Case Presentation: A 70 year old female with metastatic melanoma presented to the emergency department with fatigue and lethargy for one month. She had recently completed 6 cycles of Nivolumab and Ipilimumab and was currently receiving Nivolumab monotherapy. Over the past month, she had worsening fatigue associated with nausea and decreased appetite. Lab work one week prior to admission was significant for newly elevated TSH and low T4, and thyroid replacement therapy was initiated. On the day of admission, she had a syncopal episode at home prompting presentation. On arrival, she was hypotensive to 89/57. Lab work was significant for hyponatremia, hypokalemia, and hypochloremia. An AM serum cortisol was 1.5 and ACTH level was undetectable. FSH and LH levels were also low. An MRI of the brain was notable for enhancement of the pituitary gland suggestive of hypophysitis, which was likely a side effect of her immunotherapy. She was given stress dose hydrocortisone for adrenal insufficiency, and improved with slow taper of steroids.

Discussion: Nivolumab and Ipilimumab are novel immunotherapeutic agents that are currently used for metastatic melanoma and squamous lung carcinoma. Nivolumab antagonizes the binding of Programmed Cell Death Ligand 1 to the programmed cell death 1 receptor (PD-1), activation of which would normally promote T-cell apoptosis. Ipilimumab antagonizes the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), preventing down regulation cytotoxic T lymphocytes. Endocrinopathies are relatively common side effects of checkpoint inhibitors and are thought to be result of auto-immune inflammation. They can manifest as primary hyper/hypothyroidism, primary adrenal insufficiency and/or hypophysitis thereby affecting the multiple hormonal systems. A retrospective review from Memorial Sloan Kettering showed an incidence of hypophysitis of 8% and thyroiditis of 6% following treatment with ipilimumab. The incidence of hypophysitis and thyroiditis increased to 9% and 22% respectively in patients who received combination therapy with ipilimumab and nivolumab. Our patient seemingly developed primary hypothyroidism and hypophysitis causing a secondary adrenal insufficiency secondary to her combination therapy. The initiation of levothyroxine therapy likely precipitated her adrenal insufficiency leading to her syncopal event. 

Conclusions: Ipilimumab and Nivolumab are novel immunotherapeutic agents used in the treatment of melanoma, with research investigating their use into other malignancies as well. Endocrinopathies are relatively common side effects of these agents, especially when given as combination therapy. Non-specific complaints, such as fatigue and nausea in our patient, should warrant a thorough investigation for endocrinopathies in patients with treatment exposure to ipilimumab and/or nivolumab.