The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression

Abstract

With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone (5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5α-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5α-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5α-RIs therapy.

Keywords: 5α-Reductase inhibitors; Depression; Physiological sexual dysfunction; Prostate neoplasms.

FIG. 1

Transformation of androgens, progestins and glucocorticoids into 5α-dihydroderivatives by 5α-reductases and tetrahydro-metabolites (neurosteroids) by 3α-hydroxysteroid dehydrogenases. The rate limiting step in this pathway is the catalysis by 5α-reductases.

FIG. 2

Effects of dutasteride on erectile physiology in the animal model. Graphs showing: (A) intracavernosal pressure (ICP)/mean arterial pressure (MAP) and (B) total ICP at 2.5, 5, and 7.5 voltage levels in control, 8-week dutasteride and 6-week dutasteride plus 2-week washout groups. Data are mean±standard error of the mean (n=8-10). ^**p<0.01 and ^***p<0.001 vs. control group (analysis of variance, Bonferroni post hoc). Adapted from Oztekin CV, et al. J Sex Med 2012;9:1773-81, with permission of John Wiley & Sons, Inc. [38].

FIG. 3

Effects of long-term treatment with finasteride on corpus cavernosum smooth muscle death. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling quantification of apoptotic index of cavernous smooth muscle cells in rats with or without 5α-reductase inhibitor (5α-RI) treatment. (Left) Apoptotic indexes (ratio of apoptotic cells to all cells) of 2 groups were assessed. For each corpus cavernosum sample, 5 randomly obtained fields were selected, and the mean ratio of apoptotic cells to all cells was used to calculate the apoptotic index. Values for 5 samples in each group presented as ratio±standard deviation. ^**p<0.001 compared with 5α-RI-treatment group (unpaired t-test); (A) control group and (B) 5α-RI-treated group. Black arrows indicate apoptotic cells with dark brown-stained nuclei: (A) control group and (B) 5α-RI-treated group (ApopTag Peroxidase In Situ Apoptosis Detection Kit, Scale bar=100 µm, ×200). Adapted from Zhang MG, et al. Urology 2013;82:743.e9-15, with permission of Elsevier Inc. [40].

FIG. 4

Relative and absolute risk of prostate cancer according to modified Gleason score (mGS), PCPT and REDUCE trial. 5α-RI, 5α-reductase inhibitors. I bars indicate 95% confidence intervals. Adapted from Theoret MR, et al. N Engl J Med 2011;365:97-9, with permission of Massachusetts Medical Society [15].

FIG. 5

Effects of finasteride on the number of activated capsase-3 positive cells present in the cerebellar molecular and granular layers. Photomicrographs showing activated caspase-3 immunoreactivity in the granular layer of the cerebellum of a fetus at 24 hours after infusion with vehicle (control, A), finasteride (B), finasteride+alfaxalone (C), and alfaxalone (D). All fetuses were 131±3 days of gestation at the time of autopsy and tissue collection. (A-D: Scale bar, 10 µm). Color was visualized using streptavidin horseradish peroxidase conjugated to diaminobenzidine. Adopted from Yawno T, et al. Neuroscience 2009;163:838-47, with permission of Elsevier Inc. [82].