What is the mechanism of action of Dutasteride (5-alpha-reductase inhibitor)?

From the Guidelines

Dutasteride works by inhibiting both type 1 and type 2 isoforms of 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT), thereby reducing DHT levels in the body by approximately 90-95%. This mechanism is crucial in treating benign prostatic hyperplasia (BPH) symptoms such as urinary hesitancy, weak stream, and frequent urination by causing the prostate to shrink over time 1. Unlike finasteride, which primarily inhibits only the type 2 isoform, dutasteride's dual inhibition provides more complete suppression of DHT production throughout the body, including in the prostate, scalp, and serum 1.

The effectiveness of dutasteride in improving BPH symptoms is supported by studies such as the REDUCE trial, which showed that dutasteride reduced the risk of clinical progression of BPH, including acute urinary retention and the need for BPH-related surgery 1. Additionally, dutasteride has been shown to reduce the incidence of prostate cancer by 23% compared to placebo in the REDUCE trial, although the difference in high-grade cancers detected did not result in a mortality difference 1.

Key Points:

• Dutasteride inhibits both type 1 and type 2 isoforms of 5-alpha reductase, reducing DHT levels by approximately 90-95%.
• The medication is effective in treating BPH symptoms by causing the prostate to shrink over time.
• Dutasteride has a long half-life of approximately 5 weeks, allowing for stable DHT suppression even with occasional missed doses.
• Side effects may include sexual dysfunction, gynecomastia, and decreased ejaculate volume due to its anti-androgenic properties.
• The drug is typically dosed at 0.5 mg once daily, with effects becoming noticeable after 3-6 months of continuous use.

Overall, dutasteride is a highly effective treatment option for BPH, offering significant improvements in symptoms and quality of life for patients. Its mechanism of action, inhibiting both type 1 and type 2 isoforms of 5-alpha reductase, makes it a valuable treatment option for patients with BPH.

From the FDA Drug Label

Dutasteride inhibits the conversion of testosterone to DHT. DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2 The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.

The mechanism of action of dutasteride is the inhibition of the conversion of testosterone to DHT (dihydrotestosterone) by competitively inhibiting the 5 alpha-reductase enzyme, which exists in two isoforms: type 1 and type 2. This inhibition reduces the levels of DHT, a hormone that plays a key role in the development and enlargement of the prostate gland. Dutasteride forms a stable complex with the 5 alpha-reductase enzyme, and its dissociation from this complex is extremely slow. Additionally, dutasteride does not bind to the human androgen receptor. 2

From the Research

Mechanism of Dutasteride

• Dutasteride is a 5alpha-reductase inhibitor that inhibits both types 1 and 2 isozymes of 5alpha-reductase, the enzyme responsible for converting testosterone to dihydrotestosterone in the prostate and other tissues 3, 4, 5.
• The inhibition of 5alpha-reductase results in near-complete suppression of serum dihydrotestosterone, which is the primary cause of prostate growth and plays a key role in the development and progression of benign prostatic hyperplasia 3, 4, 6.
• Dutasteride reduces serum prostate-specific antigen levels by approximately 50% at 6 months and total prostate volume by 25% in 2 years, leading to symptomatic relief, improvements in quality of life, and peak urinary flow rate, and reduction of acute urinary retention events and the need for surgery 3, 4, 6.
• The mechanism of dutasteride also involves the inhibition of androgen action and promotion of cell death in prostate cancer cells, as shown in the LNCaP prostate cancer cell line 7.
• Dutasteride has been shown to compete for binding to the androgen receptor, inhibit DHT-induced PSA secretion and cell proliferation, and induce cell death at high concentrations, possibly by apoptosis 7.

Key Effects of Dutasteride

• Reduction of serum dihydrotestosterone levels
• Inhibition of 5alpha-reductase activity
• Decrease in prostate volume and serum prostate-specific antigen levels
• Symptomatic relief and improvement in quality of life
• Reduction of acute urinary retention events and the need for surgery
• Inhibition of androgen action and promotion of cell death in prostate cancer cells

Studies Supporting the Mechanism of Dutasteride

• Randomized placebo-controlled trials have demonstrated the efficacy of dutasteride in treating benign prostatic hyperplasia and reducing the risk of prostate cancer 3, 4, 6.
• In vitro studies have shown the antiandrogenic effects of dutasteride and its ability to induce cell death in prostate cancer cells 7.