**1. Introduction**

In 2011, the Food and Drug Administration (FDA) approved the immune checkpoint inhibitor (ICI) ipilimumab, an anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibody, for the treatment of malignant melanoma. Since then, anti-programmed cell death 1 (anti-PD-1) antibodies, such as nivolumab and pembrolizumab, and anti-programmed death ligand 1 (PD-L1) antibodies, such as atezolizumab and durvalumab, have been developed and approved for lung cancer treatment [1]. The effectiveness of cancer immunotherapy using these drugs can also be observed in cases receiving combined treatment with cytotoxic anticancer drugs and radiotherapy, and further expansion of the indications is expected in future.

CTLA-4 is a protein expressed on the surfaces of activated T-cells, and it inhibits T-cell activation after binding to antigen-presenting cells [2,3]. Anti-CTLA-4 antibodies bind to CTLA-4 and block the inhibitory receptors of activated T-cells, thus exerting antitumor effects. They also bind to the surface CTLA-4 in regulatory T-cells (Tregs), thus reducing the immunosuppressive function of Tregs and enhancing tumor immune responses [4]. Furthermore, they are thought to reduce Tregs in tumor tissue via antibody-dependent cellular cytotoxicity (ADCC) and induce tumor cell death [5–7].

PD-1 is expressed on the surfaces of activated T-cells, and its binding with one of its ligands, PD-L1, inhibits T-cell activation [8]. Anti-PD-1 and anti-PD-L1 antibodies block the inhibitory system's signal to T-cells by obstructing such bindings, thus exerting antitumor effects. Therefore, while ICIs exhibit antitumor effects via a novel mechanism, immune adjustments do not work correctly in all cases, and side effects resembling autoimmune and inflammatory diseases have been reported. These types of adverse events, termed immune-related adverse events (irAEs), are characteristic side effects of ICI treatment, being distinct from the side effects of conventional anticancer drug treatment [9]. IrAEs involve almost the entire body, including the skin, gastrointestinal tract, and liver. In particular, endocrinopathy is a relatively frequent irAE [10,11].

Hypopituitarism, adrenocortical dysfunction, thyroid dysfunction, and type 1 diabetes mellitus are common endocrine disorders caused by ICI treatment [12]. Moreover, a small association between hypoparathyroidism and ICI treatment has been reported [13–16]. Pituitary dysfunction is frequent in patients receiving anti-CTLA-4 antibodies, while thyroid dysfunction is prevalent in patients receiving anti-PD-1/anti-PD-L1 antibodies [9,12]. Adrenal insufficiency is infrequent in patients treated with either drug [9,12]. Many symptoms of adrenal insufficiency, such as anorexia and malaise, are nonspecific and often observed in tumor-bearing patients. However, adrenal insufficiency can progress to fatal disease states such as adrenal crisis, and early detection and treatment according to the cause are necessary. Finally, although the frequency of type I diabetes mellitus associated with ICI treatment is small, clinicians should be aware that some cases can develop fulminant disease and should take the necessary actions in the early stages. It is important to be aware that symptoms such as fatigue caused by endocrinopathy may be misidentified as caused by the underlying cancer, and that endocrinopathy may occur with this drug when using immune checkpoint inhibitors. Table 1 shows the major ICIs indications and irAEs.


**Table 1.** Indication and major endocrinopathies of immune checkpoint inhibitors (ICIs).

PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; CTLA-4, cytotoxic T-lymphocyte antigen-4.

Here we present a review of endocrine disorders caused by ICI treatment.
