Background/Objectives: Non-functional pituitary macroadenomas (NFPMA) are uncommon pituitary lesions that do not cause hormonal hypersecretion and are most often discovered at the macroadenoma stage. Consequently, they are more challenging to diagnose, often mimicking other non-secreting sellar masses, among which hypophysitis should be carefully considered. This study aimed to differentiate between non-functioning pituitary macroadenomas (NFPMA) and hypophysitis, two distinct sellar pathologies with overlapping MRI features, by developing a diagnostic score based on clinical, biological, and radiological criteria. Methods: We conducted a prospective study, including 56 patients with NFPMA and 16 patients with hypophysitis primarily of the lymphocytic subtype. A total of 31 clinical, biological, and radiological variables were analyzed using univariate and multivariate statistical methods to identify significant predictors and to establish a diagnostic score. Results: Nine significant criteria were identified: female sex, headaches, visual disturbances, corticotropic insufficiency, pituitary volume ≤ 7 cm³, loss of the posterior pituitary bright spot, cavernous sinus invasion, optic pathway compression, and pituitary stalk thickening. The established score demonstrated significant performance in predicting the diagnosis of hypophysitis (p < 0.001; Area Under the Curve = 0.967; 95% CI = 0.926–1). The sensitivity and specificity of this score were 93.8% and 87.5%, respectively, using a threshold ≥0.5. The median score was −2 (interquartile range = [−3.5; 0.5]), with extremes ranging from −6.5 to 9. Among these, pituitary stalk thickening emerged as a key diagnostic indicator. Conclusions: This simple and effective multi-parametric score enables rapid and accurate differentiation of hypophysitis from NFPMA, helping to avoid unnecessary surgical interventions and to improve the management of pituitary insufficiencies and may be especially valuable in settings when biopsy is unavailable or risky.

Background: Differentiating hypophysitis from non-functioning pituitary macroadenomas (NFPMA) remains a clinical and radiological challenge. Both entities present as sellar masses with overlapping features but require distinct therapeutic approaches. Accurate preoperative identification is necessary to avoid unnecessary surgery in inflammatory forms. This review aims to compare the clinical, endocrine, and imaging characteristics of hypophysitis and NFPMA, incorporating recent findings and evaluating the performance of three diagnostic scoring systems currently in use. Methods: A comprehensive narrative literature review was conducted using original articles, clinical series, radiological studies, and systematic reviews retrieved from international databases. The analysis focused on demographic characteristics, clinical presentation, hormonal profiles, magnetic resonance imaging (MRI) features, and the comparative evaluation of the three published diagnostic scoring systems designed to differentiate hypophysitis from NFPMA. Results: Hypophysitis predominantly affects women, particularly during late pregnancy or the postpartum period, and is frequently associated with autoimmune diseases. Corticotropic deficiency and central diabetes insipidus (CDI) are disproportionately frequent in hypophysitis, whereas somatotropic deficiency is more characteristic of NFPMA. Radiologically, hypophysitis typically appears as a smaller, symmetric, and homogeneous mass with intense, uniform contrast enhancement, associated with pituitary stalk thickening and loss of the posterior pituitary bright spot. In contrast, NFPMA generally present as larger, asymmetric, and heterogeneous lesions, frequently invading the cavernous sinus and compressing the optic chiasm. Analysis of the three diagnostic scores indicates that combining clinical, hormonal, and imaging data improves accuracy compared to relying on single features. The most recent score includes hormonal markers, which significantly enhance sensitivity and specificity, emphasizing the importance of integrated assessment. Conclusions: No single clinical, hormonal, or imaging feature is pathognomonic. However, integrating clinical context, endocrine profile, imaging characteristics, and validated diagnostic scores significantly enhances preoperative diagnostic accuracy. The systematic use of composite scores may help optimize therapeutic decision-making and reduce unnecessary surgical interventions in patients with hypophysitis.