal epithelium. ERα (red stain) is \nabundant in epithelial cells in the proliferative phase but downregulated \nin the secretory phase. AR (green) is localised to stromal cells in the basal \nand functional layers during the proliferative phase but only expressed in \nthe basal stromal cells in the secretory phase when its expression is \nupregulated in epithelial cells. P, proliferative phase; S, secretory phase; \nM, menstrual phase.\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR79\nReview\nD A Gibson et al. Androgens, oestrogens and \nendometrium\n246:3\nJournal of \nEndocrinology\nExpression of proteins encoded by human ESR2 splice \nvariant mRNAs (ERβ2, ERβ5) has been detected in human \nendometrial cells ( Critchley et  al. 2002 , Collins et  al. \n2009, 2019). Notably, these variants may also be present \nin primates ( Sierens et  al. 2004 ) but are not expressed \nin rodents. In vitro  studies have demonstrated that the \nvariants can have a functional impact on endometrial \ncell function by forming heterodimers with full-length \nisoforms (Collins et al. 2019). Expression of ERRs has also \nbeen detected in human endometrium with cell-based \nstudies, highlighting the potential for them to alter cell \nmetabolism or ER α-dependent cell functions ( Bombail \net al. 2010a,b).\nPlante et al. (2012) examined expression of GPER in \nendometrium using RT-qPCR and immunohistochemistry \nreporting maximal expression in the proliferative phase. \nAn earlier study by Kolkova et al. (2010) claimed protein \nexpression was less variable than the mRNA and immuno-\nstaining was more intense in the epithelial cells than stroma \nthroughout the cycle. GPER may be involved in neoplastic \ntransformation of endometrium ( Jacenik et  al. 2016 ) or \nin promotion of HIF1 α-induced expression of MMPs in \nendometrial stromal cells in women with endometriosis \n(Zhang et  al. 2017 ). A number of GPER knockout mice \nhave been generated using different targeting strategies: \nfemales are fertile with no obvious reproductive defects, \nalthough impacts on obesity and vasculature have been \nclaimed (Prossnitz & Hathaway 2015).\nExpression and functional impact of androgen \nreceptors during the menstrual cycle\nImmunostaining for AR in full-thickness endometrial \ntissue sections ( Fig. 1 ) ( Marshall et  al. 2011 ) detected \nintense staining in stromal fibroblasts which exhibited \ncyclical variation in the functional layer but remains \nunchanged within the basal compartment across the \ncycle. How this difference in expression within closely \nadjacent cells is regulated remains unknown. Epithelial \ncells in the functional layer upregulate expression of AR in \nresponse to falling levels of progesterone in a normal cycle \nor following administration of anti-progestins and this \nis associated with reduced proliferation ( Narvekar et  al. \n2004, Marshall et al. 2011). We have identified androgen-\nregulated genes in primary human endometrial stromal \ncells, several of which (e.g. CITED2, HIF1a, CD44) are \nimplicated in networks that protect cells against stress and \napoptosis (Marshall et al. 2011). These data coupled with \nthe observation that AR expression remains unchanged \nin the stromal cells of basal compartment at time of \nmenses ( Garry et  al. 2009 ) prompted us to investigate \nwhether androgens might also play a role in regulating \nendometrial breakdown and repair using a mouse \nmodel that recapitulates key features of menstruation \nin women ( Cousins et al. 2014, 2016a,b). In this model, \nadministration of a single injection of DHT at the time \nof progesterone withdrawal to induce menstruation had a \nstriking impact on both tissue breakdown and restoration \nof tissue homeostasis. Although our understanding of the \nrole of androgens in endometrial tissue function is still \nincomplete, we identified changes in expression of matrix \nmetalloproteinases (MMP3, 9) which are implicated in \nbreakdown of human endometrium (Cousins et al. 2016a).\nExpression of enzymes implicated in \nbiosynthesis and metabolism of oestrogens \nand androgens in endometrial tissue\nIn recent years there has been a rapid increase in evidence \nto support a role for local tissue (‘intracrine’) regulation \nof endometrial steroids ( Gibson et  al. 2013 , 2016a, \n2018b). Key findings have included direct measurement \nof steroids in endometrial tissue homogenates recovered \nduring the menstrual cycle: notably Huhtinen and \ncolleagues reported they did not parallel those in blood \n(Huhtinen et  al. 2012 , 2014). In women (but not in \nmice), the adrenals are an important source of sulphated \nsteroids that circulate at high concentrations in the blood \nbut are unable to bind directly to the steroid receptors. \nA brief summary of enzymes detected in endometrial \ntissue and their substrates is provided in Fig. 2  with a \nfew complementary references discussed subsequently. \nReaders interested in the topic of intracrine steroids are \nrecommended to read the comprehensive review by \nKonings et  al. which includes a systematic search for \npapers reporting expression of steroidogenic enzymes  \nin pre- and postmenopausal endometrium ( Konings  \net al. 2018).\nBriefly, a strong case has been made that the ‘inactive’ \nadrenal steroid dehydroepiandrosterone (DHEA) is \nan important precursor of bioactive androgens in \nwomen ( Labrie et  al. 2005 ), a proposal which has been \nsupported by detection of all the enzymes that regulate \nconversion of DHEA via intermediates to testosterone, \nDHT or oestrogens ( Gibson et  al. 2013 , 2016a, 2018c). \nCatalano and colleagues reported increased expression \nof AKR1C3 in the early secretory phase ( Catalano et  al. \n2011), consistent with results obtained using an in vitro \nmodel of stromal decidualisation ( Gibson et  al. 2016 a).  \nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR80\nAndrogens, oestrogens and \nendometrium\nD A Gibson et al.246:3\nJournal of \nEndocrinology\nInter-conversion of active/inactive oestrogens and \nandrogens is mediated via 17 β-hydroxysteroid \ndehydrogenase isozymes, of which several isoforms are \nexpressed in endometrium. For example, 17 βHSD type 1  \nis responsible for production of testosterone and E2, \nfrom A4 and E1, respectively, whereas 17 βHSD2 catalyses \nthe opposite reaction. HSD17B2, expressed in glandular \nepithelial cells, is markedly increased in the secretory phase \n(Maentausta et al. 1991), and reported overexpression of \n17βHSD2 is a feature of endometrium in women with \ndisorders such as endometriosis, adenomyosis, and/or \nleiomyomas (fibroids) rather than those who are disease-\nfree (Kitawaki et al. 2000).\nExpression of steroid sulphatase (STS) in endometrial \ntissue can catalyse conversion of DHEAS to DHEA (Fig. 2) \nbut can also increase the concentration of E1 by removal \nof sulphate moieties from E1S. Using an in vitro  model \nof decidualisation, we have confirmed expression of both \nSTS and aromatase ( CYP19A1) in endometrial stromal \ncells with evidence that both enzymes contribute to \nproduction of oestrogens during decidualisation ( Gibson \net al. 2013, 2018a).\nEndometrial disorders: altered expression of \nenzymes and receptors implicated in \ndisease aetiology\nImplantation failure and recurrent miscarriage\nTimely and efficient decidualization of endometrial \nstromal cells in response to ovarian-derived progesterone \nis essential for the generation of an endometrial \nmicroenvironment that can support and nurture the \nimplanting blastocyst. Disruption of decidualization \nis implicated in implantation failure and miscarriage.  \nStudies in mice using aromatase inhibitors (AI) \ndemonstrated local intra-uterine production of E2 is \ncritical for establishment of pregnancy ( Das et al. 2009). \nIn women, E2 is produced during decidualisation of \nendometrial stomal cells which regulates uNK cell \nmigration (Gibson et al. 2015, 2020). Given the evidence \nthat disturbances in the numbers/location of uNK cells \ncan predispose women to experiencing a miscarriage \n(Lash et  al. 2016 ), these data are consistent with a role \nfor E2 in regulating the endometrial microenvironment \nduring the establishment of pregnancy.\nWe have demonstrated that during in vitro  \ndecidualisation of primary human endometrial stromal \ncells there is a significant increase in the expression of \nAKR1C3, the enzyme responsible for the conversion \nof androstenedione to testosterone, which is also \naccompanied by increased secretion of testosterone \ninto the culture medium ( Gibson et  al. 2016 a). In \naddition, blocking AR action using flutamide during \nin vitro  decidualisation revealed a role for AR-mediated \ngene expression of osteopontin, a protein implicated in \nreceptivity ( Gibson et  al. 2016 a). Further studies using \nprimary human endometrial stromal cells from women \nof advanced reproductive age suggested that the age-\nrelated decline in adrenal steroids may have an impact \non the ability of the endometrium to support a pregnancy \nand that increased availability of adrenal precursors \nenhanced androgen production and secretion of \ndecidualisation markers (Gibson et al. 2018c). Intravaginal \nsupplementation with DHEA has shown promising \nresults in alleviating postmenopausal vaginal dryness \nand atrophy in clinical trials without any adverse effects \n(Labrie 2019 ), but delivery into the endometrium of \npremenopausal women has not been tested. Other studies \nhave reported a positive impact of DHT on stromal cell \nFigure 2\nSimplified diagram of key biosynthetic steroids \nimplicated in intracrine biosynthesis of \noestrogens and androgens within endometrial \ntissue. In pre-menopausal women both the \nadrenal and ovary are the primary sites of \nbiosynthesis of steroids. Expression of all \nenzymes illustrated has been validated in human \ntissue or primary endometrial stromal cells \nexposed to a decidualisation stimulus (Gibson \net al. 2013, 2016a, 2018b). For a more \ncomprehensive steroidogenic pathway,  \nreaders are referred to the review by  \nKonings et al. (2018).\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR81\nReview\nD A Gibson et al. Androgens, oestrogens and \nendometrium\n246:3\nJournal of \nEndocrinology\ndecidualisation and resistance to oxidative stress (using \nhydrogen peroxide) ( Kajihara et  al. 2012 ), expanding \nour understanding of the potentially beneficial role of \nandrogens as direct modulators of endometrial function \nas well as precursors of oestrogen biosynthesis (see review \nby Gibson et al. 2016b).\nFailure to downregulate ER α during the secretory \nphase (see Fig. 1  and discussion) has been reported in \nwomen with defects in uterine receptivity ( Lessey et  al. \n2006). A complementary study using samples from \nwomen with unexplained infertility also showed that \nin these patients elevated expression of ER α in the mid-\nluteal phase was associated with reduced expression of \nglycodelin-A, low levels of which have been implicated in \nrecurrent implantation failure ( Dorostghoal et al. 2018). \nThere is no information about dysregulation of ER β in \nimplantation failure. Fertility problems in women with \npolycystic ovaries and excess androgens might relate to \noverstimulation of AR signalling pathways, but currently \nthe evidence is quite limited (Schulte et al. 2015).\nEndometrial cancer\nThe majority of endometrial cancers (EC) present with \nabnormal endometrial bleeding in postmenopausal \nwomen: rates are rising particularly in younger women, \nwith obesity considered a significant contributing \nfactor ( Table 1, reviewed by Sanderson et  al. 2017 ). EC \nare historically classified as type 1 or type 2; type 1 \nis the most commonly diagnosed form (about 80% \nof the cases), is considered oestrogen-dependent and \ncharacterised by hyperplastic proliferation of the \nendometrial glands. A large number of studies have \ninvestigated the source and impact of oestrogens in \nendometrial cancer with landmark papers including \nthose by Sasano and collaborators who reported evidence \nof increased immunoexpression of aromatase, STS and \n17βHSD enzymes in both endometrial hyperplasia and \nEC ( Sasano et  al. 1996 , Utsunomiya et  al. 2001 , 2004). \nA recent comprehensive systematic review considered \nthe evidence that intracrine metabolism contributes \nto EC ( Cornel et al. 2019). The authors highlighted the \nimportance of sulphatase and aromatase enzymes in the \ngeneration of E1 and E2 within endometrial cancer tissue \nin promoting a pro-oestrogenic environment favouring \nproliferation of epithelial cells ( Cornel et al. 2019). The \nauthors sounded a note of caution by highlighting the \nvariability between individuals and methodologies  \nwhich may explain some variations in drug responses \n(discussed subsequently). \nThe best evidence for an impact of androgens on EC \nrisk has come from studies in women with polycystic \novarian disease, where the risk of type 1 cancers is higher \nin women with symptoms of androgen excess such as \nhirsutism and irregular periods ( Fearnley et  al. 2010 ). \nTanaka et al. reported DHT was elevated in endometrioid \nendometrial adenocarcinoma tissues compared with \nthat in normal endometrial tissues (8.0 fold) in a group \nof 41 patients ( Tanaka et  al. 2015 ). These results have \nbeen complemented by reports that AKR1C3 (conversion \nfrom A4 to testosterone) and 5 α-reductase (reduction of \ntestosterone to DHT) are both expressed in EC ( Ito et al. \n2016, Gibson et al. 2018a).\nExpression of ER α, ER β1 and splice variant isoforms \nof ERβ (ERβ2, ERβ5) in EC have been documented (Collins \net al. 2009, 2019). In a recent paper we highlighted the \npotential that ER β5, a variant unable to bind directly to \nE2, may still influence the response of EC to oestrogens \nby forming heterodimers with ER α (Collins et al. 2019). \nHigh GPER expression is predictive of poor survival in \nendometrial cancers ( Smith et  al. 2007 ). Prossnitz and \ncolleagues have reported interesting results using ER α-\nnegative/GPER-positive cells which suggest activation \nof downstream signalling in response to SERMs such as \ntamoxifen may explain why women treated with this \ndrug are at higher risk of EC ( Petrie et al. 2013). We, and \nothers, have reported widespread expression of AR in EC \n(reviewed in Gibson et  al. 2014 ). Evidence that loss of \nAR is associated with poorer prognosis, reports that AR \nwas elevated in metastases ( Kamal et al. 2016), and that \nandrogens may be anti-proliferative in EC cells have \nraised the prospect that SARMs should be explored for this \ncancer as well as those of breast (see subsequent section). \nThere are no reports of AR variants being expressed in EC.\nEndometriosis\nEndometriosis is an oestrogen-dependent \nneuroinflammatory pain disorder characterised by the \npresence of ‘lesions’ of endometrial-like tissue in sites \noutside the uterus (Horne & Saunders 2019). Endometriosis \nand adenomyosis are often found in the same patient \nand may share a common aetiology ( Yovich et al. 2019). \nInfertility is a common co-morbitity of endometriosis and \ndifferences between expression profiles of mRNAs, miRNA \nand proteins in endometrial biopsies from controls and \nwomen with endometriosis have been reported ( Burney \net al. 2007, 2009) and have recently been reviewed (Bulun \net  al. 2019 ). Notably, there remain differing views as to \nwhether receptivity is or is not affected (Lessey & Kim 2017,  \nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR82\nAndrogens, oestrogens and \nendometrium\nD A Gibson et al.246:3\nJournal of \nEndocrinology\nMiravet-Valenciano et  al. 2017 ). Studies comparing \nthe impact of a decidualisation stimulus on isolated \nendometrial stromal cells have reported alterations in the \nexpression of steroidogenic enzymes in cells from women \nwith endometriosis ( Aghajanova et  al. 2009 ). Blunted \nresponses to progesterone, often termed ‘progesterone \nresistance’, are considered a hallmark of the disorder \n(Aghajanova et  al. 2010 , Bulun et  al. 2010 ). Some have \nquestioned whether this property is an innate feature of \nthe eutopic endometrial cells or acquired when they grow \nin ectopic sites (McKinnon et al. 2018).\nSome of the best evidence for the importance of \nintracrine action of steroids has come from studies \ncomparing concentrations of steroids in lesions and eutopic \nendometrium in women with endometriosis ( Huhtinen \net  al. 2012 , 2014). To complement mass spectrometry \ndata, expression of enzymes in lesions such as aromatase, \nAKR1C3 and STS has been measured with evidence that \ntheir overexpression is responsible for generation of a \nlesion tissue environment rich in oestrogens that can \nbind ERs or GPER (Rizner 2009, 2016). Notably, aromatase \nappears to be involved in local biosynthesis of both \nE2 and the pro-inflammatory regulator prostaglandin \nE2 ( Attar & Bulun 2006 ). Upregulation of ER β is also \nconsidered a hallmark of the altered microenvironment \nof lesions, which may promote the impact of oestrogens \non inflammation, angiogenesis or pain pathways ( Bulun \net al. 2012, Greaves et al. 2014a,b).\nAdenomyosis\nAdenomyosis is a condition characterised by the \npresence of heterotopic endometrial glands and stroma \nwithin the myometrium and has traditionally been \ndifficult to diagnose as it can present with symptoms \nsuch as infertility, pain and heavy menstrual bleeding, \nwhich are also characteristics of other conditions, \nincluding endometriosis and fibroids ( Pontis et al. 2016). \nRecent advances in imaging offer hope for improved \nunderstanding of its presentation and pathogenesis \n(Chapron et  al. 2020 ). Altered gene expression in the \nendometrium of women with adenomyosis has been \nreported, although results have been based on small \nnumbers of samples ( Herndon et  al. 2016 , Xiang et  al. \n2019). It has been suggested that development of \nadenomyosis may involve mechanisms activated but not \nresolved during endometrial tissue injury with a common \naetiology to some forms of endometriosis ( Donnez et al. \n2018, 2019). Studies using tissue recovered from women \nwith adenomyosis have identified increased expression of \nGPER and some association between GPER polymorphisms \nwith the disease; however, it must be noted that study \npopulations have been small ( Li et al. 2017, Hong et al. \n2019). In vitro studies have identified pathways promoting \nE2-induced overproliferation of uterine smooth muscle \ncells from women with adenomyosis ( Sun et  al. 2015 ). \nImmunostaining of tissue sections from adenomyosis uteri \nhave detected changes in ER α, reduced PR and elevated \nexpression of ER β (Mehasseb et al. 2011) and aromatase \n(Barcena de Arellano et al. 2013), all consistent with an \noestrogen-dependent disease. In older papers, expression \nof AR has been reported (Horie et al. 1992).\nDrugs targeting sex steroid metabolism\nAromatase inhibitors\nAn excellent historical summary of the discovery of \naromatase, identification of increased expression in \nquadrants of breast containing a tumour, and the \ndevelopment and refinement of aromatase inhibitors \n(AIs) has been published by leaders in the field ( Santen \net  al. 2009 ). The development of highly effective 3 rd \ngeneration AIs (anastrozole, letrozole, exemestane) led \nto clinical trials for a number of indications including \npostmenopausal breast cancer, gynaecomastia in men \nand ovarian cancer (Miller et al. 2001, Santen et al. 2009, \nLangdon et  al. 2017 ). One key reproducible finding \nhas been a lower rate of EC and venous thrombosis in \nwomen treated with AIs compared with those treated with \ntamoxifen ( Chlebowski et  al. 2015 ). The ClinicalTrials.\ngov website lists 22 trials with search terms endometrial \ncancer+aromatase inhibitor with the main focus being \non women with more advanced disease. Many trials are \nnot yet completed but evidence of benefit in some ER+ \ncancers has been reported. For example, in 40 women \ntreated with exemestane, there was remission in 10% \nand lack of progression after 6 months in 35% of the \npatients (Lindemann et al. 2014). The PARAGON trial, a \nphase 2 open label study using anastazole in 82 patients \nwith ER and/or PR positive hormonal therapy naive \nmetastatic endometrial cancer, reported clinical benefit in \n44% of patients ( Mileshkin et al. 2019), although results \nfrom other trials have been disappointing and may have \nbeen influenced by obesity in the target population ( van \nWeelden et al. 2019). Some promising results have been \nreported following treatment of women with the rarer \ncancer low grade endometrial sarcoma with AIs (reviewed \nin Pannier et al. 2019).\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR83\nReview\nD A Gibson et al. Androgens, oestrogens and \nendometrium\n246:3\nJournal of \nEndocrinology\nLetrozole and anastrozole have also been evaluated in \nboth pre- and postmenopausal women with endometriosis \n(Pavone & Bulun 2012 ). These authors propose that \nAIs appear to be a suitable therapy for endometriosis-\nassociated pain in women who are postmenopausal \nby targeting the intracrine oestrogen biosynthesis that \ncontributes to sustained symptoms in this age group. \nRecent advances have included development of vaginal \nring delivery systems for co-administration of anastrozole \nand the androgenic progestin levonorgestrel (LNG) as a \npotential therapy for endometriosis-associated pain: a \nphase I trial reported promising findings (Schultze-Mosgau \net al. 2016). While these results seem promising, a recent \nESHRE guideline that considered whether AIs should \nbe given in combination with contraceptives or other \ntherapies concluded that due to side effects they should \nonly be prescribed to women after all other options for \nmedical or surgical treatment are exhausted ( Dunselman \net al. 2014). AIs have also been suggested as therapies for \nadenomyosis but with the caveat that further studies are \nrequired (Vannuccini et al. 2018).\nSulphatase inhibitors\nA number of potent STS inhibitors have been developed \nwith the primary indication being treatment of hormone-\ndependent cancers ( Day et  al. 2009 , Purohit & Foster \n2012). The compound STX64 (Irosustat) was effective \nin blocking oestrogen synthesis in endometrial cancer \ncells in vitro  and was tested as a therapy for advanced \nendometrial cancer before being discontinued as a \nmono-therapy by Ipsen (Pautier et al. 2017). Irosustat has \nrecently been used as an addition to aromatase inhibitors \nin women with advanced ER+ breast cancer and reported \nas having a positive clinical impact ( Palmieri et al. 2017). \nAnother inhibitor, estradiol-3-O-sufamate (E2MATE), has \nbeen reported which deceased STS activity in human \nendometrial explants and decreased lesion weight and \nsize but did not alter systemic oestrogens in a mouse \nmodel of endometriosis ( Colette et  al. 2011 ). E2MATE, \nunder the trade name PGL2001, has been shown to \nreduce STS activity in endometrium when given once a \nweek for 4 weeks ( Pohl et  al. 2014 ); the same drug was \nused in a trial for treatment of endometriosis-associated \npain (NCT01631981) but results have not been reported.\nHydroxysteroid dehydrogenase inhibitors\n17βHSD1 inhibitors were originally developed to target \nthe biosynthesis of bioactive E2 in hormone-dependent \nbreast cancer ( Day et al. 2008). Recently, with evidence \nfor expression of 17βHSD1 in endometriosis lesions, their \nuse has been expanded to treatment of endometriosis \nwith promising results reported ( Delvoux et  al. 2014 ). \nThe role of 17 βHSD5/AKR1C3 in metabolism of steroids \nand prostaglandins, both of which are implicated in \nendometriosis-associated pain, make it an attractive \ntarget as a novel therapy for this disorder. A number \nof inhibitors have been developed with the Bayer \ncompound BAY1128688 showing sufficient promise for \nit to be used in a phase 2 randomised clinical trial to \nassess efficacy of different doses in 121 women with \nsymptomatic endometriosis. The trial (NCT03373422) \nwas terminated after 8 months due to an increased \nincidence of liver toxicity highlighting the challenge \nof developing drugs that may target enzymes present \nin multiple tissues ( van Weelden et  al. 2019 ). In their \nrecent review, Rizner & Penning (2020)  concluded that \nthe ‘hepatotoxicity effect was probably compound \nrelated which does not preclude AKR1C3 as a target’ and \nthat development of other drugs targeting this enzyme \nalone or in combination with other targets is continuing \n(Wangtrakuldee et al. 2019).\nDual/combined targeting\nWhile initial studies have focused on mono-therapies, a \nnew generation of drugs with dual actions has also been \ndeveloped – examples include those that target aromatase \nand STS (DASI, Purohit & Foster 2012) or STS and 17βHSD1. \nWhile some in vitro studies seem promising, clinical trials \nare yet to be completed (reviewed in Potter 2018).\nDrugs targeting oestrogen and androgen \nreceptors and their potential to treat \nendometrial disorders\nThe solving of the crystal structure of nuclear ERs as well \nas detailed modelling of the impact of ligand binding \non conformation, recruitment of co-factors and gene \nexpression laid the foundation for the development of \nsynthetic ligands that exhibit selectivity, tissue-specific \nagonism, antagonism or induce receptor degradation; a \ncomprehensive perspective and background is provided \nby Burris et al. (2013). Table 2 summarises the specificities \nand properties of some of the novel non-steroidal ligands \ndeveloped to target ERs and AR, a number of which have \nbeen investigated in the context of endometrial disorders \nand are discussed subsequently.\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR84\nAndrogens, oestrogens and \nendometrium\nD A Gibson et al.246:3\nJournal of \nEndocrinology\nOestrogen receptors\nAgonists and antagonists with selectivity for ER α, ER β \nand GPER have been validated using a range of cell \nbased and animal models ( Table 2). When Frasor et  al. \n(2003) compared the effect of 4 × daily injections of \n4,4 ′,4″-(4-propyl-[1 H]-pyrazole-1,3,5-triyl)trisphenol \n(PPT) or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) to \nimmature (d21) female mice, they noted differences in \ntissue response which they attributed to activation of ERα \nor ERβ respectively. PPT caused epithelial cell proliferation, \nincreased uterine weight and expression of lactoferrin but \ndecreased Ar mRNA. In contrast, DPN did not increase \nuterine weight or luminal epithelial cell proliferation \nbut appeared able to reduce stimulation by PPT. These \nfindings are consistent with a large body of work that \nimplicates ER α as the major regulator of oestrogen-\ndependent proliferation in the uterus ( Hewitt & Korach \n2003, Winuthayanon et al. 2017). In contrast, it appears \nthat ERβ may have other functions including specific roles \nin inflammation and angiogenesis ( Critchley et al. 2001, \nGibson & Saunders 2012, Greaves et al. 2013, Gibson et al. \n2015). There have been fewer studies focussed on GPER, \nbut when Zhang et al. (2017) treated primary endometrial \nstromal cells with E2, G1 ((±)-1-[(3aR*,4 S*,9bS*)-4-(6-\nbromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-\n3H-cyclopenta[c]quinolin-8-yl]-ethanone) or G15 \n((3aS*,4 R*,9b R*)-4-(6-bromo-1,3-benzodioxol-5-yl)-\n3a,4,5,9b-3H-cyclopenta[c]quinolone), they reported that \nstimulation of GPER with G1 mimicked the impact of E2 \nand resulted in stabilisation of HIF protein and increased \nexpression of VEGF and MMP9. The Prossnitz group \ngenerated a GPER antagonist (G36, (±)-(3aR*,4 S*,9bS*)-\n4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-\n8-(1-methylethyl)-3H-cyclopenta[c]quinolone, Table 2 )  \nwith improved selectivity and reported that it can \nblock multiple E2-mediated second messenger \nsignalling pathways and endometrial cell proliferation  \n(Dennis et al. 2011).\nSelective oestrogen receptor modulators (SERMs)\nSelective oestrogen receptor modulators (SERMs) were \ndeveloped to treat ER α-positive breast cancers with \nthe ideal SERM being one that acts as an antagonist \nin breast but an agonist in bone ( Burris et  al. 2013 ). \nThe evolution in our understanding of tissue selective \nactivities of ligand-activated receptors coupled with the \nTable 2 Non-steroidal drugs targeting oestrogen and androgen receptors.\nName Receptor activity Clinical trials References\nPPT ERα selective agonist Stimulates epithelial cell proliferation (Frasor et al. 2003)\nDPN ERbeta selective \nagonist\nStimulates endometrial endothelial cells (Greaves et al. 2013)\nLNS8801 GPER agonist Phase 1 open label clinical trial in advanced solid and \nhematologic cancers\nNCT04130516\nG36 GPER antagonist Improved selectivity compared to G15 (Dennis et al. 2011)\nTamoxifen SERM Treatment and prevention of ERα-positive breast cancers \nin pre- and post-menopausal women. Agonist action in \nendometrium\n(Jordan 2003)\nRaloxifene, Evista SERM Prevention of invasive breast cancer in post-menopausal \nwomen. Positive effects on bone, cognition, \ncardiovascular system\n(Muchmore 2000)\nFulvestrant, Faslodex SERD Licensed as first line endocrine management for \nadvanced breast cancer in post-menopausal women\n(Blackburn et al. 2018)\nBazedoxifene, Duavee SERM/SERD Positive impacts on bone, approved for HRT, SERD in \nendometrium\n(Fanning et al. 2018)\nGTx24, Enobosarm SARM Muscle wasting in cancer, breast cancer, urinary stress \nincontinence\n(Gao & Dalton 2007)\nGTx007, Andarine SARM, partial agonist Tested in preclinical models; issues with use in doping (Kearbey et al. 2007)\nGSK2881078 SARM, long half life Muscle loss in patients with chronic disease \n(discontinued)\nImproved muscle mass in healthy women\n(Neil et al. 2018)\nAZD3514 SARD Moderate anti-tumour activity in advanced castrate-\nresistant PCa. Significant levels of nausea and vomiting\n(Omlin et al. 2015)\nEach drug is identified by its common abbreviation or registered name, the activity as reported in the literature, whether it has been used in one or more \nclinical trial(s), and a key reference is provided.\nDPN, 2,3-bis(4-hydroxyphenyl)-propionitrile; G36, (±)-(3aR*,4S*,9bS*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-8-(1-methylethyl)-3H-\ncyclopenta[c]quinoline; GPER, G protein-coupled oestrogen receptor 1; PPT, 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol; SARM, selective \nandrogen receptor modulator; SERD, selective oestrogen receptor degrader; SERM, selective oestrogen receptor modulator.\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR85\nReview\nD A Gibson et al. Androgens, oestrogens and \nendometrium\n246:3\nJournal of \nEndocrinology\ndiscovery of different ER subtypes and splice variants \nhas resulted in several generations of SERMs. Tamoxifen \nis a first generation SERM that displays agonism in the \nendometrium, increasing EC risk; second generation \nSERMs such as Raloxifene do not agonize endometrial \ngrowth and are associated with lower risk of EC and \nmay have additional positive effects on cognition and \nthe cardiovascular system ( Muchmore 2000 ). Other \nSERMs have a mixture of agonist/antagonist activity in \nendometrium, agonist activity in bone and antagonism \nin breast (Pickar et al. 2018).\nSelective oestrogen receptor degraders (SERDs)\nSelective oestrogen receptor degraders (SERDs) antagonize \nERα and induce its degradation, resulting in a decrease in \nERα protein levels: they do not show agonist properties in \nother tissues (Kieser et al. 2010). Fulvestrant was the first \nSERD to be approved as a therapeutic and is commonly \nused as a treatment for advanced breast cancer (Blackburn \net al. 2018). Although originally marketed under the trade \nname Faslodex by AstraZeneca, manufacture of generic \nversions has been approved by the US Federal Drugs \nAdministration. A number of new generation SERDs are \nin development ( Pepermans & Prossnitz 2019 ), one of \nwhich is bazedoxifene (BZA), a compound which exhibits \nSERD properties in breast cancer with beneficial properties \nin bone and no adverse impact on endometrium leading \nto its approval for hormone replacement therapies (Pickar \net al. 2018). Recent mechanistic studies suggest BZA may \nbe useful in treating cancers which contain ER α mutants \n(Fanning et  al. 2018 ). In addition to activation by \nendogenous oestrogens, there is evidence that GPER may \nalso be activated by SERMs/SERDs developed to target ERα \nwhich may explain some apparent discordant results in \nERα negative cancers (see review by Meyer et al. 2011).\nAndrogen receptors\nSelective androgen receptor modulators (SARMs) have \nbeen developed to support the beneficial impacts of \nAR-mediated cell function in bone and muscle without the \nadverse side effects seen with high doses of testosterone \nor DHT (gynaecomastia, aggression, prostate hyperplasia) \n(Burris et al. 2013, McEwan 2013) (Table 2). New generation \nSARMs have been proposed as therapeutics for women \nsuffering from breast cancer, muscle wasting or urinary \nincontinence and a number of clinical trials have been \nundertaken to evaluate their use for these indications \n(Brodie & McEwan 2005, Dalton et al. 2011).\nTargeting oestrogen receptors in \nendometrial disorders\nA high proportion of low grade EC express ER α as well as \nprogesterone receptors. In a recent systematic review, van \nWeelden and colleagues highlighted the progestins as a \nfirst-line hormonal therapy and use of antioestrogens as \nan alternative therapy option, highlighting results from \nten trials using SERMs or SERDs as monotherapies between \n1981 and 2013 ( van Weelden et  al. 2019 ). All studies \nshowed some beneficial response to therapy, although \nresults were variable and the authors concluded that \ntamoxifen or a combination of tamoxifen and progestin \nmight be the best choice when selecting second-line \nhormonal treatment. In subsequent studies, the SERM \nOspemifene has been shown as an effective in treatment \nof vaginal symptoms in postmenopausal women ( Archer \net al. 2019) and only acts as an agonist in endometrium \nin high doses. The SERD fulvestrant/faslodex (Table 2) has \nbeen investigated as a treatment for endometrial cancer \nin phase I/II trials, although well-tolerated, it has low \noral bioavailability and further trials are needed (Bogliolo \net al. 2017). Another recent study suggested dual targeting \nof ER α with tamoxifen and ERR α with XCT790 may be \nbeneficial for EC treatment, but this requires further \nvalidation (Mao et al. 2019).\nWhile administration of SERMs/SERDs may be \nappropriate for postmenopausal women with cancer, their \nuse in younger women with non-malignant endometrial \ndisorders such as endometriosis is more challenging with \ndata limited to promising results in preclinical models \n(Kulak et al. 2011, Khine et al. 2018). The observation that \nERβ is highly expressed in endometriosis lesions and the \ndevelopment of ER β-selective agonists such as ER β-041 \nwith apparent anti-inflammatory properties provided a \nrationale for testing them as therapies for endometriosis \nwith promising results obtained in preclinical models \n(Harris 2006). Several clinical trials were conducted with \nERβ-041, but no positive outcomes were reported. In a \nrecent review, Guo and Groothuis highlighted a number \nof reasons why drugs targeting ER β including the SERM \nFulvestrant and ER β-041 failed to deliver the patient \nbenefit in clinical trials. The reasons highlighted included, \nbut were not limited to, animal models that did not \nrecapitulate long-established disease, translation of dose \nfrom rodent to women and incomplete understanding \nof the role of ER β antagonism in pain mechanisms ( Guo \n& Groothuis 2018 ). SERMs are not considered suitable \ntherapies for adenomyosis (Pontis et al. 2016). The SERM \nOrmeloxifene, developed for use as a contraceptive,  \nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR86\nAndrogens, oestrogens and \nendometrium\nD A Gibson et al.246:3\nJournal of \nEndocrinology\nhas also shown promising results in treating heavy \nmenstrual bleeding (HMB) in perimenopausal women in \nIndia (Pati et al. 2017). \nGPER has also been investigated as a target for \ntreatment of endometriosis with reports that the GPER \nagonist G-1 induced cell cycle arrest and apoptosis \nof stromal cells derived from ovarian endometriosis \ncysts ( Mori et  al. 2015 ). GPER has been implicated in \nE2-stimulated nociceptive pain in endometriosis, with \nresults in a mouse model showing administration of \nthe selective GPER antagonist G36 inhibited the pain \nresponse (Alvarez et al. 2014). Properly designed clinical \ntrials are needed to explore GPER as a target for relief of \npainful symptoms in endometriosis in women.\nTargeting androgen receptors in \nendometrial disorders\nThe development of SARMs has prompted renewed \ninterest in targeting of AR in reproductive disorders while \nalso raising concerns related to side effects including \nhirsutism that are a hallmark of excess androgens in \nPCOS. Transgender individuals may be one group who \nmight benefit from SARMs, as administration of high \nconcentrations of testosterone can result in abnormal \nuterine bleeding and metabolism to oestrogen may \nexplain increased rates of endometrial cancer ( Grimstad \net al. 2019), but there are no registered clinical trials. \nDanazol is a synthetic androgen first used as a \ntreatment in the 1970s: it binds AR with high affinity \nand is also reported to reduce the activity of a number \nof enzymes including steroid sulphatase ( Carlstrom et al. \n1984). Danazol has anti-proliferative effects on uterine \ncells (Kauppila et al. 1985). A systematic review of RCTs \nusing Danazol to treat endometriosis concluded that \ntreatment was associated with reduced lesion size and relief \nof pain symptoms and that women who took Danazol \nwere more satisfied with their treatment compared with \nwomen who had placebo treatment ( Farquhar et  al. \n2007). The anti-proliferative and hormone-suppressive \nactivities of Danazol has formed the basis of treatments \nfor adenomyosis ( Vannuccini et  al. 2018 ) and heavy \nmenstrual bleeding ( Beaumont et al. 2007) with efficacy \nbeing demonstrated. The androgenic activity of Danazol \nis associated with side effects including hirsutism and \ndeepening of the voice and it is contraindicated for women \nat risk of pregnancy because of the risk of virilisation of \nthe fetus ( Farquhar et  al. 2007 ). These side effects have \nlimited its use and prompted efforts to develop therapies \nthat are less virilising.\n Using a mouse model, we have compared the impact \nof DHT with Danazol and new generation SARMs GTx-024  \nand GTx-007 ( Table 2 ) and found that both Danazol \nand GTx-024 restored uterine weight of ovariectomised \nfemale mice to that of intact animals, while GTx-007  \nhad no similar effect ( Simitsidellis et  al. 2019 ). These \npreclinical studies highlight the importance of \nconsidering impacts on the endometrium when women \nare included in clinical trials using SARMs ( Dalton et al. \n2011, Neil et al. 2018). While SARMs have been used in \nclinical trials for treatment of breast cancer, they have \nnot as yet been tested as treatments for endometrial \ncancer or endometriosis ( Narayanan et  al. 2018 ). \nStandard medical treatment for HMB involves targeting \nof the progesterone receptor either with the androgenic \nprogestagen levonorgestrol delivered in an intra-uterine \ndevice or with newly developed selective progesterone \nreceptor modulators (SPRMs; Maybin & Critchley 2016 ). \nInterestingly, administration of progesterone receptor \nantagonists or SPRMs such as UPA (ulipristal acetate) as \na treatment for heavy menstrual bleeding results in a \nsignificant increase in expression of AR ( Whitaker et al. \n2017) which may, in part, explain their anti-proliferative \naction. Treatment with new generation SARMs is yet  \nto be investigated.\nSummary and future directions\nThe endometrium is a dynamic tissue which, by virtue \nof its expression of high affinity receptors, is exquisitely \nsensitive to the actions of oestrogens and androgens. \nTemporal and spatial changes in tissue function in \nresponse to steroids play a critical role in preparation for \npregnancy and in breakdown and shedding if pregnancy \ndoes not occur. Balanced regulation of sex-steroid action \nis essential for endometrial function and is controlled via \nlocal metabolism and cell- and tissue-specific expression \nof steroid receptors/isoforms. Drugs targeting steroid \nmetabolising enzyme activity and/or receptor function \nhave reported efficacy in several endometrial disorders, \nbut their use has often been limited due to lack of tissue \nspecificity and undesirable side-effect profiles. Recent \ndevelopment of drugs that selectively target steroid \nreceptors such as next generation SERMs, SERDs, SARMs \nand SARDs show promise as new therapeutics, but \nfurther preclinical studies and clinical trials are needed to \ndetermine if these drugs have efficacy specifically for the \nindication of endometrial disorders.\nDownloaded from Bioscientifica.com at 06/23/2026 12:44:37AM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-20-0106\nhttps://joe.bioscientifica.com © 2020 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR87\nReview\nD A Gibson et al. Androgens, oestrogens and \nendometrium\n246:3\nJournal of \nEndocrinology\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\nFunding for salaries and research in the Saunders laboratory has been \nsupported by MRC programme grants MR/N024524/1 and G1100356/1.\nReferences\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)\nAghajanova L, Velarde MC & Giudice LC 2010 Altered gene \nexpression profiling in endometrium: evidence for progesterone \nresistance. Seminars in Reproductive Medicine 28 51–58. 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