Factors associated with disease control failure in acromegaly patients treated with pegvisomant: an ACROSTUDY analysis.

Purpose: The aim of this study was to examine the probability of achieving acromegaly disease control according to several patient-, disease- and treatment-related factors longitudinally. Methods: We analyzed data from ACROSTUDY, an open-label, noninterventional, post-marketing safety surveillance study conducted in 15 countries. A total of 1546 patients with acromegaly and treated with pegvisomant, with available information on baseline IGF-1 level, were included. Factors influencing IGF-1 control were assessed up to 10 years of follow-up by mixed-effects logistic regression models, taking into account changing values of covariates at baseline and at yearly visits. Twenty-eight anthropometric, clinical and treatment-related covariates were examined through univariate and multivariate analyses. We tested whether the probability of non-control was different than 0.50 (50%) by computing effect sizes (ES) and the corresponding 95% CI. Results: Univariate analysis showed that age <40 years, normal or overweight, baseline IGF-1 <300 µg/L or ranged between 300 and 500 µg/L, and all pegvisomant dose <20 mg/day were associated with a lower probability of acromegaly uncontrol. Consistently, in multivariate analyses, the probability of uncontrolled acromegaly was influenced by baseline IGF-1 value: patients with IGF-1 <300 µg/L had the lowest risk of un-controlled acromegaly (ES = 0.29, 95% CI: 0.23-0.36). The probability of acromegaly uncontrol was also lower for values 300-500 µg/L (ES = 0.37, 95% CI: 0.32-0.43), while it was higher for baseline IGF-1 values ≥700 µg/L (ES = 0.58, 95% CI: 0.53-0.64). Conclusion: Baseline IGF-l levels were a good predictor factor for long-term acromegaly control. On the contrary, our data did not support a role of age, sex, BMI and pegvisomant dose as predictors of long-term control of acromegaly. Significance statement: Among factors that could influence and predict the efficacy of pegvisomant therapy in controlling acromegaly, a central role of baseline IGF-1 values on the probability of achieving a biochemical control of acromegaly during the treatment with pegvisomant was identified, in a real-life setting.

Cutaneous lesions and other non-endocrine manifestations of Multiple Endocrine Neoplasia type 1 syndrome.

Background: Multiple Endocrine Neoplasia type 1 is a rare genetic syndrome mainly caused by mutations of MEN1 gene and characterized by a combination of several endocrine and non-endocrine manifestations. The objective of this study was to describe cutaneous lesions and other non-endocrine manifestations of MEN1 in a cohort of patients with familial (F) and sporadic (S) MEN1, compare the prevalence of these manifestations between the two cohorts, and investigate the correlation with MEN1 mutation status. Methods: We collected phenotypic and genotypic data of 185 patients with F-MEN1 and S-MEN1 followed from 1997 to 2022. The associations between F-MEN1 and S-MEN1 or MEN1 mutation-positive and mutation-negative patients and non-endocrine manifestations were determined using chi-square or Fisher's exact tests or multivariate exact logistic regression analyses. Results: The prevalence of angiofibromas was significantly higher in F-MEN1 than in S-MEN1 in both the whole (p < 0.001) and index case (p = 0.003) cohorts. The prevalence of lipomas was also significantly higher in F-MEN1 than in S-MEN1 (p = 0.009) and in MEN1 mutation-positive than in MEN1 mutation-negative (p = 0.01) index cases. In the whole cohort, the prevalence of lipomas was significantly higher in MEN1 mutation-positive compared to MEN1 mutation-negative patients (OR = 2.7, p = 0.02) and in F-MEN1 than in S-MEN1 (p = 0.03), only after adjustment for age. No significant differences were observed for the other non-endocrine manifestations between the two cohorts. Hibernoma and collagenoma were each present in one patient (0.5%) and meningioma and neuroblastoma in 2.7% and 0.5%, respectively. Gastric leiomyoma was present in 1.1% of the patients and uterine leiomyoma in 14% of women. Thyroid cancer, breast cancer, lung cancer, basal cell carcinoma, melanoma, and colorectal cancer were present in 4.9%, 2.7%, 1.6%, 1.6%, 2.2%, and 0.5% of the whole series, respectively. Conclusions: We found a significantly higher prevalence of angiofibromas and lipomas in F-MEN1 compared with S-MEN1 and in MEN1 mutation-positive compared to MEN1 mutation-negative patients. In patients with one major endocrine manifestation of MEN1 , the presence of cutaneous lesions might suggest the diagnosis of MEN1 and a possible indication for genetic screening.

Real-life Data on the Effect of Medical Therapy for Amiodarone-induced Thyrotoxicosis on CV Events and Hospitalizations.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) often receive initial therapy for thyrotoxicosis in several different medical settings before admission to a referral center. OBJECTIVE: This work aimed to determine whether first-line medical therapy (ie, therapies for thyrotoxicosis at first diagnosis of AIT) affects the outcome of AIT patients. METHODS: A single-center historical-prospective cohort study was conducted on 313 AIT patients. Clinical and biochemical data were collected at first diagnosis, at a referral center, and during the course of AIT. Primary outcomes were cardiovascular (CV) events and hospitalizations. First-line therapies were considered appropriate when they included glucocorticoids for type 2 AIT and methimazole for type 1 AIT at the approved dose, either alone (optimal medical therapy, OMT) or in combination (right-dose combination therapy, RCT). Other therapies were considered not appropriate, including no therapy. Duration of exposure to thyrotoxicosis was the time from first diagnosis of AIT to its remission. RESULTS: A total of 34.5% patients received appropriate therapies (28.1% OMT, 6.4% RCT), whereas the remaining (65.5%) received inappropriate therapies. CV events and hospitalizations were more frequent in patients who received inappropriate therapies (33.2% vs 4.5%, and 24.9% vs 6.5%, respectively; P < .0001 for both). Appropriate therapies reduced serum thyroid hormone concentrations (P = .018) from first diagnosis to referral, unlike the inappropriate therapies. The duration of exposure to thyrotoxicosis was longer in patients receiving inappropriate therapies and was a risk factor for arrhythmias (hazard ratio [HR] 1.004; P = .0008), major acute CV events (HR 1.004; P = .020), and hospitalizations (HR 1.006; P < .0001). CONCLUSION: The first medical therapy of AIT influences the exposure time to thyrotoxicosis and the occurrence of CV events and hospitalizations.

Global psychological assessment with the evaluation of life and sleep quality and sexual and cognitive function in a large number of patients with acromegaly: a cross-sectional study.

Objective: Acromegaly is associated with somatic disfigurements which impair self-perception of well-being and quality of life. Nowadays, limited data are available on the interplay between hormonal excess and psychological discomfort. The study aimed at investigating the psychological profile, sleep quality, sexual function, cognitive functions, and quality of life in patients with acromegaly. Methods: In 223 acromegaly patients from 5 referral centres, global psychological profile, sleep quality, sexual function, cognitive function, and quality of life were investigated. Results: Depression was found in ~30% of patients, and anxiety in two-thirds, together with severe discomfort in body image mainly in women. Obstructive sleep apnoea syndrome risk and sleep disorders were found in >50% of patients and daily sleepiness in ~20%. Sexual dysfunction was reported in most of the patients, with the most severe impairment in women. Cognitive functions were compromised in ~10% of cases. Disease duration and patient's age and gender were the main determinants of these psychopathological conditions. Depression (P = 0.047), somatic-affective mood lowering (P = 0.021), state (P < 0.001) and trait (P = 0.013) anxiety, and body image distortion in body uneasiness test A (P < 0.001) and B (P = 0.006) were significantly worsened in patients <45 years and slightly worsened in those with disease duration less than 2 years. Male (P < 0.001) and female (P < 0.001) sexual function scores were significantly worsened in patients aged >64 years and slightly worsened in those with disease duration for more than 10 years, particularly in presence of cardiometabolic and respiratory complications. Cognitive symptoms were slightly worsened in older patients and in those with long disease duration. Conclusions: Acromegaly is associated with a relevant impairment of psychological profile persisting despite remission and long-term medical treatment.

Early surgery: a favorable prognosticator in amiodarone-induced thyrotoxicosis-a single-center experience with 53 cases.

Fewer than 100 cases of amiodarone-induced thyrotoxicosis (AIT) managed surgically have been reported worldwide. This study aims to assess the outcome of thyroidectomy under general anesthesia in a relatively large case series. A retrospective analysis of the clinical records of 53 patients who underwent thyroidectomy for AIT between 1995 and 2019 was conducted. There were 48 (90%) males and 5 females with an average age of 63.7 years. Type 1 and 2 AIT were present in 35 (66%) and 18 (34%) of patients, respectively. The mean preoperative ejection fraction (EF) was 45 ± 13%. Salvage surgery was performed in 6 (11%) patients due to decompensating heart failure and/or malignant arrhythmias. 35 (66%) patients underwent urgent surgery due to a predicted late response to medical therapy and/or the need to discontinue it. Elective surgery was performed in the remainder. A considerable improvement in mean EF occurred 12 months post-surgery (44% vs. 49%; p < 0.001). The overall survival rate following thyroidectomy was 96% at 12 months, and 83% at 5 years. No survival differences were observed based on systolic function. Cardiac-specific mortality was 11%, and these patients demonstrated a considerably shorter survival post-surgery compared to those who died of a non-cardiac cause (27 ± 18 vs. 77.5 ± 54 months; p < 0.05). Total thyroidectomy can be safely performed under general anesthesia despite severe cardiac disease. It considerably improves cardiac function and confers a survival advantage. Therefore, it should be considered early in the treatment plan of select cases.

Identification of Two Different Phenotypes of Patients with Amiodarone-Induced Thyrotoxicosis and Positive Thyrotropin Receptor Antibody Tests.

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AIT1) due to Graves' disease (GD). However, the TRAb role and function in AIT have not been clarified. Methods: A retrospective cohort study of 309 AIT patients followed at a single academic center over a 30-year period. AIT TRAb-positive patients (n = 21, 7% of all cases) constituted the study group; control groups consisted of type 2 AIT (AIT2) TRAb-negative patients (n = 233), and 100 non-AIT patients with GD. Clinical and biochemical data at diagnosis and during the course of disease were compared. Histological samples of patients who had total thyroidectomy were reviewed. Stored serum samples were used for a functional assay of TRAb class G immunoglobulins (IgGs) in Chinese hamster ovary (CHO) cells stably transfected with complementary DNA encoding for the TSH receptor. Results: TRAb-positive patients were grouped according to color flow Doppler sonography, radioactive iodine thyroid uptake, and duration of amiodarone therapy before thyrotoxicosis in type 1 (n = 9, 43%; TRAb1) or type 2 (n = 12, 57%; TRAb2) AIT. TRAb1 patients had clinical and biochemical features indistinguishable from GD controls, and were responsive to methimazole. Conversely, TRAb2 patients had clinical features similar to AIT2 controls, and were responsive to glucocorticoids, but not to methimazole. The CHO cell functional assay demonstrated that TRAb1 IgGs had a stimulatory effect on cyclic AMP production, which was absent in TRAb2 IgGs. Pathology in TRAb1 showed hyperplastic thyroid follicles and mild lymphocyte infiltration, reflecting thyroid stimulation. On the contrary, TRAb2 samples revealed follicle destruction, macrophage infiltration, and sometimes fibrosis, consistent with a destructive process. Conclusions: Almost 60% of TRAb-positive AIT patients had a destructive thyroiditis. TRAb-positive tests in AIT patients do thus not necessarily imply a diagnosis of GD and AIT1, and should be evaluated in the clinical and biochemical setting of each AIT patient and confirmed by measuring thyroid-stimulating immunoglobulins.

PCB153 reduces apoptosis in primary cultures of murine pituitary cells through the activation of NF-κB mediated by PI3K/Akt.

Polychlorinated biphenyls (PCBs) are persistent pollutants involved in human tumorigenesis. PCB153 is a ubiquitous non-dioxin-like PCB with proliferative and anti-apoptotic effects. To explore the impact of PCB153 in the survival of pituitary cells, we exposed murine pituitary primary cells to PCB153 10 µM for 24 h. Apoptosis was assessed by RT-qPCR, Western-blot, immunoprecipitation, caspase activity, and immunofluorescence. We found that PCB153 decreased pituitary apoptosis through both the extrinsic and intrinsic pathways. PCB153 reduced the level of the pro-apoptotic protein p38-MAPK. Otherwise, PCB153 activated PI3K/Akt and Erk1/2 pathways and enhanced the expression and nuclear translocation of NF-κB. Cotreatments with specific inhibitors revealed that only PI3K/Akt changed the caspase-3 expression and NF-κB activation induced by PCB153. Also, PCB153 decreased the expression of the pro-apoptotic and pro-senescent cyclins p53 and p21. In summary, exposure to PCB153 leads to a downregulation of apoptosis in the pituitary driven by a PI3K/Akt-mediated activation of NF-κB.

Duration of Exposure to Thyrotoxicosis Increases Mortality of Compromised AIT Patients: the Role of Early Thyroidectomy.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism has not yet been settled. OBJECTIVES: Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis. METHODS: Retrospective cohort study of 64 consecutive patients with AIT selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF <40%), Group 2 (thyrotoxic, LVEF ≥40%), Group 3 (euthyroid, LVEF < 40%), Group 4 (euthyroid, LVEF ≥40%). RESULTS: Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% versus 0%, respectively (P = .048), whereas 5-year cardiovascular mortality rates were 53.3% versus 12.3%, respectively (P = .081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, interquartile range [IQR] 82.5-140, vs 76 days, IQR 24.8-88.5, P = .021). Survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% versus 4% (P = .741) and 5-year cardiovascular mortality rates were 12.5% and 20% (P = .685), respectively. Age (hazard ratio [HR] 1.104, P = .029) and duration of exposure to thyrotoxicosis (HR 1.004, P = .039), but not presurgical serum thyroid hormone concentrations (P = .577 for free thyroxine, P = .217 for free triiodothyronine), were independent predictors of death. CONCLUSIONS: A prolonged exposure to thyrotoxicosis resulted in increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.

Comparison Between Total Thyroidectomy and Medical Therapy for Amiodarone-Induced Thyrotoxicosis.

CONTEXT: It is not known whether total thyroidectomy is more favorable than medical therapy for patients with amiodarone-induced thyrotoxicosis (AIT). OBJECTIVE: To compare total thyroidectomy with medical therapy on survival and cardiac function in AIT patients. METHODS: Observational longitudinal cohort study involving 207 AIT patients that had received total thyroidectomy (surgery group, n = 51) or medical therapy (medical therapy group, n = 156) over a 20-year period. AIT types and left ventricular ejection fraction (LVEF) classes were determined at diagnosis of AIT. Cardiac and thyroid function were reevaluated during the study period. Survival was estimated using the Kaplan-Meier method. RESULTS: Overall mortality and cardiac-specific mortality at 10 and 5 years, respectively, were lower in the surgery group than in the medical therapy group (P = 0.04 and P = 0.01, respectively). The lower mortality rate of the surgery group was due to patients with moderate to severely compromised LVEF (P = 0.005 vs medical therapy group). In contrast, mortality of patients with normal or mildly reduced LVEF did not differ between the 2 groups (P = 0.281 and P = 0.135, respectively). Death of patients with moderate to severe LV systolic dysfunction in the medical therapy group occurred after 82 days (interquartile range, 56-99), a period longer than that necessary to restore euthyroidism in the surgery group (26 days; interquartile range, 15-95; P = 0.038). Risk factors for mortality were age (hazard ratio [HR] = 1.036) and LVEF (HR = 0.964), whereas total thyroidectomy was shown to be a protective factor (HR = 0.210). LVEF increased in both groups after restoration of euthyroidism, above all in the most compromised patients in the surgery group. CONCLUSIONS: Total thyroidectomy could be considered the therapeutic choice for AIT patients with severe systolic dysfunction, whereas it is not superior to medical therapy in those with normal or mildly reduced LVEF.

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.

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.

2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction.

Treatment with amiodarone is associated with changes in thyroid function tests, but also with thyroid dysfunction (amiodarone-induced hypothyroidism, AIH, and amiodarone-induced thyrotoxicosis, AIT). Both AIH and AIT may develop in apparently normal thyroid glands or in the presence of underlying thyroid abnormalities. AIH does not require amiodarone withdrawal, and is treated with levothyroxine replacement if overt, whereas subclinical forms may be followed without treatment. Two main types of AIT are recognized: type 1 AIT (AIT 1), a form of iodine-induced hyperthyroidism occurring in nodular goitres or latent Graves disease, and type 2 AIT (AIT 2), resulting from destructive thyroiditis in a normal thyroid gland. Mixed/indefinite forms exist due to both pathogenic mechanisms. AIT 1 is best treated with thionamides that may be combined for a few weeks with sodium perchlorate to make the thyroid gland more sensitive to thionamides. AIT 2 is treated with oral glucocorticoids. Once euthyroidism has been restored, AIT 2 patients are followed up without treatment, whereas AIT 1 patients should be treated with thyroidectomy or radioiodine. Mixed/indefinite forms of AIT are treated with thionamides. Oral glucocorticoids can be added from the beginning if a precise diagnosis is uncertain, or after a few weeks if response to thionamides alone is poor. The decision to continue or to stop amiodarone in AIT should be individualized in relation to cardiovascular risk stratification and taken jointly by specialist cardiologists and endocrinologists. In the presence of rapidly deteriorating cardiac conditions, emergency thyroidectomy may be required for all forms of AIT.

Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features.

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.

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.

[Amiodarone-induced thyrotoxicosis]. / Tireotossicosi indotta da amiodarone.

Amiodarone-induced thyroid dysfunction occurs in about 15-20% of patients under amiodarone therapy. Amiodarone-induced hypothyroidism (AIH) can develop in patients with an apparently normal thyroid gland or in those with an underlying chronic autoimmune thyroiditis. On a clinical ground, AIH is not challenging and can be easily treated with L-thyroxine therapy. Amiodarone-induced thyrotoxicosis (AIT) can occur in patients with (AIT 1) or without (AIT 2) an underlying thyroid disease. AIT 1 is a true iodine-induced hyperthyroidism occurring in patients with an underlying thyroid autonomy while AIT 2 is a drug-induced destructive thyroiditis. According to the different pathogenetic mechanism, AIT 2 is treated with glucocorticoids while AIT 1 usually responds to thionamides. Thyroidectomy should be considered when AIT represents an imminent risk for cardiac conditions, when patients require a prompt resolution of thyrotoxicosis or when they do not respond to the medical therapy. An effective collaboration between cardiologists and endocrinologists is crucial in each part of the management of AIT patients, including the evaluation of cardiological conditions with regard to thyroid hormone excess and whether, or not, it is necessary to continue amiodarone therapy.

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.