Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.

Steroid treatment in the management of destructive thyrotoxicosis induced by PD1 blockade.

Objective: Destructive thyroiditis is the most common endocrine immune-related adverse event (iRAEs) in patients treated with anti-PD1/PD-L1 agents. Given its self-limited course, current guidelines recommend no treatment for this iRAE. Nevertheless, in patients with enlarged thyroid volume and a poor performance status, thyrotoxicosis may be particularly severe and harmful. The aim of the study is to evaluate if steroid treatment might be useful in improving thyrotoxicosis in subjects with a poor performance status. Methods: We conducted a retrospective study, comparing the course of thyrotoxicosis of four patients treated with oral prednisone at the dosage of 25 mg/day (tapered to discontinuation in 3 weeks) and an enlarged thyroid volume to that of eight patients with similar thyroid volume who were left untreated. Results: The levels of thyroid hormones were lower in subjects treated compared to those untreated at time of 7, 14, 21, 28, 35, 42, 60 and 90 days (P < 0.05 at each time). The time to remission of thyrotoxicosis was 24 days in patients treated with steroids and 120 days in untreated patients (P < 0.001). At 6 months, the rate of evolution to hypothyroidism was similar in the two groups (4/4 in the steroid group vs 7/8 in the untreated group, P = 0.74) and no difference was found in tumor progression (P = 0.89). Conclusions: Our preliminary data suggest that in patients with a poor performance status experiencing a severe destructive thyrotoxicosis induced by PD-1 blockade, a short period of administration of oral prednisone is effective in obtaining a quick reduction of the levels of thyroid hormones.

Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade.

CONTEXT: Thyrotoxicosis is a common immune-related adverse event in patients treated with programmed cell death protein-1 (PD1) or programmed cell death protein ligand-1 (PD-L1) blockade. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy, is lacking, as are data on response to treatment and follow-up. OBJECTIVE: The aim of this study was to better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and treatment. METHODS: We conducted a retrospective study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis on PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, 99mtechnecium scintiscan, and longitudinal thyroid function tests. RESULTS: Five patients had normal or increased scintigraphic uptake (Sci+), no serum antibodies against the thyrotropin receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci-) and experienced destructive thyrotoxicosis followed by hypothyroidism (N = 9) or euthyroidism (N = 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter (P = .04). Among Sci- individuals, a larger thyroid volume was associated with a longer time to remission (P < .05). Methimazole (MMI) was effective only in Sci+ individuals (P < .05). CONCLUSION: Administration of PD1- or PD-L1-blocking antibodies may induce 2 different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2, characterized by destructive and transient thyrotoxicosis that evolves to hypothyroidism or euthyroidism. Thyroid scintigraphy and ultrasound help in differentiating and managing these 2 forms of iatrogenic thyrotoxicosis.

Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism.

CONTEXT: Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. OBJECTIVES: The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. METHODS: Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. RESULTS: The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. CONCLUSION: The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.

Firm mass in thyroid of an elderly patient: not always cancer.

SUMMARY: In elderly patients presenting with a solid thyroid mass, the differential diagnosis between benign and malignant lesion is not always straightforward. We present the case of an 85-year-old woman with fever and an enlarged, firm and painful thyroid mass. Blood exams documented a mild thyrotoxicosis with a moderate inflammatory status. Thyroid scintiscan showed an absent uptake of 131I. Ultrasound and CT scan documented a 3 cm hypoechoic nodule with infiltration of the sternocleidomastoid muscle, very suspicious for neoplastic nature. Fine-needle aspiration and tru-cut biopsy were performed. During biopsy, the lesion was partially drained and a brownish fluid was extracted. The culture resulted positive for Klebsiella pneumoniae whereas the pathological analysis of the specimen was not conclusive due to the presence of an intense inflammatory response. A targeted oral antibiotic therapy was then initiated, obtaining only a partial response thus, in order to achieve a definite diagnosis, a minimally invasive hemithyroidectomy was performed. The pathological analysis documented acute suppurative thyroiditis and the clinical conditions of the patient significantly improved after surgical removal of thyroid abscess. In elderly patients with a solid thyroid mass, although neoplastic origin is quite frequent, acute suppurative thyroiditis should be considered as a differential diagnosis. LEARNING POINTS: A solid and rapidly growing thyroid mass in elderly patients can hide a multifaceted variety of diseases, both benign and malign. A multidisciplinary team (endocrinologist, surgeon, radiologist and pathologist) could be necessary in order to perform a correct differential diagnosis and therapeutic approach. Surgery can be decisive not only to clarify a clinically uncertain diagnosis, but also to rapidly improve the clinical conditions of the patient.

Hypophysitis induced by immune checkpoint inhibitors: a 10-year assessment.

Introduction: Hypophysitis caused by immune checkpoint inhibitors (ICIs) has risen to the medical attention during the past decade. ICIs are monoclonal antibodies that block the interaction between molecules that normally inhibit the function of effector T cells, ultimately increasing their ability to destroy cancer cells but also causing immune-related adverse events, such as hypophysitis. Ipilimumab, a CTLA-4 blocker, was the first ICI approved from the Food and Drug Administration for advanced melanoma patients in 2011. Several additional ICIs targeting CTLA-4, PD-1, or PD-L1 are now used in many clinical trials, making it important for physicians to recognize and treat hypophysitis adequately.Areas covered: This review will provide insights into the mechanisms of pituitary toxicity, highlight the complexity of clinical phenotypes of ICI hypophysitis, and offer practical recommendations.Expert opinion: ICI hypophysitis differs in many respects from primary hypophysitis, and also according to the type of ICI that caused it. Its pathogenesis remains unknown, although the expression of CTLA-4 and PD-1 on pituitary cells could play a role. The diagnosis is mainly clinical since there are no specific serological markers and MRI findings are subtle. The treatment is based on long-term hormone replacement and does not typically require discontinuation of immunotherapy.

Clinical heterogeneity of hypophysitis secondary to PD-1/PD-L1 blockade: insights from four cases.

SUMMARY: Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy. LEARNING POINTS: PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade. Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities. Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease. PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases.

Graves' Disease Induced by Immune Checkpoint Inhibitors: A Case Report and Review of the Literature.

INTRODUCTION: In the last few years, immune checkpoint inhibitors (ICPis) have become a common treatment of cancer. ICPis are associated with peculiar immune side effects, termed immune-related adverse events (irAEs). Thyroid disfunction is a common irAE, but clinical manifestation, severity, and pathogenesis can be variable. While destructive thyroiditis and hypothyroidism are the most common thyroid irAEs induced by ICPis, autoimmune hyperthyroidism (Graves' disease) is rare. We describe a case of a Graves' disease induced by anti-PD-1 therapy and we review the previous reports on this issue. CASE PRESENTATION: A 51-year-old man developed an overt autoimmune hyperthyroidism 2 months after he had started nivolumab (anti-PD-1) therapy for a metastatic non-small cell lung cancer. Although TSH-receptor autoantibodies (TRAb) were negative, the persistence of hyperthyroidism, the hypervascular pattern at thyroid ultrasound, and the high uptake at thyroid scintigraphy were all features suggestive of Graves' disease. Methimazole was started with the prompt restoration of euthyroidism. TRAb remained undetectable during the entire follow-up. CONCLUSIONS: Autoimmune hyperthyroidism can be induced by anti-PD-1 treatment. TRAb were negative in both cases of nivolumab-induced Graves' disease described to date. A correct differential diagnosis between destructive thyroiditis and autoimmune hyperthyroidism is crucial for the appropriate treatment.

Diabetes mellitus induced by somatostatin analogue therapy is not permanent in acromegalic patients.

CONTEXT: Therapy with somatostatin analogues (SSAs) may have deleterious effects on glucose metabolism in patients with acromegaly, often leading to the development of diabetes mellitus (DM). AIM: The aim of the study was to evaluate whether DM, developed during therapy with SSAs, may revert after drug withdrawal and cure of acromegaly with pituitary adenomectomy. DESIGN: Retrospective cohort study, in a tertiary referral centre. PATIENTS: Eighteen acromegalic patients without DM at the diagnosis of acromegaly treated with SSAs as a primary therapy, and then cured by pituitary adenomectomy. METHODS: Endocrine status and glucose homeostasis were evaluated at diagnosis of acromegaly and at least every 6 months during SSA therapy. At each visit, patients were classified into one of the following classes: normal glucose tolerance, prediabetes, overt diabetes. RESULTS: Median follow-up after starting SSAs therapy was 69 months (IQR 54.75-132.25). During SSA therapy, all patients had controlled acromegaly defined by normal serum IGF1 concentrations for the age. Of the 13 euglycaemic patients at diagnosis, three developed prediabetes and three diabetes, whereas, of the five prediabetic patients at diagnosis, two worsened to overt diabetes and three remained in the prediabetic range (P = 0.04). After curing acromegaly with pituitary adenomectomy and subsequent SSA withdrawal, prediabetes reverted in five of six patients, and diabetes in all five patients (three reverted to euglycaemia, while two reverted to prediabetes) (P = 0.01). CONCLUSIONS: In acromegalic patients with controlled disease, changes in glycaemic status induced by SSAs are not permanent.

Immune Checkpoint Blockade Anti-PD-L1 as a Trigger for Autoimmune Polyendocrine Syndrome.

CONTEXT: The programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway is a key regulator in T-cell activation and tolerance, limiting effector T-cell function in peripheral tissues. Atezolizumab, an anti-PD-L1 monoclonal antibody, is approved for treatment of some types of advanced cancer. Its main treatment-related adverse events are immune related, such as thyroid dysfunction and hypophysitis. Autoimmune endocrinopathy can occur as isolated manifestations; only a few cases of autoimmune polyendocrine syndromes have been reported thus far. CASE: We report a case of polyendocrine syndrome type 2, characterized by Addison disease (AD), type 1 diabetes mellitus (T1DM), accompanied by hypophysitis, in a patient treated with atezolizumab. Testing was positive for 21-hydroxylase and pituitary antibodies and negative for islet cells antibodies. HLA typing revealed DRB1*04 and DQB1*03 haplotypes, which are associated with increased susceptibility to T1DM and AD. CONCLUSION: The type and severity of immune-related adverse events in polyendocrine syndrome type 2 are different and depend on the monoclonal antibody used. Although the numerous molecular mechanisms inducing autoimmune endocrine diseases are still unclear, a link exists between HLA haplotypes, gene variants involved in immune checkpoint molecule expression, and increased susceptibility to autoimmune endocrinopathies. Additional studies are needed to identify susceptible patients and adapt therapy to each patient.

Persisting Embryonal Infundibular Recess (PEIR): Two Case Reports and Systematic Literature Review.

Context: The persisting embryonal infundibular recess (PEIR) is a rare anomaly of the floor of the third ventricle with a debated pathogenesis. It can be a cause of misdiagnosis in the case of cystic lesions of the sellar and suprasellar area. Objective: To describe two recently evaluated cases and provide a systematic literature review. Evidence Acquisition and Case Descriptions: PEIR has been previously reported in six adult patients. Because in some cases it was associated with hydrocephalus and/or empty sella, a possible role of altered intracranial pressure in PEIR formation has been postulated. We evaluated two female patients, aged 34 and 50 years, referred to the Pituitary Surgery Clinic of the University of Brescia with the diagnosis of a sellar cyst and craniopharyngioma, respectively. Endocrine screening and visual field testing were normal. No signs of hydrocephalus or empty sella, as well as other indirect signs of intracranial hypertension, were visible on MRI scans. After a multidisciplinary reevaluation, diagnosis of PEIR was made in both cases. Both patients are followed but have not developed any disturbance related to the PEIR in the following 18 months. Conclusions: PEIR is a rare condition, probably unrecognized and the result of dysembriogenesis, which should be included in the differential diagnosis of cystic sellar lesions. Imaging features (funnel pituitary stalk and cyst in the sella) appear pathognomonic. A normal endocrine evaluation might help in the diagnosis and warrants conservative treatment.

Diabetes insipidus is an unfavorable prognostic factor for response to glucocorticoids in patients with autoimmune hypophysitis.

INTRODUCTION: Autoimmune hypophysitis (AH) has a variable clinical presentation and natural history; likewise, its response to glucocorticoid therapy is often unpredictable. OBJECTIVE: To identify clinical and radiological findings associated with response to glucocorticoids. DESIGN AND METHODS: 12 consecutive patients with AH, evaluated from 2008 to 2016. AH was the exclusion diagnosis after ruling out other pituitary masses and secondary causes of hypophysitis. Mean follow-up time was 30 ± 27 months (range 12-96 months). RESULTS: MRI identified two main patterns of presentation: global enlargement of the pituitary gland or panhypophysitis (n = 4, PH), and pituitary stalk abnormality only, or infundibulo-neuro-hypophysitis (n = 8, INH). Multiple tropin defects were more common in PH (100%) than those in INH (28% P = 0.014), whereas diabetes insipidus was more common in INH (100%) than that in PH (50%; P = 0.028). All 4 PH and 4 out of 8 INH were treated with glucocorticoids. Pituitary volume significantly reduced in all PH patients (P = 0.012), defective anterior pituitary function recovered only in the two patients without diabetes insipidus (50%) and panhypopituitarism persisted, along with diabetes insipidus, in the remaining 2 (50%). In all INH patients, either treated or untreated, pituitary stalk diameter reduced (P = 0.008) but diabetes insipidus persisted in all. CONCLUSIONS: Glucocorticoid therapy may improve anterior pituitary function in a subset of patients but has no effect on restoring posterior pituitary function. Diabetes insipidus appears as a negative prognostic factor for response to glucocorticoids.

Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights into Pathogenesis from an Autopsy Series.

Hypophysitis that develops in cancer patients treated with monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; an inhibitory molecule classically expressed on T cells) is now reported at an incidence of approximately 10%. Its pathogenesis is unknown, in part because no pathologic examination of the pituitary gland has been reported to date. We analyzed at autopsy the pituitary glands of six cancer patients treated with CTLA-4 blockade, one with clinical and pathologic evidence of hypophysitis, one with mild lymphocytic infiltration in the pituitary gland but no clinical signs of hypophysitis, and four with normal pituitary structure and function. CTLA-4 antigen was expressed by pituitary endocrine cells in all patients but at different levels. The highest levels were found in the patient who had clinical and pathologic evidence of severe hypophysitis. This high pituitary CTLA-4 expression was associated with T-cell infiltration and IgG-dependent complement fixation and phagocytosis, immune reactions that induced an extensive destruction of the adenohypophyseal architecture. Pituitary CTLA-4 expression was confirmed in a validation group of 37 surgical pituitary adenomas and 11 normal pituitary glands. The study suggests that administration of CTLA-4 blocking antibodies to patients who express high levels of CTLA-4 antigen in the pituitary can cause an aggressive (necrotizing) form of hypophysitis through type IV (T-cell dependent) and type II (IgG dependent) immune mechanisms.

Disease activity and lifestyle influence comorbidities and cardiovascular events in patients with acromegaly.

OBJECTIVE: The primary objective of this study is to identify the predictors of comorbidities and major adverse cardiovascular events (MACE) that can develop after diagnosis of acromegaly. The role of therapy for acromegaly in the event of such complications was also evaluated. DESIGN AND METHODS: Retrospective cohort study was conducted on 200 consecutive acromegalic patients in a tertiary referral center. The following outcomes were evaluated: diabetes, hypertension and MACE. Each patient was included in the analysis of a specific outcome, unless they were affected when acromegaly was diagnosed, and further classified as follows: (i) in remission after adenomectomy (Hx), (ii) controlled by somatostatin analogues (SSA) (SSAc) or (iii) not controlled by SSA (SSAnc). Data were evaluated using Cox regression analysis. RESULTS: After diagnosis of acromegaly, diabetes occurred in 40.8% of patients. The SSAnc group had a three-fold higher risk of diabetes (HR: 3.32, P = 0.006), whereas the SSAc group had a 1.4-fold higher risk of diabetes (HR: 1.43, P = 0.38) compared with the Hx group. Hypertension occurred in 35.5% of patients, after diagnosis. The determinants of hypertension were age (HR: 1.06, P = 0.01) and BMI (HR: 1.05, P = 0.01). MACE occurred in 11.8% of patients, after diagnosis. Age (HR: 1.09, P = 0.005) and smoking habit (HR: 5.95, P = 0.01) were predictors of MACE. Conversely, therapy for acromegaly did not influence hypertension or MACE. CONCLUSION: After diagnosis of acromegaly, control of the disease (irrespective of the type of treatment) and lifestyle are predictors of comorbidities and major adverse cardiovascular events.

Divergent Effects of Dioxin- or Non-Dioxin-Like Polychlorinated Biphenyls on the Apoptosis of Primary Cell Culture from the Mouse Pituitary Gland.

Polychlorinated biphenyls (PCBs) can disrupt the endocrine function, promote neoplasms and regulate apoptosis in some tissues; however, it is unknown whether PCBs can affect the apoptosis of pituitary cells. The study evaluated the effect of PCBs on the apoptosis of normal pituitary cells and the underlying mechanisms. Primary cell cultures obtained from mouse pituitary glands were exposed to Aroclor 1254 or selected dioxin-like (PCB 77, PCB 126) or non-dioxin-like (PCB 153, PCB 180) congeners. Apoptosis was evaluated by Annexin V staining, DNA fragmentation, and TUNEL assay. Both the expression and activity of caspases were analyzed. Selective thyroid hormone receptor (TR) or aryl-hydrocarbon receptor (AhR) or CYP1A1 antagonist were used to explore the mechanisms underlying PCBs action. Our results showed that Aroclor 1254 induced the apoptosis of pituitary cells as well as the final caspase-3 level and activity through the extrinsic pathway, as shown by the increased caspase-8 level and activity. On the other hand, the intrinsic pathway evaluated by measuring caspase-9 expression was silent. The selected non-dioxin-like congeners either increased (PCB 180) or reduced (PCB 153) pituitary cell apoptosis, affecting the extrinsic pathway (PCB 180), or both the extrinsic and intrinsic pathways (PCB 153), respectively. In contrast, the dioxin-like congeners (PCB 77 and PCB 126) did not affect apoptosis. The anti-apoptotic phenotype of PCB 153 was counteracted by a TR or a CYP1A1 antagonist, whereas the pro-apoptotic effect of PCB 180 was counteracted by an AhR antagonist. The induced apoptosis of Aroclor 1254 or PCB 180 was associated with a reduction of cell proliferation, whereas the decreased apoptosis due to PCB 153 increased cell proliferation by 30%. In conclusion, our data suggest that non-dioxin-like PCBs may modulate apoptosis and the proliferation rate of pituitary cells that have either pro- or anti-apoptotic effects depending on the specific congeners. However, the impact of PCBs on the process of pituitary tumorigenesis remains to be elucidated.

The beneficial effect of acromegaly control on blood pressure values in normotensive patients.

OBJECTIVE: Control of acromegaly may ameliorate blood pressure (BP) in hypertensive (HT) patients. We evaluated the impact of acromegaly control on BP values of normotensive (NT) acromegalics. DESIGN: Retrospective cohort study. PATIENTS: Fifty-eight naïve patients with acromegaly (39 F; age range, 30-69 years), including 28 NT and 30 HT subjects, participated in the study. MEASUREMENTS: Blood pressure was measured by clinical measurement and 24-h ambulatory monitoring at diagnosis and after 24 months of medical therapy for acromegaly. RESULTS: Acromegaly was controlled by medical therapy in 15 NT and 17 HT patients at 24 months. In the NT group, systolic (SBP) or diastolic (DBP) BP significantly increased (all P < 0·005) when acromegaly was uncontrolled, but did not change when the disease was controlled. Changes in SBP and DBP were also significantly different between uncontrolled and controlled NT patients. At 24 months, clinical hypertension was detected only in uncontrolled NT patients (46% vs 0%, P < 0·001), whereas ambulatory hypertension was found in 38% of uncontrolled and in 7% of controlled NT subjects (P = 0·035). In the HT group, ambulatory SBP increased in patients with uncontrolled acromegaly (24-h SBP P = 0·046, day SBP P = 0·005, night SBP P = 0·005), whereas ambulatory DBP decreased in subjects with controlled disease (24-h DBP P = 0·008, day DBP P = 0·026). CONCLUSIONS: Control of acromegaly has a beneficial effect on BP regulation either in HT or NT subjects; in the latter, it may prevent progression towards hypertension.

Detection of pituitary antibodies by immunofluorescence: approach and results in patients with pituitary diseases.

CONTEXT: Pituitary antibodies have been measured mainly to identify patients whose disease is caused or sustained by pituitary-specific autoimmunity. Although reported in over 100 publications, they have yielded variable results and are thus considered of limited clinical utility. OBJECTIVES: Our objectives were to analyze all publications reporting pituitary antibodies by immunofluorescence for detecting the major sources of variability, to experimentally test these sources and devise an optimized immunofluorescence protocol, and to assess prevalence and significance of pituitary antibodies in patients with pituitary diseases. STUDY DESIGN AND OUTCOME MEASURES: We first evaluated the effect of pituitary gland species, section fixation, autofluorescence quenching, blockade of unwanted antibody binding, and use of purified IgG on the performance of this antibody assay. We then measured cross-sectionally the prevalence of pituitary antibodies in 390 pituitary cases and 60 healthy controls, expressing results as present or absent and according to the (granular, diffuse, perinuclear, or mixed) staining pattern. RESULTS: Human pituitary was the best substrate to detect pituitary antibodies and yielded an optimal signal-to-noise ratio when treated with Sudan black B to reduce autofluorescence. Pituitary antibodies were more common in cases (95 of 390, 24%) than controls (3 of 60, 5%, P = .001) but did not discriminate among pituitary diseases when reported dichotomously. However, when expressed according to their cytosolic staining, a granular pattern was highly predictive of pituitary autoimmunity (P < .0001). CONCLUSION: We report a comprehensive study of pituitary antibodies by immunofluorescence and provide a method and an interpretation scheme that should be useful for identifying and monitoring patients with pituitary autoimmunity.

Growth hormone is necessary for the p53-mediated, obesity-induced insulin resistance in male C57BL/6J x CBA mice.

Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J × CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpression of suppressors of cytokine signal 1-3 and signal transducers and activators of transcription-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice.

Comparison of the effects of primary somatostatin analogue therapy and pituitary adenomectomy on survival in patients with acromegaly: a retrospective cohort study.

OBJECTIVE: Acromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality. DESIGN AND METHODS: The mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis. RESULTS: Twenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43-1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (P=0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06-28.77, P=0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56-309.04, P=0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease. CONCLUSIONS: Therapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients.

Hashimoto's thyroiditis in a benign cystic teratoma of the ovary: case report and literature review.

Ectopic thyroid tissue in ovarian teratoma or in struma ovarii appears to be histologically identical to the thyroid gland tissue and may virtually exhibit all the pathological patterns found in the thyroid gland. However, the concurrent lymphocytic infiltration of the thyroid gland, as found in Hashimoto's thyroiditis, and of the ectopic thyroid tissue is extremely rare. We describe the case of an 18-years old patient, in which a right ovarian 4 cm cyst has been found during pelvic ultrasound exam. The cyst was resected and microscopic examination of the mass revealed a mature cystic teratoma in which epidermal-like lining with skin adnexa, admixed with respiratory type epithelium, and areas of mature fatty, chondroid and dentigerous tissues were found. In a peripheral area of 0.7 cm  × â€Š0.5 cm, a prominent lymphocytic infiltrate surrounding thyroid follicles was identifiable. Thyroid function evaluation at different time points after surgery, revealed the development of mild hypothyroidism. Anti-TPO and anti-Tg autoantibodies were elevated, at fine needle aspiration biopsy a lymphocytic infiltrate, compatible with Hashimoto's thyroiditis, was present. We report here a rare case of Hashimoto's thyroiditis occurring both in the thyroid and in the ectopic thyroid tissue in the context of a benign cystic teratoma of the ovary.