Effects of immune checkpoint inhibitor associated endocrinopathies on cancer survival.

Objectives: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs), of which endocrinopathies are common. We characterized endocrine and non-endocrine irAEs in cancer patients receiving ICIs, identified risk factors for their development and established whether endocrine and non-endocrine irAEs were differentially associated with improved cancer prognosis. Design and methods: Single-center, retrospective cohort study of patients with advanced or metastatic solid tumors receiving at least one ICI treatment cycle (242 men, 151 women, median age 65 years). Main outcome measures were incidence of any irAE during the study period, overall survival and time to treatment failure. Results: Non-endocrine irAEs occurred in 32% and endocrine irAEs in 12% of patients. Primary thyroid dysfunction was the most common endocrine irAE (9.5%) and the majority of endocrinopathies required permanent hormone replacement. Women had an increased risk of developing endocrine irAEs (p = 0.017). The biggest survival advantage occurred in patients who developed both endocrine and non-endocrine irAEs (overall survival: HR 0.16, CI 0.09-0.28). Time to treatment failure was also significantly improved in patients who developed endocrine irAEs (HR 0.49, CI 0.34 - 0.71) or both (HR 0.41, CI 0.25 - 0.64) but not in those who only developed non-endocrine irAEs. Conclusions: Women may have increased risk of endocrine irAEs secondary to ICI treatment. This is the first study to compare the effects of endocrine irAEs with non-endocrine irAEs on survival. Development of endocrine irAEs may confer survival benefit in ICI treatment and future, prospective studies are needed to elucidate this.

Research hot spots and trends in endocrine-related adverse events caused by immune checkpoint inhibitors: a bibliometric analysis and visualization research.

Background: In recent years, with the widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment, the toxicity associated with immunotherapy of ICIs has attracted more attention from scholars. Endocrine toxicity is the most likely immune-related adverse events (irAEs) and is often irreversible, posing a significant clinical treatment challenge. Methods: In this study, bibliometric methods were used to analyze relevant literature in screening endocrine-related adverse events caused by ICIs in the Web of Science core collection database (WoSCC) and to summarize the status, research hot spots, and future trends in this field. Results: 321 countries, 297 institutions, 365 authors, and 305 journals had published 671 English documents on endocrine adverse reactions of ICIs as of 1 December, 2022. The United States, Japan, and China were the top three countries with the most publications. The University of Texas MD Anderson Cancer Center, Harvard Medical School, and Memorial Sloan Kettering Cancer Center were the top three research institutions in terms of publication output. F Stephen Hodi, from the Dana-Farber Cancer Institute in the United States, contributed the largest number of publications. Frontiers in Oncology, which was the most widely distributed publication in the field. The main keywords or clusters identified that current research hotspots include the management of endocrine-related adverse events, hypophysitis, thyroid dysfunction, type I diabetes mellitus, and the impact of endocrine adverse events on survival of patients in this field. Conclusion: The basic knowledge structure of the field of endocrine-related adverse events of ICIs, including publication trends, authors, institutions, countries, keywords, journals and publications, and cited documents, was visually analyzed in this bibliometric analysis. The research results comprehensively demonstrated the hot spots and future trends in the research field, as well as its broad prospects, thus providing a reference for the researchers.

Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Endocrine immune-related adverse effects of immune-checkpoint inhibitors.

INTRODUCTION: Immune-checkpoint inhibitor therapy modulates the response of the immune system acting against cancer. Two pathways impacted by this kind of treatment are the CTLA4 and the PD-1/PD-L1 pathways. ICI therapy can trigger autoimmune adverse effects, known as immune-related Adverse Events (irAEs). AREAS COVERED: This review focuses on irAEs which affect the endocrine system. This review elucidates the pathways used by these drugs with a focus on the hypothetical pathogenesis at their basis. In fact, the pathophysiology of irAEs concerns the possibility of an interaction between cellular autoimmunity, humoral immunity, cytokines, chemokines, and genetics. The endocrine irAEs examined are thyroid dysfunctions, immune related-hypophysitis, diabetes, peripheral adrenal insufficiency, and hypoparathyroidism. EXPERT OPINION: There is still much to investigate in endocrine irAES of checkpoint inhibitors. In the future, checkpoint inhibitors will be increasingly utilized therapies, and therefore it is crucial to find the proper diagnostic-therapeutic program for irAEs, especially as endocrine irAEs are nonreversible and require lifelong replacement therapies.

Endocrine side effects of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have increasingly been the mainstay of treatment for numerous malignancies. However, due to their association with autoimmunity, ICIs have resulted in a variety of side effects that involve multiple organs including the endocrine system. In this review article, we describe our current understanding of the autoimmune endocrinopathies as a result of the use of ICIs. We will review the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of the most commonly encountered endocrinopathies, including thyroiditis, hypophysitis, Type 1 diabetes, adrenalitis, and central diabetes insipidus.

Immune checkpoint inhibitor-induced hypophysitis: clinical and biochemical features.

Immune checkpoint inhibitors are a very promising novel class of immune response-regulating drugs for cancer treatment. Hypophysitis is one of their most common immune-related adverse events, occurring in a significant proportion of patients. Since this is a potentially severe entity, regular hormone monitoring is recommended during treatment to allow for a timely diagnosis and adequate treatment. Identification of clinical signs and symptoms, such as headaches, fatigue, weakness, nausea and dizziness, can also be key for its recognition. Compressive symptoms, such as visual disturbances, are uncommon, as is diabetes insipidus. Imaging findings are usually mild and transient and can easily go unnoticed. However, the presence of pituitary abnormalities in imaging studies should prompt closer monitoring, as these can precede clinical manifestations. The clinical importance of this entity relates mainly to the risk of hormone deficiency, especially ACTH, which occurs in the majority of patients and is rarely reversible, requiring lifelong glucocorticoid replacement therapy.

A Closer Look at Opioid-Induced Adrenal Insufficiency: A Narrative Review.

Among several opioid-associated endocrinopathies, opioid-associated adrenal insufficiency (OIAI) is both common and not well understood by most clinicians, particularly those outside of endocrine specialization. OIAI is secondary to long-term opioid use and differs from primary adrenal insufficiency. Beyond chronic opioid use, risk factors for OIAI are not well known. OIAI can be diagnosed by a variety of tests, such as the morning cortisol test, but cutoff values are not well established and it is estimated that only about 10% of patients with OIAI will ever be properly diagnosed. This may be dangerous, as OIAI can lead to a potentially life-threatening adrenal crisis. OIAI can be treated and for patients who must continue opioid therapy, it can be clinically managed. OIAI resolves with opioid cessation. Better guidance for diagnosis and treatment is urgently needed, particularly in light of the fact that 5% of the United States population has a prescription for chronic opioid therapy.

Pituitary and adrenal disorders induced by immune checkpoint inhibitors.

Over the past decade, the development of ICI (immune checkpoint inhibitors) has constituted a revolution in the treatment of many cancers, but with a specific toxicity profile including endocrine IRAEs (immune-related adverse events). As the indications for these molecules are constantly increasing due to their efficacy, it is important that endocrinologists and oncologists know how to detect, manage and monitor this type of toxicity. Many guidelines and recommendations have been proposed in the last few years for the management of endocrinopathies. French guidelines on immunotherapy-related endocrine IRAEs were published in 2018, with a specific algorithm for hypophysitis and primary adrenal insufficiency (PAI), based on clinical suspicion followed by biochemical and imaging evaluation, and are still relevant today. Here we present the general pathophysiological mechanisms of these toxicities, and discuss the incidence, diagnosis, treatment, progression, management and monitoring of pituitary and adrenal disorders in patients treated by immunotherapy, with emphasis on hypophysitis, which is much more frequent than PAI with this type of molecule. We also highlight several key points, such as the need for emergency treatment by hydrocortisone with the possibility of continuing immunotherapy in these endocrinopathies, and the long-term persistence of corticotropin or adrenal deficiency in most cases, requiring specific "hydrocortisone education". These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

Real-World Experience of Monitoring Practice of Endocrinopathies Associated with the Use of Novel Targeted Therapies among Patients with Solid Tumors.

BACKGROUND: Cancer treatments have gradually evolved into targeted molecular therapies characterized by a unique mechanism of action instead of non-specific cytotoxic chemotherapies. However, they have unique safety concerns. For instance, endocrinopathies, which are defined as unfavorable metabolic alterations including thyroid disorders, hyperglycemia, dyslipidemia, and adrenal insufficiency necessitate additional monitoring. The aim of this study was to assess the prevalence of monitoring errors and develop strategies for monitoring cancer patients who receive targeted therapies. METHOD: A retrospective chart review was used to assess the prevalence of monitoring errors of endocrinopathies among cancer patients who received targeted therapies over one year. All of the adult cancer patients diagnosed with a solid tumor who received targeted therapies were included. The primary outcome was to determine the prevalence of monitoring errors of endocrinopathies. The secondary outcomes were to assess the incidences of endocrinopathies and referral practice to endocrinology services. RESULTS: A total of 128 adult patients with solid tumors were involved. The primary outcome revealed a total of 148 monitoring errors of endocrinopathies. Monitoring errors of the lipid profile and thyroid functions were the most common error types in 94% and 92.6% of the patients treated with novel targeted therapies, respectively. Subsequently, 57% of the monitoring errors in the blood glucose measures were identified. Targeted therapies caused 63 events of endocrinopathies, hyperglycemia in 32% of the patients, thyroid disorders in 15.6% of them and dyslipidemia in 1.5% of the patients. CONCLUSION: Our study showed a high prevalence of monitoring errors among the cancer patients who received targeted therapies which led to endocrinopathies. It emphasizes the importance of adhering to monitoring strategies and following up on the appropriate referral process.

Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report.

BACKGROUND: The global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19. CASE PRESENTATION: A healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH < 1.5 pg/ml, cortisol 1.6 µg/dl). He was diagnosed with adrenal crisis and was emergently treated with hydrocortisone. The symptoms responded well and he recovered within a few days. Magnetic resonance images after the replacement with hydrocortisone revealed an atrophic pituitary gland. The patient was referred to our tertiary hospital for further endocrinological examination. Pituitary endocrine load tests revealed isolated adrenocortical response deficiency. After other clinical assessments, he was diagnosed as having isolated ACTH deficiency. After initiation of hydrocortisone replacement, there has been no recurrence of symptoms related to adrenocortical insufficiency nor involvement of other pituitary functions. CONCLUSION: This is the first reported case of IAD potentially associated with COVID-19 immunization. Recent reports have emphasized the importance of adjuvants in the mRNA vaccine that induce the endocrinological adverse effects through disturbance of the autoimmune system, but details are still unclear. Given the broad and rapid spread of vaccinations against COVID-19, it is clinically important to consider that there could be cases with a rare but emergent adrenal crisis even among those who present common symptoms of adverse effects following inactive SARS-CoV-2 mRNA vaccination.

Top Ten Tips Palliative Care Clinicians Should Know About Managing Immune-Mediated Endocrine Toxicities in Cancer.

Immune checkpoint inhibitors (ICI), such as PD-1/PDL-1 and CTLA-4, have become widely used in the treatment of solid and hematological malignancies; their use and side effects are increasingly seen in the palliative care (PC) population. These drugs can result in immune-mediated endocrinopathies; the thyroid is the most common endocrine gland affected, but the pituitary, adrenals, and pancreas may be affected as well. Symptoms may be insidious and nonspecific. A high index of suspicion and routine laboratory monitoring allows for prompt diagnosis and treatment, which can significantly improve symptoms and increase quality of life. In this study, we present an approach to monitoring and initial management of ICI-induced endocrinopathies in the PC patient population.

Immune checkpoint inhibitor-related hypophysitis.

Immune checkpoint inhibitors (ICIs) have been recently proposed as a strategy for treating anti-malignant neoplasms. However, this treatment leads to immune-related adverse events (irAEs) such as autoimmune endocrinopathy. Early diagnosis and appropriate treatment of ICI-related hypophysitis are essential as it can manifest as a life-threatening condition due to an adrenal crisis. In this review, we summarize the pathogenesis, risk factors, diagnostic processes, clinical characteristics, and its current management. In particular, we discuss the different aspects of anti-CTLA-4 antibody-related and anti-PD-1/anti-PD-L1 antibody-related hypophysitis. We also propose key points for early detection and diagnosis by identifying the target group that should be monitored more carefully. Specific methods of hormone replacement therapy have also been described. We hope that this review will lead to a better understanding and management of this rare but serious condition during cancer treatment and further elucidate the pathophysiology of pituitary autoimmunity.

Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy.

Immune checkpoint inhibitors are being prescribed increasingly widely for a range of malignancies. They are effective at treating certain cancers, but also have significant side effects. Evidence suggests that efficacy is greatest in patients who experience one or more immune-related adverse events (irAEs). Common irAEs include skin and hepatic reactions, and a range of immune-related endocrinopathies. These include hypophysitis, thyroid disease, and autoimmune diabetes mellitus, and rarer endocrinopathies such as primary adrenal insufficiency, diabetes insipidus, parathyroid disease, autoimmune polyglandular syndrome, lipodystrophy, and ACTH-dependent Cushing's syndrome. Herein, we review the current literature related to these rarer immunotherapy-induced endocrinopathies.

[Endocrinopathies Associated with Immune Checkpoint Inhibitors]. / Endocrinopatias Associadas ao Tratamento com Inibidores do Checkpoint Imunológico.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that increase the efficiency of the immune system in the destruction of neoplastic cells. In recent years, these drugs have been increasingly used in the treatment of many neoplasms in advanced stages. However, the change in the regulation of the immune system induced by these drugs has the potential adverse effect of inducing autoimmunity in practically all organ systems. Endocrinopathies are one of the most common autoimmune adverse eventsof these drugs. MATERIAL AND METHODS: Non-systematic review of endocrinopathies reported in the context of treatment with ICIs. A search was carried out on PubMed until January 31st, 2020, and articles were selected based on their relevance and excluded in case of redundant content. The following search terms were used: "immune checkpoint inhibitor" and "endocrinopathy" / "endocrine system diseases" / "pituitary" / "thyroid" / "diabetes" / "adrenal" / "parathyroid". RESULTS: Endocrinopathies with all classes of ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) have been reported. Thyroid dysfunction is the most frequently reported endocrinopathy, mainly with anti-PD-1 and anti-PD-L1. Hypophysitis is the most prevalent with anti-CTLA-4. The incidence of autoimmune diabetes in this context is increasing, mainly with anti-PD-1 and anti-PD-L1. Rare cases of primary adrenal insufficiency, Graves' disease and primary hypoparathyroidism have also been reported. CONCLUSION: Knowing the spectrum of endocrinopathies triggered by ICI, as well as their clinical features, diagnosis and treatment criteria is essential, given its high prevalence and the increasing number of cancer patients treated with these new drugs.

Introdução: Os inibidores do checkpoint imunológico (ICI) são anticorpos monoclonais que permitem aumentar a eficiência do sistema imunitário na destruição das células neoplásicas. Nos últimos anos, estes fármacos têm sido cada vez mais utilizados no tratamento de muitas neoplasias em estadios avançados. Contudo, a alteração da regulação do sistema imunitário induzida por estes fármacos tem como potencial efeito adverso o aparecimento de autoimunidade em praticamente todos os órgãos. As endocrinopatias são um dos eventos adversos autoimunes mais frequentes com estes fármacos.Material e Métodos: Revisão não sistemática sobre as endocrinopatias reportadas em contexto de tratamento com ICI. Foram pesquisados artigos publicados na PubMed até 31 de janeiro de 2020, selecionados com base na sua relevância e excluídos em caso de conteúdo redundante. Foram utilizados os seguintes termos de pesquisa: "immune checkpoint inhibitor" e "endocrinopathy" / "endocrine system diseases" / "pituitary" / "thyroid" / "diabetes" / "adrenal" / "parathyroid".Resultados: Foram já reportadas endocrinopatias com todas as classes de ICI (anti-CTLA-4, anti-PD-1, anti-PD-L1). A disfunção tiroideia é a endocrinopatia mais frequentemente reportada, principalmente sob anti-PD-1 e anti-PD-L1. A hipofisite é a mais prevalente sob anti-CTLA-4. É crescente a incidência de diabetes autoimune neste contexto, principalmente sob anti-PD-1 e anti-PD-L1. Foram reportados também casos raros de insuficiência suprarrenal primária, doença de Graves e hipoparatiroidismo primário.Conclusão: O conhecimento do espectro de endocrinopatias desencadeadas pela terapêutica com ICI, assim como as suas manifestações clínicas, critérios de diagnóstico e tratamento, é essencial, dada a sua elevada prevalência e o cada vez maior número de doentes oncológicos tratados com estes novos fármacos.

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review.

Tyrosine kinase inhibitors have been successfully developed in combination with immune checkpoint inhibitors to treat advanced renal cell carcinoma (RCC), further advancing treatment. While safety profiles are generally manageable with combination regimens, overlapping adverse events (AEs) and immune-related AEs can make treatment more complex. The CheckMate 9ER study evaluated the tyrosine kinase inhibitor cabozantinib in combination with the anti-programmed cell death protein-1 antibody nivolumab in patients with previously untreated advanced RCC. Cabozantinib + nivolumab demonstrated superiority over sunitinib for progression-free survival, overall survival, and objective response rate. These outcomes supported the approval of cabozantinib + nivolumab as a first-line therapy for advanced RCC. The safety profile was manageable with prophylaxis, supportive care, dose holds and reductions for cabozantinib, and dose holds and immunosuppressive therapy for nivolumab. This review discusses the safety results of CheckMate 9ER and provides guidance on managing some of the more clinically relevant AEs with a focus on overlapping AEs, including diarrhea, elevated amylase/lipase, hepatotoxicity, dermatologic reactions, fatigue, endocrine disorders, and nephrotoxicity. We discuss AE management strategies (prophylaxis, supportive care, dose modification, and immunosuppressive therapy), and provide recommendations for identifying the causative agent of overlapping AEs and for consulting specialists about organ-specific immune-related AEs. Optimizing AE management can maintain tolerability and should be a priority with cabozantinib + nivolumab treatment.

Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society.

Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease.

Per- and poly-fluoroalkyl substances (PFAS) are widespread environmental contaminants frequently detected in drinking water supplies worldwide that have been linked to a variety of adverse reproductive health outcomes in women. Compared to men, reproductive health effects in women are generally understudied while global trends in female reproduction rates are declining. Many factors may contribute to the observed decline in female reproduction, one of which is environmental contaminant exposure. PFAS have been used in home, food storage, personal care and industrial products for decades. Despite the phase-out of some legacy PFAS due to their environmental persistence and adverse health effects, alternative, short-chain and legacy PFAS mixtures will continue to pollute water and air and adversely influence women's health. Studies have shown that both long- and short-chain PFAS disrupt normal reproductive function in women through altering hormone secretion, menstrual cyclicity, and fertility. Here, we summarize the role of a variety of PFAS and PFAS mixtures in female reproductive tract dysfunction and disease. Since these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption, the role of PFAS in breast, thyroid, and hypothalamic-pituitary-gonadal axis function are also discussed as the interplay between these tissues may be critical in understanding the long-term reproductive health effects of PFAS in women. A major research gap is the need for mechanism of action data - the targets for PFAS in the female reproductive and endocrine systems are not evident, but the effects are many. Given the global decline in female fecundity and the ability of PFAS to negatively impact female reproductive health, further studies are needed to examine effects on endocrine target tissues involved in the onset of reproductive disorders of women.

The changing clinical spectrum of endocrine adverse events in cancer immunotherapy.

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.

Endocrinopathies in Inborn Errors of Immunity.

Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy.