LES INHIBITEURS DE LA 5 ALPHA RÉDUCTASE

5-alpha-reductase inhibitor drugs for BPH

The two FDA-approved 5-alpha-reductase inhibitors, dutasteride (Avodart) and finasteride (Proscar), shrink the prostate, but they are relatively slow in having an effect and do not relieve urinary symptoms as reliably as the alpha blockers.

5-alpha-reductase inhibitors work by altering hormone ratios within the prostate. Specifically, they interfere with the action of 5-alpha reductase, an enzyme that converts the well-known male hormone testosterone to its lesser-known relative, dihydrotestosterone (DHT). As a result of that interference, DHT levels in the prostate decline. Because DHT is an important player in the processes that lead to prostate growth, the gland shrinks. The same hormonal effects also make 5-alpha-reductase inhibitors effective as hair loss drugs.

In theory, dutasteride is more potent than finasteride because it blocks both varieties of the 5-alpha-reductase enzyme, whereas finasteride interferes with just one. But when the drugs are compared, including in one side-by-side clinical trial, they don’t differ much in their effects.

Treatment of Benign prostatic hyperplasia (BPH) is almost always reserved for men who are having trouble with lower urinary tract symptoms. But researchers have started to look at whether asymptomatic men with enlarged prostates might keep symptoms from occurring in the future by taking a 5-alpha-reductase inhibitor. In 2013, Canadian researchers reported that dutasteride might just do that. Analyzing data collected in a prostate cancer prevention trial, researchers found that over a four-year period, 21% of the men who took dutasteride developed BPH-related urinary tract symptoms, compared with 36% who took a placebo.

Dutasteride and finasteride tend to lower PSA levels by about 50%. For that reason, most physicians advise obtaining a baseline PSA value before beginning treatment with a 5-alpha-reductase inhibitor and then measuring levels again after six months to a year to see the difference. If the PSA level hasn’t decreased by about the expected 50% or if it is higher after a man starts dutasteride or finasteride, a biopsy may be necessary to determine if this is a sign of cancer.

Finasteride and dutasteride can adversely affect key aspects of a man’s sexual health, including libido, the ability to get an erection, and ejaculate volume. In research studies, only a small minority of men are affected—less than 10%. But doctors say that in actual practice, these side effects are much more common, affecting up to a third of their patients. A recent randomized, placebo-controlled clinical trial with more than 2700 men confirmed that view: compared with the alpha blocker doxazosin, finasteride was associated with a higher risk of retrograde ejaculation and difficulty achieving an erection.

In 2012, based on reports that it received from doctors and patients, the FDA revised the finasteride label to warn about possible sexual side effects. Men who use this drug for BPH should be aware that it may cause poor semen quality (contributing to infertility) and erectile dysfunction, although both problems should improve once they stop taking it. However, the drug may also depress libido, and the FDA warns that this problem may continue even after stopping the drug.

In a review article published in 2014, researchers acknowledged that 5-alpha- reductase inhibitors can relieve urinary tract symptoms and help to prevent infections or acute urinary retention in men who take the drugs for BPH treatment. But the authors emphasized that these benefits come with a high risk of harmful side effects, including elevated risks for high-grade prostate cancer, cardiovascular problems, erectile dysfunction, and depression. Given the mounting evidence on side effects, it is possible that the benefits of treating BPH with 5-alpha-reductase inhibitors may not outweigh the potential harms, the authors concluded.

 

Cancer and the 5-alpha-reductase inhibitors

In addition to treating BPH, 5-alpha-reductase inhibitors have also been tested as a means of preventing prostate cancer. In two separate trials, finasteride and dutasteride were shown to lower the overall risk of prostate cancer by about 25%. Here’s the catch (and it is an important one): both medications were also associated with a small, but statistically significant, increase in risks for high-grade prostate cancer. As a result, the FDA put a cancer warning on the drugs.

A 2013 update of the finasteride trial, which included more follow-up time, confirmed that the drug reduced the overall risk of prostate cancer; this time the results showed a 30% decrease in overall risk. But there was also a reprise of the earlier finding that men assigned to take finasteride were more likely to be diagnosed with a high-grade prostate cancer (3,5% in the finasteride group vs. 3% among those assigned the placebo). Moreover, the update showed that men who developed high- grade cancer after taking finasteride had a lower 10-year survival rate (66% in the finasteride group compared with 74% among who took placebo).

 

Some bibliographic elements:

Carrasquillo RJ, Nealy SW, Wang DS. 5-Alpha-Reductase Inhibitors in Diseases of the Prostate. Current Opinion in Endocrinol- ogy, Diabetes and Obesity 2014; Electronic publication ahead of print. PMID: 25268733.

Fwu CW, Eggers PW, Kirkali Z, et al. Change in Sexual Function in Men with Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia Associated with Long-Term Treatment with Doxazosin, Finasteride, and Combined Therapy. Journal of Urology 2014;191(16):1828–34. PMID: 24342143.

Lin WL, Hsieh YW, Lin CL, et al. A Popu- lation-Based Nested Case-Control Study: The Use of 5-Alpha-Reductase Inhibitors and the Increased Risk of Osteoporosis Diagnosis in Patients with Benign Prostate Hyperplasia. Clinical Endocrinology (Oxford) 2014; Electronic publication ahead of print. PMID: 25158777.

Nickel JC, Gilling P, Tammela TL, et al. Comparison of Dutasteride and Finasteride for Treating Benign Prostatic Hyperplasia: The Enlarged Prostate International Com- parator Study (EPICS). BJU International 2011;108:388–94. PMID: 21631695.

Toren P, Margel D, Kulkarni G, et al. Effect of Dutasteride on Clinical Progression of Benign Prostatic Hyperplasia in Asymp- tomatic Men with Enlarged Prostate: A Post Hoc Analysis of the REDUCE Study. BMJ 2013;346:f2109. PMID: 23587564.

Traish AM, Mulgaonkar A, Giordano N, et al. The Dark Side of 5α-Reductase Inhibitors’ Therapy: Sexual Dysfunction, High Gleason Grade Prostate Cancer and Depression. Korean Journal of Urology 2014;55(6):367– 79. PMID: 24955220.

Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. New England Journal of Medicine 2010;362:1192-202 PMID: 20357281

Thompson IM Jr, Goodman PJ, Tangen CM, et al. Long-term Survival of Participants in the Prostate Cancer Prevention Trial. New England Journal of Medicine 2013;369: 603-10. PMID: 23944298.