What are the 5-alpha reductase inhibitors?

The 5-alpha reductase inhibitors are a class of medications that inhibit the enzyme 5-alpha reductase. The enzymes 5-alpha reductase are present in two isoforms: type 1 and type 2. Type 1 is found predominantly in extraprostatic tissues such as the skin and liver, although it is also found in the prostate. Type 2 is found predominantly in the prostate. The type 2 5-alpha reductase enzyme in the prostate is responsible for converting testosterone to its active form in the prostate, dihydrotestosterone. Dihydrotestosterone mediates secondary sexual characteristics, including prostate growth (Figure 22).

Figure 22. Action of 5-alpha reductase.

Two drugs have been developed that inhibit 5-alpha reductase. The first is finasteride or Proscar, which is a type 2 or selective 5-alpha reductase inhibitor. The second is dutasteride or Avodart, which is a type 1 and type 2 or nonselective 5-alpha reductase inhibitor. (Table 12) Finasteride has been shown to reduce serum DHT levels by 70%, whereas dutasteride has been shown to reduce serum DHT by 90%. It is not yet known whether that difference in DHT suppression translates into greater efficacy for the patient. 5-alpha reductase inhibitors work best in men with noticeable enlargement of the prostate.

What are the side effects of 5-alpha reductase inhibitors?

Side effects found in the first year of 5-alpha reductase inhibitor use include: decreased sexual drive (libido), increased ejaculatory dysfunction (such as smaller amount of semen ejaculated), difficulty getting an erection, breast tenderness or enlargement. One large study demonstrated that after a year of treatment, finasteride resulted in the same level of decreased sex drive and inability to get an erection as placebo. Ejaculatory dysfunction was higher with finasteride than with placebo.

What are the results of BPH treatment using 5-alpha reductase inhibitor drugs?

As mentioned previously, finasteride (Proscar) and dutasteride (Avodart) are the two 5-alpha reductase inhibitors that are currently available in the United States. Both of these drugs require 3 to 6 months to see clinical beneficial effects. The Finasteride Study Group showed improvement in peak flow rates and symptom scores as well as a decrease in prostate volume. At 1 year, patients on 5 milligrams of finasteride had a 22% improvement in peak flow rates and a 21% decrease in symptom scores. In addition, they exhibited a 19% decrease in their prostate volume.

A recent report looking at cohort of patients treated with dutasteride showed similar improvement in urinary flow rates, a decrease in symptom scores, and a reduction in prostate volume.

What effects do 5-alpha reductase inhibitor drugs have on PSA levels?

5-alpha reductase inhibitor drugs block the conversion of testosterone to DHT, which results in shrinkage of the prostate or a decrease in prostate volume. Because prostate cells make PSA, it is reasonable to assume that as the prostate gets smaller, the PSA level will decline. This is in fact what happens; however, it takes 3 to 6 months for a significant volume decrease to occur, and thus, the PSA decline is gradual. Nonetheless, by about 6 months after starting a 5-alpha reductase inhibitor, the total PSA level is about half of the baseline value. The free fraction of PSA is not changed by treatment with 5-alpha reductase inhibitors. In patients who have been on 5-alpha reductase inhibitors for longer than 3-6 months, the PSA should remain stable and significant increases in the PSA would be worrisome for prostate cancer.

Do the 5-alpha reductase inhibitors have an effect on the risk of developing prostate cancer?

A recent study called the "Prostate Cancer Prevention Trial" (PCPT) demonstrated that finasteride (Proscar) at a dose of 5mg/day decreases the likelihood of developing

In patients who have been on 5-alpha reductase inhibitors for longer than 3—6 months, the PSA should remain stable and significant increases in the PSA would be worrisome for prostate cancer.

prostate cancer by 26% when compared to placebo (candy pill). In addition, finasteride decreased the risk of high grade PIN (which may be a precursor of prostate cancer) by about the same rate. In this study, finasteride lowered the PSA by 50% after 2 months of treatment.

“Asymptomatic men with a PSA " 3.0 ng/ml who are regularly screened with PSA or who are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of5-alpha reductase inhibitors for 7 years for the prevention of prostate cancer and the potential risks (2-4% increase in reported erectile dysfunction and gynecomastia (enlarged and/or painful breasts), and decrease in ejaculate volume in those receiving finasteride in the study compared to those receiving placebo)."

auanet.org/content/guidelines-and-quality-care/ clinical-guidelines/main-reports/pcredinh.pdf.

Results of the "Reduction by Dutasteride of Prostate Cancer" (REDUCE) trial showed that the 5-alpha reductase inhibitor dutasteride at doses of 0.5 mg/day decreased the relative risk of prostate cancer by 23% compared to placebo. Furthermore, the risk was markedly decreased in the number of high-grade tumors, with no absolute increase in incidence compared to placebo.