Clinical Features and Management Framework for Refractory Hypophysitis: A Cohort Study

BACKGROUND: Glucocorticoid (GC) therapy is the cornerstone therapy for primary autoimmune hypophysitis (PAH), yet treatment failure and relapse are common. The concept and optimal management of "refractory" PAH remain undefined. OBJECTIVE: To define the clinical entity of refractory PAH, identify its distinguishing features, develop an exploratory screening model, and propose a structured management pathway based on treatment outcomes. METHODS: A retrospective cohort study of 100 PAH patients was conducted. Refractory PAH was defined as primary GC resistance or recurrence during tapering (GC-dependent). Twenty-two patients met these criteria. Baseline characteristics were compared between groups, and a exploratory screening model developed. RESULTS: Among 100 patients with hypophysitis, 22 (22%) met the criteria for refractory disease, including 19 with GC-dependent and 3 with GC-resistant hypophysitis. Compared with the non-refractory group, GC-dependent refractory hypophysitis was characterized by a lower prevalence of pregnancy-associated hypophysitis (5.9% vs. 41.7%, p=0.006), higher serum prolactin levels (median 30.2 ng/mL vs. 17.8 ng/mL, p=0.021), a higher prevalence of hypogonadotropic hypogonadism (82.4% vs. 55.4%, p=0.040), and a larger median pituitary stalk diameter (5.5 mm vs. 3.7 mm, p=0.043). No significant differences were observed between the GC-resistant group and the non-refractory group. Combination therapy with immunosuppressive agents (e.g., mycophenolate mofetil) or rituximab was effective in achieving radiological control. Glucocorticoid-related adverse events occurred in 40.9% of patients, most commonly hyperlipidemia and hyperglycemia. CONCLUSION: This study defines and characterizes refractory PAH. The distinct clinical characteristics and the proposed structured diagnostic-therapeutic pathway offer a framework for managing this challenging condition.