Estrogen/androgen-mediated upregulation of progesterone receptor might lead to increased expression HSD17B11 which deactivates estrogens/androgens, providing a negative feedback loop: A data-driven hypothesis

Estrogen/androgen-mediated upregulation of progesterone receptor might lead to increased expression HSD17B11 which deactivates estrogens/androgens, providing a negative feedback loop: A data-driven hypothesis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Estrogen/androgen-mediated upregulation of progesterone receptor might lead to increased expression HSD17B11 which deactivates estrogens/androgens, providing a negative feedback loop: A data-driven hypothesis CAGLAR BERKEL This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9364226/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The distruption of functionality or activity of sex steroid hormones such as estrogens and androgens contributes to pathogenesis of various human diseases. Since the hormone concentrations in blood do not always explain all processes observed in hormone-dependent tissues such as ovaries, the intra-tissue sex steroid concentrations which are determined by steroid metabolising enzymes might be relatively more important in certain contexts. Hydroxysteroid (17β) dehydrogenases (HSD17Bs), a family of enzymes that are frequently expressed in sex steroid target tissues, catalyse the conversion between the less active 17-keto steroids and the highly active 17β-hydroxy steroids. One of these enzymes, HSD17B11 (Hydroxysteroid 17-Beta Dehydrogenase 11; DHRS8; PAN1B), mediates the conversion of β-estradiol to estrone (less estrogenic derivative), and of testosterone to a-dione. Here, based on previous research and novel findings reported in the present study, I hypothesized that estrogen- and/or androgen-mediated increases in progesterone receptor (PR) levels might lead to increased levels of HSD17B11, which then deactivates androgens and estrogens (by converting them to less potent steroids), thus providing a negative feedback loop, in certain cell types. In other words, estrogens / androgens might increase cellular levels of HSD17B11 by upregulating the expression of progesterone receptor (PR) (which then upregulates HSD17B11 expression), resulting in increased HSD17B11-mediated metabolism and deactivation of these steroid hormones. This feedback mechanism might potentially limit the levels of active forms of these steroid hormones (since HSD17B11 catalyzes the inactivation of these hormones), providing protection against over-activity of these steroid hormones. I also discussed the potential implications of this hypothesis in endometriosis, for which deficient metabolism of E2 by several HSD17Bs including HSD17B11 might give rise to high local concentrations of E2, also considering progesterone resistance in this disease. Endocrinology & Metabolism HSD17B HSD17B11 Estrogen Estradiol Progesterone Receptor Androgen Endometriosis Granulosa cells Estradiol 17-beta-dehydrogenase 11 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Estrogens such as 17β-estradiol (E 2 ) upregulate the expression of progesterone receptor (PR) due to the presence of estrogen response element (ERE)-like regions (ERE half sites) in its promoter [Clemens et al., 1998 ; Kastner et al., 1990 ; Bonéy-Montoya et al., 2010 ; Diep et al., 2016 ; Quadros et al., 2008; Ing and Tornesi, 1997 ; Lee and Gorski, 1996 ; Petz et al., 2004 ; Ciesiółka et al., 2016 ]. Similarly, androgens (such as 5α-dihydrotestosterone (DHT), testosterone and danazol) upregulate progesterone receptor expression in certain cell types including endometrial cells and breast cancer cells [Babayev et al., 2017 ; Liberato et al., 1993 ; Schmidt et al., 1979; Park et al., 2014 ]. For instance, 5α-dihydrotestosterone (DHT, 10 nM) treatment increases total PR mRNA levels almost five-fold in Ishikawa cells (a well differentiated endometrial carcinoma cell line) [Babayev et al., 2017 ]. Thus, certain types of both estrogens and androgens are able to upregulate progesterone receptor expression in certain contexts (as schematized in Fig. 4 ). Hydroxysteroid (17-beta) dehydrogenases (HSD17Bs) compose a family of enzymes with 14 members (in humans) which catalyse the conversion between the low-active 17-keto steroids and the highly active 17-beta-hydroxy steroids [Saloniemi et al., 2012 ]. These enzymes are commonly expressed in sex steroid target tissues [Saloniemi et al., 2012 ]. HSD17B11 (Hydroxysteroid 17-Beta Dehydrogenase 11; DHRS8; PAN1B) is a protein involved in the metabolism of certain steroids: it has NAD + -dependent oxidative activity towards β-estradiol, testosterone and certain synthetic steroids (such as methyltestosterone and nandrolone) in vitro [Lundová et al., 2016 ; Chai et al., 2003 ; Brereton et al., 2001 ; Li et al., 1998]. HSD17B11 mediates the oxidation of β-estradiol to estrone (less estrogenic derivative), and of testosterone to a-dione [Lundová et al., 2016 ; Corbet et al., 2023 ; Abaffy et al., 2023 ]. Estrone is 10- to 50-fold less potent than estradiol (its relative binding affinities for human ERα and ERβ are 4.0% and 3.5% compared to estradiol) [Escande et al., 2006 ]. HSD17B11 also metabolizes 3α-androstanediol (3α-diol, a weak androgen and estrogen) into androsterone, showing that this enzyme contributes to the catabolic processes of certain steroid hormones [Brereton et al., 2001 ]. Besides, the affinity of HSD17B11 to estradiol is several times higher in comparison to its affinity to testosterone [Lundová et al., 2016 ]. HSD17B11-mediated metabolism of these steroids generally results in deactivation of these hormones; thus, HSD17B11 may have a function in the protection against an excess of active forms of these steroid hormones [Lundová et al., 2016 ; Labrie et al., 1997 ; Baker, 2001 ]. In other words, HSD17B11 catabolic activity towards certain steroid hormones such as β-estradiol and testosterone might lead to their convertion to inactive or less active (less potent) forms, ultimately reducing hormonal activity and associated cellular processes. Datasets used, and data analysis and visualization Following publicly available gene expression datasets were used in the present study: GSE92438 [Akison et al., 2018 ], TCGA-BRCA [Cancer Genome Atlas Network, 2012 ], GSE56423 [Hewitt et al., 2014 ] and GSE6364 [Burney et al., 2007 ]. More experimental detail on these datasets can be found at GEO ( https://www.ncbi.nlm.nih.gov/geo/ ) using given accession IDs [Barrett et al., 2013 ]. Data analysis and visualization were completely performed in R programming language in this study (version 2023.3.0.386; https://cran.r-project.org/ ) [R Core Team, 2022 ], as previously reported [Berkel, 2024 ; Berkel and Cacan, 2023 ]. Following R / Bioconductor packages were used throughout the data analysis: SummarizedExperiment (package version of 1.26.1) [Morgan et al., 2022 ], tidyverse (2.0.0) [Wickham et al., 2019 ], ggpubr (0.6.0) [Kassambara, 2023 ], knitr (1.42) [Xie, 2023 ] and rmarkdown (2.21) [Allaire et al., 2023 ]. Shapiro-Wilk normality test was used to analyze the distribution of the gene expression data (using ggqqplot() and shapiro.test() functions), and if the resultant p value is less than 0.05, the normality of the data could not be assumed; and therefore, wilcox test was performed to statistically compare the group means (otherwise, t test was used) ( Kassambara, 2023 ). Novel findings guiding the hypothesis Granulosa cells of the ovary produce estrogen and, after ovulation, progesterone ( Pietrowski et al., 2023 ). In the present study, I first found that progesterone receptor (PR) knockout (KO) granulosa cells (PRKO) have decreased HSD17B11 expression compared to PR+/- (PR heterozygous) granulosa cells in mice ( Fig. 1 , second panel). The same observation is also true for cells in cumulus oocyte complexes in mice (cumulus cells are a granulosa cell type that surround the oocyte [Zhou et al., 2016 ]) ( Fig. 1 , first panel). This might suggest that PR induces or is required for the expression of HSD17B11 in these cells, since its loss results in significantly decreased expression of HSD17B11 ( Fig. 1 ). It should also be noted here that in the comparison of differentially expressed (DE) genes between PRKO and PR heterozygous granulosa cells, HSD17B11 is the top gene whose expression is most significantly changed (decreased) following PR knockout (adjusted p value of 6.69e-07, logFC of -2.507 (decreased in PRKO)), among other genes. In terms of differentially expressed genes between PRKO and PR heterozygous cells from cumulus oocyte complexes, HSD17B11 is the second top differentially expressed gene (adjusted p value of 0.00156, logFC of -2.958 (decreased in PRKO vs PR heterozygous)) following Gpt2. These point that the expression of HSD17B11 is highly responsive to the loss of PR in these cells, even the most responsive compared to other genes. The observations given above is supported by the finding that PR-positive breast cancer cells have higher expression of HSD17B11 compared to PR-negative breast cancer cells ( Fig. 2 , middle panel). Similarly, estrogen receptor (ER)-positive breast cancer cells have also increased HSD17B11 expression compared to those with ER-negative status ( Fig. 2 , first panel). Same is not true for the status of HER2 receptor, another unrelated receptor (not a steroid hormone receptor) used in the classification of breast cancer. In support of previous observations, I showed that estradiol induces HSD17B11 expression in mouse uterus cells with WT ER-alpha (ERα), but not in those with DNA binding-deficient ER-alpha, pointing to the fact that functional ER-alpha might be required for estradiol-mediated upregulation of HSD17B11 expression ( Fig. 3 ). Here, please also note that estradiol induces PR expression acting primarily through ER-alpha in diverse tissues [Mohammed et al., 2015 ; Quadros et al., 2008; Moffatt et al., 1998 ; Wagner et al., 2001 ; Kudwa and Rissman, 2003 ; Ing and Tornesi, 1997 ; Vázquez-Martínez et al., 2016 ; Yang et al., 2010 ; La Greca et al., 2022 ; Graham et al., 1995 ; Kraus and Katzenellenbogen, 1993 ; Acharya et al., 2015 ; Berkel and Cacan, 2024 ]. Hypothesis Based on these observations mentioned above and also findings reported previously, I hypothesized that estrogen- and/or androgen-mediated increases in progesterone receptor (PR) levels might lead to increased levels of HSD17B11, which then deactivates androgens and estrogens (by converting them to less potent steroids), thus providing a negative feedback loop, in certain cell types (as schematized in Fig. 4 ). In other words, estrogens / androgens might increase cellular levels of HSD17B11 by upregulating the expression of progesterone receptor (PR) (which upregulates HSD17B11 expression), resulting in increased HSD17B11-mediated metabolism and deactivation of these steroid hormones ( Fig. 4 ). This feedback mechanism might potentially limit the levels of active forms of these steroid hormones (since HSD17B11 catalyzes the inactivation of these hormones), providing protection against over-activity of these steroid hormones. Evaluation and Consequences of the Hypothesis and Discussion It was shown that HSD17B11 is abundantly expressed in human prostate cancer tissue, but not in the normal prostate, supporting androgen-mediated upregulation of HSD17B11 expression (as hypothesized here), considering increased synthesis of androgens in prostate cancer [Nakamura et al., 2009 ; Dai et al., 2017 ; Cai and Balk, 2011 ; Zhang et al., 2022 ]. In support, HSD17B11 was also found to be expressed in an androgen-dependent prostate cancer cell line [Laplante and Poirier, 2008 ]. Rotinen et al. showed that transcription factor C/EBPα upregulates HSD17B11 transcription by interacting with its promoter, in prostate cancer and hepatocellular carcinoma cells [2011; 2010]. Others showed that C/EBPα binding precedes and helps binding of progesterone receptor (PR) in response to hormone (facilitating loading of ligand-activated PR), demonstrating PR and C/EBPα cooperation in gene expression, in breast cancer cells [Nacht et al., 2019 ]. Based on these studies and data presented in the current study, it can be hypothesized that PR-mediated upregulation of HSD17B11 (suggested in the hypothesis) might also involve transcription factor C/EBPα. Possibly, C/EBPα might facilitate the binding of PR to the promoter region of HSD17B11 to induce its transcription. In support, a similar facilitating role of C/EBP has been identified for the recruitment of another steroid hormone receptor (glucocorticoid receptor) to steroid response elements in the genome [Grøntved et al., 2013 ; Beato et al., 2020 ]. HSD17B11 transcription is also induced by Sp1 in prostate cancer cell lines, due to the presence of Sp1 binding site located within the promoter of HSD17B11 [Rotinen et al., 2011 ]. Sp1 is also known to upregulate the expression of progesterone receptor in human breast cancer cells, by interacting with the promoter region of PR gene and activating it [Petz and Nardulli, 2000 ; Schultz et al., 2003 ; Petz et al., 2004 ]. This interaction between Sp1 and promoter region of PR gene is enhanced by ER-alpha [Petz and Nardulli, 2000 ; Schultz et al., 2003 ; Petz et al., 2004 ]. Therefore, it can be proposed that, in addition to directly regulating HSD17B11 expression, Sp1 might indirectly regulate HSD17B11 expression by upregulating the expression of PR, which hypothetically induce HSD17B11 expression. Our observations that ER-positive breast cancer cells have higher HSD17B11 expression (compared to those with ER-negative status), and that estradiol induces HSD17B11 expression in uterus in mice with WT ER-alpha (but not with DNA binding deficient ER−alpha) might be due to the promoting effect of ER-alpha for Sp1-mediated upregulation of PR expression, which is proposed to be associated with increased HSD17B11 expression. Alternatively, ER-alpha might be indirectly regulating HSD17B11 expression by first upregulating the expression of PR, which then induces the transcription of HSD17B11 [La Greca et al., 2022 ; Vázquez-Martínez et al., 2016 ; Acharya et al., 2015 ; Berkel and Cacan, 2024 ]. Furthermore, supporting the hypothesis presented here, progesterone was shown to stimulate the expression of HSD17B2, a related protein to HSD17B11 (both enzymes metabolize the biologically active estrogen E2 to estrone (E1), and testosterone to androstenedione; HSD17B2 also activates 20-alpha-hydroxy-progesterone to progesterone), in normal endometrium, via PR [Wu et al., 1993 ; Bulun et al., 2006 ; Miettinen et al., 1996 ; Labrie et al., 1995 ]. Very high HSD17B2 transcript levels have been found in the glandular epithelial cell fraction of the human endometrium during the mid- to late secretory phase of the ovarian cycle (i.e., during the time of high plasma levels of progesterone), suggesting that progesterone stimulates the expression of this enzyme [Casey et al., 1994 ; Mustonen et al., 1998 ]. In support, administration of a progesterone antagonist (mifepristone) was found to usually block the progesterone-mediated induction of another related protein, HSD17B1 [Mäentausta et al., 1993 ]. Besides, estradiol dehydrogenase activity (oxidation of E2 to E1) was also shown to be stimulated by progesterone in the endometrium, almost 50 years ago [Tseng and Gurpide, 1974 ; Tseng and Gurpide, 1975 ; Satyaswaroop et al., 1982 ]. The expression of HSD17B2 in the placenta was proposed to serve to maintain the presence of inactive sex steroids and attenuate the formation of biologically potent androgens and estrogens, again paralleling our hypothesis for HSD17B11 [Mustonen et al., 1998 ]. Based on high mRNA expression of HSD17B2 in the endometrium during secretory phase (i.e. high progesterone levels), the conversion of the potent estrogen E2 to a virtually inactive steroid E1 by HSD17B2 has been considered as an important protective mechanism against estrogen-induced growth, and HSD17B2 appears to be responsible for this progesterone-dependent enzymatic activity of E2 to E1 conversion in endometrial tissue [Bulun et al., 2006 ]. Furthermore, E2 was found to enhance progesterone agonist (R5020)-mediated increases in HSD17B2 expression in Ishikawa cells, again in support of the hypothesis and data presented in the current study for HSD17B11 [Bulun et al., 2006 ]. E2 was suggested to potentiate the effect of R5020 most likely via increasing PR expression [Bulun et al., 2006 ], as we proposed for HSD17B11, in which estrogen increases the expression of PR (via ER-alpha), which then increases the expression HSD17B11 [ Figure 4 ]. Aghajanova et al. found that when human endometrial stromal fibroblasts (hESF) isolated from women without endometriosis are treated with progesterone (P4) (1 µM) for up to 14 days, the expression of HSD17B11 is upregulated [2011]. However, this is not the case for human endometrial stromal fibroblasts (hESF) from women with endometriosis [Aghajanova et al., 2011 ]. In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s) which act on neighboring epithelial cells to upregulate expression of HSD17B2, which metabolizes the biologically active (potent) estrogen E2 to less active (weakly estrogenic) estrone (E1) [Bulun et al., 2006 ]. In contrast, in endometriotic tissue, progesterone fails to induce epithelial HSD17B2 expression due to a defect in stromal cells [Bulun et al., 2006 ]. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that then induce HSD17B2 expression was suggested to be due to the lack of progesterone receptor B (PR-B) and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue, resulting in deficient metabolism of E2 in endometriosis giving rise to high local concentrations of E2 which likely induces the proliferation of endometrial tissue [Bulun et al., 2006 ; Acién and Velasco, 2013 ; Bulun et al., 2010 ]. Based on these two studies by Aghajanova et al. and Bulun et al., it can be proposed that, similar to HSD17B2, HSD17B11 might be involved in progesterone-responsiveness in normal endometrium and progesterone-unresponsiveness in endometriosis. In support, I found that in normal endometrial cells, from early- to mid-secretory phase (progesterone levels increase from early- to mid-secretory phase where it peaks), HSD17B11 expression increases; however, in the case of endometriosis, HSD17B11 expression does not change from early- to mid-secretory phase, suggesting resistance to progesterone in the case of endometriosis [ Figure 5 ] [Ruiz-Alonso et al., 2012 ]. This supports previous research implying decreased progesterone response in the endometrium of women with endometriosis and highlights the need for further research into the role of HSD17B11 in this context [Burney et al., 2007 ; Gurates and Bulun, 2003 ; Reis et al., 2020 ; Vannuccini et al., 2022 ; Vierikko et al., 1985 ; Bulun et al., 2010 ]. Since HSD17B11 was found to be the top gene whose expression most significantly decreased following the deletion of PR in granulosa cells in this study, it can be suggested that HSD17B11 might be relatively more important compared to other 13 members of the HSD17B family, in terms of progesterone-mediated mechanisms in the endometrium, or in general in the ovary. Also, because HSD17B11 seems to be the most progesterone-responsive gene among other members of the protein family, general progesterone-unresponsiveness observed in endometriosis might contribute to pathological processes mainly by HSD17B11, relative to other HSD17Bs. This might result in deficient metabolism of E2 mostly by HSD17B11 in endometriosis leading to high local concentrations of E2 which potentially promotes the proliferation of endometrial tissue. Conclusions In conclusion, in this paper, I hypothesized that certain estrogens/androgens might upregulate the expression of HSD17B11 via first inducing the expression of progesterone receptor (PR), which then promotes the expression of HSD17B11. Later, HSD17B11 might catalyze the inactivation of estrogens / androgens to their less active forms, forming a negative feedback loop, decreasing its own upregulation at the transcriptional level. Abbreviations BRCA Breast Cancer DHT 5α-dihydrotestosterone E1 Estrone E2 17β-estradiol ER Estrogen Receptor ERE Estrogen Response Element GEO Gene Expression Omnibus HER2 Human Epidermal Growth Factor Receptor-2 hESF Human Endometrial Stromal Fibroblast HSD17B Hydroxysteroid (17-beta) Dehydrogenase HSD17B11 Hydroxysteroid 17-Beta Dehydrogenase 11 KO Knockout P4 Progesterone PR Progesterone Receptor TCGA The Cancer Genome Atlas Declarations Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Consent statement/Ethical approval Not required. Data Availability Statement: The data used in this study is publicly available at datasets given in “Datasets used, and data analysis and visualization” section. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9364226","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":620082918,"identity":"b3c7026c-6cc8-44ca-a0dd-d7d10dc4b421","order_by":0,"name":"CAGLAR BERKEL","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYHACxgNAIoGBgY2B4UEFREiCkB6EloQzcC0GRGpJbCNCC3/78QsHfu5hyOOXPpb4IHFerZw5A/PB2zwMf/JxaZE4k1NwsOcZQ7FkX9phg8Rtx40tG9iSrXkYDCwbcGgxYMhJOMBzgCFxwxn2NonEbccSNxzgMZMGasHpMgP+NwkH/wC17D/D3v4jcQ5IC/83/Fok0g8cBtvCw3aMIbGhBmQLG14tEjfeMByWOSBRLHGGLVki4dgBY8tmNmPLOQbGOLXw96c/fPjmgE0efw+b4YcPNXVy5uzND2+8qZDDEzE8IDl4dB9mMGCGBAsewP4AmVdHINpHwSgYBaNgJAIAJTxXRAfiVSMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-4787-5157","institution":"Tokat Gaziosmanpasa University","correspondingAuthor":true,"prefix":"","firstName":"CAGLAR","middleName":"","lastName":"BERKEL","suffix":""}],"badges":[],"createdAt":"2026-04-09 06:45:28","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9364226/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9364226/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106573835,"identity":"c29604ed-4ede-47f2-8948-21f783eaac69","added_by":"auto","created_at":"2026-04-10 04:34:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81767,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of Hsd17b11 mRNA expression between progestrone receptor (PR) heterozygous (PR+/-) and PR knockout (PRKO) cumulus oocyte complex cells (first panel) and granulosa cells (second panel) in mice.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData from GSE92438 [Akison et al., 2018]. \u003cem\u003ens (non-significant): p \u0026gt; 0.05; *: p \u0026lt;= 0.05; **: p \u0026lt;= 0.01; ***: p \u0026lt;= 0.001; ****: p \u0026lt;= 0.0001.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9364226/v1/1dd37cb3048688ab53ac4a84.jpg"},{"id":106728012,"identity":"788b53c4-6ff4-4cd3-84a7-a0ed48c7b6a5","added_by":"auto","created_at":"2026-04-12 18:41:26","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":266523,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelative expression of Hsd17b11 in tumors from breast cancer patients depending on ER (estrogen receptor), PR (progesterone receptor) or HER2 (human epidermal growth factor receptor-2) status.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData from TCGA-BRCA [Cancer Genome Atlas Network, 2012]. Expression values on y-axis are shown in log10 scale. \u003cem\u003ens (non-significant): p \u0026gt; 0.05; *: p \u0026lt;= 0.05; **: p \u0026lt;= 0.01; ***: p \u0026lt;= 0.001; ****: p \u0026lt;= 0.0001.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9364226/v1/a7ebc825b8684e1daedd2301.jpg"},{"id":106573836,"identity":"75ee393c-6aca-4099-92be-8c79d035c1ac","added_by":"auto","created_at":"2026-04-10 04:34:24","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":88869,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelative expression of Hsd17b11 in response to estradiol (250 ng of estradiol (E2) in 100 ul saline) in uterus from ovariectomized mice with WT ER-alpha (estrogen receptor alpha) (first panel) or with DNA binding deficient ER−alpha (second panel).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData from GSE56423 [Hewitt et al., 2014]\u003cem\u003e. ns (non-significant): p \u0026gt; 0.05; *: p \u0026lt;= 0.05; **: p \u0026lt;= 0.01; ***: p \u0026lt;= 0.001; ****: p \u0026lt;= 0.0001.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9364226/v1/1eb690abd703b3cc17e81093.jpg"},{"id":106725237,"identity":"84657fd2-7205-427e-be47-720684f70384","added_by":"auto","created_at":"2026-04-12 18:32:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":34130,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe schema of the hypothesis presented in the present study.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHere, I hypothesized that certain estrogens/androgens such as 17β-estradiol (E\u003csub\u003e2\u003c/sub\u003e) might upregulate the expression of HSD17B11 via first inducing the expression of progesterone receptor (PR), which then promotes the expression of HSD17B11. Later, HSD17B11 might catalyze the inactivation of estrogens / androgens to their less active forms, forming a negative feedback loop, decreasing its own upregulation at the transcriptional level.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-9364226/v1/229c981173cc60bc9034b271.png"},{"id":106725858,"identity":"e7e76754-20b3-4e62-a9ef-fdcbe0da3769","added_by":"auto","created_at":"2026-04-12 18:34:11","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":99373,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of HSD17B11 expression between early secretory and mid secretory phases, in endometrial biopsies obtained from women both with normal endometrial pathologies and no history of endometriosis (first panel: normal) and from women with laporoscopy proven moderate-severe stage endometriosis (second panel: endometriosis).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData from GSE6364 [Burney et al., 2007]. ns (non-significant): p \u0026gt; 0.05; *: p \u0026lt;= 0.05; **: p \u0026lt;= 0.01; ***: p \u0026lt;= 0.001; ****: p \u0026lt;= 0.0001. Early secretory phase: ESE; midsecretory phase: MSE.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9364226/v1/b083a1aa9d984ff60f8145a9.jpg"},{"id":106728735,"identity":"f4e2f7b7-9204-4c0b-a05d-e68db6d582f6","added_by":"auto","created_at":"2026-04-12 18:44:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1539845,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9364226/v1/e6a14ce4-64aa-4ebd-9e8e-24f2a8ad6b73.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEstrogen/androgen-mediated upregulation of progesterone receptor might lead to increased expression HSD17B11 which deactivates estrogens/androgens, providing a negative feedback loop: A data-driven hypothesis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEstrogens such as 17β-estradiol (E\u003csub\u003e2\u003c/sub\u003e) upregulate the expression of progesterone receptor (PR) due to the presence of estrogen response element (ERE)-like regions (ERE half sites) in its promoter [Clemens et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Kastner et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Bon\u0026eacute;y-Montoya et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Diep et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Quadros et al., 2008; Ing and Tornesi, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e1997\u003c/span\u003e; Lee and Gorski, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e1996\u003c/span\u003e; Petz et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Ciesi\u0026oacute;łka et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2016\u003c/span\u003e]. Similarly, androgens (such as \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e5α-dihydrotestosterone (DHT), testosterone and danazol) upregulate progesterone receptor expression in certain cell types including endometrial cells and breast cancer cells\u003c/span\u003e [Babayev et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Liberato et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eSchmidt et al., 1979;\u003c/span\u003e Park et al., \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2014\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. For instance, 5α-dihydrotestosterone (DHT, 10 nM) treatment increases total PR mRNA levels almost five-fold in Ishikawa cells (a well differentiated endometrial carcinoma cell line)\u003c/span\u003e [Babayev et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2017\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Thus, certain types of both estrogens and androgens are able to upregulate progesterone receptor expression in certain contexts (as schematized in\u003c/span\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e).\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eHydroxysteroid (17-beta) dehydrogenases (HSD17Bs) compose a family of enzymes with 14 members (in humans) which catalyse the conversion between the low-active 17-keto steroids and the highly active 17-beta-hydroxy steroids\u003c/span\u003e [Saloniemi et al., \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2012\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. These enzymes are commonly expressed in sex steroid target tissues\u003c/span\u003e [Saloniemi et al., \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2012\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. HSD17B11 (Hydroxysteroid 17-Beta Dehydrogenase 11; DHRS8; PAN1B) is a protein involved in the metabolism of certain steroids: it has NAD\u003c/span\u003e\u003csup\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e+\u003c/span\u003e\u003c/sup\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e-dependent oxidative activity towards β-estradiol, testosterone and certain synthetic steroids (such as methyltestosterone and nandrolone)\u003c/span\u003e \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003ein vitro\u003c/span\u003e [Lundov\u0026aacute; et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Chai et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Brereton et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eLi et al., 1998]. HSD17B11 mediates the oxidation of β-estradiol to estrone (less estrogenic derivative), and of testosterone to a-dione\u003c/span\u003e [Lundov\u0026aacute; et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Corbet et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Abaffy et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Estrone is 10- to 50-fold less potent than estradiol (its relative binding affinities for human ERα and ERβ are 4.0% and 3.5% compared to estradiol)\u003c/span\u003e [Escande et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2006\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. HSD17B11 also metabolizes 3α-androstanediol (3α-diol, a weak androgen and estrogen) into androsterone, showing that this enzyme contributes to the catabolic processes of certain steroid hormones\u003c/span\u003e [Brereton et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2001\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Besides, the affinity of HSD17B11 to estradiol is several times higher in comparison to its affinity to testosterone\u003c/span\u003e [Lundov\u0026aacute; et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2016\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. HSD17B11-mediated metabolism of these steroids generally results in deactivation of these hormones; thus, HSD17B11 may have a function in the protection against an excess of active forms of these steroid hormones\u003c/span\u003e [Lundov\u0026aacute; et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Labrie et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e1997\u003c/span\u003e; Baker, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2001\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. In other words, HSD17B11 catabolic activity towards certain steroid hormones such as β-estradiol and testosterone might lead to their convertion to inactive or less active (less potent) forms, ultimately reducing hormonal activity and associated cellular processes.\u003c/span\u003e\u003c/p\u003e"},{"header":"Datasets used, and data analysis and visualization","content":"\u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eFollowing publicly available gene expression datasets were used in the present study: GSE92438\u003c/span\u003e [Akison et al., \u003cspan class=\"CitationRef\"\u003e2018\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e], TCGA-BRCA\u003c/span\u003e [Cancer Genome Atlas Network, \u003cspan class=\"CitationRef\"\u003e2012\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e], GSE56423\u003c/span\u003e [Hewitt et al., \u003cspan class=\"CitationRef\"\u003e2014\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e] and GSE6364\u003c/span\u003e [Burney et al., \u003cspan class=\"CitationRef\"\u003e2007\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. More experimental detail on these datasets can be found at GEO (\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/geo/\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e) using given accession IDs\u003c/span\u003e [Barrett et al., \u003cspan class=\"CitationRef\"\u003e2013\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e].\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eData analysis and visualization were completely performed in R programming language in this study (version 2023.3.0.386;\u003c/span\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cran.r-project.org/\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e)\u003c/span\u003e [R Core Team, \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e], as previously reported\u003c/span\u003e [Berkel, \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e; Berkel and Cacan, \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Following R / Bioconductor packages were used throughout the data analysis: SummarizedExperiment (package version of 1.26.1)\u003c/span\u003e [Morgan et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e], tidyverse (2.0.0)\u003c/span\u003e [Wickham et al., \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e], ggpubr (0.6.0)\u003c/span\u003e [Kassambara, \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e], knitr (1.42)\u003c/span\u003e [Xie, \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e] and rmarkdown (2.21)\u003c/span\u003e [Allaire et al., \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Shapiro-Wilk normality test was used to analyze the distribution of the gene expression data (using ggqqplot() and shapiro.test() functions), and if the resultant p value is less than 0.05, the normality of the data could not be assumed; and therefore, wilcox test was performed to statistically compare the group means (otherwise, t test was used) (\u003c/span\u003eKassambara, \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e).\u003c/span\u003e\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Novel findings guiding the hypothesis","content":"\u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eGranulosa cells of the ovary produce estrogen and, after ovulation, progesterone (\u003c/span\u003ePietrowski et al., \u003cspan class=\"CitationRef\"\u003e2023\u003c/span\u003e). \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eIn the present study, I first found that progesterone receptor (PR) knockout (KO) granulosa cells (PRKO) have decreased HSD17B11 expression compared to PR+/- (PR heterozygous) granulosa cells in mice (\u003c/span\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003esecond panel). The same observation is also true for cells in cumulus oocyte complexes in mice (cumulus cells are a granulosa cell type that surround the oocyte\u003c/span\u003e [Zhou et al., \u003cspan class=\"CitationRef\"\u003e2016\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]) (\u003c/span\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003efirst panel). This might suggest that PR induces or is required for the expression of HSD17B11 in these cells, since its loss results in significantly decreased expression of HSD17B11 (\u003c/span\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e). It should also be noted here that in the comparison of differentially expressed (DE) genes between PRKO and PR heterozygous granulosa cells, HSD17B11 is the top gene whose expression is most significantly changed (decreased) following PR knockout (adjusted p value of 6.69e-07, logFC of -2.507 (decreased in PRKO)), among other genes. In terms of differentially expressed genes between PRKO and PR heterozygous cells from cumulus oocyte complexes, HSD17B11 is the second top differentially expressed gene (adjusted p value of 0.00156, logFC of -2.958 (decreased in PRKO vs PR heterozygous)) following Gpt2. These point that the expression of HSD17B11 is highly responsive to the loss of PR in these cells, even the most responsive compared to other genes. The observations given above is supported by the finding that PR-positive breast cancer cells have higher expression of HSD17B11 compared to PR-negative breast cancer cells (\u003c/span\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003emiddle panel). Similarly, estrogen receptor (ER)-positive breast cancer cells have also increased HSD17B11 expression compared to those with ER-negative status (\u003c/span\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003efirst panel). Same is not true for the status of HER2 receptor, another unrelated receptor (not a steroid hormone receptor) used in the classification of breast cancer. In support of previous observations, I showed that estradiol induces HSD17B11 expression in mouse uterus cells with WT ER-alpha (ERα), but not in those with DNA binding-deficient ER-alpha, pointing to the fact that functional ER-alpha might be required for estradiol-mediated upregulation of HSD17B11 expression (\u003c/span\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e). Here, please also note that estradiol induces PR expression acting primarily through ER-alpha in diverse tissues\u003c/span\u003e [Mohammed et al., \u003cspan class=\"CitationRef\"\u003e2015\u003c/span\u003e; \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eQuadros et al., 2008;\u003c/span\u003e Moffatt et al., \u003cspan class=\"CitationRef\"\u003e1998\u003c/span\u003e; Wagner et al., \u003cspan class=\"CitationRef\"\u003e2001\u003c/span\u003e; Kudwa and Rissman, \u003cspan class=\"CitationRef\"\u003e2003\u003c/span\u003e; Ing and Tornesi, \u003cspan class=\"CitationRef\"\u003e1997\u003c/span\u003e; Vázquez-Martínez et al., \u003cspan class=\"CitationRef\"\u003e2016\u003c/span\u003e; Yang et al., \u003cspan class=\"CitationRef\"\u003e2010\u003c/span\u003e; La Greca et al., \u003cspan class=\"CitationRef\"\u003e2022\u003c/span\u003e; Graham et al., \u003cspan class=\"CitationRef\"\u003e1995\u003c/span\u003e; Kraus and Katzenellenbogen, \u003cspan class=\"CitationRef\"\u003e1993\u003c/span\u003e; Acharya et al., \u003cspan class=\"CitationRef\"\u003e2015\u003c/span\u003e; Berkel and Cacan, \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e].\u003c/span\u003e\u003c/p\u003e"},{"header":"Hypothesis","content":"\u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eBased on these observations mentioned above and also findings reported previously, I hypothesized that estrogen- and/or androgen-mediated increases in progesterone receptor (PR) levels might lead to increased levels of HSD17B11, which then deactivates androgens and estrogens (by converting them to less potent steroids), thus providing a negative feedback loop, in certain cell types (as schematized in\u003c/span\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e). In other words, estrogens / androgens might increase cellular levels of HSD17B11 by upregulating the expression of progesterone receptor (PR) (which upregulates HSD17B11 expression), resulting in increased HSD17B11-mediated metabolism and deactivation of these steroid hormones (\u003c/span\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e). This feedback mechanism might potentially limit the levels of active forms of these steroid hormones (since HSD17B11 catalyzes the inactivation of these hormones), providing protection against over-activity of these steroid hormones.\u003c/span\u003e\u003c/p\u003e"},{"header":"Evaluation and Consequences of the Hypothesis and Discussion","content":"\u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eIt was shown that HSD17B11 is abundantly expressed in human prostate cancer tissue, but not in the normal prostate, supporting androgen-mediated upregulation of HSD17B11 expression (as hypothesized here), considering increased synthesis of androgens in prostate cancer\u003c/span\u003e [Nakamura et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Dai et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Cai and Balk, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2022\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. In support, HSD17B11 was also found to be expressed in an androgen-dependent prostate cancer cell line\u003c/span\u003e [Laplante and Poirier, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2008\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e].\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eRotinen et al. showed that transcription factor C/EBPα upregulates HSD17B11 transcription by interacting with its promoter, in prostate cancer and hepatocellular carcinoma cells [2011; 2010]. Others showed that C/EBPα binding precedes and helps binding of progesterone receptor (PR) in response to hormone (facilitating loading of ligand-activated PR), demonstrating PR and C/EBPα cooperation in gene expression, in breast cancer cells\u003c/span\u003e [Nacht et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2019\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Based on these studies and data presented in the current study, it can be hypothesized that PR-mediated upregulation of HSD17B11 (suggested in the hypothesis) might also involve transcription factor C/EBPα. Possibly, C/EBPα might facilitate the binding of PR to the promoter region of HSD17B11 to induce its transcription. In support, a similar facilitating role of C/EBP has been identified for the recruitment of another steroid hormone receptor (glucocorticoid receptor) to steroid response elements in the genome\u003c/span\u003e [Gr\u0026oslash;ntved et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Beato et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2020\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e].\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eHSD17B11 transcription is also induced by Sp1 in prostate cancer cell lines, due to the presence of Sp1 binding site located within the promoter of HSD17B11\u003c/span\u003e [Rotinen et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2011\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Sp1 is also known to upregulate the expression of progesterone receptor in human breast cancer cells, by interacting with the promoter region of PR gene and activating it\u003c/span\u003e [Petz and Nardulli, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Schultz et al., \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Petz et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2004\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. This interaction between Sp1 and promoter region of PR gene is enhanced by ER-alpha\u003c/span\u003e [Petz and Nardulli, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Schultz et al., \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Petz et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2004\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Therefore, it can be proposed that, in addition to directly regulating HSD17B11 expression, Sp1 might indirectly regulate HSD17B11 expression by upregulating the expression of PR, which hypothetically induce HSD17B11 expression. Our observations that ER-positive breast cancer cells have higher HSD17B11 expression (compared to those with ER-negative status), and that estradiol induces HSD17B11 expression in uterus in mice with WT ER-alpha (but not with DNA binding deficient ER\u0026minus;alpha) might be due to the promoting effect of ER-alpha for Sp1-mediated upregulation of PR expression, which is proposed to be associated with increased HSD17B11 expression. Alternatively, ER-alpha might be indirectly regulating HSD17B11 expression by first upregulating the expression of PR, which then induces the transcription of HSD17B11\u003c/span\u003e [La Greca et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; V\u0026aacute;zquez-Mart\u0026iacute;nez et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Acharya et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Berkel and Cacan, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2024\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e].\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eFurthermore, supporting the hypothesis presented here, progesterone was shown to stimulate the expression of HSD17B2, a related protein to HSD17B11 (both enzymes metabolize the biologically active estrogen E2 to estrone (E1), and testosterone to androstenedione; HSD17B2 also activates 20-alpha-hydroxy-progesterone to progesterone), in normal endometrium, via PR\u003c/span\u003e [Wu et al., \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Bulun et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Miettinen et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e1996\u003c/span\u003e; Labrie et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e1995\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Very high HSD17B2 transcript levels have been found in the glandular epithelial cell fraction of the human endometrium during the mid- to late secretory phase of the ovarian cycle (i.e., during the time of high plasma levels of progesterone), suggesting that progesterone stimulates the expression of this enzyme\u003c/span\u003e [Casey et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e1994\u003c/span\u003e; Mustonen et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e1998\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. In support, administration of a progesterone antagonist (mifepristone) was found to usually block the progesterone-mediated induction of another related protein, HSD17B1\u003c/span\u003e [M\u0026auml;entausta et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e1993\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Besides, estradiol dehydrogenase activity (oxidation of E2 to E1) was also shown to be stimulated by progesterone in the endometrium, almost 50 years ago\u003c/span\u003e [Tseng and Gurpide, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e1974\u003c/span\u003e; Tseng and Gurpide, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e1975\u003c/span\u003e; Satyaswaroop et al., \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e1982\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. The expression of HSD17B2 in the placenta was proposed to serve to maintain the presence of inactive sex steroids and attenuate the formation of biologically potent androgens and estrogens, again paralleling our hypothesis for HSD17B11\u003c/span\u003e [Mustonen et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e1998\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Based on high mRNA expression of HSD17B2 in the endometrium during secretory phase (i.e. high progesterone levels), the conversion of the potent estrogen E2 to a virtually inactive steroid E1 by HSD17B2 has been considered as an important protective mechanism against estrogen-induced growth, and HSD17B2 appears to be responsible for this progesterone-dependent enzymatic activity of E2 to E1 conversion in endometrial tissue\u003c/span\u003e [Bulun et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Furthermore, E2 was found to enhance progesterone agonist (R5020)-mediated increases in HSD17B2 expression in Ishikawa cells, again in support of the hypothesis and data presented in the current study for HSD17B11\u003c/span\u003e [Bulun et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. E2 was suggested to potentiate the effect of R5020 most likely via increasing PR expression\u003c/span\u003e [Bulun et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e], as we proposed for HSD17B11, in which estrogen increases the expression of PR (via ER-alpha), which then increases the expression HSD17B11 [\u003c/span\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e].\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eAghajanova et al. found that when human endometrial stromal fibroblasts (hESF) isolated from women without endometriosis are treated with progesterone (P4) (1 \u0026micro;M) for up to 14 days, the expression of HSD17B11 is upregulated [2011]. However, this is not the case for human endometrial stromal fibroblasts (hESF) from women with endometriosis\u003c/span\u003e [Aghajanova et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2011\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s) which act on neighboring epithelial cells to upregulate expression of HSD17B2, which metabolizes the biologically active (potent) estrogen E2 to less active (weakly estrogenic) estrone (E1)\u003c/span\u003e [Bulun et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. In contrast, in endometriotic tissue, progesterone fails to induce epithelial HSD17B2 expression due to a defect in stromal cells\u003c/span\u003e [Bulun et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that then induce HSD17B2 expression was suggested to be due to the lack of progesterone receptor B (PR-B) and very low levels of progesterone receptor A (PR-A) observed\u003c/span\u003e \u003cspan type=\"ItalicSmallCaps\" class=\"ItalicSmallCaps\" name=\"Emphasis\"\u003ein vivo\u003c/span\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ein endometriotic tissue, resulting in deficient metabolism of E2 in endometriosis giving rise to high local concentrations of E2 which likely induces the proliferation of endometrial tissue\u003c/span\u003e [Bulun et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Aci\u0026eacute;n and Velasco, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Bulun et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2010\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Based on these two studies by Aghajanova et al. and Bulun et al., it can be proposed that, similar to HSD17B2, HSD17B11 might be involved in progesterone-responsiveness in normal endometrium and progesterone-unresponsiveness in endometriosis. In support, I found that in normal endometrial cells, from early- to mid-secretory phase (progesterone levels increase from early- to mid-secretory phase where it peaks), HSD17B11 expression increases; however, in the case of endometriosis, HSD17B11 expression does not change from early- to mid-secretory phase, suggesting resistance to progesterone in the case of endometriosis [\u003c/span\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]\u003c/span\u003e [Ruiz-Alonso et al., \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e2012\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. This supports previous research implying decreased progesterone response in the endometrium of women with endometriosis and highlights the need for further research into the role of HSD17B11 in this context\u003c/span\u003e [Burney et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Gurates and Bulun, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Reis et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Vannuccini et al., \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Vierikko et al., \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e1985\u003c/span\u003e; Bulun et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2010\u003c/span\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e]. Since HSD17B11 was found to be the top gene whose expression most significantly decreased following the deletion of PR in granulosa cells in this study, it can be suggested that HSD17B11 might be relatively more important compared to other 13 members of the HSD17B family, in terms of progesterone-mediated mechanisms in the endometrium, or in general in the ovary. Also, because HSD17B11 seems to be the most progesterone-responsive gene among other members of the protein family, general progesterone-unresponsiveness observed in endometriosis might contribute to pathological processes mainly by HSD17B11, relative to other HSD17Bs. This might result in deficient metabolism of E2 mostly by HSD17B11 in endometriosis leading to high local concentrations of E2 which potentially promotes the proliferation of endometrial tissue.\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Conclusions ","content":"\u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eIn conclusion, in this paper, I hypothesized that certain estrogens/androgens might upregulate the expression of HSD17B11 via first inducing the expression of progesterone receptor (PR), which then promotes the expression of HSD17B11. Later, HSD17B11 might catalyze the inactivation of estrogens / androgens to their less active forms, forming a negative feedback loop, decreasing its own upregulation at the transcriptional level.\u003c/span\u003e \u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eBRCA\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eBreast Cancer\u003c/span\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDHT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e5α-dihydrotestosterone\u003c/span\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eE1\u003c/span\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eEstrone\u003c/span\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eE2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e17β-estradiol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eER\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEstrogen Receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eERE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEstrogen Response Element\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGEO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGene Expression Omnibus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHER2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman Epidermal Growth Factor Receptor-2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ehESF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman Endometrial Stromal Fibroblast\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSD17B\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHydroxysteroid (17-beta) Dehydrogenase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSD17B11\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHydroxysteroid 17-Beta Dehydrogenase 11\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eKO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eKnockout\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP4\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgesterone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgesterone Receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTCGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThe Cancer Genome Atlas\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eDeclaration of competing interest\u003c/span\u003e \u003c/h2\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/span\u003e \u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cb\u003eConsent statement/Ethical approval\u003c/b\u003e\u003c/p\u003e\n\u003cp\u003eNot required.\u003c/p\u003e\u003ch2\u003eData Availability Statement:\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eThe data used in this study is publicly available at datasets given in \u0026ldquo;Datasets used, and data analysis and visualization\u0026rdquo; section.\u003c/span\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbaffy T, Lu HY, Matsunami H (2023) Sex steroid hormone synthesis, metabolism, and the effects on the mammalian olfactory system. 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PeerJ 4:e1761. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7717/peerj.1761\u003c/span\u003e\u003cspan address=\"10.7717/peerj.1761\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 26966678; PMCID: PMC4782716\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HSD17B, HSD17B11, Estrogen, Estradiol, Progesterone Receptor, Androgen, Endometriosis, Granulosa cells, Estradiol 17-beta-dehydrogenase 11","lastPublishedDoi":"10.21203/rs.3.rs-9364226/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9364226/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe distruption of functionality or activity of sex steroid hormones such as estrogens and androgens contributes to pathogenesis of various human diseases. Since the hormone concentrations in blood do not always explain all processes observed in hormone-dependent tissues such as ovaries, the intra-tissue sex steroid concentrations which are determined by steroid metabolising enzymes might be relatively more important in certain contexts. Hydroxysteroid (17β) dehydrogenases (HSD17Bs), a family of enzymes that are frequently expressed in sex steroid target tissues, catalyse the conversion between the less active 17-keto steroids and the highly active 17β-hydroxy steroids. One of these enzymes, HSD17B11 (Hydroxysteroid 17-Beta Dehydrogenase 11; DHRS8; PAN1B), \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003emediates the conversion of β-estradiol to estrone (less estrogenic derivative), and of testosterone to a-dione.\u003c/span\u003e Here, based on previous research and novel findings reported in the present study, I hypothesized that estrogen- and/or androgen-mediated increases in progesterone receptor (PR) levels might lead to increased levels of HSD17B11, which then deactivates androgens and estrogens (by converting them to less potent steroids), thus providing a negative feedback loop, in certain cell types. In other words, estrogens / androgens might increase cellular levels of HSD17B11 by upregulating the expression of progesterone receptor (PR) (which then upregulates HSD17B11 expression), resulting in increased HSD17B11-mediated metabolism and deactivation of these steroid hormones. This feedback mechanism might potentially limit the levels of active forms of these steroid hormones (since HSD17B11 catalyzes the inactivation of these hormones), providing protection against over-activity of these steroid hormones. I also discussed the potential implications of this hypothesis in endometriosis, for which deficient metabolism of E2 by several HSD17Bs including HSD17B11 might give rise to high local concentrations of E2, also considering progesterone resistance in this disease.\u003c/p\u003e","manuscriptTitle":"Estrogen/androgen-mediated upregulation of progesterone receptor might lead to increased expression HSD17B11 which deactivates estrogens/androgens, providing a negative feedback loop: A data-driven hypothesis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 04:34:20","doi":"10.21203/rs.3.rs-9364226/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a0e95b1-9956-43f6-9190-7c530bd8a89b","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":65986342,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2026-04-10T04:34:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 04:34:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9364226","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9364226","identity":"rs-9364226","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}