**9. Conclusions**

In summary, endocrine dysfunction is a frequent irAE associated with ICI treatment. Anti-CTLA-4 antibodies often cause hypopituitarism, while anti-PD-1/anti-PD-L1 antibodies cause thyroid dysfunction. Primary adrenal insufficiency and type I diabetes mellitus are less frequent with all ICIs. Hypopituitarism may also cause secondary adrenal insufficiency via ACTH hyposecretion. Symptoms of adrenal insufficiency are nonspecific and common also in cancer patients; therefore, diagnosis may be difficult. Moreover, symptoms of adrenal insufficiency in cancer patients often have a background other than irAE caused by ICI in tumor bearing patients. While adrenal insufficiency leads to adrenal crisis in severe cases, type 1 diabetes mellitus may progress to fulminant disease; thus, both conditions should be detected and treated at the early stages. As the indications of ICIs expand, the number of irAEs episodes also tends to increase as shown in Figure 1. In the future, early detection

and proper management of endocrine dysfunction should be considered important for the treatment using ICI as mentioned above.

**Figure 1.** Adopted from Reference [49]. Food and Drug Administration (FDA)-reported numbers of immune-related Adverse Events (irAEs) with anti programmed cell death 1 (PD-1)/ programmed death ligand 1 (PD-L1) antibody monotherapy versus anti PD-1/PD-L1 antibody plus anti cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody combination treatment. (Number of reports up to June in 2018).

**Author Contributions:** Writing—original draft preparation, N.O., M.A., and J.U.; writing—review and editing, J.U., Y.M., M.I., Y.K., and T.Y.; supervision, M.F. and K.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
