Understanding Drug-Induced Gynecomastia
Gynecomastia is the benign enlargement of glandular breast tissue in males, a condition that arises from an imbalance between estrogen and androgen hormones [1.5.2]. While it can occur physiologically during infancy, puberty, and old age, a significant portion of cases, estimated between 10% and 25%, are caused by medications [1.5.1, 1.5.4]. This condition is distinct from pseudogynecomastia, which is fat deposition without glandular proliferation [1.7.5]. The primary mechanism behind drug-induced gynecomastia is the disruption of the normal estrogen-to-androgen ratio [1.3.2]. Drugs can achieve this through several pathways: exhibiting estrogen-like effects, blocking androgen receptors, inhibiting androgen synthesis, or increasing prolactin levels [1.3.1, 1.2.6].
Symptoms of gynecomastia include the development of a palpable, firm disc of tissue concentric to the nipple, which may be tender or painful [1.7.5, 1.2.3]. Diagnosis involves a physical examination to differentiate it from other conditions like breast cancer or pseudogynecomastia [1.7.1]. A thorough review of the patient's medication history is crucial, as a temporal relationship between starting a new drug and the onset of symptoms is often a key indicator [1.4.1].
Common Medications Associated with Gynecomastia
A wide array of medications across various therapeutic classes has been associated with gynecomastia. The quality of evidence for these associations varies, but some drugs have a well-documented link [1.2.2].
Cardiovascular Drugs
Certain medications used to treat heart conditions and high blood pressure are common culprits.
- Spironolactone (Aldactone): This diuretic is one of the most frequently associated drugs. It can inhibit testosterone production, block androgen receptors, and increase the peripheral conversion of testosterone to estradiol [1.3.4, 1.2.5]. The risk is dose-dependent, and gynecomastia is usually reversible upon discontinuation [1.8.3]. Incidence has been reported in about 9% of men in some studies [1.2.6].
- Calcium Channel Blockers: Drugs like nifedipine, verapamil, and diltiazem have been linked to gynecomastia, though the mechanism is not entirely clear [1.2.1].
- ACE Inhibitors: Captopril and enalapril are less common causes but have been reported [1.2.1].
- Digoxin: This heart medication may bind to estrogen receptors, but case reports are few and their validity has been questioned [1.2.4].
Hormones and Anti-Androgens
This category includes drugs that directly manipulate the endocrine system, often for treating prostate cancer or benign prostatic hyperplasia (BPH).
- 5-Alpha Reductase Inhibitors (Finasteride, Dutasteride): Used for BPH and hair loss, these drugs block the conversion of testosterone to dihydrotestosterone (DHT). This leads to an increase in testosterone, which can then be aromatized to estrogen, raising the risk of gynecomastia [1.2.4].
- Anti-Androgens (Bicalutamide, Flutamide): These prostate cancer drugs work by blocking androgen receptors. This not only directly inhibits androgen action but can also cause a reflexive increase in testosterone that gets converted to estradiol. The frequency of gynecomastia with these agents can be as high as 40–70% [1.2.4].
- Anabolic Steroids and Androgens: The use and abuse of these substances can lead to gynecomastia because they can be aromatized into estrogens [1.2.4].
Psychoactive Medications
Many drugs used for mental health conditions can cause gynecomastia, often by increasing prolactin levels.
- Antipsychotics: First-generation antipsychotics (e.g., haloperidol) and certain second-generation ones, particularly risperidone and paliperidone, are strongly associated with gynecomastia [1.2.4, 1.5.2]. They block dopamine D2 receptors, leading to hyperprolactinemia [1.2.4]. Risperidone is implicated in a very high number of reported cases [1.5.2].
- Antidepressants: Tricyclic antidepressants and some SSRIs (e.g., fluoxetine, sertraline) can also cause this side effect, though the risk is generally considered low for SSRIs (<1% for sertraline) [1.2.6, 1.2.1].
- Anti-Anxiety Medications: Diazepam (Valium) has been reported to induce gynecomastia [1.2.1, 1.6.3].
Other Notable Drug Classes
- Antiulcer Medications: H2-receptor blockers like cimetidine are well-known causes due to their anti-androgenic effects [1.2.5]. Proton pump inhibitors (PPIs) such as omeprazole have also been implicated [1.2.1].
- Antimicrobials: The antifungal ketoconazole inhibits testosterone synthesis [1.2.5]. Some antiretroviral therapies for HIV, particularly efavirenz, are also associated with gynecomastia [1.6.3].
- Chemotherapy Agents: Various cytotoxic agents can cause gynecomastia through Leydig cell damage, leading to primary hypogonadism [1.2.5].
| Drug Class | Common Examples | Primary Mechanism | Reported Incidence / Strength of Association |
|---|---|---|---|
| Diuretics | Spironolactone | Androgen receptor antagonism, inhibits testosterone synthesis [1.2.5] | Good evidence; up to 9-29% in some studies [1.2.6] |
| Anti-Androgens | Bicalutamide, Flutamide | Androgen receptor antagonism [1.2.5] | Good evidence; 40-70% [1.2.4] |
| 5-Alpha Reductase Inhibitors | Finasteride, Dutasteride | Inhibition of testosterone to DHT conversion [1.2.4] | Good evidence; significant increase over placebo [1.5.6] |
| Antipsychotics | Risperidone, Haloperidol | Elevated serum prolactin via dopamine antagonism [1.2.5, 1.2.4] | Good/Fair evidence; Risperidone is most frequently reported [1.5.2] |
| Antiulcer Drugs | Cimetidine, Omeprazole | Androgen receptor antagonism (Cimetidine); unknown (Omeprazole) [1.2.5, 1.2.1] | Good evidence for Cimetidine; Fair for Omeprazole [1.2.7] |
| Antiretrovirals | Efavirenz | Estrogen-like properties [1.6.3] | Fair evidence [1.2.7] |
Diagnosis and Management
If drug-induced gynecomastia is suspected, a healthcare provider will conduct a physical exam and review the patient's full medication list, including over-the-counter drugs and supplements [1.4.1, 1.7.1]. Blood tests to check hormone levels (testosterone, estradiol, LH, prolactin), liver function, and renal function may be ordered to rule out other causes [1.7.1].
The primary management strategy is to discontinue the offending medication, if clinically possible [1.4.3, 1.8.5]. In many cases, especially if caught within the first year, breast tissue enlargement may regress on its own after stopping the drug [1.8.1, 1.8.4]. A reduction in tenderness can often be noticed within a month [1.8.4]. If the medication cannot be stopped, switching to an alternative drug with a lower risk of gynecomastia is an option (e.g., switching from spironolactone to eplerenone) [1.4.4].
If gynecomastia persists for more than a year, fibrosis (scarring) can occur, making it unlikely to resolve without intervention [1.8.1]. In such chronic or severe cases, or if the condition causes significant psychological distress, further treatment may be considered [1.4.2].
- Medical Therapy: Off-label use of medications like tamoxifen (a SERM) can be effective in reducing breast tissue, especially in painful or recent-onset cases [1.4.5, 1.4.1].
- Surgical Intervention: For long-standing, fibrotic gynecomastia that doesn't respond to other measures, surgical removal of the glandular tissue (subcutaneous mastectomy) may be necessary [1.4.2, 1.8.4].
Conclusion
Drug-induced gynecomastia is a common and often reversible side effect of many medications. It stems from a disruption in the balance of estrogen and androgen hormones. Numerous drugs, from cardiovascular agents like spironolactone to antipsychotics like risperidone, are known culprits. Recognizing the association between a medication and the onset of breast enlargement is key. The first line of management is always to review and, if possible, discontinue or substitute the causative drug under medical supervision. If the condition persists, medical or surgical options are available to address both the physical and psychological impact.
For more detailed information from a professional medical source, you can visit the Merck Manual page on Gynecomastia.
