What is the appropriate use of spironolactone (potassium-sparing diuretic) in men?

Spironolactone Use in Men

Spironolactone is appropriate for men in specific clinical contexts—primarily heart failure (NYHA Class III-IV), resistant hypertension, and edema from cirrhosis or nephrotic syndrome—but requires careful consideration of dose-dependent sexual side effects including gynecomastia and decreased libido, which can be minimized by using the lowest effective dose (typically 25-50 mg daily) and considering alternative agents like eplerenone when sexual side effects become problematic. 1

FDA-Approved Indications in Men

Spironolactone is indicated for men in the following conditions 1:

• Heart failure (NYHA Class III-IV) with reduced ejection fraction to increase survival, manage edema, and reduce hospitalization 1
• Resistant hypertension as add-on therapy when blood pressure is inadequately controlled on other agents 1
• Edema associated with cirrhosis or nephrotic syndrome when other diuretics produce inadequate response 1
• Primary hyperaldosteronism for preoperative treatment or long-term maintenance 1

Dosing Considerations for Men

Heart Failure

• Initiate at 25 mg once daily in patients with serum potassium ≤5.0 mEq/L and eGFR >50 mL/min/1.73 m² 1
• May increase to 50 mg once daily if tolerated 1
• This low-dose regimen (25 mg daily) reduced mortality by 30% in severe heart failure (relative risk 0.70, P<0.001) 2

Hypertension

• Start with 25-100 mg daily in single or divided doses 1
• Doses of 75-100 mg daily are as effective as 150-300 mg daily but with substantially fewer sexual side effects 3
• Low-dose spironolactone (25-50 mg) added to resistant hypertension regimens reduced blood pressure by 26.0/10.7 mm Hg at 6 months 4

Critical Sex-Specific Side Effects in Men

Gynecomastia

Gynecomastia is the most problematic sex-specific side effect in men, occurring in a dose-dependent manner 5, 6:

• 6.9% incidence at 50 mg/day 7, 3
• 52.2% incidence at ≥150 mg/day 7, 3
• Occurred in 10% of men in the landmark RALES heart failure trial (mean dose 26 mg) 2
• 5.2% of men developed gynecomastia with low-dose therapy (25-50 mg) for resistant hypertension 4

Management of gynecomastia 6:

• Switch to amiloride (10-40 mg/day) as first-line intervention, particularly in cirrhosis patients 6
• Tamoxifen 20 mg twice daily can manage tender gynecomastia if spironolactone must be continued 6
• Consider eplerenone as an alternative with reduced affinity for androgen receptors 8, 9

Decreased Libido and Sexual Dysfunction

Decreased libido is a frequent side effect in men due to spironolactone's potent anti-androgenic activity 5:

• Spironolactone inhibits testosterone and dihydrotestosterone binding to androgen receptors 5
• Decreases testosterone production and potentially inhibits 5-alpha-reductase activity 5
• Sexual side effects including impotence are particularly common in men with cirrhosis 5
• Severity is dose-dependent, with higher doses carrying significantly increased risk 5

Monitoring Requirements Specific to Men

Potassium Monitoring

Critical monitoring is required due to hyperkalemia risk 8, 1:

• Check serum potassium and creatinine at 1,4,8, and 12 weeks, then at 6,9, and 12 months, then every 6 months 8
• If potassium rises to 5.5-6.0 mEq/L, reduce dose to 25 mg every other day 8, 1
• If potassium >6.0 mEq/L, seek specialist advice and consider discontinuation 8
• Hyperkalemia led to discontinuation in 4.1% of patients with resistant hypertension 4

Drug Interactions to Avoid

Avoid concomitant use with 8, 1:

• ACE inhibitors or angiotensin receptor blockers (increases hyperkalemia risk) 8
• Other potassium-sparing diuretics 8
• Potassium supplements 8
• NSAIDs (nephrotoxic and increase hyperkalemia risk) 8
• Potent CYP3A4 inhibitors 8
• "Low salt" substitutes with high potassium content 8

Alternative Agents to Minimize Sexual Side Effects

When sexual side effects become problematic, consider 8, 5, 6, 9:

• Eplerenone: More selective mineralocorticoid receptor antagonist with 3- to 10-fold decrease in anti-androgenic effects compared to spironolactone 5, 9

  • Start at 25 mg once daily, titrate to 50 mg once daily within 4 weeks 9
  • Gynecomastia and sexual side effects are less likely than with spironolactone 8, 9

• Amiloride: Potassium-sparing diuretic without anti-androgenic effects 6

  • Dose: 10-40 mg/day 6
  • Particularly useful for cirrhosis-related edema when gynecomastia develops 6

Common Pitfalls and Caveats

• Do not use spironolactone as first-line monotherapy for heart failure; it should be added to ACE inhibitors and beta-blockers 8, 1
• Avoid initiating in patients with baseline potassium >5.0 mEq/L or eGFR <30 mL/min/1.73 m² 1
• Do not exceed 100 mg daily for hypertension, as higher doses provide no additional blood pressure benefit but substantially increase sexual side effects 3
• Warn patients about sexual side effects upfront to improve adherence and allow for early intervention 8
• Temporarily discontinue if diarrhea/vomiting occurs to prevent hyperkalemia 8