Reconsidering Diagnostic Cutoffs for Prolactin in Pituitary Adenomas: Impact of Sex, Age, and Tumor Size

Objective: To assess the relationship between prolactin levels (PRL), and patient sex, age and tumor size in a large surgical cohort of prolactinomas and clinically non-functioning pituitary tumors (CNFs), testing the adequacy of commonly referenced diagnostic PRL cutoffs. Methods: Medical records from a quaternary referral center were reviewed for patients undergoing first-time resection of a pituitary neuroendocrine tumor (PitNET) with pathologic diagnosis of prolactinoma or CNF. Patients with ACTH- or GH-secreting tumors were excluded. Maximum preoperative PRL (ng/mL) was recorded. Preoperative MRI was reviewed for maximum diameter, and volume was estimated by the ABC/2 method. Statistical analyses were performed in R (v4.5.1). Results: A total of 459 patients met inclusion criteria, including 119 prolactinomas (25.9%) and 340 CNFs (74.1%); 238 were female (51.9%) and 221 male (48.1%, Table 1 ). • Prolactin levels: Median maximum PRL was higher in prolactinomas than CNFs—female: 100.9 ng/mL (IQR 63.4–181.8) vs 26.8 (10.9–56.2); male: 157.0 (48.3–1200.0) vs 16.3 (10.2–25.3); all p < 0.001—yet with substantial overlap between groups. • Sex differences: In CNFs, women had higher PRL than men (median 26.8 vs 16.3 ng/mL, p < 0.001, Fig. 1A ). After normalizing PRL to tumor volume, females also had significantly higher values than males in both CNF and prolactinoma groups (both p < 0.001, 1B). • Tumor size: Prolactinomas were smaller in women than men at surgery (median diameter 9 mm vs 19 mm, p < 0.001, 1C), consistent with earlier, symptom-driven detection (e.g., amenorrhea). CNFs presented as macroadenomas of comparable size in both sexes. There were distinct sex-specific patterns in PRL to tumor size relationship per pathology (1D). • Age correlations: PRL negatively correlated with age in women for both prolactinomas (R≈–0.30, p = 0.004) and CNFs (R≈–0.30, p < 0.001) ([ Fig. 2 ]). In men, correlations were weaker and not significant (CNF R≈–0.15; prolactinoma R≈–0.30). • Tumor size and age: When PRL was examined relative to tumor size across age quartiles, distinct sex-specific patterns emerged ([ Fig. 3 ]). Men and women demonstrated differing trends in both prolactinoma and CNF groups, highlighting the complex interplay of biology, tumor burden, and age in shaping PRL secretion. • Outliers: Although categorized as CNFs for analytic clarity, mammosomatotrophs (PIT1-lineage) tumors sometimes secreted PRL at prolactinoma-like levels, representing notable outliers within the CNF group. Conclusion: PRL secretion in pituitary adenomas is not determined by pathology alone; sex, age, and tumor size materially shape serum levels, creating overlap between prolactinomas and CNFs. A single diagnostic PRL cutoff is therefore inadequate. Integrating patient sex, age, and tumor size into PRL interpretation may improve diagnostic accuracy, minimize unnecessary dopamine-agonist trials in non-prolactinomas, expedite neurosurgical referral when appropriate, and enhance patient counseling. Fig. 1 Fig. 2 Fig. 3 Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany