In a 79-year-old obese man with low total and free testosterone who is taking spironolactone and has developed gynecomastia, what is the most appropriate next step in management?

Management of Spironolactone-Induced Gynecomastia

The most appropriate next step is to discontinue spironolactone and switch to an alternative potassium-sparing agent such as eplerenone, which has a significantly lower risk of gynecomastia due to reduced anti-androgenic activity. 1, 2

Understanding Spironolactone-Induced Gynecomastia

Spironolactone is definitively associated with gynecomastia, with approximately 9% of male patients developing this adverse effect at typical doses (mean 26 mg daily in heart failure trials), and the risk increases in a dose-dependent manner. 1, 3 The mechanism involves dual anti-androgenic effects: spironolactone both impairs testicular testosterone biosynthesis and directly inhibits androgen receptor binding at target tissues, without affecting 5α-reductase activity. 4 Onset varies widely from 1-2 months to over a year, and the condition is usually reversible upon discontinuation. 1

Immediate Management Algorithm

Step 1: Discontinue Spironolactone

• Stop spironolactone immediately, as gynecomastia typically resolves within 1 month of drug cessation, with pain subsiding first followed by reduction in breast tissue size. 2
• The FDA label explicitly warns that gynecomastia is a known adverse effect that occurs in a dose-dependent manner and is usually reversible. 1

Step 2: Switch to Eplerenone

• Initiate eplerenone as a safer alternative, which is a selective aldosterone antagonist with minimal anti-androgenic activity and therefore substantially lower gynecomastia risk. 2
• Eplerenone provides equivalent potassium-sparing and aldosterone-blocking effects without the sex hormone interference that characterizes spironolactone. 2

Step 3: Monitor for Resolution

• Expect pain resolution within 2-4 weeks and gradual reduction in breast tissue size over the following 1-3 months after spironolactone discontinuation. 2
• If gynecomastia persists beyond 3-6 months after stopping spironolactone, measure serum estradiol to evaluate for other causes, as recommended by the AUA for men presenting with breast symptoms. 5

Diagnostic Workup for Persistent Gynecomastia

If gynecomastia does not resolve after spironolactone discontinuation, the following evaluation is warranted:

• Measure serum estradiol prior to any testosterone therapy consideration, as men with elevated baseline estradiol should be referred to endocrinology. 5
• Assess testosterone status with two separate morning measurements (8-10 AM) if hypogonadism is suspected, along with LH and FSH to distinguish primary from secondary hypogonadism. 5, 6
• Consider pituitary imaging if testosterone is <150 ng/dL with low or low-normal LH, as non-secreting adenomas may be present. 5

Critical Pitfalls to Avoid

• Do not continue spironolactone while attempting to manage gynecomastia with other interventions—the drug must be stopped for resolution to occur. 1, 2
• Do not assume bilateral presentation is required for drug-induced gynecomastia; spironolactone can cause unilateral gynecomastia, and clinicians should maintain high suspicion even with asymmetric presentation. 2
• Do not initiate testosterone therapy without first discontinuing spironolactone and allowing time for gynecomastia resolution, as testosterone therapy itself carries a risk of gynecomastia (listed as a potential side effect), particularly if estradiol levels rise during treatment. 5, 6
• Do not overlook the patient's age and obesity as contributing factors to potential underlying hypogonadism; at 79 years with obesity, he may have secondary hypogonadism from increased aromatization of testosterone to estradiol in adipose tissue, but this should only be addressed after resolving the spironolactone-induced gynecomastia. 6, 7

Long-Term Considerations

• Educate patients about gynecomastia risk before prescribing spironolactone, as this is a well-established adverse effect that should be discussed during informed consent. 2
• Reassure regarding cancer risk: despite spironolactone's association with gynecomastia, there is no evidence of increased breast cancer risk with long-term use (>1 year before diagnosis). 8
• Monitor potassium levels when switching from spironolactone to eplerenone, checking within 1 week of initiation and regularly thereafter, as both agents can cause hyperkalemia. 1