A 62-year-old man comes to the office due to decreased libido and failure to achieve satisfactory erections. The patient has coronary artery disease and heart failure with reduced ejection fraction and was prescribed spironolactone therapy several months ago. Other medications include aspirin, lisinopril, furosemide, and metoprolol. Blood pressure is 110/70 mm Hg and pulse is 70/min. Oxygen saturation is 95% on room air. Examination shows a left ventricular S3 and trace pitting ankle edema. Breast examination demonstrates bilateral enlargement with mild tenderness. Which of the following is the most likely cause of this patient's current symptoms?
Medication-induced gynecomastia* | |
Drug | Mechanism |
Estrogens | Direct stimulation of ductal epithelial hyperplasia |
Antiandrogens | Competitive inhibition of testosterone receptor |
5-alpha reductase | ↓ Conversion of testosterone to dihydrotestosterone |
Spironolactone | ↓ Testosterone synthesis & inhibition of testosterone receptor |
Ketoconazole | ↓ Synthesis of steroid hormones (↓ androgen > ↓ estrogen) |
Cimetidine | Inhibition of testosterone receptor |
Androgen-anabolic | Aromatization of androgens to estrogen |
*Drugs that increase the estrogen/testosterone ratio are associated with gynecomastia. | |
This patient has gynecomastia and hypogonadal symptoms (eg, decreased libido, erectile dysfunction) after starting spironolactone, an aldosterone antagonist that acts as a potassium-sparing diuretic. In patients with heart failure, it reduces retention of sodium and water and attenuates the pathologic cardiac remodeling and deterioration in left ventricular function caused by local effects of aldosterone.
However, spironolactone also has broad antiandrogenic effects due to blockade of the androgen receptor and decreased testosterone production. Gynecomastia is abnormal growth of male breast tissue caused by an increase in the physiologic estrogen/androgen ratio and is a common adverse effect of spironolactone. Eplerenone, a more selective aldosterone antagonist, has fewer endocrine adverse effects and can be used in place of spironolactone.
(Choice A) Estrogens are metabolized primarily in the liver, largely by cytochrome P-450 enzymes. Patients with cirrhosis have diminished metabolism of estrogen, leading to gynecomastia and other signs of hyperestrogenism (eg, spider angiomas). However, spironolactone does not affect hepatic estrogen metabolism.
(Choice B) Continuous administration of GnRH agonists (eg, leuprolide), such as in patients with metastatic prostate cancer, suppresses the release of FSH and LH, which leads to lower testosterone levels. FSH and LH are also suppressed by starvation, leading to lower testosterone production and possible gynecomastia.
(Choice D) Sex hormone–producing adrenal tumors are rare neoplasms that can produce excessive quantities of androgens, estrogens (leading to gynecomastia), or both. Spironolactone decreases testicular production of testosterone, but adrenal estrogen production is not significantly increased.
(Choice E) Secretion of hCG by testicular germ cell tumors impairs testosterone production in testicular Leydig cells while increasing aromatase activity and conversion of androgens to estrogens; the increased estrogen/androgen ratio can cause gynecomastia.
Educational objective:
Spironolactone is an aldosterone antagonist commonly used to treat heart failure. It has significant antiandrogenic effects and can cause gynecomastia, decreased libido, and impotence. Eplerenone is a more selective aldosterone antagonist with fewer adverse effects.