What are the potential adverse effects of dutasteride (5-alpha-reductase inhibitor) in older males with a history of benign prostatic hyperplasia (BPH) or androgenetic alopecia?

Adverse Effects of Dutasteride

Dutasteride causes sexual dysfunction in approximately 16% of patients, with impotence, decreased libido, ejaculation disorders, and breast disorders being the most common adverse effects, all of which are typically mild to moderate in severity and reversible upon discontinuation. 1, 2

Sexual Adverse Effects

Erectile Dysfunction

• Erectile dysfunction occurs in 4-15% of patients treated with dutasteride, representing approximately a twofold higher incidence compared to placebo (16% vs 8%) 3, 4, 2
• The severity is typically mild to moderate and does not lead to treatment discontinuation in most cases 2
• Long-term dutasteride therapy (36-42 months) has been associated with worsening erectile dysfunction as measured by the International Index of Erectile Function (IIEF-EF) scores 5

Decreased Libido

• Decreased libido affects 6.4% of patients in the first year of treatment, decreasing to 2.6% in years 2-4 6
• This side effect is expected, reversible, and occurs at approximately twice the rate of placebo 2

Ejaculatory Dysfunction

• Ejaculation disorders occur in 3.7% of patients in the first year, decreasing to 1.5% in years 2-4 6
• All ejaculatory adverse events reported in clinical trials were mild to moderate and resolved either during treatment or after discontinuation 2

Temporal Pattern of Sexual Side Effects

• Sexual side effects typically decrease after the first year of therapy 6, 3
• Long-term usage beyond 4 years does not reveal increased new onset of sexual side effects 7
• All sexual adverse events in clinical trials resolved while on study treatment or after the end of treatment 2

Breast-Related Adverse Effects

• Gynecomastia (breast enlargement) occurs in 0.5-2.2% of patients versus 0.1-1.1% with placebo 4
• Breast tenderness affects 0.4-0.7% of patients 4
• Breast disorders are reported in ≥1% of subjects and more commonly than placebo 1

Metabolic and Hormonal Effects

Long-term dutasteride therapy (36-42 months) has been associated with significant metabolic alterations that are not observed with alpha-blocker monotherapy: 5

• Increased blood glucose and glycated hemoglobin (HbA1c) levels 5
• Elevated total cholesterol and LDL-cholesterol levels 5
• Increased liver enzyme activities (ALT and AST) 5
• Reduced total testosterone levels, potentially contributing to a state of hypogonadism 5
• These metabolic effects represent a serious concern that should be discussed with patients prior to initiating long-term therapy 5

Prostate-Specific Antigen (PSA) Effects

• Dutasteride reduces serum PSA concentration by approximately 50% after 1 year of therapy 3, 1
• PSA reductions continue over time, reaching median reductions of 59.5% at 2 years and 66.1% at 4 years 3
• Any confirmed increase in PSA while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if values remain within the normal range for untreated men 1
• The measured PSA value should be doubled after 1 year of dutasteride therapy for accurate prostate cancer screening interpretation 3

Prostate Cancer Risk

• Dutasteride may increase the risk of high-grade prostate cancer 1
• Delayed cancer diagnosis may occur if PSA adjustment is not performed, potentially leading to detection of higher-grade disease 6
• Dutasteride is not approved for the prevention of prostate cancer 1

Post-Discontinuation Syndrome

• The FDA amended dutasteride labels to warn about persistent symptoms after discontinuation, including erectile dysfunction, decreased libido, ejaculation disorders, and orgasm disorders 6
• Post-finasteride/dutasteride syndrome remains poorly defined and controversial, based primarily on anecdotal patient reports rather than prospective trials 6, 4
• The robustness of data supporting persistent sexual dysfunction after discontinuation remains unclear 6

Drug Interactions and Special Precautions

• Use with caution in patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) 1
• Women who are pregnant or may be pregnant should not handle dutasteride capsules due to potential risk to a male fetus 1
• Patients should not donate blood until 6 months after their last dose of dutasteride 1
• Dutasteride is contraindicated in pregnancy and in patients with previously demonstrated clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) 1

Discontinuation Rates

• Overall discontinuation rates are approximately 15% for both dutasteride and placebo groups 4
• Discontinuation specifically due to adverse events is 6-7% in both treatment and placebo groups 4
• Sexual adverse events in clinical trials did not lead to treatment discontinuation 2

Critical Counseling Points

• Patients should be counseled that sexual side effects typically decrease after the first year but may persist in a small subset of individuals 6
• The disadvantages of therapy, including sexual dysfunction and metabolic effects, should be presented against the benefits of preventing disease progression 6, 5
• Physicians should discuss the potential serious adverse effects of long-term dutasteride therapy, including metabolic alterations and testosterone reduction, prior to instituting treatment 5

Common Pitfalls to Avoid

• Using dutasteride in patients without prostatic enlargement (<30cc) exposes patients to unnecessary side effects without therapeutic benefit 6, 3
• Failing to adjust PSA interpretation (doubling the value after 1 year) can lead to delayed cancer diagnosis 6, 4
• Dismissing patient concerns about persistent sexual side effects, as the FDA has acknowledged these may occur despite limited prospective data 6
• Failing to monitor metabolic parameters (glucose, lipids, testosterone, liver enzymes) during long-term therapy 5