Endocrine Adverse Events in Cancer Immunotherapy

Immune checkpoint inhibitors have transformed the management of various malignancies by releasing the brakes on T-cell activation and promoting antitumour immunity. However, by modulating immune tolerance, these agents can provoke endocrine immune-related adverse events that affect the pituitary, thyroid, pancreas and adrenal glands. Hypophysitis, characterised by inflammation of the pituitary gland, leads to deficiencies of corticotropic, thyrotropic or gonadotropic hormones and may present with headache, fatigue and hyponatraemia. Thyroid dysfunction ranges from painless thyroiditis with transient thyrotoxicosis to overt hypothyroidism requiring lifelong thyroxine replacement. Insulin-dependent diabetes mellitus and adrenal insufficiency can also arise abruptly, sometimes life-threatening, demanding prompt recognition and hormone replacement. Combination therapy amplifies both the incidence and severity of endocrinopathies, emphasising the need for vigilant monitoring, multidisciplinary management and patient education. Advances in biochemical screening, imaging and pharmacovigilance have deepened understanding of risk factors, temporal patterns and recovery profiles, guiding tailored surveillance and improving long-term outcomes.

Research from Nature Portfolio

A national pharmacovigilance analysis of cases reported to a European adverse event database delineated the profile of hypophysitis following immune checkpoint blockade. In over ninety confirmed instances, ipilimumab was most frequently implicated and often produced corticotropic deficiency of grade 3 severity. Pituitary magnetic resonance imaging supported the diagnosis in half of cases, and no patients regained baseline hormonal function on follow-up, underlining the permanence of certain deficits. The average onset was shorter with CTLA-4 inhibition than with PD-1 or PD-L1 agents, highlighting agent-specific risk patterns. This work emphasises the necessity for coordinated onco-endocrinological pathways to manage chronic hormone replacement and monitor sequelae in survivors.

Endocrine Adverse Events in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in endocrine adverse events in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint inhibitor (ICI): A monoclonal antibody that blocks regulatory pathways in T cells (such as CTLA-4 or PD-1/PD-L1) to enhance antitumour immunity.

Immune-related adverse event (irAE): A deleterious inflammatory reaction in healthy tissues triggered by cancer immunotherapy.

Hypophysitis: Inflammation of the pituitary gland leading to secondary hormone deficiencies.

Thyroiditis: Inflammation of the thyroid gland causing transient or permanent thyroid hormone dysregulation.

Adrenal insufficiency: Inadequate production of cortisol and other adrenal hormones, potentially leading to life-threatening crises.

References

1. Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database. Scientific Reports (2019).
2. Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group. Cancer Treatment Reviews (2024).
3. Adrenal crisis mainly manifested as recurrent syncope secondary to tislelizumab: a case report and literature review. Frontiers in Immunology (2024).
4. Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system. Journal for ImmunoTherapy of Cancer (2019).