PD16-10: 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, Nashville, TN, Douglas Strand, Dallas, TX, Qi Liu, Marisol Ramirez-Solano, Justin M Cates, Ned A Porter, Hye-Young H Kim, Phillip Wages, Nashville, TN, James L Mohler, Buffalo, NY, Robert J Matusik, Ren Jie Jin, Nashville, TN

Introduction: 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).