Immune Checkpoint Inhibitor-Related Hypophysitis: A Call for Vigilance

Ju Hee Lee

doi:10.3803/EnM.2025.2477

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Editorial Hypothalamus and pituitary gland Immune Checkpoint Inhibitor-Related Hypophysitis: A Call for Vigilance: Ju Hee Lee; Endocrinology and Metabolism 2025;40(3):391-393.
DOI: https://doi.org/10.3803/EnM.2025.2477
Published online: June 24, 2025

Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea

Corresponding author: Ju Hee Lee. Department of Internal Medicine, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea Tel: +82-42-280-6801, Fax: +82-42-280-8713, E-mail: serenaj@cnu.ac.kr

• Received: May 30, 2025 • Accepted: June 5, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the Original "Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study" on page 459.

The advent of immune checkpoint inhibitors (ICIs) has significantly advanced cancer therapy by introducing agents that harness the host immune system to target and eliminate tumor cells. These agents function by blocking inhibitory checkpoint proteins—primarily programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)—which normally suppress T-cell activation. This modulation of the immune response has substantially improved survival outcomes in various malignancies, including malignant melanoma, non-small cell lung cancer, and renal cell carcinoma [1].

PD-1 and CTLA-4 are key immune checkpoints that regulate T-cell responses. PD-1, expressed on T cells, binds to PD-L1 on tumor cells, inhibiting immune activity. CTLA-4 competes with the co-stimulatory receptor CD28 for binding to B7 ligands on antigen-presenting cells and downregulates T-cell activation due to its higher binding affinity. Blocking these checkpoints with monoclonal antibodies enhances T-cell function and promotes tumor cell destruction [1].

However, the therapeutic benefits of ICIs are accompanied by a distinct spectrum of immune-related adverse events (irAEs), resulting from excessive immune activation and T-cell infiltration into peripheral organs [2]. The pathophysiology of irAEs shares characteristics with autoimmune diseases. Proposed mechanisms include autoantibody production, T-cell–mediated inflammation, and cytokine dysregulation—particularly involving interleukins [3]. IrAEs can affect almost all organ systems, commonly involving the skin, gastrointestinal tract, nervous system, and endocrine glands. Endocrinopathies are especially frequent [4,5], prompting the publication of clinical practice guidelines by several endocrine societies [6,7].

A systematic review and meta-analysis of 38 randomized clinical trials involving 7,551 patients reported that approximately 10% developed clinically significant endocrine disorders during ICI therapy [8]. Among these, hypophysitis was the second most frequent endocrine irAE, following thyroiditis. Interestingly, the development of grade ≥3 irAEs—regardless of the involved organ—has been associated with improved survival and higher response rates. Furthermore, patients experiencing irAEs affecting multiple endocrine or mixed organ systems exhibited superior therapeutic outcomes [9].

While hypophysitis is generally rare, its incidence has increased notably with the broader use of ICIs [10]. For example, three large studies on patients treated with ipilimumab (an anti–CTLA-4 antibody) found that 11% to 17% developed hypophysitis, characterized by a triad of headache, pituitary enlargement, and hypopituitarism. The median time to diagnosis ranged from 8 to 10 weeks following treatment initiation [11]. Although pituitary enlargement often resolved, hypopituitarism typically persisted. In a retrospective cohort of 839 patients treated with CTLA-4, PD-1, or PD-L1 inhibitors, with a median follow-up of 19.4 months, hypophysitis was diagnosed in 1.9% of patients [12].

A recent prospective study by Iwama et al. [13] assessed 822 cancer patients treated with either PD-1/CTLA-4 combination therapy or PD-1 monotherapy. Adrenocorticotropic hormone (ACTH) and cortisol levels were measured every 6 weeks after treatment initiation. If both hormone levels fell below normal, further evaluation with pituitary stimulation tests and magnetic resonance imaging was conducted. Pituitary dysfunction occurred in 16 of 74 patients receiving combination therapy and in 25 of 748 patients receiving PD-1 monotherapy (21.6% vs. 3.3%, P<0.01). Multiple hormone deficiencies, including ACTH deficiency, occurred in nine of 74 patients in the combination group and two of 748 patients in the monotherapy group (12.2% vs. 0.3%, P<0.01). Isolated ACTH deficiency was observed in seven of 74 and 23 of 748 patients in the combination and monotherapy groups, respectively (9.5% vs. 3.1%, P=0.014). Pituitary enlargement (37.5% vs. 0%, P=0.002) and multiple hormone deficiencies (56.3% vs. 8.0%, P=0.001) were significantly more frequent with combination therapy. The median time to diagnosis was also shorter in the combination group (88 days vs. 168 days, P=0.012). These findings underscore the importance of ongoing surveillance for pituitary dysfunction, particularly in patients receiving combination ICI therapy.

Given the potentially life-threatening consequences of ICI-induced hypophysitis—especially adrenal crisis—clinical attention and appropriate hormonal replacement therapy are essential [14]. As immunotherapy continues to evolve and new agents are introduced, the prevalence and severity of ICI-related endocrinopathies, including pituitary dysfunction, are expected to increase. Therefore, a clear understanding of each agent’s mechanisms and toxicity profiles is crucial. Clinicians must maintain high suspicion and promptly conduct appropriate evaluations in patients presenting with nonspecific symptoms such as fatigue, nausea, or hypotension, which could indicate underlying pituitary involvement.

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References

1. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;359:1350–5.Article PubMed PMC
2. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158–68.Article PubMed
3. Yin Q, Wu L, Han L, Zheng X, Tong R, Li L, et al. Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol 2023;14:1167975.Article PubMed PMC
4. Yoo WS, Ku EJ, Lee EK, Ahn HY. Incidence of endocrine-related dysfunction in patients treated with new immune checkpoint inhibitors: a meta-analysis and comprehensive review. Endocrinol Metab (Seoul) 2023;38:750–9.Article PubMed PMC PDF
5. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16:563–80.Article PubMed PDF
6. Arima H, Iwama S, Inaba H, Ariyasu H, Makita N, Otsuki M, et al. Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society. Endocr J 2019;66:581–6.Article PubMed
7. Husebye ES, Castinetti F, Criseno S, Curigliano G, Decallonne B, Fleseriu M, et al. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline. Eur J Endocrinol 2022;187:G1–21.Article PubMed PMC PDF
8. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2018;4:173–82.Article PubMed PMC
9. Iwamoto Y, Kimura T, Dan K, Iwamoto H, Sanada J, Fushimi Y, et al. Clinical outcomes of endocrine and other disorders induced by immune checkpoint inhibitors in Japanese patients. Sci Rep 2025;15:390.Article PubMed PMC PDF
10. Gubbi S, Hannah-Shmouni F, Verbalis JG, Koch CA. Hypophysitis: an update on the novel forms, diagnosis and management of disorders of pituitary inflammation. Best Pract Res Clin Endocrinol Metab 2019;33:101371.Article PubMed PMC
11. Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 2016;19:82–92.Article PubMed PDF
12. Johnson J, Goldner W, Abdallah D, Qiu F, Ganti AK, Kotwal A. Hypophysitis and secondary adrenal insufficiency from immune checkpoint inhibitors: diagnostic challenges and link with survival. J Natl Compr Canc Netw 2023;21:281–7.Article PubMed
13. Iwama S, Kobayashi T, Izuchi T, Suzuki K, Murase T, Ando M, et al. Combined PD-1 and CTLA-4 blockade increases the risks of multiple pituitary hormone deficiency and isolated adrenocorticotropic deficiency: a prospective study. Endocrinol Metab (Seoul) 2025;40:459–468.Article PubMed PDF
14. Kwon H, Roh E, Ahn CH, Kim HK, Ku CR, Jung KY, et al. Immune checkpoint inhibitors and endocrine disorders: a position statement from the Korean Endocrine Society. Endocrinol Metab (Seoul) 2022;37:839–50.Article PubMed PMC PDF

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