Primary hyperparathyroidism is defined as an elevated serum calcium with an elevated or inappropriately normal parathyroid hormone (PTH), and rarely it can be due to an ectopic mediastinal parathyroid [1].

The present guideline (GL) is aimed to improve and standardize the treatment of primary hypothyroidism in non-pregnant adults and to offer all the patients the best possible care across the Italian country. Non-pregnant adults with hypothyroidism. This GL does not cover the treatment of hypothyroidism in children and adolescents under 18 years of age, in women who are pregnant or breastfeeding, nor in subjects with central hypothyroidism. Also patients who require suppressive therapy with levothyroxine after thyroidectomy for thyroid cancer and those with transient iatrogenic hypothyroidism were not considered in this GL. The direct costs and the utilization of resources over time were evaluated for the implementation of the appropriate management within the National Health Service. Recommendations were based on the analysis, according to the GRADE methodology, of the evidence from literature. Patients preferences were collected and verified by means of specific bibliographic research and the active participation of two patients’ representatives in the GL development group. The present GL provides 4 formal graded recommendations and 16 ungraded indications for good clinical practice. An elevated agreement was consistently obtained among the panel members. The present GL provides operative recommendations—based on the best available evidence and cost-effectiveness analysis—for the treatment of adult patients with primary hypothyroidism. The expected benefits from the dissemination, application and implementation of this GL are the improvement of the quality of care, its homogenization across the national territory and the rationalization of health expenditure in the respect of patient preferences.

Although biochemical parameters have always been the basis for assessing acromegaly disease activity, other factors such as symptoms and comorbidities should also be considered. To assist clinicians in diagnosis and follow-up both the Acromegaly Disease Activity Tool (ACRODAT®) and SAGIT® (Signs and Symptoms, Associated morbidity, GH, IGF-1, Tumor) instrument were developed. This study aimed to evaluate the real-life utility of ACRODAT® and SAGIT® in assessing acromegaly disease activity across four centers of Veneto region in north-east Italy. 162 patients were enrolled in this multicenter study. Patients’ disease activity was classified by: clinician’s judgment categories (A: active disease; MA: mild activity; CO: controlled disease; CU: cured), ACRODAT® (green: well-controlled, yellow: partially controlled, red: active), and SAGIT® (lower scores indicate better control). The disease activity data derived from these methods were compared. The four centers showed similar results in terms of acromegaly disease-related data. ACRODAT® categorized 48

Introduction: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered.Methods: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations.Results: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the first-choice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide.Conclusion: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Scopo della presente linea guida (LG) è produrre raccomandazioni operative per il trattamento dei pazienti adulti (>18 anni) con adenoma ipofisario prolattino (PRL)-secernente, sulla base delle evidenze disponibili e nel rispetto delle preferenze del paziente, valutando l’ambito e il consumo di risorse per la contestualizzazione più appropriata nel Servizio Sanitario Nazionale (SSN). La finalità è migliorare e standardizzare il trattamento del prolattinoma, in base all’evidenza dei dati di letteratura analizzata secondo il metodo GRADE, offrendo ai pazienti la possibilità della migliore cura su tutto il territorio nazionale. Il presente documento prende in esame le opzioni di trattamento per l’adenoma ipofisario PRL-secernente nell’adulto. Non verranno qui considerati i casi che riguardano i minori di 18 anni, le donne in gravidanza o durante l’allattamento, le forme familiari e gli adenomi ipofisari a secrezione pluri-ormonale. Il beneficio atteso da questa LG è il miglioramento della qualità delle cure e l’omogeneizzazione delle stesse su tutto il territorio nazionale. La popolazione di pazienti adulti con prolattinoma è il target della presente LG, che mira a definire i tempi e le modalità terapeutiche più opportune per la loro gestione clinica. Le preferenze dei pazienti sono state indagate nella letteratura e verificate mediante la partecipazione al gruppo di elaborazione della LG di un paziente. La presente LG è destinata a medici e operatori sanitari coinvolti nella gestione clinica dei pazienti con prolattinoma, in particolare specialisti in endocrinologia del territorio e di centri di 2° livello, medici di medicina generale (MMG), neurochirurghi, ginecologi. La LG è, inoltre, un riferimento per le Associazioni dei Pazienti, per raggiungere una corretta informazione sullo stato dell’arte nella gestione del prolattinoma. Gli interventi terapeutici oggetto della LG si attuano a livello ambulatoriale e ospedaliero.

Background: Immunotherapy with immune checkpoint inhibitors is a new frontier for cancer treatment. On the safety profile, this drugs class is associated with a new spectrum of side effects, the so-called immune-related adverse events that can potentially affect any organs, mainly endocrine glands. Scant data are available to inform the appropriate strategy of their management and treatment. Case Presentation: A 74-years old man with a squamous non-small cell lung cancer on nivolumab was hospitalized for fatigue, nausea, vomiting and severe hyponatremia. Biochemical tests were significant for hypotonic hyponatremia with a high urine sodium concentration. Endocrine tests showed overt primary hypothyroidism and low serum cortisol and aldosterone levels associated with an elevated circulating level of adrenocorticotrophic hormone. Adrenal antibody screening and the search of adrenal lesion on CT abdomen were negative. Thus, a nivolumab-induced primary adrenal insufficiency was diagnosed. Nivolumab withdrawal and replacement treatment with glucocorticoid and mineralocorticoid allowed clinical and biochemical recovery. Conclusion: Physicians need to be aware of potential immune-related adverse events in all patients treated with an immune checkpoint inhibitor. Their timely recognition is essential to carry out the proper treatment.

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Coronaviruses are a big family of viruses that can infect mammalians and birds. In humans they mainly cause respiratory tract infections, with a large spectrum of severity, from mild, self-limited infections to highly lethal forms as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and Coronavirus Disease 2019 (COVID-19). Scanty data are reported for the involvement of endocrine glands in human coronaviruses, in particular SARS-CoV-2. In this review, we summarize endocrinological involvement in human coronaviruses, including data on animal coronaviruses. Avians, ferrets and bovine are affected by specific coronavirus syndromes, with variable involvement of endocrine glands. SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a target receptor, so ACE2 plays a central role in viral transmission and initial organ involvement. Autoptic studies on SARS patients revealed that thyroid, parathyroid, pituitary gland, endocrine pancreas and especially adrenals and testis could be impaired by different mechanisms (direct damage by SARS-CoV, inflammation, vascular derangement and autoimmune reactions) and few clinical studies have evidenced functional endocrine impairment. Only few data are available for COVID-19 and gonads and endocrine pancreas seem to be involved. International endocrinological societies have brought some recommendations for the COVID-19 pandemic, but further studies need to be performed, especially to detect long-term hormonal sequelae.

BACKGROUND:The effect of chronic use of renin-angiotensin-aldosterone system (RAAS) inhibitors on the severity of COVID-19 infection is still unclear in patients with hypertension. We aimed to investigate the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19-related outcomes in hypertensive patients.METHODS:A single-center study was conducted on 133 consecutive hypertensive subjects presenting to the emergency department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9 and 31 March 2020.RESULTS:All patients were grouped according to their chronic antihypertensive medications (ACEIs, N = 40; ARBs, N = 42; not on RAAS inhibitors, N = 51). There was no statistical difference between ACEIs and ARBs groups in terms of hospital admission rate, oxygen therapy, and need for noninvasive ventilation. Patients chronically treated with RAAS inhibitors showed a significantly lower rate of admission to semi-intensive/intensive care units, when compared with the non-RAAS population (odds ratio (OR) 0.25, confidence interval (CI) 95% 0.09-0.66, P = 0.006). Similarly, the risk of mortality was lower in the former group, although not reaching statistical significance (OR 0.56, CI 95% 0.17-1.83, P = 0.341).CONCLUSIONS:Our data suggest that chronic use of RAAS inhibitors does not negatively affect clinical course of COVID-19 in hypertensive patients. Further studies are needed to confirm this finding and determine whether RAAS inhibitors may have a protective effect on COVID-19-related morbidity and mortality.

Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas. The therapeutic management of acromegaly always requires a personalized strategy. Normal age-matched IGF-I values are the treatment goal. Transsphenoidal surgery by an expert neurosurgeon is the primary treatment modality for most patients, especially if there are neurological complications. In patients with poor clinical conditions or who refuse surgery, primary medical treatment should be offered, firstly with somatostatin analogs (SSAs). In patients who do not reach hormonal targets with first-generation depot SSAs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with SSA) should be offered. Irradiation could be proposed to patients with surgical remnants who would like to be free from long-term medical therapies or those with persistent disease activity or tumor growth despite surgery or medical therapy. Since the therapeutic tools available enable therapeutic targets to be achieved in most cases, the challenge is to focus more on the quality of life.

Acromegaly is a rare disease. Improvements in lifespan in these patients have recently been reported due to transsphenoidal surgery (TSS), advances in medical therapy, and strict criteria for defining disease remission. This document reports the opinions of a group of Italian experts who have gathered together their prolonged clinical experience in the diagnostic and therapeutic challenges of acromegaly patients. Both GH and IGF-I (only IGF-I in those treated with Pegvisomant) are needed in the diagnosis and follow-up. Comorbidities (cardio-cerebrovascular disease, sleep apnea, metabolic derangement, neoplasms, and bone/joint disease) should be specifically addressed. Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas.

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.

La polidipsia primaria (PP) è un condizione clinica rilevante per la frequenza con cui si manifesta nei pazienti psichiatrici e per le conseguenze gravi e potenzialmente fatali legate allo sviluppo di iponatriemia. Sebbene l’80% dei pazienti con PP siano schizofrenici, essa può presentarsi in un ampio spettro di malattie psichiatriche e anche nei decadimenti cognitivi. La PP ha una prevalenza del 20% nei pazienti istituzionalizzati ma è presente anche nel 15% dei pazienti ambulatoriali. Il quadro clinico può evolvere dalla semplice polidipsia con poliuria, allo sviluppo di iponatremia di varia severità fino al quadro della water intoxication. La PP si pone in diagnosi differenziale con le sindromi poliuriche-polidipsiche che, escluse le forme osmotiche o legate a disionie, comprendono le forme complete o parziali di diabete insipido centrale e nefrogenico. Il test indiretto, test all’assetamento seguito da somministrazione di desmopressina, e i test diretti, dosaggio AVP e copeptin, sono utili ma presentano limiti di accuratezza nella diagnosi differenziale della PP. Pertanto necessitano di essere integrati da dati anamnestici, di imaging ipotalamo-ipofisario e, talora, da terapia ex adjuvantibus con desmopressina. La terapia comportamentale risulta efficace ma è molto spesso difficile da attuare e deve essere supportata dal trattamento farmacologico antipsicotico, anche se gli studi clinici sono scarsi. In caso di presenza di iponatriemia si dovranno seguire le corrispettive linee guida tenendo presente il rischio di mielinolisi.

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Pituitary adenomas are neoplasms of the anterior pituitary lobe and account for 15-20% of all intracranial tumors. Although most pituitary tumors are benign they can cause severe symptoms related to tumor size as well as hypopituitarism and/or hypersecretion of one or more pituitary hormones. Most pituitary adenomas are sporadic, but it has been estimated that 5% of patients have a familial background. Germline mutations of the tumor suppressor gene aryl hydrocarbon receptor-interacting protein (AIP) predispose to hereditary pituitary neoplasia. Recently, it has been demonstrated that AIP mutations predispose to pituitary tumorigenesis through defective inhibitory GTP binding protein (G alpha(i)) signaling. This finding prompted us to examine whether germline loss-of-function mutations in inhibitory guanine nucleotide (GTP) binding protein alpha (GNAI) loci are involved in genetic predisposition of pituitary tumors. To our knowledge, this is the first time GNAI genes are sequenced in order to examine the occurrence of inactivating germline mutations. Thus far, only somatic gain-of-function hot-spot mutations have been studied in these loci. Here, we have analyzed the coding regions of GNAI1, GNAI2, and GNAI3 in a set of young sporadic somatotropinoma patients (n = 32; mean age of diagnosis 32 years) and familial index cases (n = 14), thus in patients with a disease phenotype similar to that observed in AIP mutation carriers. In addition, expression of Gai proteins was studied in human growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH)-secreting and non-functional pituitary tumors. No pathogenic germline mutations affecting the Gai proteins were detected. The result suggests that loss-of-function mutations of GNAI loci are rare or nonexistent in familial pituitary adenomas.

Amar Agha Faisal Ahmed Gianluca Aimaretti Fulya Akin Keya Ali Bruno Allolio Olaf Ansorge Baha Arafah Emanuela Arvat Simon Aylwin John Ayuk Stephanie Baldeweg A. Beckers Gary Bell Anat Ben-Shlomo Rita Berardelli John Bevan Antonio Bianchi Nienke Biermasz Jens Bollerslev V. Bonert Marco Boscaro Karin Bradley Marcello Bronstein Antonia Brooke Michael Buchfelder Fabio Buzi John Carmichael Paul Carroll David Carvalho Patrizio Caturegli Francesco Cavagnini William Chandler Vera chesnokova Sossio Cirillo Carmen Clapp Peter Clayton Annamaria Colao Bernard Corenblum W. T. Couldwell Mehul Dattani Annamaria De Bellis Laura de Marinis Ernesto de Menis Ettore degli Uberti Neil Dorward Will Drake Malek El Muayed P. Fainstein Day William Farrell Maria Fleseriu Pamela Freda L. Frohman Mônica Gadelha Carles Gaston-Massuet N. J. L. Gittoes Andrea Giustina Y. Greenman Ashley Grossman Silvia Grottoli Amir Hamrahian Ian Holdaway Juergen Honegger Wenyu Huang Adriana Ioachimescu Ivor Jackson Andy James John A Jane Jens Jorgensen Niki Karavitaki Laurence Katznelson David Keeling Fahrettin Kelestimur Laurence Kennedy Anne Klibanski George Kontogeorgos K. Kovacs Ed Laws Marco Losa Pietro Maffei Dominique Maiter Adam Mamelak Juan Pedro Martinez-barbera Gherardo Mazziotti Moises Mercado George Merriam Ozgur Mete Giuseppe Minniti Pietro Mortini Lisa Nachtigall Sebastian Neggers J. Newell-Price Leena Patel Alberto Pereira Stephan Petersenn Vera Popovic

Acromegalic patients have a higher risk of developing colorectal tumours (CRT). The common C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene is a well-documented CRT risk factor in the general population, but its role in acromegaly has never been examined.

Il 5% di tutti gli adenomi ipofisari ha una base eredo-familiare. Le forme più comuni sono la MEN1 e la FIPA, mentre più rare sono la Carney Complex e la MEN4. Nuovi geni, ad esempio AIP, sono risultati associati a queste forme genetiche. È necessario conoscere l’esistenza di forme familiari di adenomi ipofisari, il corretto iter diagnostico anche genetico, l’appropriato screening e follow-up dei familiari.