Regular monitoring and recognizing tell-tale signs upon first presentation are important in managing endocrine immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs), for optimized cancer treatment outcomes, stressed Dr David Lui from the University of Hong Kong, at the 8th Endocrinology, Diabetes & Metabolism Hong Kong Annual Meeting (EDM HK 2025).
“ICIs are rapidly becoming a central pillar in cancer therapy. ICI-induced irAEs are common and tend to occur quite early. Typically, most of these events occur within 12 weeks after initiation of ICIs, which means after about four treatment cycles,” said Lui, who shared patient cases from his clinical practice to illustrate the process of identification and management of common ICI-induced endocrine irAEs, namely, pituitary and thyroid dysfunctions, primary adrenal insufficiency, and less common ones such as type 1 diabetes (T1D) and hypoparathyroidism. [Clin Diabetes Endocrinol 2019;5:1]
Monitoring & diagnosis
Sometimes patients may be asymptomatic. In other cases, nonspecific symptoms such as fatigue, malaise, vomiting or abdominal pain – symptoms associated with cortisol insufficiency or diabetic ketoacidosis (DKA) – may be wrongly attributed to or overlap with those from the underlying cancer or gastrointestinal side effects of anticancer therapy, and consequently overlooked. “Hence, routine monitoring and high vigilance are important to detect them in a timely manner and avoid life-threatening situations or death,” emphasized Lui. [Endocr Connect 2020;9:R207-R228; Nat Rev Endocrinol 2025;21:289-300]
Usually, tests for glucose, electrolytes (sodium, potassium, calcium), thyroid-stimulating hormone (TSH), free T4 (fT4) levels, morning levels of cortisol, as well as clinical evaluation of symptoms should be conducted at baseline before ICI initiation, then every cycle for the first 6 months, and every 2–3 months for the next 6 months, followed by every 6 months thereafter. The same tests may need to be done 4–6 weeks after the last cycle of ICIs to pick up late-onset complications, as some irAEs may occur after ICI discontinuation. [Endocr Connect 2020;9:R207-R228; ESMO Open 2021;6:100011]
It has been observed that certain irAEs may be more common with one class of ICIs than others. There may also be differences in occurrence patterns of a particular irAE between different classes of ICIs. For example, hypophysitis is more frequently seen with anti–CTLA-4s, and tends to occur earlier with anti–CTLA-4s than with anti–PD-1s/PD-L1s (onset time, around 9 weeks vs 25.8 weeks). Hypophysitis induced by anti–CTLA-4s also tends to be more severe and involve other pituitary axes, while isolated adrenocorticotropic hormone (ACTH) deficiency is more common with anti–PD-1s/PD-L1s. T1D, on the other hand, is usually seen with anti–PD-1s/PD-L1s and rarely with anti–CTLA-4s. [Eur J Endocrinol 2019;181:211-219; Nat Rev Endocrinol 2025;21:289-300]
ICI-induced thyroid dysfunction is usually due to destructive thyroiditis, presenting mostly as hypothyroidism, with some patients having a preceding transient thyrotoxic phase (if the damage is more severe). ICI-induced Graves’ disease is rare. [Nat Rev Endocrinol 2025;21:289-300; Endocr Rev 2019;40:17-65]
Diagnosis at first presentation often poses a challenge because of the possibility of multiple endocrinopathies with overlapping and nonspecific symptoms presenting simultaneously. Systematic checking and differentiation of the dysfunctions is thus necessary.
For example, in the case of hypophysitis, if low morning cortisol and low ACTH levels are detected (and recent steroid therapy can confound assessment), a central cause of adrenal insufficiency is implicated. In this case, checks for central or secondary hypothyroidism (confirmed if fT4 and TSH levels are low) and hypogonadism (confirmed if levels of sex hormones, luteinizing and follicle-stimulating hormones are low) are necessary, and sometimes ACTH stimulation test may be needed to ascertain diagnosis. In cases where patients present with headache, diplopia or palsy, MRI of the brain or pituitary to assess pituitary morphology or rule out brain metastasis is recommended. [Sci Rep 2019;9:19419; J Clin Endocrinol Metab 2023;108:1514-1525]
Conversely, if signs of thyrotoxicosis (eg, palpitation, tachycardia) are recognized on presentation, the diagnosis would be overt thyrotoxicosis (and primary hypothyroidism due to thyroiditis) only if fT4 is elevated and TSH is low. Otherwise, central or secondary hypothyroidism is to be suspected if levels of fT4 and TSH are low or normal, and immediate evaluation for concomitant secondary adrenal insufficiency should be done and glucose levels checked for the rare occurrence of ICI-induced T1D. [Nat Rev Endocrinol 2021;17:389-399]
Management
“Note that if secondary hypothyroidism due to hypophysitis is suspected, or if ACTH and TSH deficiencies coexist, start hydrocortisone replacement first to prevent adrenal crisis before initiating thyroid hormone replacement,” reminded Lui. [Nat Rev Endocrinol 2021;17:389-399; Endocr Rev 2019;40:17-65; J Clin Endocrinol Metab 2023;108:1514-1525]
Hormone replacement therapy is usually used to manage hormone deficiency due to ICI-induced endocrinopathy. High-dose steroid is usually not necessary, unless in cases of adrenal crisis. “ICI interruption or discontinuation is also usually not necessary, except on rare occasions such as severe thyroid eye disease or large-volume hypophysitis with optic nerve compression, in which case ICI cessation should be considered,” noted Lui. [Endocr Rev 2019;40:17-65; Nat Rev Endocrinol 2021;17:389-399; Nat Rev Endocrinol 2025;21:289-300]
Unfortunately, many of the ICI-induced endocrinopathies are irreversible. Hence, patients should be properly informed and educated about the need for long-term hormone replacement (eg, hydrocortisone or insulin) even after discharge from hospital or discontinuation of ICI therapy, as failure to continue with the hormone therapy may result in life-threatening conditions (eg, adrenal crisis or DKA). [J Clin Oncol 2018;36:1714-1768; Cancer Immunol Immunother 2017;66:1399-1410]
Patients should also be informed that they will need high doses of steroid when their bodies are under stress (eg, when they have an infection or acute illness), and they are to visit the A&E to receive parenteral steroid replacement if unable to take their oral medication. Additionally, patients with ACTH deficiency should be provided with steroid cards so that attending A&E physicians could be alerted in case of emergencies. [J Clin Endocrinol Metab 2016;101:364-389; Endocr Connect 2021;10:R116-R124]