Pituitary Adenoma Risk Factors Include Female Sex, Non-Missense Variants in MEN1

Prior primary hyperparathyroidism, non-missense pathogenic variants, and female sex are associated with increased risk for pituitary adenoma among patients with multiple endocrine neoplasia type 1 (MEN1), according to study results published in The Journal of Clinical Endocrinology & Metabolism.

In a multicenter nationwide study, researchers used data from the Spanish Online Registry on Multiple Endocrine Neoplasia and Pheochromocytoma and Paragangliomas (MENPhePar Registry), which includes demographic, clinical, radiological, histological, and genetic data on MEN1 patients. Patients were diagnosed according to MEN1 clinical guidelines, and genetic testing was performed in most cases. Pituitary adenomas were classified by size (Hardy’s classification) and function (secreting vs non-secreting).

Among 240 patients from 57 unrelated families, the median follow-up was 6 years. The patients were either index cases (28.3%), identified through biochemical screening (17.9%), or identified through genetic screening (53.8%). Additionally, 74.6% of the diagnoses were made after 1999, and 49.6% were made after 2010. A MEN1 germline pathogenic variant was identified among 95.3% of patients, of whom 58 had distinct pathogenic variants and 14 had novel variants.

Pituitary adenomas occurred among 46.6% of patients at a mean (SD) age of 36.1 (13.9) years, with an age-related penetrance of 50% reached at a mean (SD) age of 50.0 (3.6) years (95% CI, 42.7-57.2). Pituitary adenomas were more common among women vs men (54.5% vs 36.8%; P =.005), who also reached 50% penetrance earlier (mean [SD] age, 46.0 [3.9] vs 66.0 [11.3] years; P =.016). Coexisting primary hyperparathyroidism and adrenal tumors were more frequent among patients with pituitary adenomas. Nonsense and non-identified pathogenic variants were enriched in pituitary adenoma cases, whereas missense pathogenic variants were more common in the absence of pituitary adenomas.

Among all patients with pituitary adenomas, 36.6% were diagnosed before MEN1 (median gap, 4 years; mean [SD] age, 40.2 [14.8] years). Screening detected 63.3% of all pituitary adenomas (23.1% at first MEN1 assessment; 21.1% during median follow-up of 7.0 years). Incidence peaked between the third and fourth decades (45%) and declined thereafter.

For the screened cohort, 50% penetrance occurred at a mean (SD) age of 60.4 (2.3) years and occurred earlier among women vs men (55.1 [3.0] vs 64.2 [2.9] years; P =.007). Of 112 pituitary adenomas, 62.5% were secreting. Prolactinomas were the most common type (49.1%), showed earlier penetrance than other pituitary adenomas (31.0 vs 67.0 years; P <.001), and were more frequent among women vs men (76.4% vs 23.6%; P <.001).

Microadenomas predominated (68.7%) and were mainly screen-detected, whereas macroadenomas were more often pre-MEN1. Micro- vs macro-nonfunctioning pituitary adenoma penetrance differed (mean age, 46.0 vs 61.0 years; P =.005). Non-missense vs missense pathogenic variant carriers were more likely to have pituitary adenomas (51.3% vs 26.3%; P =.001), receive pituitary adenoma diagnosis at an earlier age (50.5 vs 58.4 years; P =.011), and have prolactinomas (26.3% vs 8.8%; P =.003).

Multivariable predictors of pituitary adenoma included:

• Younger age (hazard ratio [HR] per year, 0.916; 95% CI, 0.934-0.993; P <.001);
• Prior hyperparathyroidism (HR, 3.090; 95% CI, 1.943-4.914; P <.001);
• Non-missense pathogenic variants (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).

Study limitations include biases due to the retrospective nature of the study, variability and inconsistencies due to retrieval of data from assessments conducted by referring physicians, and the derivation of findings from a single national registry.

The study authors concluded, “These findings could assist clinicians in better informing patients about their individual risk and in guiding personalized [pituitary adenoma] screening strategies.”

This article originally appeared on Endocrinology Advisor