Why Spironolactone Has Unusual Side Effects
Spironolactone has unusual side effects primarily because it acts as both a potassium-sparing diuretic and an anti-androgen, affecting multiple hormonal pathways beyond its primary aldosterone antagonist mechanism. 1
Mechanism of Action and Hormonal Effects
- Spironolactone is a synthetic 17-lactone steroid that antagonizes the androgen and progesterone receptors, explaining many of its unusual side effects 1
- It was originally developed as a potassium-sparing diuretic but has significant anti-androgenic properties that affect hormone balance throughout the body 1
- Spironolactone decreases testosterone production and competitively inhibits binding of testosterone and dihydrotestosterone to androgen receptors in the skin and other tissues 1
- It may also inhibit 5-alpha-reductase and increase steroid hormone-binding globulin, further affecting hormone metabolism 1, 2
- The drug reduces synthesis of androgen precursors in the adrenal glands, creating systemic hormonal changes 1
Gender-Specific Side Effects
Female-Specific Side Effects
- Menstrual irregularities occur in 15-30% of women taking spironolactone, with dose-dependent risk (RR 4.12 at 200mg/day compared to lower doses) 1
- Breast tenderness (3-5%) and breast enlargement are common due to the shift in estrogen/androgen balance 1
- Postmenopausal bleeding can occur in older women, requiring investigation 3
Male-Specific Side Effects
- Gynecomastia develops in men due to the anti-androgenic effects and relative increase in estrogen activity 4, 5
- Impotence and decreased libido can occur from the hormonal alterations 6, 5
- Feminization of male fetuses has been observed in animal studies, making it pregnancy category C 1, 7
Electrolyte and Cardiovascular Effects
- As a potassium-sparing diuretic, hyperkalemia is a potential complication, especially in patients with renal insufficiency or heart failure 1, 8
- Young healthy women with acne have minimal risk of hyperkalemia, but older adults and those with comorbidities require monitoring 1, 3
- Cardiovascular effects can include hypotension, hypertension, and in rare cases, thrombotic events 3, 8
Neurological and Other Effects
- Dizziness (3-4%), headache (2%), fatigue (1-2%), and nausea (2-4%) are common neurological and systemic side effects 1
- Polyuria (1-2%) occurs due to the diuretic effect 1
- Confusion and somnolence can occur, particularly in older adults 3
- Impaired glucose tolerance may develop, especially concerning in patients with pre-existing metabolic issues 3
Dose-Dependent Nature of Side Effects
- Side effects are generally dose-dependent, with higher incidence at doses of 200mg/day compared to lower doses 1, 6
- For acne treatment, doses up to 200mg/day can be used, but side effects increase significantly at higher doses 1
- Starting at lower doses (50mg twice daily) can reduce the incidence of side effects like menstrual irregularities 6
Managing Side Effects
- Concomitant use of combined oral contraceptives (COCs) or hormonal intrauterine devices can minimize menstrual irregularities in women 1
- Potassium monitoring is not required in young healthy women but should be considered in older patients and those with risk factors for hyperkalemia 1
- Cyclical administration (days 4-21 of menstrual cycle) rather than continuous dosing may reduce menstrual irregularities 6
- Patients should be counseled to avoid becoming pregnant while on spironolactone due to potential teratogenic effects 1, 7
Special Considerations
- Spironolactone has a black box warning regarding tumorigenicity in animal studies, though large human cohort studies with over 30 million person-years of follow-up have not confirmed such risks 1
- The drug should be used with caution in patients with renal impairment, hepatic disease, or those taking medications like ACE inhibitors, ARBs, or NSAIDs 3, 7
- In post-menopausal women, the risk-benefit profile shifts significantly, with greater potential for adverse effects 3