AReductase Inhibitor Monotherapy

© 5a-Reductase inhibitors reduce the static factor, which results in shrinkage of an enlarged prostate. They do so by inhibiting 5a-reductase, which is responsible for intraprostatic conversion of testosterone to dihydrotestosterone, the active androgen that stimulates prostate tissue growth. In the prostate, there are two subtypes of 5a-reductase; the majority is the type II isoenzyme type and the minority is the type I isoenzyme type. In addition, 5a-reductase inhibitors induce apoptosis of prostatic epithelial cells.4 The onset of action is slow with peak shrinkage of the prostate taking up to 6 months.10 Unlike a-adrenergic antagonists, 5a-reductase inhibitors are used to prevent BPH-related complications and disease progression. Finasteride has been shown to reduce the incidence of acute urinary retention and need for prostate surgery in patients with significantly enlarged prostate glands (greater than 40 g [1.4 oz]),14 and those with serum levels of PSA of at least 1.5 ng/mL (1.5 mcg/L).11 Because 5a-reductase inhibitors do not produce cardiovascular adverse effects, they are preferred for men with moderate to severe BPH who are at risk of developing complications of BPH (i.e., the patient has an enlarged prostate of at least 30 g [1.05 oz]), and has a PSA of greater than 1.5 ng/mL (1.5 mg/L).8,11,41

With regard to their use for the symptomatic treatment of BPH, 5a-reductase inhibitors relieve BPH symptoms in 30% to 70% of patients and increase urinary flow rate by 1 to 2 mL/s, which is less improvement than that seen with a-adrenergic antagonists.10,14 A minimum of 6 months is required to evaluate the effectiveness of treatment. This is a disadvantage in patients with moderate to severe symptoms, as it will take that long to determine if the drug is or is not effective. Durable responses have been demonstrated in responding patients treated up to 6 years with finasteride and 4 years with dutasteride. 2,43 These agents are hepatically metabolized. No specific recommendations for dosage modification are currently available in patients with significant hepatic dysfunction; however, due to drug specificity for its enzyme target, it is unlikely that any dosage adjustment will be required. No dosage adjustment is needed in patients with renal impairment. Adverse effects include decreased libido, erectile dysfunction, and ejaculation disorders, which general3ly3,4d0ecrease in frequency with continued use, and gynecomastia and breast tenderness.3 ,40 Serum testosterone levels increase by 10% to 20% in treated patients; however, the clinical significance of this is not clear at this time.10 Drug interactions are uncommon. These drugs do produce a mean 50% decrease in serum levels of PSA. Therefore, to preserve the usefulness of this laboratory test as a diagnostic and monitoring tool, it is recommended that prescribers obtain a baseline PSA prior to the start of treatment and repeat it at least annually during treatment. A significantly elevated PSA in treated patients is an indicator for further diagnostic workup.44 Exposure to 5a-reductase inhibitors is con-traindicated in pregnant females, as the drugs may cause feminization of a male fetus. Pregnant females should not handle these drugs unless they are wearing gloves.

5a- Reductase inhibitors include finasteride and dutasteride. Finasteride is a selective type II 5a-reductase inhibitor, whereas dutasteride is a nonselective type I and II 5a-reductase inhibitor. When compared to finasteride, dutasteride produces a faster and more complete inhibition of 5a-reductase in prostate cells. However, no difference in clinical efficacy or adverse effects has been demonstrated between these two agents. Thus, finasteride and dutasteride are considered therapeutically interchangeable (Table 52-7)45

By reducing serum levels of dihydrotestosterone, which is linked to the development of prostate cancer, it has been hypothesized that 5a-reductase inhibitors may prevent the development of prostate cancer. The Predict Trial reported that finasteride reduced the detection of prostate cancer with prostatic needle bicvpsy by 25%; however, higher-grade tumors were more common in treated patients.4 This finding is likely due to the fact that the drug-induced shrinkage of the prostate increased the probability that the prostate needle biopsy procedure was able to obtain cancerous tissue.46 The ongoing Reduce Trial, which will follow dutasteride-treated patients for 4

years, may provide more clarification on this issue. Combination Therapy

A combination of an a-adrenergic antagonist and 5a-reductase inhibitor may be considered in symptomatic patients at high risk of BPH complications, which are defined as those with an enlarged prostate of at least 30 g (1.05 oz) and a PSA of at least 1.5 ng/mL (1.5 mcg/L). In such patients, combination therapy will relieve voiding symptoms and also may reduce the risk of developing BPH-related complications and reduce the need for prostatectomy by 67%.12,14 Because combination therapy is more expensive and associated with the array of adverse effects associated with each drug in the combination, clinicians should discuss the advantages and disadvantages of each treatment regimen with the patient before a final decision is made.10

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