Case Presentation: A 55-year-old female with a history of renal cell carcinoma treated with left-nephrectomy and Pembrolizumab-immunotherapy presents with complaints of weakness, orthostatic hypotension, nausea, and vomiting with food aversion. She had been admitted with similar complaints 9 times since her left nephrectomy, each time having received full workups including extensive sub-specialty evaluations including cardiology, gastroenterology, pain medicine, neurology, oncology, and hematology, to no avail. On admission, the patient was found to be hypoglycemic, and hypotensive with orthostatic vital signs. This constellation of symptoms was initially concerning for an adrenal insufficiency picture. Initial endocrine workup demonstrated a low AM cortisol of 0.9 ug/dL, with a low ACTH at 5.0 pg/mL. Given these findings, concern for central adrenal insufficiency was increased. Further endocrine workup included a cosyntropin stimulation test, which resulted in a stepwise increase in cortisol in 30-60-90 minute intervals after cosyntropin administration, confirming central etiology. This was followed by an MRI-sella, which was negative for pituitary masses, however, it resulted positive for hypophysitis, which was ultimately attributed as a side effect of her prior immunotherapy with Pembrolizumab. She was subsequently trialed and discharged on hydrocortisone, which provided both immediate and lasting relief of the patient’s symptoms.
Discussion: Immune checkpoint inhibitors (ICIs) such as Pembrolizumab have swiftly emerged as the primary therapeutic choice for the treatment of various cancers, consequently giving rise to the emergence of multiple cited endocrinopathies. Of various side effects of the ICIs, hypophysitis resulting from the use of single-agent programmed cell death protein-1 (PD-1) inhibitors is an exceedingly infrequent occurrence; the estimated incidence constitutes a mere 0.5% of the treated population [1].Our patient presents a unique clinical picture of hypophysitis secondary to Pembrolizumab, a single-agent PD-1 inhibitor. The observations in this case diverge from the prevailing pattern, as most side effects involving ICIs predominantly affect the thyroid, with hypophysitis being the least common side effect, even more so in the case of anti-PD1 agents [1,2]. To the best of our knowledge, this patient represents a unique case, being the first to manifest these symptoms in the context of Pembrolizumab monotherapy specifically for renal cell carcinoma, as well as being the first case involving a patient who has undergone both unilateral nephrectomy and adrenalectomy in this context. Interestingly, our patient’s late presentation of persistent symptoms being almost 5 months removed from ending Pembrolizumab treatment suggests that the drug can cause lasting effects on the hypothalamic-pituitary system. While PD-1 inhibitors are predominantly administered in conjunction with other targeted therapies and chemotherapy regimens, the patient’s monotherapy with Pembrolizumab allowed us to characterize the effects of this medication in isolation [3].
Conclusions: PD-1 inhibitors, such as pembrolizumab can cause hypophysitis, even in cases of monotherapy in the setting of renal cell carcinoma. This hypophysitis can be irreversible and can cause lasting endocrine derangements, as can be seen in our case. Further research should look into further characterizing these effects, which can help inform physicians and patients to optimize treatment.