Risk of Gynecomastia with Users of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are commonly prescribed for many gastrointestinal diseases. A number of case reports have linked PPIs to gynecomastia in men, but large epidemiologic studies are lacking.

To quantify the risk of gynecomastia with PPIs in male patients.

Using the PharMetrics Plus™ health claims database from the United States, a retrospective cohort study of new PPI users and new amoxicillin users from 2006 to 2016 was conducted. Diagnosis of gynecomastia was identified by the International Classification for Diseases, 9th edition (ICD-9) and 10th edition (ICD-10) codes. Cases were defined as patients with two codes for gynecomastia within 90 days, with the first code as the event code. Hazard ratios (HRs) were computed by adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, and obesity, as well as the use of ketoconazole, risperidone, spironolactone, and androgen deprivation therapy. A sensitivity analysis defining exposure with two PPI prescriptions was also undertaken.

There were 389 cases of gynecomastia diagnosed among 220,791 new PPI users, and 996 gynecomastia cases were diagnosed among 837,740 new amoxicillin users. The crude HR for PPI use compared to amoxicillin use was 1.70 (95% confidence interval [CI]: 1.461-1.976). The adjusted HR for the sensitivity analysis was 1.299 (95% CI: 1.146-1.473). The adjusted HR was 1.4795 (95% CI: 1.2431-1.7609) for patients over 50 years old and 1.324 (95% CI: 1.1133-1.5745) for patients 50 years old or younger.

This large retrospective cohort study suggests that patients who used PPIs are at higher risk of developing gynecomastia. Clinicians may want to convey this information to male patients who require long-term PPI therapy.