Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled Trials.

CONTEXT: Few meta-analyses on incidence of endocrine immune-related adverse effects (eirAEs) have been published and many trials have been published since. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Pregnancy-related hypophysitis revisited.

OBJECTIVE: The aim of the study is to assess the distinguishing features of pregnancy-related hypophysitis (PR-Hy) compared to non-pregnancy autoimmune hypophysitis and to evaluate the changing therapeutic approaches and outcomes in PR-Hy over time. DESIGN: Retrospective analysis of all published cases with PR-Hy and 6 own cases. METHODS: A PubMed search was performed and abstracts screened for publications with information on cases with PR-Hy from which full-text review was performed. Clinical features, diagnostic findings, and outcome in relation to treatment modalities in PR-Hy were assessed. RESULTS: One hundred and forty-eight cases with PR-Hy were identified. PR-Hy was significantly delimited from non-PR-Hy by the frequent occurrence of the chiasmal syndrome (50% vs 13%, P < .0001), higher rate of intrasellar origin (94% vs 74%, P = .0005), lower rate of pituitary stalk involvement (39% vs 86%, P < .0001), and low rate of diabetes insipidus (12% vs 54%, P < .0001). The role of surgery in PR-Hy decreased over time while noninvasive treatment modalities increased. The recurrence rate after high-dose glucocorticoid therapy (33%) was high and exceeded that of surgery (2%) and conservative management (2%). In contrast to initial reports on PR-Hy, recent literature regarding outcome of mother's and child's health was positive. The frequency of spontaneous preterm delivery was not increased. Recurrent PR-Hy in a subsequent pregnancy was reported in only two females. CONCLUSION: PR-Hy has distinct features that delineate the disorder from non-PR-Hy. With increasing experience in diagnosis, availability of adequate replacement therapy, and improved treatment modalities, PR-Hy has lost its threat and the outcome is encouraging.

Hypophysitis.

OBJECTIVE: Hypophysitis is considered a rare inflammatory disease of the pituitary gland. For a long time, primary autoimmune hypophysitis has stood out as the most relevant type of hypophysitis. However, with the advent of immunotherapy for the treatment of malignancies and identification of hypophysitis as an immune-related adverse event, hypophysitis has garnered increasing interest and recognition. Therefore, awareness, early recognition, and appropriate management are becoming important as the indication for immunomodulatory therapies broaden. METHODS: In this review, we discuss the epidemiology, diagnosis, and treatment of hypophysitis with a focus on recent data and highlight subtypes of particular interest while recognizing the gaps in knowledge that remain. RESULTS: Regardless of cause, symptoms and signs of hypophysitis may be related to mass effect (headache and visual disturbance) and hormonal disruption that warrant prompt evaluation. In the vast majority of cases, a diagnosis of hypophysitis can be made presumptively in the appropriate clinical context with radiologic findings consistent with hypophysitis and after the exclusion of other causes. CONCLUSION: Although subtle differences currently exist in management and outcome expectations between primary and secondary causes of hypophysitis, universally, treatment is aimed at symptom management and hormonal replacement therapy.

Characterisation of the onset and severity of adrenal and thyroid dysfunction associated with CTLA4-related hypophysitis.

CONTEXT: The use of the CTLA4 inhibitor, ipilimumab, has proven efficacious in the treatment of melanoma, renal carcinoma and non-small cell lung cancer; however, it is associated with frequent immune-related adverse events (irAE). Ipilimumab-induced hypophysitis (IIH) is a well-recognised and not infrequent endocrine irAE. OBJECTIVE: To investigate the timing of onset and severity of adrenal and thyroid hormone dysfunction around the development of IIH in patients treated for melanoma. DESIGN: Aretrospective review of hormone levels in consecutive adult patients treated with ipilimumab (3 mg/kg) for advanced melanoma as monotherapy or in combination with a PD-1 inhibitor. RESULTS: Of 189 patients, 24 (13%; 13 males; 60.5 ± 12.2 years) presented with IIH at a median of 16.1 (range: 6.7-160) weeks after commencing treatment, occurring in 14 (58%) after the fourth infusion. At the presentation of IIH, corticotroph deficiency was characterised by an acute and severe decrease in cortisol levels to ≤83 nmol/L (≤3 µg/dL) in all patients, often only days after a previously recorded normal cortisol level. Free thyroxine (fT4) levels were observed to decline from 12 weeks prior to the onset of cortisol insufficiency, with the recovery of thyroid hormone levels by 12 weeks after the presentation of IIH. A median fall in fT4 level of 20% was observed at a median of 3 weeks (IQR: 1.5-6 weeks) prior to the diagnosis of IIH. CONCLUSION: IIH is characterised by an acute severe decline in cortisol levels to ≤83 nmol/L at presentation. A fall in fT4 can herald the development of ACTH deficiency and can be a valuable early indicator of IIH.

Corticotropic insufficiency in a monocentric prospective cohort of patients with lung cancer treated with nivolumab: Prevalence and etiology.

INTRODUCTION: Cancer therapy has greatly progressed in the past few years, due to development of immune checkpoint proteins. These immunotherapies, when applied to eligible patients, have significantly reduced mortality but are prone to induce immune side-effects, including pituitary disorder and low adreno-corticotropic hormone (ACTH) and cortisol levels. We aimed to assess the prevalence and etiology of corticotropic insufficiency through a systematic screening of cortisol and ACTH levels in patients with lung cancer treated with nivolumab perfusion. MATERIAL AND METHODS: All patients from our Center with indications for nivolumab treatment for pulmonary squamous cell carcinoma or adenocarcinoma resistant to chemotherapy were successively included and underwent cortisol and ACTH assay before each nivolumab perfusion. When cortisol was below normal without ACTH elevation, we screened for pituitary metastasis, hypophysitis or corticosteroid treatment that could explain the corticotropic insufficiency. RESULTS: Data from 75 patients (80.0% men, 20.0% women) showed 10.7% asymptomatic corticotropic insufficiency, with a mean cortisol level of 2.76±1.27µg/dl. Diagnosis was made during the first 2 months of nivolumab treatment in 88% of cases. Corticosteroid treatment explained the low cortisol level in 25.0% of cases. No pituitary metastases were found. Hypophysitis was suspected in 75.0% of cases. CONCLUSION: In a 75-patient cohort with non-small cell lung cancer treated with the PD1 antibody nivolumab and systematically screened for cortisol abnormalities, 10.7% of patients showed asymptomatic corticotropic insufficiency. Excluding corticotropic insufficiency secondary to corticosteroid treatment, 8.0% of patients presented cortisol level<5µg/dl attributed to hypophysitis. Cortisol screening enables hydrocortisone replacement treatment to be prescribed if necessary, preventing risk of adrenal crisis.

Clinical Characteristics of Primary Hypophysitis - A Single-Centre Series of 60 Cases.

OBJECTIVE: Clinical data on primary hypophysitis are still scarce. Especially non-surgical cases are underreported. We sought to analyse clinical characteristics of primary hypophysitis, particularly in clinically diagnosed patients. DESIGN: Retrospective single centre study in 60 patients with primary hypophysitis. METHODS: Symptoms, MRI, histopathological findings, treatment and outcomes were analysed in 12 histopathologically and 48 clinically diagnosed patients. Diagnostic criteria for clinical diagnosis were: a) MRI findings compatible with primary hypophysitis; b) course of disease excluding other differential diagnoses. Mean duration of follow-up was 69 months. RESULTS: Female sex was predominant (73%). Fatigue (52%), headache (38%) and diabetes insipidus (38%) were the most frequent symptoms. 42% had a concomitant autoimmune disease. The corticotropic, thyrotropic, gonadotropic, somatotropic axis was impaired in 67%, 57%, 52%, 20%, respectively. Men had a higher number of impaired hormone axes (p=0.022) with the gonadotropic axis being affected more frequently in men (p=0.001). Infundibular thickening (56%) and space occupying lesions (46%) were typical MRI findings. Pituitary size was frequently enlarged at presentation (37%) but diminished during observation (p=0.029). Histopathologically and clinically diagnosed cases did not differ. CONCLUSIONS: The cohort of clinically diagnosed patients did not differ from our histopathologically diagnosed patients or from published cohorts with predominantly surgical patients. Thus, diagnosis of primary hypophysitis using clinical criteria seems feasible.

A Novel Etiology of Hypophysitis: Immune Checkpoint Inhibitors.

Checkpoint inhibitors trigger an immune process against cancer cells while causing cytotoxicity and self-antibody production against normal cells. Hypophysitis is a common endocrine toxicity. Hypophysitis may occur at any time during and after therapy, necessitating close clinical monitoring and screening for pituitary deficiencies. Treatment with high-dose glucocorticoids and temporary cessation of immunotherapy is indicated for severe hypophysitis with intractable headaches and vision changes, and for adrenal crisis. Increased awareness about this novel hypophysitis and multidisciplinary collaboration are needed to improve outcomes. This article reviews the function of immune checkpoint inhibitors and pituitary adverse effects with immune checkpoint inhibitor use.

Presence of CD3+ and CD79a+ Lymphocytes in the Pituitary Gland of Dogs at Post-mortem Examination.

Hypophysitis has been reported occasionally in dogs, with most cases resembling primary lymphocytic hypophysitis in man. Although it is generally assumed that lymphocytes are not present normally in the canine pituitary gland, few studies have investigated this hypothesis. However, lymphocytes are recognized in the pituitary gland of people and horses without signs of pituitary disease. It is unknown to what degree lymphocyte infiltration of the pituitary gland might occur as an incidental finding in dogs. The aim of the present study was to investigate the presence and distribution of lymphocytes in the pituitary gland of dogs without clinical suspicion of pituitary disease. Twenty dogs were subjected to routine necropsy examination. Formalin-fixed and paraffin wax-embedded sections of pituitary were stained with haematoxylin and eosin (HE) or subjected to immunohistochemistry (IHC) using primary antibodies specific for the T-cell marker CD3 and the B-cell marker CD79a. The number of CD3+ and CD79a+ cells per area unit (CPA) was determined for different pituitary regions. Two dogs had extensive neoplastic lesions in the pituitary gland and were excluded from analysis. In the remaining 18 dogs, occasional scattered CD3+ cells were found in the pituitary gland. There was a significant difference in CD3+ CPA between pituitary regions (P = 0.001). The highest CD3+ CPA was found in the pars tuberalis (median 41.3 cells/mm2, interquartile range 20.9-50.5 cells/mm2). In six of the 18 dogs (33%), CD79a+ cells were detected in small number (median total cell number 0 cells/section, interquartile range 0-1.0 cells/section). This study shows that T cell, and fewer B cells, may be found in the pituitary gland of dogs without clinical suspicion of pituitary disease. Regional difference in T-cell density, with the highest CD3+ CPA in the pars tuberalis, may imply regional immunoregulatory functions in the canine pituitary gland.

Clinical Characteristics, Management, and Treatment Outcomes of Primary Hypophysitis: A Monocentric Cohort.

Primary hypophysitis (PH) is a rare autoimmune inflammatory disease of the pituitary gland. The aim of the study was to evaluate clinical characteristics, disease management, and outcomes of cases with PH. Medical records of PH patients admitted to Hacettepe University Hospital between 1999 and 2017 were analyzed retrospectively. Paraffin-embedded pathology blocks were obtained for both re-examination and IgG4 immunostaining. Twenty PH patients (15 females, 5 males) were evaluated. Mean age at diagnosis was 41.5±13.4 years. Some form of hormonal disorder was present in 63.2% of cases, hypogonadism (66.6%) being the most common. Panhypopituitarism was present in 36.8%. All patients had pituitary gland enlargement on magnetic resonance imaging; stalk thickening and loss of neurohypophyseal bright spot were present in 17.6 and 23.5%, respectively. Lymphocytic hypophysitis was the most common histopathological subtype (50%). Among pathology specimens available for IgG and IgG4 immunostaining (n=10), none fulfilled the criteria for IgG4-related hypophysitis. Four patients were given glucocorticoid treatment in diverse protocols; as initial therapy in 3. Sixteen cases underwent surgery, 7 of whom due to neuro-ophthalmologic involvement. Only 1 patient was observed without any intervention. Reduction of pituitary enlargement was seen in all surgical and glucocorticoid treated cases. None of the surgical patients showed hormonal improvement while one case in glucocorticoid group improved. PH should be considered in the differential diagnosis of sellar masses causing hormonal deficiencies. MRI findings are usually helpful, but not yet sufficient for definitive diagnosis of PH. Treatment usually improves symptoms and reduces sellar masses while hormonal recovery is less common.

Endocrine-related adverse events associated with immune-checkpoint inhibitors in patients with melanoma.

BACKGROUND: Immune-checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune-related endocrinopathies, especially hypophysitis and thyroid dysfunction. METHODS: To assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune-checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow-up. RESULTS: The total incidence of endocrinopathies was 11.8%, 13.4% due to anti-PD1/PDL1, 5% due to anti-CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty-one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow-up. Endocrinopathies occurred after a median of 22 weeks (range: 4-156) from treatment initiation. Of note, sequential and/or combination therapy with anti-CTLA4 and anti-PD1/anti-PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti-CTLA4 monotherapy developed primary hypothyroidism. CONCLUSIONS: Our cohort demonstrated an increased incidence of hypophysitis with anti-PD1/anti-PDL1 in contrast to the rarity of primary thyroid dysfunction with anti-CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy.

Cancer immunotherapy-associated hypophysitis.

The advances in cancer therapy have included the development of drugs that inhibit immune checkpoint ligands. Two types of immune checkpoint inhibitors, both antibodies that target CTLA-4 and PD-1, have been approved for its use in NSCLC and melanoma as first-line or second-line therapy. Sadly, not desirable consequences of immunotherapy are immune-related adverse events. immune-related hypophysitis is the most common endocrine adverse event after thyroid disfunction. The particularity of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if this form of therapy is used in the future for earlier stages of cancer. Therefore, hypophysitis represents a challenge for the physician, sometimes occurring without specific symptomatology and which should be considered for clinical management. In this review, we describe the current data regarding the pathophysiology and management for immune-related hypophysitis.

The Changing Clinical Spectrum of Hypophysitis.

Hypophysitis is a rare and potentially life-threatening disease, characterized by an elevated risk of complications, such as occurrence of acute central hypoadrenalism, persistent hypopituitarism, or extension of the inflammatory process to the neighboring neurological structures. In recent years, a large number of patients have been described as being affected by hypophysitis, due to the increased administration of immuno-chemotherapies. At the present time, the heterogeneous nature of hypophysitis diagnostic criteria and of the treatment protocols makes the management of affected patients difficult. We review the current data and evidence on primary and secondary hypophysitis, in order to suggest a diagnostic and therapeutic protocol that should be focused on a multidisciplinary approach, for reaching a prompt diagnosis and an appropriate and safe treatment.

New causes of hypophysitis.

Hypophysitis is a rare entity characterized by inflammation of the pituitary gland and its stalk that can cause hypopituitarism and/or mass effect. Etiology can be categorized as primary or secondary to systemic disease, but may also be classified according to anatomical and hispathological criteria. Newly recognized causes of hypophysits have been described, mainly secondary to immunomodulatory medications and IgG4-related disease. Diagnosis is based on clinical, laboratory and imaging data, whereas pituitary biopsy, though rarely indicated, may provide a definitive histological diagnosis. For the clinician, obtaining a broad clinical and drug history, and performing a thorough physical examination is essential. Management of hypophysitis includes hormone replacement therapy if hypopituitarism is present and control of the consequences of the inflammatory pituitary mass (e.g. compression of the optic chiasm) using high-dose glucocorticoids, whereas pituitary surgery is reserved for those unresponsive to medical therapy and/or have progressive disease. However, there remains an unmet need for controlled studies to inform clinical practice.

Primary hypophysitis and other autoimmune disorders of the sellar and suprasellar regions.

The pituitary gland and the hypothalamus can be affected by autoimmune-mediated structural and functional disruption. These autoimmune-mediated diseases occur more commonly in females and are often found during pregnancy or in the post-partum period. Autoimmune diseases can either affect parts of the pituitary or hypothalamus, or can involve both sellar and suprasellar structures. Most of these cases comprise primary hypophysitis (PRH). Over the years, there has been a tremendous increase in the number of reported PRH cases and related disorders, including hypophysitis induced by immune checkpoint inhibitors. With this increasing data, more light is being shed on the spectrum of clinical presentations, biochemical and imaging abnormalities of these disorders. Regardless, these disorders are still relatively rare. The clinical presentation can vary vastly, based on the type of pituitary cell or the area of the suprasellar region affected. The severity can range from clinically silent disease to progressive and rapid deterioration and death, likely due to unrecognized central adrenal insufficiency. Although biopsy remains a gold standard for diagnosing these disorders, the current standard of practice is biochemical assessment for hormonal deficiencies and imaging studies. In several instances, these disorders spontaneously resolve, but medical or surgical intervention might be necessary to treat symptomatic disease. Due to the subtlety and a vast spectrum of clinical manifestations which could often be asymptomatic, and the rarity of the occurrence of these diseases in clinical practice, the diagnosis can be easily missed which could potentially lead to substantial morbidity or mortality. Therefore, it is crucial to have a strong clinical suspicion and pursue timely biochemical and imaging studies to initiate prompt treatment. In this article, we review the various autoimmune conditions that affect the sellar and suprasellar structures, their diagnostic approach and management of these disorders.

The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma.

OBJECTIVE: Endocrine immune-related adverse events (endocrinopathies) are increasingly prevalent with the use of immune checkpoint inhibitors for the treatment of metastatic melanoma and other malignancies. There are no evidence-based guidelines for the screening or management of such patients. To describe the spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors. DESIGN: A prospective study conducted at Melanoma Institute Australia between April 2014 and October 2015. METHODS: A total of 177 patients were treated with (a) ipilimumab (n = 15), (b) anti-PD-1 (nivolumab, pembrolizumab) (n = 103) or (c) combination ipilimumab and anti-PD-1 (n = 59) and were screened and managed for the subsequent endocrinopathies. The main outcome measures were the incidence and kinetics of endocrinopathy by immunotherapy drug class. RESULTS: Thirty-one patients (18%) developed an endocrine immune-related adverse event (thyroid dysfunction: 14%, hypophysitis: 6% and autoimmune diabetes: 0.6%). Combination immunotherapy was more likely to result in a single or multiple endocrinopathy compared to anti-PD-1 monotherapy (27% vs 9% and 7% vs 0% respectively, P < 0.01). Endocrinopathies occurred after a median of 8 weeks from treatment commencement (range: 12-225 days), with combination immunotherapy resulting in significantly earlier onset compared to ipilimumab (median: 30 vs 76 days, P = 0.046). The majority of endocrinopathies were identified in asymptomatic patients with hormonal screening. There were no baseline predictors for endocrinopathy. CONCLUSIONS: Combination immunotherapy has a greater risk of development of endocrinopathy compared to anti-PD-1 monotherapy. Regular biochemical profiling of patients, particularly within the first twelve weeks, results in early detection of endocrinopathy to minimise morbidity.

Hipofisitis linfoplasmocitaria con expresión de IgG4 / IgG4- related lymphoplasmacytic hypophysitis

La hipofisitis linfoplasmocitaria con expresión de inmunoglobulina G4 (IgG4) es una entidad de reciente conocimiento. Pertenece al grupo de enfermedades relacionadas a IgG4 (IgG4-RD, del inglés: IgG4-related disease), donde uno o varios órganos pueden estar comprometidos, con síntomas compresivos u obstructivos, o disfuncionalidad por infiltración celular. La hipófisis puede estar afectada en forma aislada. Clínicamente, se presentan con diabetes insípida, hipopituitarismo y/o síntomas de masa ocupante selar, siendo los principales diagnósticos diferenciales los adenomas selares no secretantes, y otros tipos de hipofisitis. Para arribar al diagnóstico de este tipo patología es necesaria la presencia de una imagen de agrandamiento selar o engrosamiento del tallo pituitario en la resonancia magnética nuclear, una histopatología característica con inmunomarcación positiva para IgG4 en más de 10 células plasmáticas por campo de gran aumento y la presencia de IgG4 sérica elevada. Tienen una excelente respuesta a glucocorticoides, por lo que una sospecha diagnóstica oportuna evitaría una cirugía innecesaria en la mayoría de los pacientes con esta entidad.

Immunoglobulin G4 (IgG4)-related lymphoplasmacytic hypophysitis is a recently known entity. It belongs to the IgG4-related diseases (IgG4-RD), in which one or more organs may be involved, with compressive or obstructive symptoms, or dysfunctionality due to cellular infiltration. The pituitary gland can be isolatedly affected. Clinically, lymphoplasmacytic hypophysitis presents with diabetes insipidus, hypopituitarism and/or symptoms of an occupying sellar mass, being the non-secreting sellar adenomas and other types of hypophysitis the main differential diagnosis. In order to reach the diagnosis, the presence of pituitary enlargement or pituitary stalk thickening on an MRI scan, a distinctive histopathology with positive for IgG4 immunostaining in more than 10 plasma cells per high-powerfield, and elevated serum IgG4 levels, confirms this type of hypophysitis. As this entity has an excellent response to glucocorticoids, the diagnosis suspicion may avoid an unnecessary surgery in most patients.

Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab.

OBJECTIVE: Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4, that has been shown to significantly improve survival in patients with metastatic melanoma. Blocking cytotoxic T-lymphocyte antigen-4 elicits T cell activation, proliferation and anti-tumor response, but can also trigger immune-related adverse events. Among immune-related endocrinopathies, hypophysitis represents the most frequent, with an incidence up to 17% in patients treated with ipilimumab. DESIGN AND METHODS: We report nine cases of ipilimumab-induced hypophysitis in a cohort of 273 patients treated with ipilimumab between 2006 and 2015, as part of clinical trials or after its marketing. Thyroid function tests were scheduled at screening and during follow up (every 21 days) in all patients. Cortisol, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, and estradiol (for females) or testosterone (for males), prolactin, growth hormone, insulin-like growth factor 1 were measured only in case of clinical suspicion. RESULTS: The incidence of hypophysitis was 3.3%. The most frequent pituitary failure was adrenocorticotropic hormone and thyroid stimulating hormone secretion with a complete recovery of thyroid stimulating hormone, but not of adrenocorticotropic hormone during follow up. All patients had negative pituitary antibodies. The main symptoms at diagnosis were fatigue and headache. CONCLUSION: Clinicians should be aware about the risk of hypophysitis during treatment with immune check-point inhibitors and the necessity of investigating pituitary function during therapy. Pituitary magnetic resonance imaging does not seem pivotal for a definite diagnosis if not performed at the onset of disease.