SAT-288 - Three Axes Down: Concurrent Hypophysitis, Primary Hypothyroidism, and Primary Hypogonadism Associated with Nivolumab Therapy

Background:
Immune checkpoint inhibitors (ICIs) are associated with endocrine adverse events, frequently thyroid dysfunction and hypophysitis. Dual endocrinopathies occur in 5–10% of patients; however, simultaneous involvement of three endocrine axes is rare. Although reproductive toxicity is more often reported with combination therapy, isolated cases of primary hypogonadism have been described with PD-1 inhibition. Rare reports of orchitis or epididymo-orchitis associated with ICIs demonstrate low testosterone with elevated gonadotropins consistent with primary hypogonadism. Testicular imaging may be normal, as subclinical autoimmune orchitis can be difficult to detect. In this case, primary hypogonadism temporally associated with nivolumab monotherapy supports the plausibility of immune-mediated gonadal dysfunction.

Case Presentation:
A 73-year-old male with stage III (T4N1) melanoma receiving nivolumab presented with fatigue, lightheadedness, and dyspnea. Laboratory evaluation revealed severe primary hypothyroidism (TSH 66.7 µIU/mL with undetectable free T3 and free T4) and secondary adrenal insufficiency, with morning cortisol < 1 µg/dL, suppressed adrenocorticotropic hormone ( < 5 pg/mL), and an inadequate cosyntropin response (peak 5.6 µg/dL), consistent with immune-mediated hypophysitis. Baseline endocrine testing prior to nivolumab therapy was unavailable, and symptoms developed approximately 12 months after therapy initiation. Pituitary magnetic resonance imaging showed no discrete adenoma or suprasellar mass and was not definitive for hypophysitis.
The patient was treated with stress-dose glucocorticoids followed by physiologic hydrocortisone replacement, resulting in rapid clinical improvement. Thyroid hormone replacement was initiated after steroid therapy. Subsequent outpatient evaluation revealed primary hypogonadism, with free testosterone of 10.9 pg/mL, total testosterone of 15 ng/dL, and elevated luteinizing hormone (6.88 mIU/mL) and follicle-stimulating hormone (13.52 mIU/mL). Testicular ultrasound was unremarkable. Testosterone replacement led to biochemical improvement. Prolactin and other anterior pituitary hormones were not significantly abnormal, and there was no evidence of diabetes insipidus. Nivolumab was temporarily held and later continued with ongoing hormone replacement.

Conclusion:
This case highlights a rare presentation of multiglandular endocrine toxicity during nivolumab therapy, with secondary adrenal insufficiency & concurrent primary hypothyroidism and hypogonadism. Recognition of secondary pituitary and primary gland dysfunction is essential to guide appropriate sequencing of hormone replacement including glucocorticoid, thyroid hormone, and testosterone therapy to prevent adrenal crisis, restore endocrine function, and support safe continuation of immunotherapy.

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