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Background: SARS-CoV-2 pandemic resulted in lifestyle change of world's population because of the measures adopted by governments to contain the virus spread., Design and Methods: This study examined whether lockdown impacted anthropometric indices, Mediterranean Diet (MD) adherence, Physical Activity Level (PAL), and Quality of Life (SF-12) in a cohort of 116 patients (96 F, aged 57.2 ± 13.1 years) affected by thyroid disorders. Before lockdown, data were collected during the endocrinological examination; after lockdown they were collected through a tele-phone interview (via video call)., Results: Data revealed an overweight condition in 59% of patients, with no significant differences between the two observations (BMI values: 26.5 ± 4.9 vs 26.6 ± 4.9 kg/m 2 ), whereas waist circumference values significantly increased over time (93.3 ± 12.6 vs 94.4 ± 12.5 cm; p  = 0.003). Moreover, a lower adherence to the MD (PREDIMED score: 7.3 ± 1.8 vs 7.0 ± 1.8; p  = 0.003) and a significant increase of sitting time (6.4 ± 3.2 h/die vs 9.0 ± 4.2; p  < 0.001) were observed. A not significant decrease in PAL, which revealed a sedentary condition in pre- and post-lockdown (648 and 562 METs/week respectively), was found. The SF-12 score did not show relevant changes between the two observations., Conclusion: Our study highlights that patients with thyroid diseases are often sedentary and exhibit a high prevalence of over-weight, underscoring the need for a systematic anthropometric evaluation and, at times, lifestyle interventions., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objective: This study aimed to assess the long-term outcome of patients with acromegaly., Design: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up., Methods: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population., Results: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population., Conclusions: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes., (© 2024. The Author(s).)

Pasireotide-LAR is recommended as a second-line treatment for patients with acromegaly. Although the effects of pasireotide-LAR have been well characterized in clinical studies, real-practice evidence is scant, especially in the long term and within the individualization of therapy in patients with comorbidities. To provide additional insight on the individualized approach to acromegaly management, six clinical cases of complex acromegaly treated with pasireotide-LAR for more than 5 years were reported. Pasireotide-LAR allowed the normalization of insulin-like growth factor 1 (IGF1) values in all patients and reduced tumour residue volume where present. A good safety profile and long-term tolerability were also reported., Competing Interests: Disclosure and potential conflicts of interest: AM: competing interests with Bayer, EISAI, Eli Lilly, Recordati Rase Diseases. All Authors served as Advisors for Recordati Rase Diseases. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2024/04/dic.2024-1-2-COI.pdf, (Copyright © 2024 Chiloiro S, Appetecchia M, Bianchi A, Costa D, De Acetis C, Gargiulo P, Giampietro A, Isidori AM, Jaffrain-Rea M-L, Passeri M, Pigliaru F, Poggi M, De Marinis L.)

Introduction: Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys., Methods: There were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure., Results: There were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters., Discussion: We present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases., Competing Interests: LC was the recipient of a fellowship by Alexion, AstraZeneca Rare Disease. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cinque, Pugliese, Salcuni, Trombetta, Battista, Biagini, Augello, Nardella, Conti, Corbetta, Fischetto, Foiadelli, Gaudio, Giannini, Grosso, Guabello, Massuras, Palermo, Politano, Pigliaru, Ruggeri, Scarano, Vicchio, Cannavò, Celli, Petrizzelli, Mastroianno, Castori, Scillitani and Guarnieri.)

Purpose: The main purpose of this study was to investigate the effects of 12 months of rhPTH (1-84) (Natpar ® ) treatment in a cohort of patients selected according to the indications of hypoparathyroidism guidelines. The use of recombinant human PTH (1-84) [rhPTH (1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy., Methods: It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations., Results: Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1-84) for 12 months. At 12 months of rhPTH (1-84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p = 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p = 0.014). No severe adverse events were described., Conclusions: Biochemical and clinical results confirm the efficacy and safety of rhPTH (1-84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy., (© 2022. The Author(s).)

Background: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD)., Methods: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined., Results: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases., Conclusions: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions., (© 2021. The Author(s).)

Summary: A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted., Learning Points: A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.

Background: Adrenal cortex autoantibodies (ACAs) and/or 21-hydroxylase (21OHAb) are markers of autoimmune Addison's disease (AAD) and progression to overt AAD. The reported cumulative risk of developing AAD varies from 0 to 90% in different studies., Aim: To assess the predictive value of different parameters in the progression toward AAD in patients with ACA and/or 21OHAb-positive patients with autoimmune polyendocrine syndromes (APS)., Materials and Methods: Twenty-nine patients with APS-1 and 114 patients with APS-2 or APS-4 were followed up for a median of 10 years (range 6 months to 33 years) and were assessed using ACTH test. The risk of AAD was estimated according to age, gender, stage of adrenal dysfunction, associated diseases and antibody titer. Univariate and multivariate Cox proportional hazard models were used for statistical analysis., Results: The cumulative risk (CR) of developing AAD was higher in APS-1 patients (94.2%) than in patients with APS-2/APS-4 (38.7%). The CR was high in both male and female APS-1 patients, while in patients with APS-2/APS-4 it was high only in males. Stage 1 (increased plasma renin) for patients with APS-1 and Stage 2 (no response of cortisol to ACTH test) for patients with APS-2/APS-4 were established as the points of no return in the progression to AAD. Adjusted hazard ratio analyses by multivariate Cox model for AAD showed that gender, diseases and adrenal function were independent risk factors for developing clinical AAD. The risk of developing clinical AAD appears to subside after 19 years of follow-up., Conclusions: A model for estimating the probability to survive free of AAD has been developed and should be a useful tool in designing appropriate follow-up intervals and future therapeutic strategies.

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.

It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18-1.68, P  < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07-2.58, P  = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55-5.34, P  < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32-6.87, P  < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk., (© 2017 Society for Endocrinology.)

Background: Patients with a thyrotropin-secreting pituitary adenoma (TSHoma) are exposed to unregulated and inappropriately high levels of thyrotropin (TSH). Given the rarity of this condition, it is not known whether this chronic TSH stimulation of the thyroid gland might represent a risk factor for the development of differentiated thyroid cancer (DTC). We analyzed the incidence of DTC in a large cohort of patients with TSHomas., Methods: The study population consisted of all consecutive patients who underwent neurosurgery for a TSHoma between 1990 and 2013. Criteria for the diagnosis of TSHoma in patients without previous thyroid ablative procedures included elevated free thyroid hormones and normal/high serum TSH concentrations, presence of a lesion at magnetic resonance imaging (MRI), and abnormal response of TSH to at least one dynamic test. Patients who had received thyroid ablative procedures were required to have a pituitary lesion on MRI and TSH levels not suppressed while on levothyroxine therapy at doses causing elevation of free thyroid hormone levels., Results: Sixty-two patients (32 females, 30 males) underwent surgery for a TSHoma at our center. Among them, 3 patients had a coexistent diagnosis of DTC with an estimated incidence of 4.8%. In 2 patients, DTC was diagnosed during the evaluation for suspected TSH-dependent hyperthyroidism, whereas in the third patient, diagnosis of DTC preceded the detection of the pituitary tumor., Conclusions: The elevated incidence of DTC in patients with TSHoma suggests a possible role of TSH hypersecretion in the development of thyroid tumors. A formal high-resolution ultrasound of the thyroid is recommended in patients diagnosed with a TSHoma, especially if a long history of the pituitary tumor is suspected. Moreover, suspicion about the presence of TSHoma should be raised by the lack of suppression of TSH levels despite adequate doses of levothyroxine after thyroidectomy for DTC.

Background: Casual detection of an adrenal mass, the so called incidentaloma (AI) requires an in-depth analysis of imaging phenotype together with hormonal investigation, in order to evaluate both its potential malignancy and the occurrence of a preclinical condition of hypercortisolism (Subclinical Cushing Syndrome, SCS). Aim of the present work is to evaluate surgical indications and results of surgery in patients harbouring an AI with inapparent hypercortisolism., Methods: The study has been carried on in a series of 26 Laparoscopic Adrenalectomies (LA) performed from January 2009 and January 2015. Indications to surgery included AI (11 cases), Cushing's syndrome (7 cases), suspected metastases (5 cases) and Conn's disease (3 cases). Six patients with AI had a SCS associated with variable forms of a metabolic syndrome: they were evaluated in detail analysing cortisol secretion and values of Arterial Hypertension, Diabetes Mellitus and BMI before and after surgery., Results: As far as SCS is concerned, LA was completed in 5 patients (one case converted). Pathology revealed 5 adenomas and one nodular hyperplasia. Four cases required oral cortisone administration at the discharge. At a mean follow- up of 33 months cortisol secretion returned to normal range in all patients; an improvement of metabolic condition was observed in 60, 25, and 50 per cent of hypertensive, diabetic and obese patients respectively., Conclusion: Indications to LA in case of AI and SCS is strongly supported by the presence of an associated metabolic syndrome. In spite of a limited number, our experience confirms the favourable results of surgery in such patients., Key Words: Adrenal incidentaloma, Laparoscopic adrenalectomies, Subclinical Cushing syndrome.

Background: Anti-pituitary antibodies (APA) were described in patients with Type 1 Diabetes (T1D) but their prevalence and relevance remain controversial., Materials and Methods: We evaluated the APA prevalence in Sardinian sera from 100 T1D patients, 70 Type 2 Diabetes (T2D) patients and 62 healthy controls, using indirect immunofluorescence on bovine pituitary sections. To compare two different substrates, we tested using bovine sections, further T1D patient sera (n = 11, from Pisa) previously analysed for APA on monkey sections, while some T1D Sardinian patient sera (n = 22) were tested on monkey sections. According to preliminary experiments, positivity were considered ≥1:200 and ≥1:20 for bovine and monkey substrates, respectively., Results and Discussion: Using bovine sections, APA were detected in 7/100 Sardinian T1D patients (at 1:200 titer) and in none of the other Sardinian sera tested. When the T1D sera from Pisa were tested on bovine and the T1D Sardinian sera were tested on monkey, none of these sera showed corresponding positivity for APA. Pituitary hormone dysfunctions were not found in the 7 APA-positive Sardinian T1D patients. The present study shows that the presence of APA at low-titer is highly related to T1D but not associated with any pituitary dysfunction while the animal species used as substrate appears crucial., Conclusion: Further studies are needed to ascertain whether APA detected by different animal species may have different pathological relevance in T1D and/or whether APA in the long run may predict future anterior pituitary dysfunction.

Context: Hepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome., Objective: To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment., Design and Setting: Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy., Patients: A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled., Interventions: Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping., Results: No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25; P=0.04) and the number of concomitant medications, other than SSTa (B=3.9; P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found., Conclusions: UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

Objective: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients., Design: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months., Results: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 μg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality., Conclusions: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

Context: The influence of full-length GH receptor (GHR) and exon 3-deleted GHR (d3GHR) on responsiveness to pegvisomant (PEG-V) in acromegalic patients is uncertain., Objective: The aim of the study was to assess the distribution of GHR genotypes in a large series of patients on PEG-V therapy and their influence on treatment efficacy and adverse effects., Design and Setting: A cross-sectional multicenter pharmacogenetic study was conducted in 16 Italian endocrinology centers of major universities and tertiary care hospitals., Patients: The study included 127 acromegalic patients enrolled from 2009 to 2010 not cured by previous surgery, radiotherapy, and long-acting somatostatin (SST) analogs, treated with PEG-V., Intervention and Main Outcome Measure: Sixty-three of 127 patients received combined PEG-V + SST analog therapy. Clinical and hormonal data at diagnosis and before and during PEG-V therapy were inserted in a database. GHR exon 3 deletion and other polymorphisms were genotyped by the coordinator center. Differences in PEG-V dosage required for IGF-I normalization and occurrence of adverse effects between carriers and noncarriers of GHR variants were evaluated., Results: d3GHR variants were not in Hardy-Weinberg equilibrium (P = 0.008). No association of these variants with PEG-V dose required for IGF-I normalization, adverse effects occurrence, and tumor regrowth was found in patients on PEG-V and on PEG-V + SST analog treatment. Similar data were obtained considering the GHR variant rs6180., Conclusions: This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments.

Background: Diabetes mellitus is frequently observed in patients with acromegaly. Current therapies for acromegaly may impact glucose regulation, influencing insulin sensitivity and secretion. The question whether these therapies modify control and progression of diabetes once present is still open., Aim: Aim of our study is to analyze glucose control in acromegalic patients with diabetes, evaluating the relation with treatments for GH excess and for diabetes., Methods: Seventy patients with acromegaly and diabetes were studied. Duration and treatments of acromegaly and diabetes were recorded, together with clinical and metabolic parameters., Results: Most patients (92.8%) were treated with somatostatin analogs (SSA), either alone or in combination with dopamine-agonists (20%) or pegvisomant (15.7%); 7.1% of patients had been treated by surgery alone. Metformin (65.7%), alone or in combination with other hypoglycemic drugs, was the most frequent treatment for diabetes, followed by insulin (21.5%). Only 15.7% were treated with diet alone. The whole cohort showed a very good control of diabetes and acromegaly. Median glycated hemoglobin was 6.4% (5.9-7). IGF-I was within normal range for age in most patients. No relation was observed between duration of acromegaly or diabetes and metabolic control. SSA had a negative effect on insulin secretion, but these effects did not influence glucose control. Finally, we observed a low prevalence of nephropathy (6%) and retinopathy (20%)., Conclusions: Our study shows that a good control of hyperglycemia can be obtained with success in the majority of acromegalic patients with diabetes, independently of the type of treatment for GH excess.

Autoimmunity is not believed to be involved in tissue damage of Β-Thalassemia (Β-Thal), although nonspecific triggering of autoimmunity by iron overload has been suggested. We recently re-evaluated thyroid function and autoimmunity in 132 Β-Thal patients born and living in Sardinia Island, where a high prevalence of both Β-Thal and autoimmune disease is well documented and in 1002 age and sex-matched euthyroid individuals from the general population. The prevalence of primary hypothyroidism in Β-Thal patients was 28.7% (38/132), without significant difference between males (M) and females (F). Hypothyroidism was associated with smaller and hypoechoic glands, while no difference in the prevalence of anti-thyroid antibodies (ATA) was found between Β-Thal patients with or without thyroid failure. Interestingly, the prevalence of ATA in Β-Thal women (9.2%) was significantly lower than that found in age-matched euthyroid women (20.0%). Our study confirms that thyroid autoimmunity has no role in the pathogenesis of hypothyroidism in b-Thal. Moreover, the lower ATA prevalence in Β-Thal women suggests that iron overload may inhibit rather then trigger thyroid autoimmunity.

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.

Objective: To investigate the clinical relevance of l-thyroxine (l-T(4)) substitution therapy in borderline hypothyroidism., Design: To assess whether and to what extent administration of l-T(4) is able to modify systolic and diastolic function in patients with subclinical hypothyroidism and in subjects with autoimmune thyroiditis and normal serum TSH., Methods: We studied 26 patients with classical Hashimoto's thyroiditis [18 with increased serum TSH (>3 mU/ml - Group A), and 8 with normal serum TSH (<3 mU/ml) - Group B]; a third group (C) included 13 healthy controls. All subjects underwent Pulsed Wave Tissue Doppler Imaging (PWTDI) to accurately quantify the global and regional left ventricular function., Results: In both groups A and B we confirmed a significant impairment of systolic ejection (p<0.001 and p<0.05, respectively), a delay in diastolic relaxation (p<0.001 and p<0.05, respectively) and a decrease in the compliance to the ventricular filling (p<0.05). Administration of 50 microg/day of l-T(4) produced a progressive reduction of serum TSH (within the normal range) and normalization of all PWTDI parameters, which began after 6 months and finished after 12 months., Conclusion: Our data confirm previous evidence that subclinical hypothyroidism is associated with a cardiac dysfunction, even when this is very mild (i.e. with serum TSH still comprised in the normal range), and show that these abnormalities are reversible with l-T(4) replacement therapy.

The aim of the present multicentric, open-label, non-comparative study was to evaluate the role of octreotide long-acting repeatable (LAR) as primary therapy for the treatment of GH-secreting pituitary macroadenomas. The patients received octreotide LAR 20 mg every 4 weeks for 12 weeks; afterwards the dose was confirmed or adjusted at 30 mg every 4 weeks, for the remaining 12 weeks, for responder or non-responder patients, respectively. Responder patients continued the study until 48 weeks. Twenty-one naive active acromegalic patients were enrolled. In all patients, GH profile, IGF-I levels and magnetic resonance imaging (MRI) were evaluated at baseline and during treatment. The ability of octreotide LAR to decrease mean GH < 2.5 microg/I and/or normalize IGF-I levels, adjusted for age and gender, was defined respectively as total or partial success. Total success was achieved in 5/21 (23.8%), 6/20 (30%) and 4/14 (28.6%) patients after 12, 24 and 48 weeks; partial success in 7/21 (33.3%), 9/20 (45%) and 9/14 (64%) patients at 12, 24 and 48 weeks according to GH levels, while according to IGF-I levels in 7/21 (33.3%), 7/20 (35%) and 5/14 (35.7%) patients at 12, 24 and 48 week. Tumor size was notably decreased after treatment with octreotide LAR: in 16 macroadenoma patients completing the study, the tumor sizes were 1609 +/- 1288, 818 +/- 616 (49.1 +/- 23.7%) and 688 +/- 567 mm3 (54.6 +/- 24.4%) at baseline, 24 and 48 weeks. This study shows that octreotide LAR is effective in suppressing GH/IGF-I secretion and inducing tumor shrinkage in GH-secreting macroadenomas in a 48-week treatment. Octreotide LAR could be used as primary therapy in patients harbouring large pituitary tumors, who are less likely to be cured by neurosurgery.

Objective: In subclinical hypothyroidism (SH), impaired diastolic function has been documented at rest and on effort, while systolic dysfunction has only been assessed on effort., Design: The aim of the present study was: (a) to further assess systolic function at rest in SH; and (b) to ascertain whether cardiac dysfunction could precede TSH increase in euthyroid patients with a high risk of developing SH., Methods: We studied 32 patients with classical Hashimoto's thyroiditis (22 with increased serum TSH (> 3 mU/ml - group A), and 10 with normal serum TSH (< 3 mU/ml - group B)); a third group (C), which included 13 healthy controls. All subjects underwent pulsed wave tissue Doppler imaging (PWTDI) to accurately quantify the global and regional left ventricular function., Results: When compared with group C, PWTDI indices showed that in both groups A and B there was a significant impairment of systolic ejection (P < 0.001 and P < 0.05, respectively), a delay in diastolic relaxation (P < 0.001 and P < 0.05, respectively) and a decrease in the compliance to the ventricular filling (P < 0.05). Several significant correlations were found between PWTDI parameters and serum-free T(3) and T(4) and TSH concentrations., Conclusion: PWTDI is a sensitive technique that allows detection of both diastolic and systolic abnormalities, not only in patients with SH, but also in euthyroid subjects with a high risk of developing thyroid failure. Futhermore, the significant correlations of several PWTDI indices with serum FT(3) and TSH concentrations strongly support the concept of a continuum spectrum of a slight thyroid failure in autoimmune thyroiditis extending to subjects with serum TSH still within the normal range.

Objective: To verify whether the accuracy of data on myocardial function provided by pulsed-wave tissue Doppler imaging (PWTDI), a new echocardiographic application that allows quantitative measurements of myocardial wall velocities, could help towards a better understanding of the natural history of acromegalic cardiomyopathy., Design: Eighteen patients with active acromegaly (ten men and eight women; mean age 48.0+/-15.0 years) with no other detectable cause of heart disease underwent PWTDI. Thirteen healthy individuals matched for age and body mass index acted as a control group., Methods: Ejection fraction (EF), transmitral early/late diastolic velocity (E/A) ratio and isovolumic relaxation time (IVRT) were measured by conventional echocardiography; systolic peak (Sv) and early (Ev) and late (Av) diastolic peak velocities, Ev/Av ratio and regional IVRT (IVRTs) were obtained by PWTDI., Results: All patients showed appreciably abnormal left ventricular global diastolic function represented by prolongation of the IVRT (P<0.001). Using PWTDI we found a prolongation of IVRTs and inversion of the Ev/Av ratio. In addition, the Ev/Av ratio proved to be significantly negatively correlated with IVRT; this correlation was not present in the case of the E/A ratio. Furthermore, a decrease in Sv was detected in the basal segment of the lateral wall (P<0.01), which had the greatest degree of diastolic dysfunction., Conclusions: PWTDI confirmed the acknowledged diastolic dysfunction that accompanies acromegalic cardiomyopathy and highlighted the greater sensitivity of regional PWTDI with respect to global Doppler diastolic indexes. Furthermore, by revealing an impairment of regional systolic function in presence of a normal EF, the findings with PWTDI contradicted the largely accepted theory that systolic function remains normal for several years in patients affected by acromegalic cardiomyopathy.

As recently claimed, TSH-suppressive therapy with L-T4 may have adverse effects on the heart, but these results have not been consistently confirmed. We assessed cardiac function by clinical, echocardiographic, and ergometabolic criteria in 19 patients (16 women and 3 men) receiving long term L-T4 at a fixed daily dose ranging from 1.8-4.0 microg/kg. The results showed significant alterations in several cardiac parameters suggestive of subclinical hyperthyroidism. In particular, intraventricular septum thickness (10.0+/-1.4 vs. 8.1+/-1.1 mm), left ventricular posterior wall thickness (9.4 1.5 vs. 8.1+/-1.1 mm), end-diastolic dimension (47+/-4 vs. 44+/-3 mm), and left ventricular mass index (102+/-15 vs. 75+/-15 g/m2) were significantly increased compared to values in age- and sex-matched euthyroid controls. Exercise tolerance (expressed as maximal tolerated workload; 102+/-14 vs. 117+/-12 watts), maximal VO2 achieved at peak exercise (maximum VO2, 17.3+/-3.3 vs. 21.9+/-2.5 mL/min x kg), and anaerobic threshold (expressed as a percentage of VO2max, 46.5+/-8.4 vs. 56.2+/-6.6) were significantly reduced in L-T4-treated patients. The L-T4 dose was then reduced to the minimal amount able to keep the serum TSH concentration at 0.1 mU/L or less in 7 patients who were reevaluated 6 months after the initial study. This individual tailoring of the TSH-suppressive L-T4 dose was in all cases associated with normalization of all echocardiographic and ergometabolic parameters. In conclusion, our findings show that abnormalities of heart morphology associated with impaired exercise performance occur as a consequence of long term therapy with fixed TSH-suppressive doses of L-T4, but that these abnormalities improve or disappear after careful tailoring of TSH-suppressive therapy.