# Immune Checkpoint Inhibitor-Related Hypophysitis and Pituitary Dysfunction: A Systematic Review of Diagnosis and Management

## TL;DR

This review summarizes how immune checkpoint inhibitors can cause pituitary issues, focusing on symptoms, diagnosis, and treatment strategies to improve patient outcomes.

## Contribution

A systematic review of 84 studies provides insights into the management and diagnosis of hypophysitis caused by immune checkpoint inhibitors.

## Key findings

- Hypophysitis is more common with CTLA-4 inhibitors and often leads to hypopituitarism.
- MRI is key for diagnosis but may miss early pituitary changes.
- Glucocorticoids and hormone replacement are standard treatments for managing ICPi-related hypophysitis.

## Abstract

With an objective to review the clinical presentation, diagnosis, and management of immune checkpoint inhibitor (ICPi)-associated hypophysitis and pituitary dysfunction, we conducted a systematic review of 84 studies (2005-2025) involving 7,259 patients evaluated pituitary immune-related adverse events (irAEs) linked to CTLA-4 inhibitors, programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors, and combination therapies. Data included ICPi type, demographics, cancer type, treatment duration, imaging, pituitary dysfunction, symptoms and management.

Following statistical analysis, the weighted mean of male patients was 68.3%, with a pooled mean age of 63.9 years. Common symptoms included fatigue, headache, hyponatraemia, nausea, anorexia, and neuropsychiatric changes. While MRI is a key diagnostic tool, it may not always detect subtle or early-stage pituitary involvement.

In the CTLA-4 group, patients received ipilimumab for 2-12 cycles (mean: 3.3) before hypophysitis onset. In the PD-1/PD-L1 group, median time to onset was 28 weeks (range: 10-46 weeks). Hypophysitis induced by CTLA-4 inhibitors, particularly ipilimumab and CTLA-4-based combination therapies, were more commonly associated with hypopituitarism. In contrast, isolated adrenocorticotropic hormone (ACTH) deficiency, often linked to PD-1/PD-L1 inhibitors, presents as secondary adrenal insufficiency without distinct MRI abnormalities.

Reported MRI abnormalities included hypophysitis, pituitary stalk abnormalities, pituitary enlargement, microadenoma, pituitary atrophy, and empty sella. The most common biochemical abnormalities in the combination group were hypopituitarism and secondary adrenal insufficiency. High-dose glucocorticoid initiation, careful tapering, and tailored long-term hormone replacement remained the mainstays of management.

In conclusion, our systematic review highlights hypopituitarism as a frequent and often persistent consequence of ICPi-associated hypophysitis. Early recognition through combined clinical, biochemical, and radiological assessment is essential to reduce long-term endocrine morbidity and optimise patient outcomes.