PD16-10 5-ALPHA REDUCTASE INHIBITORS SUPPRESS DIHYDROTESTOSTERONE IN BENIGN PROSTATE HYPERPLASIA REQUIRING SURGERY, AND CAUSE STEROIDOGENESIS VIA 5ARI INDUCED PATHWAY

Abstract

You have accessJournal of UrologyCME1 May 2022PD16-10 5-ALPHA REDUCTASE INHIBITORS SUPPRESS DIHYDROTESTOSTERONE IN BENIGN PROSTATE HYPERPLASIA REQUIRING SURGERY, AND CAUSE STEROIDOGENESIS VIA 5ARI INDUCED PATHWAY Connor Forbes, Nicole L Miller, Thomas Case, Douglas Strand, Qi Liu, Marisol Ramirez-Solano, Justin M. Cates, Ned A. Porter, Hye-Young H. Kim, Phillip Wages, James L. Mohler, Robert J. Matusik, and Ren Jie Jin Connor ForbesConnor Forbes More articles by this author , Nicole L MillerNicole L Miller More articles by this author , Thomas CaseThomas Case More articles by this author , Douglas StrandDouglas Strand More articles by this author , Qi LiuQi Liu More articles by this author , Marisol Ramirez-SolanoMarisol Ramirez-Solano More articles by this author , Justin M. CatesJustin M. Cates More articles by this author , Ned A. PorterNed A. Porter More articles by this author , Hye-Young H. KimHye-Young H. Kim More articles by this author , Phillip WagesPhillip Wages More articles by this author , James L. MohlerJames L. Mohler More articles by this author , Robert J. MatusikRobert J. Matusik More articles by this author , and Ren Jie JinRen Jie Jin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002548.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 5-alpha reductase inhibitors (5ARIs) reduce the concentration of the active metabolite dihydrotestosterone (DHT) by inhibiting the conversion of testosterone (T) to DHT. Some patients have progression despite maximal medical therapy including with 5ARIs. How these patients escape 5ARI suppression of DHT is not previously established. METHODS: With Institutional Review Board approval, tissue from patients with BPH requiring surgery was collected (Surgical BPH; S-BPH). For controls, non-cancerous transitional zone tissue from patients who underwent radical prostatectomy for low grade prostate cancer was collected (Incidental BPH; I-BPH). Concentrations of androgens and androgen precursors were analyzed, as were other steroid levels. In vitro BPH cell lines were stimulated with the steroid dexamethasone based upon results and assessed for morphologic changes. RNA-sequencing was performed on patient and in vitro cells. RESULTS: Patients who underwent surgery for BPH who were taking 5ARIs had low DHT and elevated precursor T. Other DHT precursors dehydroepiandrosterone (DHEA) and androstenedione (ASD) were also elevated. A 5ARI induced pathway was noted in patients on this medicine, whereby certain glucocorticoids were elevated, through a suggested mechanism in Figure 1. Dexamethasone induced morphologic changes to in vitro cells lines; branching-type morphology was induced compared to controls in 4 BPH cell lines. RNA-sequencing of patient tissue and in vitro cells yielded a unique signature of upregulated genes. CONCLUSIONS: Patients on 5ARIs who progress to requiring surgery for BPH have elevated precursor T and lowered DHT. This confirms that there is no successful escape mechanism either through direct or backdoor pathways for DHT synthesis for patients on 5ARIs who fail medical therapy. A 5ARI-induced glucocorticoid pathway was observed. Glucocorticoids induce morphologic changes in vitro stimulating prostate branching. Source of Funding: The Bray Foundation, NIDDK 5R01 DK111554 to RJ, R01 DK115477 to DWS. This work was supported by National Cancer Institute (NCI) grant P30CA016056 and used the Roswell Park Comprehensive Cancer Center Bioanalytical, Metabolomics, and Pharmacokinetics Shared Resource (BMPK) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e272 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Connor Forbes More articles by this author Nicole L Miller More articles by this author Thomas Case More articles by this author Douglas Strand More articles by this author Qi Liu More articles by this author Marisol Ramirez-Solano More articles by this author Justin M. Cates More articles by this author Ned A. Porter More articles by this author Hye-Young H. Kim More articles by this author Phillip Wages More articles by this author James L. Mohler More articles by this author Robert J. Matusik More articles by this author Ren Jie Jin More articles by this author Expand All Advertisement PDF DownloadLoading ...