Pituitary Enlargement and Hypopituitarism in Patients Treated with Immune Checkpoint Inhibitors: Two Sides of the Same Coin?

**Background:** Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but can cause immune-related adverse events (IRAEs), including immunotherapy-induced hypophysitis (IIH). IIH presents diagnostic and management challenges, particularly in distinguishing it from ICI-induced hypopituitarism without radiological findings. The role of autoantibodies and the optimal therapeutic approach remain areas of active investigation.

**Methods:** This retrospective observational study was conducted across four hospitals in Rome, Italy. Nine patients meeting inclusion criteria (IIH diagnosis, age ≥18 years, available serum at diagnosis) were enrolled. All patients underwent contrasted pituitary MRI using a standardized 1.5 T protocol with thin-section images before and after gadolinium administration. Endocrine assessment included measurement of TSH, free triiodothyronine, free tetraiodothyronine, ACTH, cortisol, IGF-I, prolactin, LH, FSH, testosterone (males), and estradiol (females). Anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) were measured using indirect immunofluorescence on monkey hypophysis and hypothalamus slides at a dilution of 1:8.

**Key Results:** Nine patients were included (6 male, 66.7%; mean age 59 years, SD 16.8, range 41-83). Seven had metastatic melanoma (grade 4), one had metastatic lung adenocarcinoma (grade 4a), and one had metastatic kidney adenocarcinoma (grade 4). Six patients received nivolumab and three received ipilimumab. All patients developed new-onset asthenia after a mean of 7.5 ICI cycles (SD 5.9, range 3-19). Secondary hypoadrenalism was diagnosed in all 9 patients (100%). No patient had prior endocrine or autoimmune disorders. Pituitary MRI showed anterior pituitary enlargement with non-homogeneous contrast enhancement in 2 cases (22.2%) and no pathological features in 7 cases (77.8%). All patients received hydrocortisone replacement; 2 patients required parenteral hydrocortisone and hospitalization. ICI was withdrawn in 2 patients until clinical stability was achieved. High-dose immunosuppressive glucocorticoids were never prescribed. At 3-month follow-up, pituitary enlargement had spontaneously resolved in both affected patients. Central hypoadrenalism persisted in all patients at last examination. APA were positive in 57.1% of cases and AHA in 85.7% of cases. Patients with radiological hypophysitis were more frequently female, while those without radiological findings were more frequently male. Six patients were partially or completely ICI-responsive; one experienced cancer progression.

**Clinical Implications:** This study identifies two distinct clinical phenotypes of IIH: one with radiological pituitary enlargement and one with isolated hypopituitarism without MRI abnormalities. The presence of anti-pituitary and anti-hypothalamus antibodies in both groups suggests shared autoimmune mechanisms. The finding that patients with radiological hypophysitis were more frequently female and treated with ipilimumab (a CTLA-4 inhibitor) aligns with known CTLA-4 expression on pituitary cells. The persistence of hypoadrenalism in all patients despite resolution of pituitary enlargement suggests permanent pituitary damage. The study's small sample size (n=9) and lack of pituitary tissue pathology are major limitations. Multidisciplinary management by endocrinologists and oncologists is essential to avoid unnecessary ICI withdrawal and high-dose glucocorticoid administration, which may negatively impact cancer prognosis. Larger molecular studies are needed to clarify whether IIH and ICI-induced hypopituitarism represent different manifestations of the same disease or distinct entities.