What is the primary mode of action of 5 Alpha-Reductase Inhibitors (5 ARIs)?

Primary Mode of Action of 5-Alpha-Reductase Inhibitors (5-ARIs)

5-Alpha-Reductase Inhibitors (5-ARIs) work primarily by inhibiting the 5-alpha-reductase enzyme, which converts testosterone to dihydrotestosterone (DHT), thereby reducing DHT levels by approximately 50% after 12 months of therapy. 1

Mechanism of Action

• 5-alpha-reductase is an enzyme that converts testosterone into the more potent androgen dihydrotestosterone (DHT) 2
• There are two isoenzymes (isoforms) of 5-alpha-reductase:
  • Type 1 isoenzyme
  • Type 2 isoenzyme
• Finasteride selectively inhibits the type 2 isoenzyme 2
• Dutasteride inhibits both type 1 and type 2 isoenzymes, providing more complete DHT suppression 2
• This inhibition prevents the conversion of testosterone to DHT without lowering circulating testosterone levels 1

Physiological Effects

The inhibition of DHT production by 5-ARIs leads to several important physiological effects:

1. Prostate tissue effects:

   • Reduction in prostate volume (shrinkage of the prostate) 3
   • Involution of prostate tissue 3
   • Decreased growth of both normal and abnormal prostate tissue 4

2. Hormonal effects:

   • Reduction in serum DHT levels by approximately 50% after 12 months of therapy 1
   • Preservation of normal testosterone levels 1
   • Reduction of intraprostatic DHT concentration 3

3. PSA effects:

   • Decrease in PSA levels by approximately 50% after 12 months of therapy 2
   • This effect must be considered when interpreting PSA values in men taking 5-ARIs 2

Clinical Applications

The primary mode of action of 5-ARIs translates into several clinical applications:

• Benign Prostatic Hyperplasia (BPH):

  • Reduction in prostate volume
  • Improvement in lower urinary tract symptoms (LUTS)
  • Increased urinary flow rates
  • Reduced risk of acute urinary retention (AUR)
  • Decreased need for BPH-related surgery 3, 5

• Male Pattern Baldness:

  • At lower doses (1mg finasteride), 5-ARIs reduce male hair loss 6
  • The 1mg dose has similar effects on DHT levels as the 5mg dose used for BPH 1

• Prostate Cancer Prevention:

  • Reduction in period prevalence of prostate cancer by approximately 25% 2

Differences Between 5-ARI Medications

• Finasteride:

  • Inhibits only type 2 isoenzyme of 5-alpha-reductase
  • Dosage: 5mg daily for BPH, 1mg daily for male pattern baldness
  • Reduces DHT by approximately 50% 1

• Dutasteride:

  • Inhibits both type 1 and type 2 isoenzymes
  • Causes greater and more consistent decrease in DHT
  • May provide more complete suppression of DHT 2, 5

Important Considerations

• The full effect of 5-ARIs on DHT levels and prostate volume takes several months to develop
• PSA levels decrease by approximately 50% after 12 months of therapy, requiring adjustment when interpreting PSA for prostate cancer screening 2
• Unlike alpha-blockers which provide immediate symptomatic relief for BPH, 5-ARIs work through a hormonal mechanism that requires time to demonstrate clinical benefit 4
• 5-ARIs are particularly effective in men with larger prostates (>30-40ml) 7

In summary, the primary mode of action of 5-ARIs is the inhibition of the 5-alpha-reductase enzyme, preventing the conversion of testosterone to DHT, which results in decreased prostate volume and improvement in BPH-related symptoms over time.