Risk Factors for Pituitary Adenoma Development in Multiple Endocrine Neoplasia Type 1: A Nationwide Study of 240 Cases

Abstract Objective Pituitary adenomas (PAs) are one of the three major lesions in Multiple Endocrine Neoplasia type 1 (MEN1), with a prevalence of 32% to 58%, yet their specific risk factors remain unidentified. This study aimed to identify predictors influencing PA occurrence in MEN1. Methods This nationwide, multicenter, retrospective cohort study involved 240 MEN1 patients, 55.8% female. The main variables were age-related penetrance, PA subtype and size, and MEN1 germline pathogenic variants (PVs). The primary outcome was PA development. Cox regression was applied first to the full cohort and then to a prospectively screened subgroup (n = 199) free of symptom-driven bias. Results PAs were detected in 112 (46.6%) patients at a mean age of 36.1 ± 13.9 years; most (63.3%) were diagnosed through screening. Prolactinomas (49.1%) and microadenomas (62.5%) predominated. In the full cohort, the following independent factors were related to PA development: age (per additional year; HR 0.916, 95% CI 0.893-0.993; P < .001), prior primary hyperparathyroidism (HR: 3.090, 95% CI: 1.943-4.914, P < .001), non-missense MEN1 PVs (HR: 1.976, 95% CI: 1.125-3.468, P = .018), and female sex (HR: 1.706, 95% CI: 1.082-2.689, P = .022). The same factors remained significant in the screened subgroup. Conclusion Risk of PA in MEN1 clusters at younger ages and declines thereafter. Prior primary hyperparathyroidism, non-missense MEN1 PVs, and female sex further mark higher-risk profiles. These findings may help personalize PA follow-up—prioritizing closer imaging in early adulthood and allowing longer intervals when baseline imaging is normal and additional risk markers are absent—pending validation in larger multicenter studies.