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Home , Empty sella syndrome, Endocrine disease, Hypophysitis, Hypopituitarism, Pituitary adenoma, Pituitary disease

176:6

S Pekic and V Popovic Unusual causes of 176:6 R269–R282 Review PROOF ONLY DIAGNOSIS OF Expanding the cause of hypopituitarism

Sandra Pekic1,2 and Vera Popovic1 Correspondence 1School of , University of Belgrade, Belgrade, Serbia and 2Clinic of , and should be addressed Metabolic Diseases, University Clinical Center Belgrade, Belgrade, Serbia to V Popovic Email [email protected]

Abstract

Hypopituitarism is defined as one or more pituitary deficits due to a lesion in the hypothalamic–pituitary region. By far, the most common cause of hypopituitarism associated with a sellar mass is a pituitary . A high index of suspicion is required for diagnosing hypopituitarism in several other conditions such as other massess in the sellar and parasellar region, brain damage caused by radiation and by traumatic brain , vascular lesions, infiltrative/immunological/inflammatory diseases (lymphocytic , sarcoidosis and hemochromatosis), infectious diseases and genetic disorders. Hypopituitarism may be permanent and progressive with sequential pattern of hormone deficiencies (radiation-induced hypopituitarism) or transient after with possible recovery occurring years from the initial event. In recent years, there is increased reporting of less common and less reported causes of hypopituitarism with its delayed diagnosis. The aim of this review is to summarize the published data and to allow earlier identification of populations at risk of hypopituitarism as optimal hormonal replacement may significantly improve their quality of life and life expectancy.

European Journal of Endocrinology (2017) 176, R269–R282 European Journal European of Endocrinology Introduction

Hypopituitarism is an uncommon condition with of underlying etiology of hypopituitarism is the a prevalence of ~46 per 1 00 000 (1). It is defined as challenge. The most common cause of hypopituitarism one or more hormone deficiencies associated with a sellar mass is nonfunctioning pituitary caused by a variety of structural lesions or trauma macroadenoma. Hypopituitarism may occur as a in the hypothalamic–pituitary region. The diversity consequence of treatment of pituitary with

Invited Authors’ profile Prof Dr Vera Popovic-Brkic MD, PhD, FRCP is a Professor of Internal Medicine at Belgrade University School of Medicine, Belgrade, Serbia. She is principal investigator with a research grant funded by the Ministry of Science, Serbia since 1985. Her research studies include investigations in the field of new molecules in the regulation of GH secretion (GHRP-6 and ghrelin), long-acting GH molecules for GH replacement, and new molecules in energy homeostasis (leptin and ghrelin). Her special clinical interests are hypopituitarism and the management of pituitary adenomas. Vera Popovic-Brkic

Sandra Pekic MD, PhD is currently Associate Professor of Internal Medicine and Endocrinology, University of Belgrade, Serbia. Her clinical research is mainly devoted to pituitary adenomas, hypopituitarism and disorders.

Sandra Pekic

www.eje-www.eje-online.orgonline.org © 2017 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-16-1065 Printed in Great Britain

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10.1530/EJE-16-1065 Review S Pekic and V Popovic Unusual causes of 176:6 R270 hypopituitarism

pituitary and/orPROOF radiotherapy. Other less prevalent Neoplastic ONLY lesions in the sellar and causes of hypopituitarism such as radiation-induced and suprasellar region traumatic brain injury-induced hypopituitarism have been studied more extensively in the recent years. More Hypopituitarism may be the consequence of many rarely, vascular causes (, Sheehan’s sellar and parasellar masses that include , syndrome, and aneurysm), germinoma, , astrocytoma, , gang­ infiltrative/immune/inflammatory processes such as lioneuroma, , pituitary lymphoma, plasma­ lymphocytic hypophysitis, sarcoidosis, hemochromatosis cytoma and metastases (6). and infectious diseases have been associated with hypopituitarism (Table 1). Pituitary lymphoma Whatever the cause, hypopituitary patients usually exhibit nonspecific symptoms/signs. For the clinician, it Recently published systematic review of primary sellar remains challenging to ascribe specific features for each lymphoma reported a total of 33 cases of this isolated pituitary hormone deficiency. The recently published localization of lymphoma in the sella (7). The vast majority guidelines on hormonal replacement in hypopituitarism of CNS lymphomas are non-Hodgkin B-cell lymphomas. in adults discuss in great detail the diagnosis and T-cell lymphoma and NK/T-cell lymphoma are much management of hypopituitarism (2). more rare. Patients do not have systemic lymphoma or Hypopituitarism is associated with increased other brain lesions. Even rarer is an intravascular large mortality (3). Highest mortality is among younger B-cell lymphoma characterized by massive proliferation patients, women and patients with (4). of lymphoid cells within the small and medium blood A recent study from Sweden shows a decline in mortality vessels. We reported a rare case of hypopituitarism in in patiens optimally replaced including GH replacement a patient with intravascular large B-cell lymphoma therapy (5). who after complete hematological remission, reversed Given the complexity of hypopituitarism, its insidious hypopituitarism after more than two years (8). Anterior onset with a delay in the diagnosis by decades, here pituitary deficiencies are present in 70% of cases (most we review contemporary studies on the less common/ have panhypopituitarism), diabetes insipidus is frequent unusual causes of hypopituitarism in adults. (in 36% of cases), unlike in pituitary adenomas (7). MRI usually shows diffusely enlarged pituitary with invasion of both cavernous sinuses mimicking a pituitary European Journal European of Endocrinology Table 1 Causes of hypopituitarism. adenoma. Usually a preoperative presumptive diagnosis of is made and only pathologic evaluation Neoplastic Pituitary and non-pituitary tumors Metastases reveals the diagnosis of the pituitary lymphoma. Invasive Hematological malignancy sellar mass with rapid growth pattern and cranial nerve Langerhans cell palsies in an elderly patient (60–70 years) may be Brain damage Traumatic brain injury Cranial irradiation discriminative and suggestive of lymphoma. Congenital causes Isolated or multiple pituitary hormone deficiencies Vascular Postpartal pituitary Intrasellar plasmacytoma (Sheehan’s syndrome) Aneurysm Intrasellar plasma cell tumors are rare, may mimic Pituitary apoplexy nonfunctioning pituitary tumors and may present as Subarachnoid hemorrhage Snake bite the first manifestation of multiple myeloma 9( ). The Inflammatory/ Sarcoidosis radiological and clinical features of sellar plasmacytoma infiltrative are nonspecific. Cranial nerve affection and intact Lymphocytic hypophysitis (primary, secondary) pituitary function are usually present. The diagnosis Haemochromatosis is made histologically. The diagnosis of intrasellar Amiloidosis plasmacytoma should be suspected in patients with Wegener’s granulomatosis invasive sellar mass, intact anterior pituitary function and Infectious diseases Bacterial, viral, fungal, parasital Other causes Congenital chronic hydrocephalus cranial nerve palsies in the presence of significant sellar Primary empty sella destruction (Fig. 1).

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Figure 2 Figure 1 (A) A 62-year-old woman with euthyroid multinodular goiter (A and B) A 57-year-old woman presenting with , presenting with and moderate dyplopia and ptosis. Sellar MRI ((A) sagittal and (B) coronal hypeprolactinemia. (B) Sellar MRI shows a large suprasellar views) shows an invasive sellar mass with propagation to the mass. (C) Pathology report: from papillary and clivus. Pathology report: Pituitary of not previously diagnosed. From: plasmacytoma IgA kappa+. Stojanovic M et al. European Thyroid Journal 2013 1 277–284. Pituitary metastasis (reproduced with permission). from myeloid progenitor cells that express CD34 Metastatic tumors represent a small fraction of sellar surface antigen. Recently, somatic oncogenic BRAFV600E masses. A rise in incidence is due to longer life expectancy mutations were detected in 25–60% of LCH patients, in patients with malignant disease and advances in suggesting that LCH is likely a neoplastic disorder (12). diagnostic imaging. In most cases, the nature of a metastasis Positive response to a BRAF inhibitor vemurafenib in to the sellar region is suggested by the primary tumor, but patients with BRAFV600E-mutated LCH is described (13). when the primary tumor is unknown, sellar metastasis is Central nervous system is affected in 6% of patients diagnosed postmortem. Breast and lung are the with LHC, mostly the hypothalamopituitary region and

European Journal European of Endocrinology most common sources of metastases (10, 11). Pituitary , cerebellum and basal ganglia (14). Patients metastases of prostate, renal cell, gastrointestinal, thyroid present with central DI and thickening. and pancreatic cancers are far less common. Sudden onset This may be a diagnostic challenge with broad differential of diabetes insipidus (DI) or rapid deterioration of visual diagnosis. Nowadays, fluorodeoxyglucose-positron fields, severe headache and acute onset hypopituitarism emission tomography scanning (FDG-PET) is used in a patient aged more than 50 years of age are hallmarks as a potentially better imaging modality in patients of metastatic . DI is prevalent and the presenting with central DI when the cause is unclear and predilection for the posterior lobe involvement is thought when pituitary stalk biopsy carries a significant risk. FDG- to be due to the direct arterial supply. Rapidity of symptom PET scanning is used for assessing the extent of LHC, its development is a consequence of rapid tumor growth. progression and the response to treatment (15). There are Pituitary metastases are most often identified in the late reports suggesting the use of chemotherapy as a first-line stage of the malignant disease, although cases presenting treatment for these patients after biopsy confirmation of with sellar masses as the first manifestation of malignancy the diagnosis. LCH is rare among the adult population have also been reported (Fig. 2). and is most commonly diagnosed in children (Fig. 3). Erdheim–Chester disease (ECD) is a rare non- Langerhans cell histiocytosis: a Langerhans cell form of histiocytosis characterized by neoplastic disease? infiltration of lipid-laden macrophages and multinucleated giant cells. Xanthomatous or xanthogranulomatous Langerhans cell histiocytosis (LCH) is a rare histiocytic infiltration occurs in the bone, brain, skin, heart, lung, disorder of unknown etiology characterized by and kidney. Similar to LHC, in more than 50% of monoclonal proliferation of Langerhans cells derived patients, BRAF (V600E) mutations are found in the early

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Figure 3 (A and B) A 10-year-old boy developed a sudden onset of diabetes insipidus, somnolence and impairment. Sellar MRI (A sagittal and B coronal views) shows a large suprasellar mass. Pathology report: non-Langerhans cell histiocytosis WHO grade III.

multipotent hematological precursors or local tissue histiocytes (16). In a recent large French study involving 64 patients with ECD, central diabetes insipidus was reported in 33% of patients with a high percentage of concomitant pituitary involvement (91% of patients had partial anterior pituitary failure) (17). In that study, Figure 4 anterior pituitary dysfunction was more frequent than A 33-year-old man who at an age of 8 years received cranial pituitary MRI anomalies (pituitary stalk thickening). irradiation for medulloblastoma and at an age of 18 years was Recently, FDG-PET/CT has been shown to be helpful for diagnosed with isolated GH deficiency. He did not receive GH locating the pituitary lesion (elevated metabolic activity) therapy. MRI scan shows empty sella and a large meningioma. and for discovering the multisystem involvement. irradiation (19). Why is GH the first pituitary hormone

European Journal European of Endocrinology to become deficient after cranial irradiation remains Radiotherapy and traumatic brain injury unclear. Lengthy follow-up is needed. Hypopituitarism after cranial radiation is progressive and irreversible and Cranial irradiation periodical testings of the hypothalamo–pituitary axes are Patients treated with cranial irradiation for head and mandatory. Special attention is payed to the excess of neck tumors, pituitary or hypothalamic tumors, for brain second malignant after all childhood cancers tumors or children who received prophylactic cranial (20). There is a concern that GH treatment has a causal irradiation (childhood survivors) and those who role in the development of subsequent in the received total body irradiation for various malignancies are CNS in childhood cancer survivors. However, this is a at risk of hypopituitarism many years after radiotherapy. group already at increased risk of malignancy and cranial There are still controversies about the site and may be the culprit (Fig. 4). pathophysiology of radiation damage. Radiation-induced damage is primarily hypothalamic and mechanisms Traumatic brain injury (TBI) include direct injury to hypothalamic , vascular damage with reduction of cerebral flow and fibrosis and A great number of people are subjected to traumatic brain altered neurotransmitter input to the injury (TBI) worldwide every day. With improvements from other brain centers (18). The risk of hypopituitarism in emergency and neurosurgical care, there are more TBI is time and dose dependent with sequential pattern survivors nowadays. Traffic are the most prevalent of hormonal deficiencies. GH deficiency is the most cause of TBI; however, sports-related chronic repetitive common pituitary hormone deficiency and occurs in head trauma of low intensity (boxing, kickboxing, 50% of childhood cancer survivors treated with cranial football and ice hockey) and blast-related mild TBI

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among soldiers in militaryPROOF operations are more and more hypopituitarism ONLY in the chronic phase between 15% and prevalent (21). The greatest challenge in individuals with 50%, with the decrease to 12% if repeated testing is TBI is early recognition of subtle clinical manifestations of applied (25). Growth hormone deficiency was found to be hypopituitarism. The reality may be that TBI is a common the most common deficit (9%), followed by ACTH (6%), cause of hypopituitarism nowadays. LH/FSH (5%) and TSH (1%) deficiencies 25( ). That TBI is underdiagnosed is demonstrated by Several mechanisms have been suggested to play a evidence of postmortem findings in fatal cases. First role in the development of neuroendocrine abnormalities reports of hypopituitarism caused by TBI were described in TBI: focal shear injury lesions (severed ), vascular/ more than a century ago as case or reports. hypoxic insult and inflammatory changes with activation Autopsy studies in fatal TBI demonstrated a fairly high of the immune system (). Vascular damage prevalence of hypothalamic lesions (22). ( and hemorrhages) in the hypothalamus is Data emerging since 2000 demonstrate the the most likely explanation of acute neuroendocrine importance of traumatic brain injury (TBI) as a cause of dysfunction after TBI. The spreading of proinflammatory hypopituitarism, but the prevalence varies widely (15– response initiated by TBI and axonal injury (diffuse and 90%) (23, 24) (Fig. 5). TBI is a very common public health focal shear) that induces degenerative processes in distant problem worldwide, and recent studies have shown that brain regions (progressive demyelination) may explain partial hypopituitarism in particular is not rare among the evolution of posttraumatic hypopituitarism with TBI victims. Since a great number of people are subjected time (26). to TBI around the world every day, even low rates of The TBI severity does not seem to correlate with hypopituitarism mean a very high number of patients the prevalence of hypopituitarism (isolated deficiency with TBI might have hypopituitarism (21). or panhypopituitarism). Pituitary functions generally Studies are heterogeneous regarding TBI severity, improve with time as shown when repeated confirmatory preselection precedures for testing, optimal timing testing was applied (24). In a few cases, new pituitary after TBI, the diagnostic tests used and the prevalence deficiencies (mainly in the somatotropic and gonadotropic of hypopituitarism after TBI. Diabetes insipidus occurs axis) may develop during the follow-up. particularly in the acute phase of TBI and usually is Screening is costly and logistically difficult but still reversible, whereas partial or complete hypopituitarism remains a great challenge! The most appropriate time may develop during an acute phase or months and years for endocrine assessment is 1 year after TBI (21). Any after TBI (21). Recently published analysis of 16 studies with unexplained onset of malaise and generally decreased European Journal European of Endocrinology 1291 TBI patients reported the frequency of posttraumatic vital signs with associated stagnation of rehabilitation progress should prompt the clinician to suspect the presence of hypopituitarism (24). We should bear in mind that pituitary dysfunction is an important and modifiable determinant of poor functional outcome after TBI.

Vascular causes of hypopituitarism are rare

Intracranial aneurysm

Intracranial aneurysms localized predominantely in the internal carotid artery and anterior or posterior communicating artery are rare causes of space- occupying lesions in sellar and suprasellar region, some of them causing hypopituitarism as an acute or chronic complication (27, 28). Aneurysms may present as primary disease or as a complication of pituitary Figure 5 surgery and radiotherapy i.e. traumatic aneurysm. A Traumatic brain injury and the number of pituitary hormonal large retrospective study reported a very low prevalence deficits: studies since the year 2000. From: Klose & Feldt- of intrasellar aneurysm as a cause of hypopituitarism Rasmussen, Journal of Clinical Medicine 2015 4 1480–1497. (0.17%) (29). These patients have anterior pituitary

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PROOF ONLYFigure 6 (A and B) A 61-year-old woman presenting with , confusion and unsteady gait (Na 110 mmol/L). Sellar MRI scan (A sagittal and B coronal views) shows a cystic mass in the sellar region. (C) Angiogram shows giant thrombosed aneurysm of the left internal carotid artery in the sellar region. From: Miljic et al. Journal of Endocrinological Investigation 2003 26 450–452 (reproduced with permission).

hormone abnormalities and hyperprolactinemia, whereas with the the most crucial deficit of corticotrophin diabetes insipidus is not reported. Sometimes syndrome (ACTH) reported in 70% of patients. Apoplexy is a of inadequate ADH secretion occurs (27) (Fig. 6). medical emergency requiring prompt commencement of therapy. Further management (conservative or surgical) is recently proposed by the UK guidelines for Subarachnoid hemorrhage (SAH) the management of PA (34).

Subarachnoid hemorrhage (SAH) is an important cause of morbidity and mortality, and there is evidence that SAH Sheehan’s syndrome – the postpartum may adversely affect pituitary function in both the acute pituitary necrosis and chronic phases (30, 31). The prevalence of endocrine Sheehan’s syndrome or the postpartum pituitary necrosis dysfunction caused by SAH ranges from 0 to 55% (31, is the leading cause of hypopituitarism in underdeveloped 32). Isolated pituitary hormone deficiencies are more and developing countries, but it is rare and has become frequently found than multiple. Currently, there is not a neglected cause of hypopituitarism in Western society enough evidence to recommend routine endocrinological (35). Sheehan’s syndrome is caused by in the evaluation in patients after SAH. pituitary precipitated by massive uterine hemorrhage

European Journal European of Endocrinology during the peripartum period or postpartum. Necrotized areas of the pituitary form a fibrous scar. Mechanisms of Pituitary apoplexy (PA) Sheehan syndrome include autoimmunity and a genetic Between 2% and 12% of patients with pituitary adenomas predisposition. Predisposing factors for postpartum experience clinically manifest apoplexy. PA is a clinical pituitary necrosis or Sheehan’s syndrome are for women syndrome characterized by sudden onset of acute severe who delivered at home, women with severe postpartum headache accompained by , ocular palsies, hemorrhage who are given a blood transfusion, women reduced visual acuity and impaired visual fields with with higher number of and deliveries, those reduced consciousness, all caused by hemorrhage and/ with genetic factors involved in the coagulation cascade or infarction of the pituitary tumor. The diagnosis of and those with small sella size (35, 36). apoplexy is delayed because 3 of 4 patients do not have Recent Turkish study showed that Sheehan’s a previous history of pituitary adenoma. Frequently, syndrome was present in 13.8% of patients with pituitary apoplexy is subclinical (asymptomatic), is hypopituitarism, compared with 3.1% in developed diagnosed on MRI imaging as hemorrhagic or necrotic countries (37, 38). The onset of hypopituitarism is usually areas in the pituitary tumor and resolves spontaneously. insidious, and there is often a delay in diagnosis of several Precipitating factors for pituitary apoplexy can be decades (a median delay is 10 years). Patients can present with identified in about 40% of patients and include major a wide variety of symptoms (failure to lactate and to resume surgery (cardiac and orthopedic), dynamic pituitary tests, menses) (39, 40). Most symptoms are nonspecific, that is, anticoagulation treatment, coagulopathies, , patients feel generally unwell and patients are managed by agonists, acute systemic illness, symptoms (secondary amenorrhoea). Appropriate guidance and oral contraceptives (33). Hypopituitarism is frequent is not provided after an eventful delivery. Hypopituitarism is

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PROOFplasmacytic ONLY (immunoglobulin G4 related), necrotizing, xanthomatous and mixed forms (45). The incidence of hypophysitis is 1/10 milion per year, and lymphocytic hypophysitis (LH) is the most common form of the disease. It represents less than 1% of sellar lesions and presents with symptoms similar to those seen in patients with pituitary adenoma (46). However, unlike in patients with pituitary adenoma, the early loss of ACTH secretion in lymphocytic hypophysitis is intriguing and remains unexplained. LH predominanly affects females frequently Figure 7 associated with pregnancy and other autoimmune diseases, (A, B, C) A 45-year-old woman presenting with headache, with spontaneous resolution. Hypophysitis presents severely impaired vision on the left eye, hypocorticism and on MRI as a symmetric enlargement hyperprolactinemia (due to stalk compression). Sellar MRI scan with homogenous enhancement of the pituitary mass, (A T1-weighted sagittal view, B T1-weighted coronal view, thickened pituitary stalk and with appearence of dural tail C T2-weighted coronal view) shows a contrast-enhancing mass (contrast enhancement of dura adjacent to the pituitary) with direct contact to the , pushing the pituitary (47). Empty sella is seen as a characteristic finding on upwards. Pathology report: sellar glomangioma. MRI in the late stage of (48). Pathogenetic mechanism in primary hypophysitis progressive, with no recovery of the pituitary function. MRI involves lymphocytic infiltration and autoimmunity, with of the sella reveals partial or complete empty sella in the detected autoantibodies specific for pituitary autoantigens. chronic phase (35). The disease may resolve spontaneously or rarely be severe with invasion of the causing ocular nerve palsies. Then, transsphenoidal decompression is needed Glomangioma for diagnostic and therapeutic purposes. In difficult cases There are only a few case reports on glomangioma tumor when and surgery fail, immunosupressive in the sellar region (41, 42). This is a benign vascular tumor drugs such as azathioprine, methotrexate, cyclosporin A that originates from gomitoli of the hypophyseal portal and/or radiotherapy/radiosurgery have been used (49). vessels. Patients present with sellar mass effects (visual field European Journal European of Endocrinology disturbances) and hypopituitarism. Sellar MRI reveals a large Secondary hypophysitis contrast-enhancing mass, hyperintense on T1-weighted MRI scans. Pathology evaluation of the surgical specimen Secondary hypophysitis is diagnosed in cases of preexisting reveals that the mass represents glomangioma (Fig. 7). tumors (germinoma, Rathke’s cleft cyst and meningioma) or systemic disease (sarcoidosis, tuberculosis, histiocytosis and Wegener’s granulomatosis) or it can be induced by Snakebite drugs (CTLA-4 blocking antibodies, anti-PD-1 antibodies Snakebites are important health problem in the tropics and interferon-α) (49) (Fig. 8). with significant mortality rate. Hypopituitarism is a Ipilimumab is a cytotoxic T-lymphocyte antigen-4 rare complication after snakebite. Isolated case reports (CTLA-4) inhibitor, a IgG1 monoclonal antibody and small series of patients with acute or chronic against CTLA-4, used for unresectable or metastatic hypopituitarism as a complication of snakebite have been melanoma. CTLA-4 inhibitors (ipilimumab) increase published (43, 44). T-cell proliferation and activity. Recently, it was reported that 10–15% of patients treated with ipilimumab may develop hypophysitis as a consequence of immune Immunological/infiltrative/ activation (50). Its pathogenesis is unkonwn. Recently inflammatory diseases at autopsy, the pituitary of six cancer patients who were treated with monoclonal antibody blocking Primary hypophysitis CTLA-4 were analyzed. CTLA-4 antigen was expressed Primary hypophysitis can be classified into several by pituitary endocrine cells with the highest levels histologic types: lymphocytic, granulomatous, found in patients with severe hypophysitis. In patients

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PROOFsyndrome’ ONLY was described (55, 56). An autoantibody against pituitary PIT-1 (POU1F1) was detected in patients with adult-onset combined GH, PRL and TSH deficiencies.

Sarcoidosis

Sarcoidosis is a chronic multisystemic disorder of unknown etiology characterized by a deposition of epithelioid granulomas without caseation necrosis (57). Central nervous system is affected in 5–15% of cases, and may be the first presenting feature of these systemic diseases (57). Lesions of sarcoidosis Figure 8 in the sellar region are found in the hypothalamus, the (A and B) A 12-year-old girl presenting with diabetes insipidus. stalk and pituitary gland; are rare and account for 1% of Sellar MRI scan (A sagittal and B coronal views) shows intense sellar masses (58). The classic MRI feature is thickening diffuse and homogenous enhancement of sellar mass and of the stalk. A large French study on 24 patients with stalk thickening. Biopsy revealed hypophysitis secondary to a hypothalamo-pituitary sarcoidosis showed that 22/24 germinoma. patients had anterior pituitary deficiencies, whereas 10 patients had diabetes insipidus (59). Results of with severe hypophysitis, immune reactions induced this large study analyzed with other 4 studies showed aggressive necrotizing form with extensive destruction that central was the most common of the adenohypophyseal architecture (51). Pituitary neuroendocrine abnormality (87.5–89%), followed by autoantiboides against thyrotrophs, corticotrophs and central (56%), central hypocorticism gonadotrophs were identified in the sera of patients (37%) and GH deficiency (30%). One third of patients had who developed hypophysitis (52). Ipilimumab-induced panhypopituitarism. With treatment, infiltrative lesions hypophysitis appears more frequently in men, in older dissapeared, but hypopituitarism persisted (59). patients, with higher dose of ipilimumab (50). Pituitary enlargement is usually mild and patients present with European Journal European of Endocrinology Hemochromatosis and hemosiderosis headache and , very rare with visual field defects. Hypopituitarism is diagnosed 2–3 months or later after the Hereditary hemochromatosis is a genetic disorder of initiation of ipilimumab, and most patients have multiple iron overload and organ damage, whereas hemosiderosis pituitary hormone deficiencies. Central hypothyroidism may develop as a complication of frequent blood is the most frequent abnormality, followed by central transfusions for severe congenital or acquired . hypocorticism and hypogonadism. Pituitary enlargement Iron overload presents with two endocrinopathies: central is transient and resolves within 3–8 weeks after the hypogonadism (pituitary) and diabetes mellitus () diagnosis of hypophysitis. Hypopituitarism persists and (60). The most common pituitary manifestation of iron patients must be replaced with , thyroid overload is hypogonadotropic hypogonadism. The reason and later with sex steroid hormones. why gonadotropes are most sensitive to iron overload is Hypopituitarism is a rare complication (1% of patients) not known (61). Pituitary function can improve after iron of novel family of immune-checkpoint inhibitors, depletion therapy. anti-PD-1 monoclonal antibodies (anti-programmed cell death protein 1) (nivolumab and pembrolizumab) used in several malignancies, including melanoma (53, 54). Wegener’s granulomatosis Wegener’s granulomatosis is a multisystemic autoimmune disease characterized by inflammation of small-to-medium Other autoimmune forms of hypopituitarism vesells (necrotizing granulomatous vasculitis), which Recently, a novel clinical entity of acquired combined typically affects the upper respiratory tract, lungs, kidney pituitary hormone deficiencies named ‘anti-PIT-1 antibody and skin. Pituitary involvement is a late manifestation of

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Wegener granulomatosisPROOF (62). Contiguous propagation of image ONLY suggestive of a pituitary abscess is ring-enchancing the granulomatous inflammatory lesion from the sinuses cystic sellar/suprasellar mass (69). Surgery is diagnostic, or orbits appears years after the primary diagnosis. In and microbiological cultures are frequently negative (in two recent studies, diabetes insipidus and 50% of cases). The chance of complete hormonal recovery deficiency were the most common presenting features is unlikely and requires continued follow-up. including moderate (63, 64). After remission of the Wegener’s granulomatosis, the majority of patients had permanent hypopituitarism, whereas very Tuberculosis few recovered pituitary function. The incidence of tuberculosis is rising both in the developing and developed countries (due to spreading of HIV ). Incidence and prevalence of intrasellar Pituitary tuberculosis are expected to grow, given the increasing Pituitary infections are rare disorders caused by bacteria, level of population migration and multi-ehnic nature tuberculosis, viruses, fungal and parasitic infections of societies. Tuberculous is not rare and (65). They occur by hematogenous spread in immuno- tubercular abscess of the brain has been reported (70, compromised hosts or by contiguous extension from 71). Tuberculous lesion may affect the hypothalamus, the adjacent anatomical sites (meningeal infection, sphenoid pituitary or infundibulum. MRI scan shows thickening of sinus, cavernous sinus and ) or from previous the pituitary stalk or pituitary tuberculoma, which may infectious diseases of the CNS of different etiologies mimic pituitary adenoma. Previous history of systemic and by iatrogenic inoculation during trans-sphenoidal tuberculosis should prompt the diagnosis of pituitary adenoma resection. Risk factors for pituitary infections tuberculosis (Fig. 9). are diabetes mellitus, tuberculosis, organ transplantation, In an Indian study, multiple pituitary hormone human immunodeficiency virus (HIV) infection, non- deficiency was reported in 29.3% of cases, and no patient Hodgkin lymphoma, chemotherapy and Cushing’s had evidence of diabetes insipidus (72). After treatment syndrome. Patients may present with , with antituberculous drugs, the pituitary tuberculoma partial or complete hypopituitarism, hyperprolactinema may disappear with the reversal of hypopituitarism in or central diabetes insipidus. Hypopituitarism may occur some cases (71). early in the acute phase of infection or at a late stage as a sequelae of infection (66, 67). European Journal European of Endocrinology Syphilis

The incidence of syphilis has been increasing in Western Pituitary abscess countries. Neurosyphilis is a rare cause of hypopituitarism Pituitary abscesses are uncommon. About 200 cases are that occurs either during acute phase of the disease or as reported. The diagnosis is diffucult as symptoms can be a chronic complication. Recently, the first case of HIV- unspecific without signs of systemic infection. Very few positive patient with acute neurosyphilis, hypophysitis are diagnosed preoperatively. The most common clinical and hypopituitarism was published (73). The patient are headache, hypopituitarism and was successfully treated with ceftriaxone and replaced diabetes insipidus. Pituitary abscess may develop as a with and . Another case complication; eg, infection of Rathke’s cleft cyst (68). MRI of acute syphilitic hypophysitis and partially reversible

Figure 9 (A and B) A 62-year-old male presenting with systemic tuberculosis. Sellar MRI scan (A sagittal and B coronal views) enlargement of the pituitary and stalk thickening due to tubercular hypophysitis. (C) Computed tomography of the thorax shows pulmonary tuberculosis (TB caverna and pleural effusion).

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hypopituitarism in PROOFa non-HIV-infected patient was ONLY described (74). There is only one publication on chronic Treponema pallidum infection, psychosis and hypopituitarism as a late complication of this infection (75).

Fungal infections

Fungal infections of the pituitary region are extremely rare, and they usually occur in immunocompromised patients. Fungal pituitary abscess must be considered in the differential diagnosis of a sellar or parasellar mass. They are caused by Aspergillus, Nocardia or Candida albicans and present with central diabetes insipidus, hyperprolactinemia and gonadal dysfunction (76). The is more often involved because of blood supply coming directly from the systemic circulation. MRI scan shows a sellar mass (Fig. 10). Treatment consists of transsphenoidal operation, followed by antimycotics (amphotericin B, itraconazole, voriconazole and caspofungin). In very rare cases, allergic fungal sinusitis may spread from sinuses to the sellar region. This can occur in immunocompetent patients in whom the overshooting response of eosinophylic granulocytes against fungi causes chronic inflammatory infiltrate, which may erode the sellar floor, displace the pituitary and compresses the pituitary stalk (77).

Figure 10 European Journal European of Endocrinology Viral hypophysitis A 57-year-old female presenting with headache and hyperprolactinemia. Sellar MRI scan (sagittal view) shows a Various viruses may affect the central nervous system large sellar mass pushing the pituitary upwards. (CNS) causing meningitis (herpes simplex, varicella and reports fungal pituitary abscess spreading from fungal enterovirus), meninogoencephalitis (herpes simplex, sinusitis. influenza and Coxsackie), (tick borne, herpes simplex and cytomegalovirus) or neuroborreliosis. In some transmitted by rodents. Especially soldiers and farmers cases, partial or complete hypopituitarism may develop are at risk for Hantavirus infection via aerosolized rodent either during the acute phase of CNS infection or as a late , feces or saliva. During the acute phase of the HFRS, complication of the infection despite good neurological the virus has been demostrated in recovery. A large study investigated patients two years with direct pituitary invasion causing viral hypophysitis after CNS infections, and isolated corticotroph deficiency (78). Viruses may infect the neuroendocrine and vascular was diagnosed in some patients (66). Hemorrhagic fever endothelial cells of the pituitary and also may cause the with renal syndrome (HFRS) is a viral infection caused pituitary ischemia/infarction with necrosis and subse­ by Hantaviruses, with acute , vascular leakage, quent hypopituitarism. Sporadic cases of hypopituitarism thrombocytopenia, and acute renal failure. as a complication of HFRS and autopsy results are Hantaviruses are RNA viruses (serotypes Hantaan, Seul, reported (78, 79). In a large retrospective study (60 adults Puumala and Dobrava–Belgrade) endemic in some parts who recovered from HFRS), high prevalence of partial or of Europe and in the Balkans, with outbreakes during complete hypopituitarism was found in HFRS survivors wars and with a mortality rate of 6.6%. Hantaviruses are (80). In a recent study, a group of patients suffering from

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Received 25 December 2016 Revised version received 17 February 2017 Accepted 2 March 2017 European Journal European of Endocrinology

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