What is the comparison between spironolactone and eplerenone in terms of antiandrogenic effect in patients with polycystic ovary syndrome (PCOS) or hirsutism?

Spironolactone Has Significantly Greater Antiandrogenic Effects Than Eplerenone

Spironolactone is the clear choice for treating hirsutism, acne, or other androgen-related conditions in women, as eplerenone was specifically engineered to avoid antiandrogenic activity and is not effective for these indications. 1

Mechanism Explaining the Difference

• Spironolactone exhibits potent antiandrogen activity through multiple mechanisms: it decreases testosterone production, competitively inhibits binding of testosterone and dihydrotestosterone to androgen receptors in the skin, may inhibit 5-alpha-reductase, and increases steroid hormone-binding globulin. 2

• Eplerenone was deliberately designed with a 9,11-epoxide group to achieve selective binding to mineralocorticoid receptors with minimal affinity for progesterone and androgen receptors, specifically to avoid the hormone-related side effects of spironolactone. 1

• This structural modification makes eplerenone essentially devoid of antiandrogenic properties, which is why it causes significantly less gynecomastia in men but also renders it ineffective for treating androgen-excess conditions. 1

Clinical Evidence for Spironolactone's Antiandrogenic Efficacy

• Spironolactone at 100-150 mg daily achieves improvement in 85% of hirsute patients, with complete remission in 55%, making it a recommended add-on therapy when oral contraceptives alone provide inadequate response after 6-9 months. 3

• Treatment with spironolactone 200 mg daily results in clear beneficial effect on facial hair growth in 19 of 20 patients with moderate to severe hirsutism, with regression noticeable within two months and maximal effect at six months. 4

• The American Academy of Dermatology guidelines support the use of spironolactone in the management of acne in select women, with a retrospective review showing 66% of women were clear or markedly improved at doses of 50-100 mg daily. 2

• Spironolactone reduces anagen hair shaft diameters by 19-30% at doses of 100-200 mg daily, with the antiandrogenic effects primarily related to peripheral receptor blockade rather than systemic androgen suppression. 5

Why Eplerenone Cannot Substitute for Spironolactone

• Eplerenone is used exclusively for cardiovascular indications (heart failure, resistant hypertension, primary aldosteronism) where its lack of antiandrogenic activity is actually advantageous, particularly in male patients who would otherwise develop gynecomastia. 1

• No clinical trials or guidelines support the use of eplerenone for hirsutism, PCOS, acne, or female pattern hair loss because it lacks the necessary androgen receptor antagonism. 1, 3

• The selective mineralocorticoid receptor binding that makes eplerenone preferable in cardiovascular disease is precisely what eliminates its utility in androgen-excess disorders. 1

Clinical Algorithm for Antiandrogen Selection

For women with hirsutism or androgen-related conditions:

• Start with combined oral contraceptives as first-line therapy to suppress ovarian androgen secretion. 3
• Add spironolactone 100-150 mg daily if inadequate response after 6-9 months of oral contraceptives alone. 3
• Spironolactone can be used at 50-200 mg daily depending on severity and tolerability, with higher doses (200 mg) showing greater efficacy. 2, 4
• Always use effective contraception with spironolactone due to pregnancy category C status and risk of feminization of male fetuses. 2

For cardiovascular indications in women:

• Both spironolactone and eplerenone are equally effective mineralocorticoid receptor antagonists for heart failure and hypertension. 1
• Eplerenone may be preferred if the patient has no androgen-related concerns and requires twice-daily dosing for blood pressure control. 1
• Spironolactone produces gynecomastia more frequently in men but this is not a concern in women; however, it does cause breast tenderness (17%) and menstrual irregularities (22%). 2

Critical Monitoring Requirements

• Both medications require monitoring of serum potassium at baseline, 2-3 days, 7 days, monthly for 3 months, then every 3 months, with therapy held if potassium >5.5 mEq/L and discontinued if >6.0 mEq/L. 1

• Both are contraindicated if baseline potassium >5.0 mEq/L or creatinine >2.5 mg/dL in men (>2.0 mg/dL in women) or eGFR <30 mL/min/1.73m². 1

• Discontinue potassium supplements when initiating either agent. 1

• Hyperkalemia is rare in young healthy individuals but remains a potentially serious side effect requiring vigilance. 2