Non–Prostate Cancer‐Related Factors That Influence Serum Prostate‐Specific Antigen: A Narrative Review of 45 Non‐Malignant PSA Modifiers

Background To consolidate into a single review more than forty non‐cancer‐related factors that have been found to elevate or reduce prostate‐specific antigen (PSA) levels in the peer‐reviewed literature, emphasizing their contribution to false‐positive and false‐negative clinical interpretations. Materials and Methods A narrative literature review was conducted using PubMed, focusing on human studies describing benign physiologic, infectious, inflammatory, iatrogenic, hormonal, pharmacologic, and laboratory‐related factors that influence PSA values. The review emphasizes contemporary studies but incorporates earlier foundational literature where relevant. Results Forty‐five non‐cancer‐related factors were identified that influence PSA values through biologic, mechanical, pharmacologic, or analytic mechanisms. Thirty factors were associated with transient or persistent PSA elevation, whereas fifteen were associated with PSA reduction. Some factors varied substantially in the strength, magnitude, and consistency of reported PSA effects across studies. PSA elevations were reported in association with prostatic inflammation or infection, urinary retention, ejaculation, non‐instrumental prostatic physical stimulation, urologic instrumentation, and systemic inflammatory conditions. PSA reductions were observed with medications including 5‐alpha‐reductase inhibitors, nonsteroidal anti‐inflammatory drugs, statins, thiazide diuretics, metformin, and certain lifestyle factors. Inter‐assay and inter‐laboratory variability alone has been reported to result in PSA differences exceeding 20%. Tables summarizing the approximate magnitude and duration of PSA change for each modifier were developed, along with a patient questionnaire intended to support, not replace, clinician judgment. Conclusion PSA interpretation must incorporate awareness of more than forty influencers that can alter PSA independent of any malignancy. Accounting for these PSA level‐altering variables can improve PSA test result specificity and enhance confidence in prostate cancer risk assessment. Use of a structured patient questionnaire, a thorough consideration of benign factors that can alter PSA, repeat testing when transient factors are present, and consistent blood assay methodology can reduce unnecessary imaging, unneeded biopsies, and missed malignancies.