{"paper_id":"83e50d7d-8b65-4706-a3c7-e962d313ab3c","body_text":"EDITORIAL\nUnderstanding the diversity of sex steroid action\nMatti Poutanen\nDepartment of Physiology, Institution of Biomedicine and Turku Center for Disease Modelling, University of Turku, Turku FI-20014, Finland\n(Correspondence should be addressed to M Poutanen; Email: matti.poutanen@utu.fi)\nSteroidal estrogens are lipid-soluble compounds that are able\nto pass through the plasma membrane of cells by diffusion.\nAccording to the current knowledge, the three main naturally\noccurring estrogens are estrone (E\n1), estradiol (E 2), and\nestriol. E2 is the most active estrogen and the predominant\nfemale sex steroid during the reproductive years. In addition\nto these classical estrogens, there are various other steroidal\nand non-steroidal compounds that are able to interact with\nestrogen receptors (ERs), and thus at least partially act as\nestrogens. These include novel endogenous ligands (Saijo et al.\n2011), pharmacological ( McDonnell & Wardell 2010 ) and\ndietary compounds ( Mu¨ller et al . 2004), as well as synthetic\nagents, such as pesticides and plasticizers (Craig et al. 2011).\nT wo nuclear ER subtypes have been well characterized,\nnamely ESR1 (ER a) and ESR2 (ER b). The nuclear ERs\nact as transcription factors, activated by ligand binding, and\nresulting in the recruitment of various receptor-interacting\nproteins and transcription factors of the general transcription\nmachinery ( Bulynko & O’Malley 2011 , Hedengran Faulds\net al . 2012). Several splice variants of both ERs have been\nfound in normal and cancerous tissue, but their specific\nbiological functions are still partially unclear. Despite the\nsimilarities between the two ERs, many studies have clearly\ndemonstrated that there are subtype-specific actions, and,\naccordingly, the responses elicited by certain ligands differ\ndepending on the receptor subtype. Furthermore, ER a and\nERb display partially overlapping tissue distribution, but they\nalso possess receptor-specific expression patterns, and when\nexpressed in the same tissue, the receptors often localize to\ndifferent cell types. Several studies indicate that rapid estrogen\nsignaling is not mediated via the nuclear ERs, but through the\nG-protein-coupled ER1 ( GPER, also known as GPR30).\nGPER activates epidermal growth factor receptor (EGFR) by\ninducing a release of heparin-binding EGF , which activates\nEGFR leading to ERK1/2 activation ( Prossnitz & Barton\n2011). Moreover, E\n2-mediated activation of GPER induces\ncAMP production, intracellular calcium mobilization, and\nPI3K activation (for review, see Prossnitz & Barton (2011) ).\nThe distinct properties of ERa,E Rb and GPER have gained\na lot of interest from the pharmaceutical industry, and there\nare several ongoing projects to develop selective ER\nmodulators (Nilsson et al. 2011).\nThe structure and availability of the ligand is one of the\nkey determinants in the regulation of ER-mediated actions.\nIntratissue estrogen concent rations are determined by\ncirculating hormones, as well as by target tissue steroid\nmetabolism, which enables a concentration gradient between\nthe blood circulation and the target tissue. As an example,\nP450 aromatase (cytochrome P450, family 19, subfamily A,\npolypeptide (CYP19A1)), converting androgens (C-19\nsteroids) to estrogens (C-18 steroids), is widely expressed in\nperipheral tissues in humans, and P450 aromatase inhibitors\nare clinically used to inhibit estrogenic effects in various\nindications such as inhibiting the locally formed estrogens in\npost-menopausal breast cancer. More recently, the relevance\nof the hydroxysteroid (17 b) dehydrogenases (HSD17Bs),\nconverting the weak 17-keto steroids (e.g. E\n1) to highly active\n17b-steroids (e.g. E 2), and vice versa, has also become\napparent, and the enzymes are expected to be involved in the\nlocal production of both classical and novel ligands for ERs\nin several normal and diseased tissues (for example, Chang\net al . 2011, Mohler et al . 2011, Saijo et al . 2011, Saloniemi\net al . 2012). It is thus likely that yet unknown endogenous\nsmall molecular compounds modulating ERs are to be\ndiscovered in the future.\nIn the three thematic reviews of the present issue ofJournal\nof Endocrinology, the authors have summarized some of the\nrecent advances in studies aimed at understanding the\ndiversity in sex steroid action.\nThe regulation of the ligand availability for ERs by the\nfamily of HSD17B enzymes is discussed by Saloniemi et al .\n(2012) with special emphasis on novel findings obtained by\nusing genetically modified mouse models.In vivo models have\nproven to be essential in defining the physiological processes\nwhere HSD17B enzymes are involved. The recent data\nindicate that these enzymes catalyze reactions also in other\nmetabolic pathways in addition to those involved in sex\nsteroid activation and inactivation and are likely to regulate\nligand availability for numerous nuclear receptors.\nThe identification of ERb was a fundamental milestone in\nthe understanding of the mechanisms of estrogen signaling,\n1\nJournal of Endocrinology (2012) 212, 1–2 DOI: 10.1530/JOE-11-0414\n0022–0795/12/0212–001 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org\nDownloaded from Bioscientifica.com at 06/11/2026 05:59:36AM\nvia free access\n\n\nproviding an explanation to a series of physiological actions\nof estrogens that are not mediated by ER a. Interestingly, in\nseveral organ systems, ER a and ERb exert opposite effects,\nand the balance between the activation of the two ER\nsubtypes regulates cell and tissue homeostasis. In this thematic\nreview, Hedengran Faulds et al. (2012) have summarized the\nrole of ERs in central metabolism, and the data provided\nindicate that in addition to their role in reproduction, ERs are\ncentrally involved in the maintenance of metabolic control.\nEndometrium is a classical estrogen target tissue, with\nmarked morphological and physiological changes during the\nmenstrual cycle. Furthermore, endometriosis (presence of\nendometrial tissue outside the uterine cavity) affects up to\n10% of women at the reproductive age ( Giudice 2010), and\nendometrial cancer is the most common malignancy of the\ngenital tract in women in the western population ( http://\nwww.cancer.gov/cancertopics/types/endometrial ). In this\nthematic review, Lam et al . (2012) have summarized the\ncurrent knowledge on the molecular mechanism of sex\nsteroid action in normal and diseased endometrium, with a\nspecial emphasis on the interaction of nuclear estrogen and\nprogestin receptors with other transcription factors, such as\nFOXO proteins. Furthermore, they provide an outline of the\nnovel mechanisms by which mRNA, small non-coding\nRNAs, and epigenetic mechanisms regulate steroid hormone\nresponses in the endometrium.\nDeclaration of interest\nThe author declares that there is no conflict of interest that\ncould be perceived as prejudicing the impartiality of the\nresearch reported.\nFunding\nThis research did not receive any specific grant from\nany funding agency in the public, commercial or not-\nfor-profit sector.\nReferences\nBulynko YA & O’Malley BW 2011 Nuclear receptor coactivators: structural\nand functional biochemistry. Biochemistry 50 313–328. (doi:10.1021/\nbi101762x)\nChang K-H, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ &\nSharifi N 2011 Dihydrotestosterone synthesis bypasses testosterone to drive\ncastration-resistant prostate cancer. PNAS 108 13728–13733. (doi:10.\n1073/pnas.1107898108)\nCraig ZR, Wang W & Flaws JA 2011 Endocrine-disrupting chemicals in\novarian function: effects on steroidogenesis, metabolism and nuclear receptor\nsignaling. Reproduction 142 633–646. (doi:10.1530/REP-11-0136)\nGiudice LC 2010 Clinical practice. Endometriosis. New England Journal of\nMedicine 362 2389–2398. (doi:10.1056/NEJMcp1000274)\nHedengran Faulds M, Zhao C, Dahlman-Wright K & Gustafsson J-A˚ 2012\nRegulation of metabolism by estrogen signaling. Journal of Endocrinology\n212.\nLam EW-F , Shah K & Brosens JJ 2012 The role of microRNAs and FOXO\ntranscription factors in cycling endometrium and cancer. Journal of\nEndocrinology 212.\nMcDonnell DP & Wardell SE 2010 The molecular mechanisms underlying\nthe pharmacological actions of ER modulators: implications for new drug\ndiscovery in breast cancer. Current Opinion in Pharmacology 6 620–628.\n(doi:10.1016/j.coph.2010.09.007)\nMohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, T omer KB & Wilson EM\n2011 Activation of the androgen receptor by intratumoral bioconversion of\nandrostanediol to dihydrotestosterone in prostate cancer.Cancer Research 71\n1486–1496. (doi:10.1158/0008-5472.CAN-10-1343)\nMu¨ller SO, Simon S, Chae K, Metzler M & Korach KS 2004 Phytoestrogens\nand their human metabolites show distinct agonistic and antagonistic\nproperties on estrogen receptor a (ERa) and ERb in human cells.\nT oxicological Sciences80 14–25. (doi:10.1093/toxsci/kfh147)\nNilsson S, Koehler KF & Gustafsson J-A˚ 2011 Development of subtype-\nselective oestrogen receptor-based therapeutics. Nature Reviews. Drug\nDiscovery 10 778–792. (doi:10.1038/nrd3551)\nProssnitz ER & Barton M 2011 The G-protein-coupled estrogen receptor\nGPER in health and disease. Nature Reviews. Endocrinology (In press).\nSaijo K, Collier JG, Li AC, Katzenellenbogen JA & Glass CK 2011 An\nADIOL-ERb-CtBP transrepression pathway negatively regulates\nmicroglia-mediated inflammation. Cell 145 584–595. (doi:10.1016/j.cell.\n2011.03.050)\nSaloniemi T, Jokela H, Strauss L, Pakarinen P & Poutanen M 2012 Novel\nfunctions of hydroxysteroid (17beta) dehydrogenases as revealed by\ngenetically modified mouse models. Journal of Endocrinology 212.\nReceived in final form 31 October 2011\nAccepted 31 October 2011\nM POUTANEN . The diversity of estrogen action2\nJournal of Endocrinology (2012) 212, 1–2 www.endocrinology-journals.org\nDownloaded from Bioscientifica.com at 06/11/2026 05:59:36AM\nvia free access","source_license":"CC0","license_restricted":false}