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.

Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction

“…Finasteride therapy is used as long-term treatment for prostate disease and is generally well tolerated, although rare side effects such as sexual dysfunction, depression, and high Gleason grade prostate cancer were described. 43 Another 5-α-reductase inhibitor, the more potent substance dutasteride (but not finasteride), has been associated with increased risk of the development of heart failure in 1 study of patients with prostate disease, although reanalysis of the data by the US Food and Drug Administration corrected this effect to be statistically insignificant. 44 In addition, a recent meta-analysis including >18 000 patients could not verify any cardiovascular adverse events during dutasteride therapy.…”

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

“…Indeed, while most of the actions of 5α-R inhibitors on sexual functions are posited to reflect the action of 5α-R type 2, the role of the three main isoforms of this enzyme in the neuropsychiatric and metabolic effects of 5α-RIs remains elusive. As pointed out by Traish et al [206] 5α-RIs have a long lasting impact on sexual dysfunction. Caution should be exercised to utilization of data from studies that did not address the inaccuracy of reporting of adverse events, especially those from studies on hair restoration [207], as pointed out very clearly by Belknap and his colleagues [89].…”

Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome

“…Gynecomastia has also been experienced by subjects prescribed dutasteride therapy (0.5 mg) for BPH [36,37,38,39]. Study results obtained by Kaplan et al [40 ]comparing safety and efficacy of BPH patients treated with finasteride or dutasteride suggest that the incidence of gynecomastia is greater in dutasteride users than in finasteride users.…”