Endocrine Abstracts

Aim: To describe 2 cases of immune-mediated hypophysitis due to the therapeutic use of Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA4)-blocking antibody.

Case 1: A 62 year-old male with history of metastatic melanoma was started on Ipilimumab. After finishing the 4th at 2 months he complained of weakness, fatigue, and fever, prescribed ciprofloxacin and prednisone 20 mg daily, and felt better. 2 days later he was hospitalized with weakness, BP 86/65 mmHg and temperature 101.7F. TSH was 0.050 uIU/ml, free T4 0.48 ng/dl, and free T3 1.20 pg/ml FSH 1.2 mIU/ml, LH 0.8 mIU/ml, and prolactin 0.3 n/ml (all low). A Cosyntropin Stimulation Test showed the following cortisol levels (in ug/dl): baseline 2.60, 30 min post-injection 6.30, and 60 min post-injection 7.90. Pituitary MRI was normal. The clinical picture was consistent with severe, recent-onset panhypopituitarism. The patient was treated with IV fluids, stress-dose dexamethasone, and levothyroxine, and discharged on hormonal replacement. He continues to do well on multi-hormonal endocrine replacement therapy.

Discussion: Ipilimumab (Yervoy*) is a monoclonal CTLA4 antibody and immune checkpoint protein-modulator approved for treatment of melanoma, and being studied in lung, prostate, and bladder cancer. Mechanisms of overcoming tumor-induced immune tolerance trigger ‘Immune-related adverse events’ (IRAEs) as side effects from autoimmunity and disruption of self-tolerance. They include colitis/diarrhea, dermatitis, hepatitis, and endocrinopathies (hypophysitis (0–17%), thyroid dysfunction (0–4%) and primary adrenal insufficiency (0.3–1.5%). Ipilimumab-associated hypophysitis is a new form of autoimmune pituitary disease with an average time of 11 weeks after starting therapy, suggesting a cumulative effect. Patients may present with weakness, headache, nausea, anorexia, confusion, memory loss, behavior change, hallucinations, visual impairment, loss of libido, temperature dysregulation, fever, and chills. Hormone levels show varying degrees of hypopituitarism, and MRI may be normal or reveal pituitary gland enlargement and thickening of the stalk. Symptoms resolve after withdrawal of the drug and starting hormone replacement; however, pituitary function may be impaired for considerably longer or even lifelong.

Conclusion: The increasing use of immune checkpoint inhibitors such as ipilimumab is an emerging cause of hypophysitis that generalists, ER physicians, oncologists, and endocrinologists need to be aware of.