Immune-related adverse events (irAEs), including endocrine irAEs, can occur in response to cancer immunotherapy using immune checkpoint inhibitors (ICIs). Of the endocrine irAEs, pituitary and thyroid irAEs are most frequently observed, followed by primary adrenal insufficiency, type 1 diabetes mellitus and hypoparathyroidism. Notably, pituitary irAEs and type 1 diabetes mellitus can be lethal if overlooked, potentially leading to adrenal crisis and diabetic ketoacidosis, respectively. On the other hand, pituitary and thyroid irAEs are reported to be associated with more favourable prognoses in some cancers if treated appropriately with hormone-replacement therapies. It would be useful to identify those people who are likely to develop endocrine irAEs before initiating therapy with ICIs. Anti-pituitary antibodies and thyroid autoantibodies have been identified as potential biomarkers for the development of pituitary and thyroid irAEs, respectively. This Review elaborates on the clinical characteristics and management strategies of several endocrine irAEs, using the latest research findings and guidelines published by several academic societies.

BackgroundImmune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of various malignancies. Unfortunately, ICI therapy has been associated with multiple immune related adverse events (irAEs) resulting in organ damage. One rare, but potentially devastating side effect, is adrenal insufficiency.MethodsA retrospective analysis of all patients receiving anti-PD-1/PD-L1 or anti-CTLA-4 therapy at Gundersen Health System from 2011 to 2023 was conducted.ResultsPatients (n = 684) receiving anti-PD-1/anti-PD-L1/anti-CTLA-4 therapy at Gundersen Health System were included in our retrospective analysis. There were eleven (1.6%) patients that were diagnosed with an adrenal irAE after beginning immunotherapy. The median days from first treatment to diagnosis of irAE was 304 days. Most common symptoms at the time of onset included fatigue (82%) and syncope (36%). Five patients (45%) required treatment delay or cessation and eight (73%) patients were referred to endocrinology after original diagnosis.DiscussionDetection of adrenal insufficiency secondary to immunotherapy requires a degree of high suspicion. Given the potential significant morbidity and mortality associated with adrenalitis/adrenal insufficiency, prompt diagnosis is of the utmost importance. Liberal use of early morning/8 am cortisol screening should be implemented as a standard part of clinical work up in acute onset of fatigue, hypotension, fever, weakness, weight loss, dehydration, oral intolerance, gastrointestinal upset, hyponatremia, and hyperkalemia. Immunotherapy related adrenal insufficiency is a rare complication, with most cases being secondary adrenal insufficiency. Multidisciplinary care with oncology and endocrinology is an important aspect of comprehensive management.

Immune checkpoint inhibitors (ICIs), namely, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody Ipilimumab and anti- and programmed cell death 1 (PD-1) monoclonal antibodies Nivolumab, and Pembrolizumab, have improved the treatment outcomes for many other cancer types. However, their impact on fertility remains under-explored.

The possible direct effects of ICIs on human sperm was investigated. Spermatozoa from ten normozoospermic donors were exposed to Ipilimumab, Nivolumab, or Pembrolizumab at concentrations ranging from 1 to 100 ng/mL. Sperm motility was assessed through standard laboratory process. Cell viability and apoptosis markers were evaluated by flow-cytometry using fluorescent Annexin-V probe and Terminal Uridine Nick-End Label (TUNEL) assays. Protein-A-purified therapeutic antibodies (IgG) were also evaluated.

Spermatozoa had high PD-1 (>99%) and negligible CTLA-4 expression. Exposure to ICIs, was associated with a concentration-dependent impairment of sperm motility, noticeable for Pembrolizumab and Ipilimumab since 10 ng/mL, and for Nivolumab since 100 ng/mL. However, no significant effect on cell apoptosis or viability was shown. Purified IgG from ICIs maintained the adverse effect on cell motility without affecting viability.

ICIs, specifically Pembrolizumab, Nivolumab, and Ipilimumab, adversely affect human sperm motility in vitro. Further research is required to understand the underlying mechanisms and clinical implications.

A 70-year-old man developed anorexia, general malaise, and hyponatremia with a serum sodium level of 120 mEq/L after the fifth cycle of pembrolizumab administration for bladder cancer. A rapid adrenocorticotropic hormone (ACTH) loading test result was within the normal range (basal and peak cortisol levels of 8.2 μg/dL and 20.0 μg/dL, respectively), and his serum sodium level recovered by salt loading. However, about two weeks later, his anorexia and malaise worsened, and his serum sodium level decreased to 122 mEq/L. A rapid ACTH loading test performed again four weeks after the first test showed a peak cortisol level of 13.4 μg/dL, and a corticotropin-releasing hormone (CRH) loading test showed basal ACTH and cortisol levels of 19 pg/mL and 6.3 μg/dL and peak levels of 34 pg/mL and 8.7 μg/dL, respectively. Therefore, secondary adrenal insufficiency (SAI) was diagnosed. Although he underwent nonfunctioning pituitary neuroendocrine tumor resection at the age of 55 years, the tumor was not significantly different from the postoperative findings. The possible cause of SAI was ACTH deficiency after pembrolizumab administration. Four months after diagnosis, the basal ACTH and cortisol levels had decreased from 19 to 17 pg/mL and from 6.0 to 3.2 μg/dL, respectively. We were able to follow the atypical, slowly progressive course of SAI due to pembrolizumab.

Immune checkpoint inhibitors, such as pembrolizumab, have transformed cancer therapy by enhancing the immune system's ability to combat tumors, but they can also lead to immune-related adverse events, including adrenal insufficiency. This case report presents a 52-year-old male with a history of malignant melanoma who developed adrenal insufficiency after four months of pembrolizumab therapy. The patient was admitted with symptoms of malaise, vomiting, abdominal pain, and poor appetite. Laboratory tests revealed significant metabolic abnormalities including hyponatremia, hypokalemia, and elevated thyroid-stimulating hormone. Further endocrine evaluation confirmed the diagnosis of secondary adrenal insufficiency, likely due to pembrolizumab-induced inflammation of the pituitary gland. The patient was treated with corticosteroid replacement therapy, leading to clinical improvement, and pembrolizumab was discontinued due to the risk of worsening adrenal insufficiency. This case underscores the importance of early recognition and management of adrenal insufficiency in patients receiving pembrolizumab. While the exact cause of pembrolizumab-induced adrenal insufficiency is not fully understood, it may involve an autoimmune attack on cells in the pituitary gland. Prompt identification and treatment are essential to prevent potentially life-threatening complications, and this case highlights the need for clinicians to maintain a high level of awareness for adrenal insufficiency in patients presenting with nonspecific symptoms during or after immunotherapy.

Immune checkpoint inhibitors (ICIs), have emerged to the forefront of management for various advanced cancers, such as melanoma, lung cancer and renal cell carcinoma. Immune checkpoints such as CTLA-4 and PD-1 serve to inhibit T cell activation and signaling; therefore through blockade of these pathways, ICIs promote anti-tumour immune activation. However, as a result of T cell disinhibition, ICIs have been reported to cause immune related adverse events (irAEs) affecting numerous organ systems. One of the most serious and potentially life-threatening irAE is inflammatory myositis. Myositis, which generally presents with progressive proximal muscle weakness and elevated serum creatine kinase (CK), has been reported in <1% of patients who have received ICI therapy. A rare cause of elevated CK is adrenal insufficiency, which has been reported in up to 6% of ICI users. Here we report a case of ICI-related hypophysitis related myopathy that was initially misdiagnosed as ICI-associated inflammatory myositis. This case illustrates the importance of considering a wide differential when assessing hyperCKemia in the setting of ICI use.

As the positive results of multiple clinical trials were released, the Programmed cell death 1 (PD-1) and Programmed cell death ligand 1 (PD-L1) inhibitors emerge as the focus of integrative breast cancer treatment. PD-1/PD-L1 inhibitors are often used as a sequential agent to be combined with other agents such as chemotherapeutic agents, targeted agents, and radiation therapy. As multiple therapies are administered simultaneously or in sequence, they are prone to a variety of adverse effects on patients while achieving efficacy. It is a challenge for clinicians to maintaining the balance between immune-related adverse effects(irAEs) and treatment efficacy. Previous literatures have paid lots of attention on the adverse effects caused by immunosuppressive agents themselves, while there is a dearth of the research on the management of adverse immune effects during the combination of immunotherapy with other treatments. In this review, we discuss the overall incidence of irAEs caused by PD-1/PD-L1 inhibitors in combination with various types of treatments in breast cancer, including chemotherapy, CTLA-4 inhibitors, targeted therapy, and radiotherapy, and systematically summarizes the clinical management to each organ-related adverse immune reaction. It is important to emphasize that in the event of irAEs such as neurological, hematologic, and cardiac toxicity, there is no alternative treatment but to terminate immunotherapy. Thus, seeking more effective strategy of irAEs' management is imminent and clinicians are urged to raise the awareness of the management of adverse immune reactions.

Few meta-analyses on incidence of endocrine immune-related adverse effects (eirAEs) have been published and many trials have been published since.

We performed a comprehensive meta-analysis with updated literature to assess risk and incidence of eirAEs of any grade and grade 3 to 5 by immune checkpoint inhibitor (ICI) monotherapy or combination therapy in solid tumors.

An electronic search using PubMed/Medline, Embase, and the Cochrane Library was performed. Randomized controlled studies (RCTs) assessing eirAEs under ICI monotherapy or ICI combination therapy were selected. Stata software (v17) was used for statistical analyses and risk of bias was evaluated using Review Manager version 5.3.

A total of 69 RCTs with 80 independent reports, involving 42 886 patients, were included in the study. Meta-analysis revealed the following pooled estimates for risk ratio and incidence, respectively: for any grade hypothyroidism 7.81 (95% CI, 5.68-10.74, P < .0001) and 7.64% (95% CI, 6.23-9.17, P < .0001); significantly increased also for hyperthyroidism, hypophysitis/hypopituitarism, and adrenal insufficiency; and for insulin-dependent diabetes mellitus 1.52 (95% CI, 1.07-2.18, P = .02), and 0.087% (95% CI, 0.019-0.189, P = .0006), respectively. Meta-regression showed that combination of ICIs (nivolumab plus ipilimumab; durvalumab plus tremelimumab) is an independent risk factor for any grade hypophysitis/hypopituitarism, and that ICI agent is an independent factor of risk for adrenal insufficiency, but that cancer type is not an independent risk factor for eirAEs.

We showed that risk, independent from cancer type, and incidence of eirAEs are substantially increased with ICI therapy. Combination of ICIs increases risk for eirAEs, especially for hypophysitis/hypopituitarism.

Immune checkpoint inhibitors (ICIs) have significantly improved the outcomes of patients with cancer; however, these agents may initiate immune-related adverse events (irAEs). Previous studies have demonstrated a robust correlation between disease prognosis and the occurrence of irAEs, specifically skin or endocrine irAEs. Herein, we aimed to evaluate the correlation between irAE-related adrenal insufficiency (AI) and ICI treatment efficacy.

Patients diagnosed with gastrointestinal, respiratory, head and neck, urological, skin and gynecologic cancers treated with anti-programmed cell death 1 (PD-1)/anti-programmed cell death ligand 1 (PD-L1) antibody as monotherapy or combined therapy (combined with chemotherapy or targeted therapy) were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs) and non-irAE groups. Immunotherapy efficacy was assessed based on the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival probabilities were estimated using the Kaplan-Meier method with the log-rank test.

Of the 192 patients enrolled in our study, 17 developed irAE-related AI and 83 developed other irAEs. The DCR of the irAE-A and irAE-B groups were higher than that of the non-irAE group (P<0.05). Multiple extended Cox regression analyses showed that irAE status (irAE-A vs non-irAE, P=0.008; irAE-B vs non-irAE, P=0.020), Eastern Cooperative Oncology Group (ECOG) status (P=0.045), tumor-node-metastasis (TNM) stage (P=0.000), and treatment line (P=0.002) were independent predictors of PFS. Contrarily, irAE status (irAE-A vs non-irAE, P=0.009; irAE-B vs non-irAE, P=0.013), ECOG status (P=0.007), TNM stage (P=0.035), treatment line (P=0.001) and treatment modality (P=0.008) were independent predictors for OS.

IrAE-related AI was significantly associated with ICI treatment efficacy in patients with cancer, which could be a potentially predictable marker. Due to the destruction of adrenal tissue by T cells with enhanced activity, AI reflects enhanced T cell activity to some extent.

Pembrolizumab can cause immune-related adverse events such as adrenal insufficiency (AI). However, there is no consensus regarding appropriate monitoring of adrenal function during subsequent chemotherapy in patients who have received immune checkpoint inhibitors (ICIs) such as pembrolizumab.

In this report, we discuss the case of a 60s-year-old male patient with non-small cell lung cancer receiving chemotherapy who developed secondary AI due to adrenocorticotrophic hormone (ACTH) deficiency 8 months after the discontinuation of pembrolizumab, which was 17 months after the initiation of pembrolizumab immunotherapy. After 5 months of chemotherapy, he developed fever and diarrhoea, after which chemotherapy was discontinued. Thereafter, he was hospitalised owing to the development of general fatigue and anorexia. Although cortisol and ACTH levels were not measured during chemotherapy, they were measured before hospitalisation, and secondary AI was suspected. After admission, a detailed endocrine workup was performed, and the patient was diagnosed with secondary AI due to ACTH deficiency. Treatment with hydrocortisone was initiated, which markedly improved his general fatigue and anorexia. The patient showed no evidence of progressive disease 9 months after the discontinuation of pembrolizumab.

Although rare, the possibility of AI should be considered in patients who have received ICIs when nonspecific symptoms develop during or after subsequent chemotherapy, and measurements of endocrine function (including cortisol and ACTH levels) should be performed.

Immunotherapy with immune checkpoint inhibitors (ICI) has shown promising activity against many tumor types. However, they can also induce a wide array of immune-related adverse events, ranging from mild to fatal. Primary 3 endocrine gland insufficiency during treatment with ICI has rarely been reported.

We report the case of a 33-year-old man with Ewing sarcoma who was treated with toripalimab as a second-line treatment. Approximately 11 months after initiating treatment, the patient developed subclinical hypothyroidism, which was followed by adrenal insufficiency and hypogonadism 6 months later. Consequently, the decision was made to discontinue ICI therapy and initiate hormone replacement therapy to manage endocrine deficiencies.

Serum adrenocorticotropic hormone, thyroid stimulating hormone, and prolactin levels increased significantly, while cortisol, estradiol, and testosterone levels decreased (Table 1). The patient had negative findings on the pituitary MRI.

As part of the management strategy, ICI therapy was ceased and hormone replacement therapy was commenced to address endocrine deficiencies.

After hormone replacement therapy, his symptoms improved and follow-up examinations showed normalization of hormone levels.

Clinicians should be aware of the potential of immune checkpoint inhibitor therapy to cause endocrine dysfunction. Prompt recognition and management of these adverse events are crucial for patient health and quality of life.

As an immune checkpoint inhibitor (ICI), tislelizumab is an anti-programmed cell death protein 1 (PD-1) drug. With the extensive application of ICIs, there is an ever-increasing proportion of immune-related adverse events (irAEs) in clinical settings, some of which may even be life-threatening. Herein, we present a patient with tislelizumab-induced adrenal crisis. The main clinical manifestation was recurrent syncope accompanied by high-grade fever. Timely identification and hormone replacement therapy helped the patient overcome the crisis well. Finally, the patient discontinued tislelizumab and switched to antibody-drug conjugate (ADC) therapy. We report this case to improve our understanding of this situation, identify this kind of disease, and prevent adrenal crisis in time. Eventually, limiting toxicities reduces the interruption of immunotherapy. Since irAEs are multisystem damage with more non-specific symptoms, except for oncologists, general practitioners who endorse the need for taking a holistic approach to the patient should play a vital role in the management of cancer treatment.

The increasing use of immune checkpoint inhibitors (ICIs) for treating malignant tumors result in the concomitant rise of immune-related adverse events (irAEs). This case report may provide useful insight to understanding the etiology of ICI-induced hypophysitis, a severe irAE leading to potentially fatal secondary adrenal insufficiency.

An 81-year-old Japanese man was hospitalized for diabetic ketoacidosis following 4 courses of ICI combination therapy with nivolumab and ipilimumab for metastatic renal cell carcinoma.

Insulin secretion was depleted, leading to diagnosis of fulminant type 1 diabetes. Adrenocorticotropic hormone (ACTH) and cortisol levels were very high (60.8 pmol/L and 1575 nmol/L, respectively) upon admission. ACTH and cortisol returned to normal ranges on the 2nd day. On the 8th day, an ACTH loading test showed intact cortisol response (peak value 519 nmol/L). However, on the 14th day, there was a sharp decrease in ACTH and cortisol levels (10.5 pmol/L and 47 nmol/L, respectively) accompanied by fatigue and a drop in blood pressure to 97/63 mm Hg. As secondary adrenal insufficiency was suspected, hydrocortisone replacement was initiated. An ACTH loading test on the 17th day revealed low cortisol peak (peak value 232 nmol/L), indicating sudden disruption of adrenal function. Magnetic resonance imaging showed no abnormal findings and there was no other pituitary hormone deficiency. These findings, along with the patient clinical course, suggest that secondary adrenal insufficiency was caused by acute ACTH producing cell destruction as an irAE associated with ICI therapy.

The patient hyperglycemia and ketoacidosis were treated using extracellular fluid and insulin therapy. After development of adrenal insufficiency, hydrocortisone 20 mg was started, and the patient symptoms improved.

He was continued on insulin therapy, hydrocortisone, and reinitiated nivolumab.

This case provides a detailed course of the fulminant onset of ACTH deficiency during ICI administration, emphasizing the importance of close monitoring.

Adrenal insufficiency (AI) caused by immune checkpoint inhibitors (ICIs) is an extremely rare immune-related adverse event (irAE). The detailed clinical characteristics and outcomes of patients with ICI-induced AI are unavailable. This study aimed to explore the clinical characteristics and efficacy of treatment in patients with ICI-induced AI.

We retrospectively collected information on patients diagnosed with AI caused by ICIs at LiShui Municipal Central Hospital and Zhejiang Cancer Hospital, including baseline characteristics, laboratory results, symptoms, treatment outcomes of AI, and hormone use. Survival outcomes were calculated using the Kaplan-Meier method and stratified according to the different situations.

From December 2020 to February 2023, among 1014 patients treated with ICI therapy, a total of twenty patients were diagnosed with ICI-induced AI. Most of the patients were men (80%, n = 16), with a performance status (PS) of 0 - 1 (95%, n = 19). The median (range) age was 65.9 (49-80) years and 14 patients (70%) were treated with ICIs as first-line therapy. The majority of the patients (70%, n = 14) experienced grade 3 - 4 AI. All patients received corticosteroid replacement therapy, and only 7 patients recovered. The median time to the diagnosis of AI after starting ICI therapy was 5.2 (3.0 - 7.5) months. The objective response rate was 70% and  median progression-free survival in these patients was 16.0 months (95% confidence interval: 11.7 - 20.3 months).

ICI-induced AI is a rare irAE, and close monitoring of cortisol levels is important. Patients diagnosed with AI after receiving immunotherapy seem to have a favorable outcome.

This study investigated the incidence of endocrine immune-related adverse events (irAEs) for recently developed immune checkpoint inhibitor (ICI) drugs.

We collected studies on newly developed ICI drugs using PubMed/Medline, Embase, and Cochrane Library from inception through January 31, 2023. Among ICI drugs, nivolumab, pembrolizumab, and ipilimumab were excluded from the new ICI drugs because many papers on endocrine-related side effects have already been published.

A total of 44,595 patients from 177 studies were included in this analysis. The incidence of hypothyroidism was 10.1% (95% confidence interval [CI], 8.9% to 11.4%), thyrotoxicosis was 4.6% (95% CI, 3.8% to 5.7%), hypophysitis was 0.8% (95% CI, 0.5% to 1.1%), adrenal insufficiency was 0.9% (95% CI, 0.7% to 1.1%), and hyperglycemia was 2.3% (95% CI, 1.6% to 3.4%). Hypothyroidism and thyrotoxicosis occurred most frequently with programmed cell death protein-1 (PD-1) inhibitors (13.7% and 7.5%, respectively). The rate of endocrine side effects for the combination of a programmed death-ligand 1 inhibitor (durvalumab) and cytotoxic T lymphocyte-associated antigen 4 inhibitor (tremelimumab) was higher than that of monotherapy. In a meta-analysis, the combination of tremelimumab and durvalumab had a 9- to 10-fold higher risk of pituitary and adrenal-related side effects than durvalumab alone.

Newly developed PD-1 inhibitors had a high incidence of thyroid-related irAEs, and combined treatment with durvalumab and tremelimumab increased the risk of pituitary- and adrenal-related irAEs. Based on these facts, it is necessary to predict the endocrine side effects corresponding to each ICI drug, diagnose and treat them appropriately, and try to reduce the morbidity and mortality of patients.

Atezolizumab and bevacizumab are currently available as first-line treatments for unresectable hepatocellular carcinoma, but immune-related adverse events are a major concern. We herein report two cases of isolated adrenocorticotropic hormone (ACTH) deficiency. Both patients presented with general fatigue, appetite loss, eosinophilia, and hyponatremia after nine cycles in case 1 and three months after stopping treatment for inflammatory arthritis in case 2. Endocrinological investigations revealed unsatisfactory ACTH and cortisol responses despite the preservation of other anterior pituitary hormones, suggesting isolated ACTH deficiency. As it is rapidly improved by steroid replacement therapy, an early diagnosis and treatment make it possible to resume immunotherapy.

Immune checkpoint inhibitors (ICIs) are a new type of antitumor drug which can achieve antitumor goals by blocking the binding of immune checkpoints to their ligands, thereby enhancing the activity of T cells. Meanwhile, ICIs block the binding of immune checkpoints to their ligands, disrupting the immune tolerance of T cells to self-antigens, which may lead to a series of immune-related adverse events (irAEs). Immune checkpoint inhibitor-induced hypophysitis (IH) is a relatively rare irAE. Due to the lack of specificity in clinical manifestations, it is difficult to accurately diagnose IH in a timely manner in clinical practice. However, the risk of adverse events, especially IH, for patients receiving ICIs has not been adequately investigated. Missed or delayed diagnosis may lead to poor prognosis or even adverse clinical outcomes. In this article, we summarize the epidemiology, pathogenesis, clinical manifestations, diagnosis and treatment of IH.

In recent years, a wide range of cancer immunotherapies have been developed and have become increasingly important in cancer treatment across multiple oncologic diseases. In particular, immune checkpoint inhibitors (ICIs) offer promising options to improve patient outcomes. However, a major limitation of these treatments consists in the development of immune-related adverse events (irAEs) occurring in potentially any organ system and affecting up to 76% of the patients. The most frequent toxicities involve the skin, gastrointestinal tract, and endocrine system. Although mostly manageable, potentially life-threatening events, particularly due to neuro-, cardiac, and pulmonary toxicity, occur in up to 30% and 55% of the patients treated with ICI-monotherapy or -combination therapy, respectively. Imaging, in particular computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT), plays an important role in the detection and characterization of these irAEs. In some patients, irAEs can even be detected on imaging before the onset of clinical symptoms. In this context, it is particularly important to distinguish irAEs from true disease progression and specific immunotherapy related response patterns, such as pseudoprogression. In addition, there are irAEs which might be easily confused with other pathologies such as infection or metastasis. However, many imaging findings, such as in immune-related pneumonitis, are nonspecific. Thus, accurate diagnosis may be delayed underling the importance for adequate imaging features characterization in the appropriate clinical setting in order to provide timely and efficient patient management. ¹⁸F-FDG-PET/CT and radiomics have demonstrated to reliably detect these toxicities and potentially have predictive value for identifying patients at risk of developing irAEs. The purpose of this article is to provide a review of the main immunotherapy-related toxicities and discuss their characteristics on imaging.

To describe the frequency of hypophysitis and hypopituitarism in cancer patients who are undergoing antineoplastic treatment with immunotherapy, as well as to describe the clinical, epidemiological, and demographic characteristics of these patients.

A systematic search of the literature in PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Controlled Register of Trials took place on May 8 and 9, 2020. Randomized and nonrandomized clinical trials, cohort studies, case-control studies, case series and case reports were included.

A total of 239 articles were obtained, in which 963 cases of hypophysitis and 128 cases of hypopituitarism were found in a treated population of 30,014 individuals (3.20% and 0.42% of the evaluated population, respectively). In the cohort studies, the incidence of hypophysitis and hypopituitarism ranged from 0% to 27.59% and from 0% to 17.86%, respectively. In the non-randomized clinical trials, the incidence of hypophysitis and hypopituitarism ranged from 0% to 25% and from 0% to 14.67%, and in randomized clinical trials from 0% to 16.2% and from 0% to 33.33%. The most common hormonal changes were in the corticotrophic, thyrotrophic and gonadotrophic axes. The main magnetic resonance imaging (MRI) findings were enlargement of the pituitary gland and enhanced contrast uptake. The main symptoms presented by patients with hypophysitis were fatigue and headache.

The present review reported a frequency of hypophysitis and hypopituitarism of 3.20% and 0.42%, respectively, in the evaluated population. The clinical-epidemiological characteristics of patients affected by hypophysitis were also described.

https://www.crd.york.ac.uk/prospero/, identifier CRD42020175864.

A 63-year-old man with hepatitis C was treated with atezolizumab plus bevacizumab for unresectable diffuse hepatocellular carcinoma (HCC). After four cycles of atezolizumab plus bevacizumab, the diffuse HCC markedly shrank; however, he complained of general fatigue, loss of appetite, and slight loss of muscle strength in the lower legs. He was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD), hypothyroidism, and myopathy, suggesting multisystem immune-related adverse events (irAEs). After administration of hydrocortisone, the clinical symptoms rapidly disappeared. Patients with multisystem irAEs can have favorable outcomes; thus, to continue immune-checkpoint inhibitors therapy, a correct diagnosis and management of multisystem irAEs are important.

Our study aimed to investigate the prevalence and demographic characteristics of immune checkpoint inhibitor-associated primary adrenal insufficiency (ICI-PAI) and to explore the risk factors of its clinical outcome using data from the US FDA Adverse Event Reporting System (FAERS).

This was a retrospective study. All cases of new-onset or newly diagnosed primary adrenal insufficiency associated with FDA-approved ICIs from 1 January 2007 to 31 December 2020 were identified and collected using FAERS. Data on age, sex category, body weight of the participating individuals, the reporting year and the prognosis of cases, and other accompanying endocrinopathies related to ICIs, were analysed.

The incidence of ICI-PAI was 1.03% (1180/114121). Of the 1180 cases of PAI, 46 were "confirmed PAI", and 1134 were "suspected PAI". Combination therapy with anti-CTLA-4 and anti-PD-1 was related to a higher risk of PAI compared with the anti-PD-1-only group (χ² = 92.88, p < 0.001). Male and elderly individuals showed a higher risk of ICI-PAI (male vs. female, 1.17% vs. 0.94%, χ² = 12.55, p < 0.001; age < 65 vs. ≥ 65, 1.20 vs. 1.41%, χ² = 6.89, p = 0.009). The co-occurrence rate of endocrinopathies other than PAI was 24.3%, which showed a higher trend in patients on nivolumab-ipilimumab treatment than in those on PD-1 inhibitors (χ² = 3.227, p = 0.072). Body weight was negatively associated with the risk of death in the study population [p = 0.033 for the regression model; B = - 0.017, OR 0.984, 95% CI (0.969-0.998), p = 0.029].

ICI-associated PAI is a rare but important irAE. Male and elderly patients have a higher risk of ICI-PAI. Awareness among clinicians is critical when patients with a lower body weight develop PAI, which indicates a higher risk of a poor clinical outcome.

Aggressive pituitary adenomas (APAs) are pituitary tumors that are refractory to standard treatments and carry a poor prognosis. Current treatment guidelines are not standardized but combine surgical resection, radiation therapy, and chemotherapy. Temozolomide is the only chemotherapeutic agent with documented effectiveness and is recommended for APA in European Society of Endocrinology clinical guidelines.

A 57-year-old man presented with visual deterioration and bitemporal hemianopsia. MRI of the brain demonstrated a sellar mass suspected to be pituitary macroadenoma with displacement of the stalk and optic nerve impingement. The patient underwent stereotactic endoscopic transsphenoidal resection of the mass. Postoperative MRI demonstrated gross total resection. Pathology revealed a sparsely granulated corticotroph adenoma with malignant transformation. Immunohistochemistry showed loss of expression of MLH1 and PMS2 in the tumor cells. Proton therapy was recommended given an elevated Ki67 index and p53 positivity. Before radiotherapy, there was no radiographic evidence of residual tumor. Temozolomide therapy was initiated after surveillance MRI showed recurrence at 16 months postoperatively. However, MRI demonstrated marked progression after 3 cycles. Next-generation sequencing using the MSK-IMPACT platform identified somatic mutations in MLH1 Y548lfs*9 and TP53 R337C . Immunotherapy with ipilimumab/nivolumab was initiated, and MRI demonstrated no residual tumor burden 34 months postoperatively.

APA is a tumor with frequent recurrence and a short median expected length of survival. Here, we demonstrate the utility of immunotherapy in a single case report of APA, with complete resolution of recurrent APA and improved survival compared with life expectancy.

Recognition and management of adverse events (AEs) associated with immune checkpoint inhibitor (ICI) use by cancer patients requires expertise from multiple disciplines. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes.

The primary objective of this overview of systematic reviews was to synthesize and consolidate systematic review evidence describing the incidence proportion and severity of AEs associated with various ICI therapies across different cancers.

A systematic literature search of four databases was conducted to identify systematic reviews that describe the incidence proportion and severity of AEs related to ICI therapy in cancer patients. A systematic review was eligible if it included adults with cancer; on ICI alone or in combination with another ICI, chemotherapy, or targeted therapy; severity (graded according to the Common Terminology Criteria for Adverse Events) and incidence proportion of AEs and whether it reported its eligibility criteria. AEs of interest were identified through an iterative ranking exercise by key stakeholders and knowledge users. Extraction of PICOTTS elements and quality indicators (AMSTAR-2) were used to manage overlap of primary studies across systematic reviews at the outcome level. Cancer subtypes were mapped to drug class and AE severity.

Overall, 129 systematic reviews met the inclusion criteria for data mapping. Systematic reviews reported incidence proportions for more than 76 AEs, of which 34 were identified as AEs of interest. After overlap assessment, 65 systematic reviews were chosen for data extraction. The three AEs with the highest median incidence were fatigue (18.3%, interquartile range [IQR] 15.0-28.0%), diarrhea (15.3%, IQR 9.7-29.2%) and rash (14.4%, IQR 10.3-19.2%). The three AEs (high-grade) with the highest median incidence were diarrhea (1.5%, IQR 1.2-6.0%), colitis (1.3%, IQR 0.6-6.1%) and neutropenia (1.2%, IQR 0.4-3.3%). Incidence proportions of high-grade AEs were often considerably lower than all-grade AEs and combination therapy (ICI combinations or combinations of ICI with chemotherapy or targeted therapy) was responsible for some of the highest incidence proportions regardless of AE. Rare AEs and certain cancer subtypes were not well reported.

Early recognition of AEs associated with ICIs requires expertise from diverse specialists, not just oncologists. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes.

CRD42021231593.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several malignancies, improving patient survival and quality of life. Endocrinopathies have emerged as a clinically significant group of immune-related adverse events (IRAEs). Although the mechanism of ICI toxicities has not been clarified, inhibition of immune checkpoints reduces immune tolerance to autoantigens, resulting in the development of autoimmunity disorders. We report current evidence regarding endocrine IRAEs that may have diagnostic and therapeutic implications. Management should be focused on a multidisciplinary approach to reach a prompt diagnosis and an appropriate and safe treatment.

Adrenal insufficiency (AI) is an easily treatable, potentially life-threatening condition, which is increasingly recognized in malignancy. The recent introduction of immune checkpoint inhibitors, in particular, and increasing use of tyrosine kinase inhibitors have increased the frequency of AI in patients with malignancy. A review is therefore warranted to summarize current knowledge on the topic and guide safe clinical practices.

Malignancy may directly impact the hypothalamic-pituitary-adrenal axis and cause AI, or their treatment including surgery, radiotherapy and medication. In this narrative review, we discuss new causes of AI, recognition of suggestive clinical features, diagnosis and subsequent treatment, aiming to avoid potentially fatal adrenal crisis (AC). Standard literature searching and authors assessment of clinical applicability were used.

Adrenal insufficiency can be easily treated once identified but life threatening if unrecognized. While use of new agents such as immune checkpoint inhibitors (ICIs) is increasing, greater understanding of the mechanism of AI is needed to target prediction tools and enhance risk stratification.

Hypophysitis is defined as inflammation of the pituitary gland. It is a heterogeneous condition as it can originate from different parts of the pituitary gland, can be caused by different pathophysiological processes, and can be isolated or the manifestation of a underlying systemic disease. Hypophysitis usually presents with endocrine deficiencies, including diabetes insipidus, with varying patterns. A subset of patients presents with mass effects. The last decades major progress has been made in the understanding of this disease. New forms are now recognized, new diagnostics are being developed, and specific treatments are proposed. This review provides an overview of the current knowledge on hypophysitis using an aetiology-based approach and provides the clinician with a stepwise approach to the patient with (suspected) hypophysitis.

Immunotherapy with immune checkpoint inhibitor (ICI) monoclonal antibodies has shown to be an effective therapeutic alternative in several malignant tumors. However, adverse effects related to an activation of the immune system may accompany ICI therapy. Among the immune-related adverse events (irAEs) are autoimmune endocrine adverse effects, such as thyroiditis, and hypophysitis. Secondary adrenal insufficiency due to isolated ACTH deficiency (IAD) has also been recently reported to be associated with ICI antibodies. We carried out a systematic review of IAD cases induced by cancer immunotherapy published to date using PubMed's database. We selected 35 articles that reported 60 cancer patients diagnosed with IAD induced by ICI therapy. The prevalence was higher in men (ratio 1.6/1). Mean age at diagnosis was 63.2 ± 11.6 (range,30-87). Melanoma was the tumor most commonly reported (35%) followed by lung (28.3%) and kidney cancer (18.3%). The ICI monoclonal antibody most frequently associated was nivolumab in monotherapy (60%), followed by pembrolizumab (18.3%). Median (IQR) time to develop IAD after starting ICI therapy was 6 (4-8) months. The main symptoms at IAD diagnosis were fatigue (82.8%) and anorexia (67.2%). Hyponatremia (68%) and eosinophilia (31.8%) were the laboratory abnormalities most frequently associated with IAD. Pituitary magnetic resonance imaging (MRI) was normal in most patients (93%). Thyroiditis was the most prevalent (35%) endocrine irAE associated with IAD. In conclusion, ICI-induced IAD is a rare and potentially life-threatening condition that must be taken into account whenever treatment with immunotherapy in cancer patients is started due to their potential serious prognostic implications.

Immune-related adverse events were reported in patients treated with immune checkpoint inhibitors (ICIs). However, with the increasing number of immune-related adverse events (irAEs), the differences of each immune checkpoint inhibitor regimen had not been fully assessed.

Disproportionality analysis was used in data mining of the suspected adverse events after ICIs administration based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019. The onset time and fatality proportion of ICI-associated irAEs were further evaluated.

A total of 32,441 reports of ICI-associated irAEs were gathered. This study showed that all ICI regimens generated lung toxicity and endocrine toxicity signals. Colitis, pneumonitis and interstitial lung disease were the most common ICI-associated irAEs. Five regimens including durvalumab monotherapy, ipilimumab monotherapy, ipilimumab plus nivolumab, ipilimumab plus pembrolizumab, durvalumab plus tremelimumab were associated with irAEs. Anti-PD-1 agents generated more signals of ocular toxicities than anti-PD-L1 agents, while anti-PD-L1 agents reported more signals of hematologic toxicities. Anti-CTLA-4 agents showed more signals of gastrointestinal toxicities compared with anti-PD-1 or anti-PD-L1 agents. The highest fatality proportion of lung toxicities with durvalumab monotherapy, hematological toxicities with avelumab monotherapy, renal and skin toxicities with cemiplimab monotherapy were found.

Our results demonstrated that each ICI regimen had different characteristics of irAEs. Pembrolizumab had the highest fatality proportion. Ipilimumab plus pembrolizumab had the shortest median time to onset irAEs. Further studies were expected to assess whether there were clinically relevant differences exist among ICIs.

Adrenal insufficiency (AI) is a condition characterized by an absolute or relative deficiency of adrenal cortisol production. Primary AI (PAI) is rare and is caused by direct adrenal failure. Secondary AI (SAI) is more frequent and is caused by diseases affecting the pituitary, whereas in tertiary AI (TAI), the hypothalamus is affected. The most prevalent form is TAI owing to exogenous glucocorticoid use. Symptoms of AI are non-specific, often overlooked or misdiagnosed, and are related to the lack of cortisol, adrenal androgen precursors and aldosterone (especially in PAI). Diagnosis is based on measurement of the adrenal corticosteroid hormones, their regulatory peptide hormones and stimulation tests. The goal of therapy is to establish a hormone replacement regimen that closely mimics the physiological diurnal cortisol secretion pattern, tailored to the patient's daily needs. This Primer provides insights into the epidemiology, mechanisms and management of AI during pregnancy as well as challenges of long-term management. In addition, the importance of identifying life-threatening adrenal emergencies (acute AI and adrenal crisis) is highlighted and strategies for prevention, which include patient education, glucocorticoid emergency cards and injection kits, are described.

The aim of this meta-analysis was to assess the risks of endocrine adverse events in patients with malignancies treated with different types and different doses of immune checkpoint inhibitors (ICIs). PubMed and Embase were searched for randomized controlled trials on ICIs and endocrine adverse events since 2000, and meta-analysis was carried out. Twenty-six randomized controlled trials comprising 13 824 patients with malignancies were included. Compared with the other tumor therapies (used as a control group), patients treated with programmed death-1 inhibitors appeared to be at higher risks of hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis or hypopituitarism, and type 1 diabetes mellitus, while there was no difference in the risk of primary adrenal insufficiency. It was also found that patients treated with cytotoxic T-lymphocyte-associated protein-4 inhibitors were at higher risk of hypophysitis or hypopituitarism, primary adrenal insufficiency, and hypothyroidism. In comparison, patients treated with programmed death-ligand 1 inhibitors were at higher risk of hyperthyroidism and hypothyroidism. Compared with the control group, both low-dose and high-dose ICI groups were at higher risk of hypothyroidism and hyperthyroidism, and the low-dose group had increased risk of thyroiditis and primary adrenal insufficiency. There was no significant difference in the risk of type 1 diabetes between the low-dose group and the high-dose group. The risk of hypophysitis or hypopituitarism in the high-dose group (relative risk, 20.12; 95% confidence interval, 8.02-50.46) was significantly higher than that in the low-dose group (relative risk, 4.92; 95% confidence interval, 2.11-11.47). The risk of endocrine adverse events was increased in patients treated with ICIs. Different types and doses of ICIs have varying characteristics of endocrine adverse events.

Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.

Adrenal crises are severe manifestations of adrenal insufficiency that result in hospital admission and incur a risk of cardiovascular events, acute renal injury, and death. Evidence from population-based studies indicate that adults older than 60 years have the highest adrenal insufficiency incidence, contribute to the highest number of adrenal crises, and have the highest age-specific incidence of adrenal crisis, which doubles between the age groups of 60-69 years and 80 years or older. Older patients might be more susceptible to adrenal crises because of a higher prevalence of comorbidities and a consequently higher risk of acute illness. This susceptibility might be compounded by shortfalls in the implementation of prevention strategies for adrenal crisis, because of individual and social factors that increase with age. Although little research has focused on adrenal crisis prevention in older patients, it seems logical that a timely diagnosis of adrenal insufficiency and the use of consensus driven adrenal crisis prevention and attenuation strategies might reduce adrenal crises in patients older than 60 years old.

Cancer immunotherapies have changed the landscape of cancer treatment during the past few decades. Among them, immune checkpoint inhibitors, which target PD-1, PD-L1 and CTLA-4, are increasingly used for certain cancers; however, this increased use has resulted in increased reports of immune-related adverse events (irAEs). These irAEs are unique and are different to those of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or system. These effects are frequently low grade and are treatable and reversible; however, some adverse effects can be severe and lead to permanent disorders. Management is primarily based on corticosteroids and other immunomodulatory agents, which should be prescribed carefully to reduce the potential of short-term and long-term complications. Thoughtful management of irAEs is important in optimizing quality of life and long-term outcomes.

With the growing use of immune checkpoint inhibitors (ICIs), case reports of rare yet life-threatening pituitary-adrenal dysfunctions, particularly for hypopituitarism, are increasingly being published. In this analysis, we focus on these events by including the most recent publications and reports from early phase I/II and phase III clinical trials and comparing the incidence and risks across different ICI regimens. PubMed, Embase, and the Cochrane Library were systematically searched from inception to April 2019 for clinical trials that reported on pituitary-adrenal dysfunction. The rates of events, odds ratios (ORs), and 95% confidence intervals (CIs) were obtained using random effects meta-analysis. The analyses included data from 160 trials involving 40 432 participants. The rate was 2.43% (95% CI, 1.73%-3.22%) for all-grade adrenal insufficiency and 3.25% (95% CI, 2.15%-4.51%) for hypophysitis. Compared with the placebo or other therapeutic regimens, ICI agents were associated with a higher incidence of serious-grade adrenal insufficiency (OR 3.19, 95% CI, 1.84 to 5.54) and hypophysitis (OR 4.77, 95% CI, 2.60 to 8.78). Among 71 serious-grade hypopituitarism instances in 12 336 patients, there was a significant association between ICIs and hypopituitarism (OR 3.62, 95% CI, 1.86 to 7.03). Substantial heterogeneity was noted across the studies for the rates of these events, which in part was attributable to the different types of ICIs and varied phases of the clinical trials. Although the rates of these events were low, the risk was increased following ICI-based treatment, particularly for CTLA-4 inhibitors, which were associated with a higher incidence of pituitary-adrenal dysfunction than PD-1/PD-L1 inhibitors.