Immune-Related Adverse Events (irAEs) - Hypophysitis

Primarily seen with anti-CTLA-4, estimated prevalence of 3.2%. Rarely with anti-PD-1/PD-L1 agents (0.5%).

 • Mechanistically distinct from other irAEs; thought to be mediated by direct binding of ipilimumab to CTLA-4 expressed on normal cells of the anterior pituitary.

Timing: Median onset is 8 weeks

Signs/sx: Headaches (can be severe) most common; fatigue, N/V, dizziness, weight loss, hot flashes, cold intolerance, hyponatremia (anterior hypopituitarism); not associated with central diabetes insipidus (posterior pituitary spared)

 • Diagnosis: MRI brain/pituitary shows transient (generally resolved by 2 months), diffuse pituitary enlargement; test hormonal axes: 8AM serum cortisol + ACTH and/or cort stim; TSH w/ fT4/T4/T3; PRL; LH/FSH, serum testosterone/SHBG (in men); IGF-1.

Treatment: Symptoms resolve with appropriate hormone substitution; hormone deficiencies tend to persist

 • Hypocortisolism: physiologic glucocorticoid replacement (prednisone 3-5mg daily equivalent; increase x2-3 with infection/illness), high-dose glucocorticoids do not improve outcomes (may be associated with reduced survival); counsel about adrenal crisis; obtain medical bracelet

 • Hypothyroidism (can also occur independent of hypophysitis): thyroid hormone replacement with levothyroxine (hyperthyroidism can also occur, but rarer; consult endocrine)

 • Hypogonadism: consider testosterone replacement if persists

 • GH deficiency: GH theoretically contraindicated due to active malignancy, although no supportive evidence



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