HYPOTHYROIDISM

ICI-mediated hypothyroidism can present as primary or secondary hypothyroidism (secondary to hypophysitis, which is discussed below). Primary hypothyroidism usually ensues after an occurrence of ICI-induced thyrotoxicosis. In a study by Abdel-Rahman et. al., authors found a higher risk of all-grade hypothyroidism compared to hyperthyroidism associated with ICIs therapy (15).

THYROTOXICOSIS

ICI-mediated thyrotoxicosis can present as transient thyrotoxicosis or persistent hyperthyroidism. Transient thyrotoxicosis is far more common among patients treated with ICIs and is often followed by primary hypothyroidism; persistent hyperthyroidism is less frequent. Hyperthyroidism is more commonly reported with combination therapy and is rare with PD-L1 inhibitors. Patients with hyperthyroidism can be symptomatic and need supportive care with beta-blockers and anti-thyroid medications in some cases.

Treatment

For patients with minimal symptoms of thyroiditis-associated thyrotoxicosis, and presence of suppressed TSH and elevated free T4, supportive treatment with non-selective beta-blockers such as propranolol should be considered (24). When propranolol is used, the recommended dose is 10-20 mg every 4 to 6 hours for symptomatic management and until thyrotoxicosis resolves. As most of the time, patients with ICI-induced thyrotoxicosis progress to develop primary hypothyroidism (defined by elevated TSH levels), further treatment with thyroid hormone replacement should be considered. However, in the minority of cases (such as prominent initial symptoms, significantly elevated free T4 levels, signs of Graves’ orbitopathy, or persistent thyrotoxicosis), further evaluation and treatment for Graves’ disease should be considered (30, 34). Graves’ disease should be treated with anti-thyroid medications, radioactive iodine, or surgery depending on the clinical setting and patient preference (35). Rarely, patients can develop thyroid storm and high-dose steroids should be used in conjunction with standard management among these patients (34). If asymptomatic or only mildly symptomatic, continuation of ICIs is recommended (24, 25).

Figure 2.

Algorithm suggested to diagnose and treat ICI thyroid disease.

INCIDENCE

Hypophysitis estimated incidence was one in nine million people per year (38). ICI-induced hypophysitis has been reported in 0-17% of ICI-treated patients. Some studies showed the incidence increased up to 25% while using higher doses of ipilimumab of 10 mg/kg (36, 37, 39). There have been some variations in the observed incidence rate of ICI-induced hypophysitis which has been attributed to not only the dose of the medication but also to the difference in the use, the intensity, and the frequency of hormonal monitoring, in addition to clinical awareness of and suspicion for the condition (37, 40).

Adrenocorticotropic hormone (ACTH) is one of the most common hormone deficiencies in hypophysitis. In a study of ipilimumab-induced hypophysitis, 80% had central adrenal insufficiency. Lu et. al. found hypophysitis occurred in 3.25% of patients using ICIs. Of these, it was more common with combination therapy at 7.68% followed by anti-CTLA-4 at 4.53% then anti-PD-1 and anti-PD-L1 at less than 1% of cases (41). Chang et. al. found the combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) caused hypophysitis in 6.4% of patients. Incidence of anti-CTLA-4 alone was 3.2%, anti-PD-1 alone is 0.4%, and anti-PD-L1 alone was 0.1% (42). Overall, the evidence suggests that combination therapy and anti-CTLA-4 have the highest incidence of hypophysitis, while anti-PD-1 and anti-PD-L1 are less common causes of hypophysitis.

PATHOPHYSIOLOGY

The actual pathogenesis is not well defined. Since many patients had no previous immune-related disease before the development of ICI-associated hypophysitis, it was suggested that this condition is not triggered by a pre-existing immune condition. Hypophysitis was initially considered a specific irAE of ipilimumab considering the presence of pituitary expression of CTLA-4 antigens in the TSH, follicle stimulating hormone (FSH), ACTH, and prolactin-secreting cells. Now more recent data suggested that it can occur with any ICI target (CTLA-4, PD-1, or PD-L1) (43, 44). Garon Czmin et. al. reported that the time to develop hypophysitis following initiation of ICIs was significantly shorter with ipilimumab alone or combined with nivolumab (83 days) compared to nivolumab or pembrolizumab alone (165 days). Moreover, ICI-associated hypophysitis is more common in men while autoimmune lymphocytic hypophysitis has a higher prevalence in the female population (43, 45). In one study, hypophysitis with anti-CTLA was four times more common in males compared to females. This may be related to more men having melanoma, but studies controlling for this factor have found similar results (42). Corticotrophs and thyrotrophs are the most common cell types affected while gonadotroph deficiency was more common in male patients. The somatotroph axis and prolactin levels were rarely involved (36).

CLINICAL CHARACTERISTICS

Hypophysitis can occur weeks to months after the initiation of ICIs. In the study by Albarel et. al., mean hypophysitis occurred at 9-9.5 weeks ± 6 weeks after the treatment initiation with a mean age at diagnosis of 55.2 years (36). The initial symptoms are usually related to tumor mass or hormone deficiencies, and rarely visual disturbance or diabetes insipidus. Symptoms may be acute or subacute, but they are usually nonspecific, including headaches, anorexia, dizziness, nausea, weight loss, and/ or fatigue. More serious signs are hypotension, lethargy, confusion, and electrolyte abnormalities including hyponatremia. Hyponatremia occurs due to increased antidiuretic hormone (ADH) stimulated by hypothalamic secretion of CRH. The most common hormone deficiencies include TSH, ACTH, FSH, luteinizing hormone (LH). Panhypopituitarism is less likely to happen. Although hypogonadotropic hypogonadism and central hypothyroidism may resolve, central adrenal insufficiency is permanent requiring lifelong treatment (36, 42). Although, hypo enhancing lesions in the anterior pituitary are characteristic of ICI-associated hypophysitis, a few cases of PD-1/PD-L1 induced-hypophysitis have been reported in the absence of any radiographic abnormalities and just on clinical grounds (46). This suggests that PD-1/PD-L1 may not always show classic pituitary enlargement or enhancement on MRI (47).

SCREENING AND MONITORING

The National Comprehensive Cancer Network (NCCN) guidelines recommend initial serum pituitary hormonal evaluation including morning cortisol, ACTH, TSH, FT3, LH, FSH, testosterone in men, estrogen in premenopausal women, prolactin, growth hormone, and IGF1. The sodium and potassium levels should also be checked. Cosyntropin stimulation test can be normal in acute secondary adrenal insufficiency. Diagnostics radiology reports of brain MRIs in patients receiving ICIs should routinely include comparisons of pituitary size with prior studies. In case of suspected hypophysitis, a dedicated pituitary MRI is recommended. MRI usually showed a pituitary enlargement with or without mass effect however some cases showed pituitary adenoma, empty sella syndrome, or a normal pituitary gland on the imaging studies.

TREATMENT

Once high suspicion for ICI-induced hypophysitis, an endocrinology consult is recommended. High-dose glucocorticoids should be initiated for patients with ipilimumab-induced hypophysitis who have serious mass-effect-related symptoms, such as severe headache, visual-field disturbance, or simultaneously the presence of other irAEs. Patients should be started on methylprednisolone/prednisone at 1-2 mg/kg /day until symptoms resolve, typically 1-2 weeks then taper the steroids rapidly to a physiological dose. In patients without mass effect, studies have suggested that high dose glucocorticoid therapy was not associated with improved outcomes in patients nor change in the natural history of hypophysitis, thus physiological replacement doses can be considered in these patients (28, 36, 48). ICIs should be held until acute symptoms or symptoms related to mass effect have resolved and hormone replacement is initiated (42). One study compared discontinuing ipilimumab to restarting ipilimumab and found no effect on the resolution of hypophysitis (42). In the case of central hypothyroidism, replacement should be started after steroids are initiated. Testosterone and estrogen replacement should be considered in patients with central hypogonadism after discussing the risks and benefits of the medications (28).

INCIDENCE

PAI is a rare side effect of ICIs, but early identification is essential given the risk of severe outcomes including death. Early evidence of adrenal insufficiency from ICIs came from case reports, but increasingly more evidence is available from larger studies and meta-analyses (50).

A review and meta-analysis by Barroso-Sousa et. al. that included 62 studies with 5831 patients, found the incidence of PAI was 0.7% for single ICI and 4.2% for combinations of ICIs (8). Another review and meta-analysis by Lu et. al. that included 160 studies and 40,432 patients, examined the rate of pituitary-adrenal dysfunction but did not distinguish the cause of adrenal insufficiency. One complicating factor in the study of PAI is that similar symptoms could occur from hypophysitis or discontinuation of steroids (41). Lu et. al. found adrenal insufficiency occurred in patients on ICIs in 2.43% of cases (ranging from 0-6.4% in studies) with serious grade adrenal effects in 0.15% of cases (ranging from 0-3.3%). Anti-CTLA-4 was associated with higher rates of adrenal insufficiency at 5.32% and serious grade events at 0.42%. Combination therapy also resulted in higher rates of adrenal insufficiency at 4.05%. Anti-PD-1 and anti-PD-L1 accounted for a smaller proportion of events at 0.49% and 0.43% respectively (41).

Grouthier et. al. used the World Health Organization global database, VigiBase, to examine individual safety reports for PAI and ICIs (4). The study found 451 cases of PAI, of which 45 were definite PAI and 406 possible PAI. In the study, 90% of cases involved significant morbidity including prolonged hospitalization, life-threatening illness, and disability. The mortality rate was 7.3%. Importantly the mortality rate appeared to be similar across immunotherapy treatments and combination treatments (4). This suggests that despite a relatively low incidence rate of PAI from ICIs, providers need to be able to identify these cases to prevent the significant risk of morbidity and mortality.

PATHOPHYSIOLOGY

PAI is most frequently caused by autoimmune adrenal insufficiency (AI). Autoimmune AI is seen predominantly in women who make up between 54% to 83% of cases. In contrast, males accounted for the majority of ICI-related PAI cases at 58%, while females accounted for 36% of cases. In the remaining 6%, sex was unspecified. Autoimmune AI generally occurs between 30 to 50 years of age. In contrast, the age of onset with PAI caused by ICIs was 66 years on average with a range of 30-95 years old (1). In autoimmune AI, antibodies to the adrenal cortex including anti-21-hydroxylase are found in 83% to 88% of cases (4). The same antibodies have been found in case reports of ICI-related PAI (42). Adrenal metastasis should be excluded during the workup of adrenal insufficiency.

CLINICAL CHARACTERISTICS

Symptoms of PAI related to ICIs are similar to PAI from other causes. Symptoms include fatigue, postural dizziness, orthostatic hypotension, anorexia, weight loss, and abdominal pain. Adrenal crisis is suggested by altered mental status, weakness, syncope, nausea, and vomiting (42). In 52% of cases, other irAEs were also present. Other endocrinopathies made up 14.9% of these irAEs. The median time to onset was 120 days (ranging from 6-576 days) from starting the ICIs (4). Lab findings include hyponatremia, hyperkalemia, hypoglycemia, hypercalcemia, low aldosterone, elevated renin, elevated ACTH, and low to low normal cortisol. Imaging may reveal adrenalitis with enlarged adrenal glands. Interestingly, one case report found imaging evidence of adrenalitis present on a positron emission tomography (PET) scan after starting ipilimumab, but no symptoms or biochemical evidence of adrenal insufficiency. Repeat imaging revealed normal adrenal glands months later. This case suggests adrenalitis may occur without adrenal insufficiency (42).

SCREENING AND MONITORING

The NCCN guidelines recommend checking morning cortisol before each treatment or every four weeks during treatment. Additionally, follow-up testing is recommended for an additional six to twelve weeks. If cortisol is low or subnormal, ACTH monitoring is recommended. To monitor for pituitary and thyroid dysfunction, TSH and T4 monitoring at similar intervals are also recommended (28). In a review by Chang et. al., monitoring was recommended only in symptomatic patients, but a low index for suspicion was recommended as symptoms are nonspecific. When a patient has suspicious symptoms for adrenal dysfunction, ACTH and cortisol should be obtained before corticosteroid treatment only if this can be done safely. Additionally, measuring renin and aldosterone is helpful to determine if mineralocorticoid deficiency is present. This can be particularly helpful as case reports of central and PAI coexisting have been reported. The utility of adrenal autoantibodies, including 21-hydroxylase, is not well-established (42).

TREATMENT

PAI caused by ICIs is treated the same as other causes of PAI. If adrenal crisis or other critical illness is present, stress dose steroids with 100mg IV then 50mg IV every six hours is initiated. In stable patients, 15-25mg hydrocortisone is started in divided doses. Fludrocortisone is used to treat mineralocorticoid deficiency in PAI starting at 0.5-1mg daily. Additionally, patients will need to be educated on sick day rules and be provided with medical alert bracelets, and have high-dose corticosteroids for emergency purposes (28). The other important aspect of treatment is the decision to continue the ICIs. Holding the ICIs is recommended upon identification of adrenal insufficiency. Restarting immunotherapy can be considered after stabilization on hydrocortisone and fludrocortisone replacement.

INCIDENCE

The incidence of ICI-induced T1D comes from large case series at academic medical centers reporting 27 cases out of 2960 patients receiving ICI therapy (0.9%) (52) and 1/1163 (1.8%) (53). Additionally, the prescription label for nivolumab reports that 17/1994 (0.9%) cases developed T1D (54). However, when examining the clinical trials evaluating the efficacy of PD-1 and PD-L1 inhibitors, there is a wide range of reported hyperglycemia and diabetes (55-64) (Table 1). From this analysis, hyperglycemia or diabetes was reported in approximately 2.5% of treated individuals.

Of note, most of the clinical trials in Table 1 excluded patients with a preexisting autoimmune condition, and some even excluded patients with a family history of autoimmunity. As these therapies are now being more widely used in clinical practice, there is an increased reporting of ICIs-induced diabetes (65). This is likely due to the increasing use of ICIs therapy and differences in patient populations between phase 2/3 clinical trials and clinical practice. Although T1D is a relatively rare occurrence with ICIs therapy, the events are clinically significant.

PATHOPHYSIOLOGY

The first case series reporting ICIs-induced autoimmune diabetes was described in 2015 (66). In this series of five patients, both humoral and cellular diabetes-associated autoimmunity were described. Some patients had positive T1D associated autoantibodies and diabetes-specific CD8+ T cells in the peripheral blood, consistent with findings from childhood-onset T1D (66).

The role of the PD-1/PD-L1 pathway in preclinical animal models of T1D has been appreciated for over a decade. Non-obese-diabetic (NOD) mice develop spontaneous autoimmune diabetes so it has been used extensively as an animal model to understand the mechanisms of T1D development (67). NOD mice with a knockout of either PD-1 or PD-L1 (but not PD-L2) have accelerated onset of diabetes with lymphocytic infiltration of the pancreatic islets (e.g., insulitis) compared to mice with these immune regulatory molecules (68, 69). Furthermore, administration of anti-PD-1 or PD-L1 monoclonal antibodies to NOD mice also accelerated the onset of T1D (70). When examining the islets in NOD mice, insulin-producing beta-cells express PD-L1 during the progression of autoimmune diabetes (71). Similar to NOD mice, human islets from T1D organ donors exhibit upregulation of PD-L1, which was strongly associated with insulitis (72). This likely represents a protective mechanism for beta-cells to lessen their autoimmune destruction. These studies may explain why anti-PD-1/PD-L1 therapies induce T1D, while there is an absence of diabetes with anti-CTLA-4 therapy, whose ligands are CD80 and CD86 on antigen-presenting cells such as B cells, dendritic cells, and macrophages.

CLINICAL CHARACTERISTICS

Over the last 4 years, cases have described rapid-onset insulin-dependent diabetes with undetectable C-peptide levels (a measure of residual beta-cell function) and both positive and negative T1D associated autoantibodies at presentation (73, 74). Cases of ICIs-induced T1D have remained insulin-dependent even upon stopping therapy. Steroid treatment has not been able to reverse T1D, and as expected, blood glucose worsens with steroid administration (75, 76).

ICIs-induced T1D is mostly reported in older patients (50-70 years old) due to the nature of end-stage cancers developing later in life. More cases have been reported with anti-PD-1 therapies (nivolumab and pembrolizumab) as these agents were approved before monoclonal antibodies targeting anti-PD-L1 (51, 66, 73, 74, 77). Melanoma is the most common cancer in patients that present with ICIs-induced T1D, likely due to this being the first approved indication for ICIs therapy, and more patients with melanoma have been exposed to ICIs therapy compared to other cancer types. However, with the expanding indications and recent approval of ICIs therapy for use in pediatric cancers, ICIs-induced T1D may increase and present in younger individuals (78).

METABOLIC FEATURES

ICIs-induced T1D presents within days to a year after the initiation of PD-1 or PD-L1 therapy. HbA1c, which is a measure of the average blood glucose over the preceding three months, is generally lower than 10% at presentation with most patients presenting between 7 to 8%. As these values are mildly elevated, this suggests significant hyperglycemia over a short period rather than a gradual increase in hyperglycemia over a longer period. Most of the patients present with severe DKA that can be life-threatening. In most cases, C-peptide levels were inappropriately low for the presenting blood glucose or undetectable; ‘honeymoon’ periods tend to be absent after diagnosis. These observations suggest a destruction of beta-cell mass. In some patients, increased amylase and/or lipase has been reported, suggesting more generalized pancreatic inflammation (52, 79).

IMMUNOLOGIC FEATURES

At least one T1D associated autoantibody, directed against insulin, glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8), was reported in 40-50% of the cases (52, 79). Almost all antibody-positive cases had GADA antibodies; however, not all four major autoantibodies were reported or measured in these case series. It is speculated that there is an association between antibody presence and earlier onset of ICIs-induced T1D in a subset of patients. In one case, positive conversion of antibodies after ICIs therapy was reported (52). Polyclonal and predominantly IgG₁ subclass for GADA was shown at the presentation of another case that developed T1D five days after the initiation of PD-1 inhibitor therapy. Since IgG antibodies are involved in memory immune response and the short time interval from the initiation of anti-PD-1 treatment to the onset of T1D, these antibodies were likely present before the start of therapy (51). Based on these findings, a subset of patients developing ICIs-induced T1D likely have preexisting T1D associated antibodies which may be an early form of latent autoimmune diabetes of adulthood (LADA); however, prospective studies measuring T1D associated antibodies before the start of ICIs therapy are needed to evaluate this hypothesis.

GENETIC RISKS

Human leukocyte antigen (HLA) genes on chromosome 6 confer genetic risk for many autoimmune disorders including childhood-onset T1D (80). The polymorphic class II HLA genes (DQ, DR, and DP) confer this risk, especially the DR4-DQ8 and DR3-DQ2 haplotypes (81, 82). Only a small number of cases with ICIs-induced T1D have reported HLA genes with some having T1D risk alleles. In one case series, the frequency of HLA-DR4 was found to be enriched in those with ICIs-induced T1D compared to rates among Caucasians in the US population (52, 79). Further research is necessary to identify HLA and other genetic variants that may confer risk for ICIs-induced T1D.

COMPARISON TO CHILDHOOD-ONSET TYPE 1 DIABETES

We believe it is useful to compare the current knowledge of ICIs-induced T1D to prototypical childhood-onset T1D (Table 2). The age of onset is distinctly different between the two types of diabetes. Presentation with DKA is more common and the onset of diabetes more rapid than traditional T1D. T1D associated autoantibodies are present in ~90% of children and adolescents with T1D compared to half of the reported cases in ICIs-induced T1D. There is a predominance of GAD autoantibodies at the presentation of ICIs-induced T1D; however, more research is needed to measure all four major T1D associated autoantibodies in these patients and those directed against post-translationally modified antigens may also reveal insights into the pathogenesis of the disorder. C-peptide levels are low or undetected in those treated with ICIs therapy that develops T1D compared to C-peptide levels that vary and gradually go down after the diagnosis of childhood T1D. As a corollary, the honeymoon phase is generally absent in ICIs-induced T1D (80-83).

SCREENING AND MONITORING

The most updated recommendation on screening for diabetes in patient receiving ICIss comes from 2018 American Society of Clinical Oncology (ASCO) clinical practice guidelines, which recommends monitoring blood glucose at baseline, with each treatment cycle for 12 weeks and then every 3-6 weeks thereafter (24). In cases with suspected T1DM such as new onset hyperglycemia >200 mg/dl, random blood sugar >250 or history of T2DM with glucose levels >250 mg/dl, further testing for ketosis and anion gap is recommended (24). Discussing the risk of developing T1D with patients and educating them about the signs and symptoms of diabetes and DKA are recommended. Based on the current evidence, patients who have positive T1D associated antibodies and certain HLA alleles may have an increased risk to develop diabetes, so screening antibodies and reporting HLA alleles before the initiation of treatment may identify these patients with greater risk.

A retrospective study evaluated fasting blood glucose levels of patients receiving ICIs treatment during patient visits and showed no detectable upward drift of glycemia before DKA presentation (83). This is likely due to the rapid onset and progression of ICI-induced T1D. However, we believe monitoring blood glucose and HbA1c levels during patient visits are still necessary. Considering the rapid onset of diabetes, this approach alone may miss a significant amount of hyperglycemia and DKA. We recommend routine self-monitoring of blood glucose by patients and/or using continuous glucose monitoring to recognize hyperglycemia before DKA presentation. Close monitoring of patients with preexisting autoimmunity may also be useful (51). Our suggested screening and monitoring algorithm is depicted in Figure 3.

Figure 3.

Proposed algorithm to screen and manage patients for ICI-induced T1D. (DKA = diabetic ketoacidosis; HbA1c = Hemoglobin A1c, T1D= Type 1 diabetes, HLA = human leukocyte antigen, CGM = continuous glucose monitor)

INCIDENCE

Although, ICI-associated hypogonadism can be seen in patients who develop panhypopituitarism secondary to ICI-associated hypophysitis, the true occurrence of primary hypogonadism is uncommon and is based on a few case reports and ongoing studies (84-86). A recent analysis of VigiBase, the WHO global database of individual case safety reports between 2011 and 2019, found only 1 case of primary hypogonadism (87). This surprisingly low incidence may in fact be due to lack of proper evaluation looking for primary hypogonadism. For example, many studies reporting occurrence of secondary hypogonadism lacked data on the levels of pituitary gonadotropins, FSH and LH, which is necessary to differentiate between primary and secondary hypogonadism (43). Moreover, the majority of the pivotal trials leading to FDA approval of ICIs lacked information regarding fertility, menopause status, sex hormone levels, or sexual health-related quality of life. Additionally, not much is known about ICI-associated infertility. In a study of patients with malignant melanoma treated with ICIs, 6 of 7 men (86%) with testicular autopsy tissue samples had impaired spermatogenesis (88). This may suggest higher prevalence of infertility among men receiving ICIs. No data on potential effects on female fertility are currently available.

PATHOPHYSIOLOGY

ICIs may cause irAEs affecting any organ in the body by blocking regulators of self-tolerance. The understanding of pathophysiologic mechanism of ICI-induced primary hypogonadism comes from limited number of cases reports (85, 86). In the first case, the patient developed bilateral orchitis two weeks following administration of nivolumab and laboratory workup confirmed diagnosis of primary hypogonadism (decreased testosterone with elevated LH) (85). However, it self-resolved within one week without use of steroids or any other therapy, and there was no recurrence. The intensity and timing of the orchitis suggests an intense immune stimulation leading to orchitis and primary hypogonadism (85). In another case, the patient developed bilateral epididymo-orchitis following administration of the third dose of pembrolizumab and needed high-dose steroids resulting in complete resolution (86). The testis is considered an immune-privileged organ due to its ability to tolerate autoantigens. The use of experimental autoimmune orchitis (EAO) in rats has allowed analysis of the autoimmune inflammatory response to spermatic antigens, providing a steppingstone towards understanding the ICI-induced primary hypogonadism. The main mechanisms responsible for preventing autoimmune disease of testes are: (a) secretion of immunosuppressive factors by macrophages, Sertoli cells, and Leydig cells, (b) presence of blood-testis barrier (BTB), and (c) presence of regulatory T cells. There is a fine equilibrium between dendritic cells, macrophages, T cells, and cytokines in maintaining immunosuppression in testes. While there have been no studies to date specifically evaluating the mechanism of ICI-induced orchitis, the examination of the normal and altered autoimmune immunobiology elucidates the possible mechanisms involved (89). This is briefly described below:

LONG-TERM OUTCOMES AND TREATMENT

It is well established that inflammation and infection of the male reproductive tract may lead to infertility in males (94). Therefore, it is reasonable to postulate that ICI-induced orchitis may also lead to male infertility, a consequence that should be addressed by providers. The long-term outcomes of ICIs are just beginning to be explored. One retrospective review assessed patients who became infertile after ICI therapy and subsequently died. Retrospective cohort cadaver study analyzing tissue specimens of the testes showed 86% of men who received ICI therapy had impaired spermatogenesis (88). Notably, there was no increased peritubular hyalinization or fibrosis in the treated group, and no changes in Leydig cells (88). These findings support the previously mentioned pathophysiology of ICI-induced orchitis and address the possibility of infertility as a long-term consequence. Given the limited information on the effects of ICIs in spermatogenesis, providers should provide patients with their options, such as sperm banking and cryopreservation (95).

ACQUIRED GENERALIZED LIPODYSTROPHY

Lipodystrophy is characterized by absent of visceral or subcutaneous adipose tissue in the settings of normal non-starvation nutritional state. It is a known common side effect from certain medications such as older HIV protease inhibitor, which is a reversible side effect. While the mechanism of lipodystrophy from ICIs is currently unclear, it is believed that the medication may induced an autoimmune process that leads to fat destruction by forming anti-adipocyte antibodies. In ICI-induced lipodystrophy, the more common form appears to be acquired generalized lipodystrophy (AGL) in which all fat tissues are affected but may spare the neck and face region. Onset of AGL, can be as early as 2-4 months which is roughly after 4-5 doses of ICIs. Currently, most of the cases of ICI-induced AGL are associated with nivolumab therapy (96, 97).

HYPOPARATHYROIDISM AND HYPOCALCEMIA

Another rare but crucial endocrine irAEs is hypocalcemia secondary to hypoparathyroidism. While the exact mechanism is unclear, the proposed etiology is due to calcium-sensing receptor (CaSR) activating autoantibodies. This antibody is also present in patients with autoimmune polyendocrine syndrome type 1 (APS1) or idiopathic hypoparathyroidism. The clinical presentation can be as abrupt as an acute symptomatic hypocalcemia episode which includes paresthesia, tetany, and potential arrhythmias requiring hospitalization but may also present as very mild to asymptomatic hypocalcemia. For both circumstances, calcium and vitamin D replacement are adequate therapy but patients should be closely monitored for severe symptoms (98).

CENTRAL DIABETES INSIPIDUS

Posterior pituitary hormone secretion can also be affected with ICIs, mainly antidiuretic hormones (ADH), which can subsequently lead to sodium and water dysregulation. To our knowledge only 3 cases of central diabetes insipidus (CDI) has been reported with the use of nivolumab (PD-1 inhibitor) and Azelumab (PD-L1 inhibitor) (99-101).The patients presented with classic polyuria/polydipsia symptoms along with hypernatremia which responded well to desmopressin (99-101). In the case report described by Fosci et. al., the authors described coexistence of metastatic localization and infundibulo-neurohypophysitis on MRI (100) while in the case report by Deligiori et. al., there was no signs of hypophysitis on imaging (99). Thus, further investigation is needed to fully understand the possible mechanisms for CDI.

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH)

SIADH is the opposite scenario in which patients present with euvolemic hyponatremia. It is somewhat difficult to distinguish for certain that SIADH is truly from ICIs since SIADH is quite common in patients with underlying malignancies. Additionally, pain in patients with cancer itself can be the underlying cause of SIADH. Additionally, there are some reports of hyponatremia as a manifestation of adrenal insufficiency in patients on ICIs and hence it is crucial to rule out adrenal insufficiency for any patient with hyponatremia, as immediate recognition and treatment can be lifesaving (102, 103).

VITILIGO

Depigmentation of skin or vitiligo is thought to be from inducing an immune response to normal melanocyte antigens leading to the destructive process. While vitiligo itself may not be directly endocrine-related, its presence has been strongly associated with common endocrinopathies such as thyroid and adrenal disease as well as autoimmune diabetes. Interestingly, when vitiligo is present as one of the side effects from ICIs, this may represent a better prognosis in melanoma cases (104).

Figure 4.

Proposed algorithm to screen and manage patients with endocrine irAEs