What is the role of spironolactone (aldosterone antagonist) in the treatment of Polycystic Ovary Syndrome (PCOS)?

Spironolactone for PCOS: Role in Treatment

Primary Role: Antiandrogen Therapy for Hirsutism and Acne

Spironolactone is an effective antiandrogen agent for treating hirsutism and acne in women with PCOS, typically dosed at 50-200 mg daily, and works best when combined with oral contraceptives for menstrual regulation and pregnancy prevention. 1

Mechanism and Efficacy

• Spironolactone decreases testosterone production and competitively inhibits testosterone and dihydrotestosterone binding to androgen receptors in the skin 1
• It may also inhibit 5α-reductase and increase sex hormone-binding globulin 1
• For hirsutism specifically, spironolactone (100 mg/day) shows superior efficacy compared to finasteride and cyproterone acetate in idiopathic hirsutism, though results are more variable in PCOS patients 2
• In PCOS patients, spironolactone 50 mg daily significantly reduces hirsutism scores from baseline (12.9 to 8.7 at 6 months) and improves menstrual cyclicity 3

Optimal Treatment Strategy

The combination of spironolactone with oral contraceptives is more effective than either agent alone for managing PCOS-related hyperandrogenism 4:

• Oral contraceptives suppress ovarian androgen production while spironolactone blocks peripheral androgen effects 4
• This combination addresses both the source and the target-organ effects of excess androgens 4
• Concomitant use of spironolactone with drospirenone-containing oral contraceptives does not increase hyperkalemia risk or adverse effects requiring discontinuation 1

Dosing Considerations

• Start with 50-100 mg daily for most patients, as lower doses (50 mg) show comparable efficacy to metformin for hirsutism with fewer adverse events 3
• Higher doses up to 200 mg daily can be used for refractory cases, though side effects are dose-dependent 1, 5
• Clinical improvement in hirsutism takes 3-6 months to become apparent 3

Metabolic Effects: Limited but Potentially Beneficial

Insulin Resistance and Metabolic Parameters

• Spironolactone 50 mg daily shows no significant difference compared to metformin alone on insulin resistance (HOMA-IR), FSH, LH, BMI, or menstrual cyclicity 2, 3
• However, combining low-dose spironolactone (25 mg) with metformin produces greater reduction in HOMA-IR than either drug alone (1.71 vs 1.92 for metformin alone, P<0.05) 6
• The combination of metformin plus low-dose spironolactone (25 mg) induces more marked reduction of clinical and biochemical hyperandrogenism than metformin alone 7

Hormonal Effects

• Spironolactone reduces serum testosterone and androstenedione levels in PCOS patients 3
• It decreases LH/FSH ratio, though less effectively than cyproterone acetate combined with estrogen 5
• Dehydroepiandrosterone sulfate (DHEA-S) decreases more significantly when spironolactone is combined with metformin 7

Safety Profile and Monitoring

Common Side Effects

• Menstrual irregularities (22-40%) are the most common side effect, which are dose-dependent and less common when combined with oral contraceptives 1, 2
• Diuresis (29%), breast tenderness (17%), breast enlargement, fatigue, headache, and dizziness occur in a dose-related manner 1
• Mild nausea, vomiting, and diarrhea may occur but are generally well-tolerated 2

Contraindications and Precautions

• Spironolactone is pregnancy category C due to risk of feminization of male fetuses; concomitant oral contraceptive use is strongly recommended in sexually active women 1
• Hyperkalemia is rare in young healthy individuals with no renal impairment 1
• Potassium monitoring should be considered in older patients, those with comorbidities (hypertension, diabetes, chronic kidney disease), and those taking medications affecting renal/adrenal function (ACE inhibitors, ARBs, NSAIDs) 1

Clinical Algorithm for Use

When to Use Spironolactone

1. First-line for hirsutism and acne in women with PCOS not attempting to conceive 4
2. Always combine with oral contraceptives for optimal efficacy and pregnancy prevention 1, 4
3. Consider adding low-dose spironolactone (25 mg) to metformin if metabolic therapy alone inadequately controls hyperandrogenic symptoms 7

When NOT to Use as Monotherapy

• In PCOS patients attempting to conceive (use clomiphene citrate instead) 1, 4
• As sole therapy for metabolic dysfunction (lifestyle modification and metformin are superior) 1, 8
• For menstrual regulation alone (oral contraceptives are first-line) 4

Important Caveats

• Spironolactone is not FDA-approved for PCOS or acne treatment; this is off-label use 1
• Treatment addresses symptoms (hirsutism, acne) rather than underlying PCOS pathophysiology 9
• For idiopathic hirsutism, spironolactone as monotherapy is as effective as cyproterone acetate combined with estradiol, but in PCOS patients, combination therapy is necessary for optimal hormonal and metabolic management 5
• Clinical response requires 3-6 months; patients should be counseled about delayed onset of action 3