# Association between the use of proton pump inhibitors and serum PSA levels in the general U.S. population

## TL;DR

This study found that proton pump inhibitors (PPIs) are linked to lower PSA levels in older U.S. men, contradicting previous suggestions of increased prostate cancer risk.

## Contribution

The study provides new population-level evidence that PPI use is associated with decreased PSA levels in older adults, not increased prostate cancer risk.

## Key findings

- PPI use was associated with a 0.24 ng/mL decrease in total PSA levels in older adults.
- No significant association was found between PPI use and free/total PSA ratio.
- The effect was observed only in participants aged 60 years or older.

## Abstract

Proton pump inhibitors (PPIs) are widely prescribed drugs that have been associated with increased prostate cancer (PCa) cell proliferation in vitro and worse oncological outcomes in vivo. However, data on their influence on PSA levels in the general population are lacking.

We extracted individual participant data from the 2001–2010 cycles of the National Health and Nutrition Examination Survey (NHANES), in which PSA levels were measured in all male participants aged 40 years or older. The association of PPI use with total PSA levels and free/total PSA ratio was evaluated through multivariable linear regression analyses, adjusted for potential confounders.

A total of 7366 subjects were included (median age: 53 years; median serum PSA: 0.9 ng/mL), of whom 746 were receiving PPI treatment at the time of the study. After adjustment for potential confounders, ongoing PPI use was associated with lower total PSA levels (-0.24 ng/mL, 95%CI: [-0.37,-0.11], p < 0.001), while no significant association with free/total PSA ratio was found (p = 0.881). A significant effect modification was observed according to age, with the association being limited to older participants (≥ 60 years) at stratified analyses.

Contrary to the available data in the context of PCa, we found no evidence of increased PSA levels in PPI users with no prostate malignancy. Instead, PPI use was associated with a decrease of total PSA in older adults. This adds knowledge on how PPIs may influence PSA in population-based screening programs.

The online version contains supplementary material available at 10.1007/s00345-025-05469-9.