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Paolo Beck-Peccoz and Luca Persani

Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 1994;131:331–40. ISSN 0804–4643

Thyroid-stimulating hormone (TSH), like the other pituitary glycoprotein hormones, is produced and secreted as a mixture of isoforms, the majority of which represent differences in oligosaccharide structure and possess different bioactivity. When samples are quantified simultaneously by immunometric assay and bioassay, the ratio between bioactivity (B) and immunoreactivity (I) may serve as an index of the overall potency of TSH. Variations of the TSH B/I ratio have been documented in both physiological and pathological conditions associated with alteration of the two most important mechanisms controlling TSH synthesis and secretion, i.e. TRH release and the thyroid hormone feedback system. Major examples of this assumption are the low TSH bioactivity found in samples from patients lacking TRH and thus bearing a hypothalamic hypothyroidism, and the enhanced bioactivity that is invariably found in TSH from patients with thyroid hormone resistance. Moreover, variations of TSH bioactivity have been recorded in normal subjects during the nocturnal TSH surge, in normal fetuses during the last trimester of pregnancy, in patients with primary hypothyroidism and in patients with TSH-secreting pituitary adenoma and non-thyroidal illness. In conclusion, the secretion of TSH molecules with altered bioactivity plays an important pathogenetic role in various thyroid disorders, while in some particular physiological conditions the bioactivity of TSH may vary in order to adjust thyroid hormone secretion to temporary needs.

Paolo Beck-Peccoz, Istituto di Scienze Endocrine, Ospedale Maggiore IRCCS, Via F. Sforza 35, 1-20122 Milano, Italy

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Luca Persani, Tiziana de Filippis, Carla Colombo and Davide Gentilini

The technological advancements in genetics produced a profound impact on the research and diagnostics of non-communicable diseases. The availability of next-generation sequencing (NGS) allowed the identification of novel candidate genes but also an in-depth modification of the understanding of the architecture of several endocrine diseases. Several different NGS approaches are available allowing the sequencing of several regions of interest or the whole exome or genome (WGS, WES or targeted NGS), with highly variable costs, potentials and limitations that should be clearly known before designing the experiment. Here, we illustrate the NGS scenario, describe the advantages and limitations of the different protocols and review some of the NGS results obtained in different endocrine conditions. We finally give insights on the terminology and requirements for the implementation of NGS in research and diagnostic labs.

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Marcello Filopanti, Uberta Verga, Federica Ermetici, Luca Olgiati, Cristina Eller-Vainicher, Sabrina Corbetta, Luca Persani, Paolo Beck-Peccoz and Anna Spada


Primary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine neoplasia (MEN1) due to the high postsurgery recurrence rate. The aim was to evaluate the efficacy of cinacalcet in MEN1 patients in comparison with patients with sporadic PHPT (sPHPT) and the effect of Arg990Gly calcium-sensing receptor (CASR) polymorphism on the response to treatment.


This is a randomized, crossover, double-blind study carried out in the University Hospitals.


Fifteen MEN1 patients with PHPT were randomized to two groups, one administered with 30 mg daily cinacalcet, titrated until calcium normalization, and one with placebo. After 3 months, patients were reassessed and after washout switched to the other treatment. For comparison, 20 sPHPT patients with similar calcium levels were administered with cinacalcet for 3 months. Ionized and total calcium, phosphate, and parathyroid hormone (PTH) were evaluated. CASR Arg990Gly was genotyped on blood DNA by direct sequencing.


Cinacalcet normalized calcium, increased phosphate, and reduced PTH levels in all patients. Cinacalcet dosage required to normalize calcium in MEN1 and sPHPT was not significantly different (45±21 vs 54±25 mg/day). Few mild adverse events, not requiring drug withdrawal, were observed in both the groups. No association between Arg990Gly CASR polymorphism and response to cinacalcet was found.


This short-term prospective study demonstrated that the efficacy profile of cinacalcet in patients with MEN1-related PHPT and in those with sPHPT was similar and was not influenced by the 990 CASR variant. Although long-term safety and efficacy data are required, cinacalcet might be considered a treatment option in MEN1 patients who have contraindications to surgery or persistent PHPT after surgery.

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Giovanna Mantovani, Ernesto De Menis, Giorgio Borretta, Giorgio Radetti, Sara Bondioni, Anna Spada, Luca Persani and Paolo Beck-Peccoz

Objective: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC.

Design: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment.

Methods: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients’ peripheral blood leukocytes and the coding region, splice sites, and promoter (−240 bp) region of DAX1 were directly sequenced.

Results: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelvemonth treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis.

Conclusions: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.

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Irene Campi, Giovanni B Perego, Antonella Ravogli, Antonella Groppelli, Gianfranco Parati, Luca Persani and Laura Fugazzola


Amiodarone-induced thyrotoxicosis (AIT) affects up to 3% of treated patients. Type 2 AIT (AIT2) is a destructive thyroiditis and is usually treated with medium-high oral doses of prednisone. As AIT may worsen the underlying heart disease, a rapid control of thyroid function is desirable. We aimed to determine whether a combined intravenous methylprednisolone (IVMP) pulses therapy associated to prednisone in the interpulse period can represent an efficient and safe alternative to urgent total thyroidectomy in patients with AIT2 not responsive to prednisone alone.

Design and methods

Patients presenting with a severe AIT2 studied in a tertiary referral Center from August 2018 to April 2019. We included four patients requiring a rapid improvement of thyroid function for their underlying cardiac disorders. The baseline doses of oral prednisone (range: 5–12.5 mg/day) and IVMP (range: 250–500 twice a week) were determined according to the severity of the thyrotoxicosis and were titrated based on clinical response.


Combined treatment was effective in all patients in the prompt restoration of euthyroidism and no major adverse events were reported during the follow-up. In all cases, FT4 and FT3 levels normalized at 3–5 weeks of treatment. A permanent hypothyroidism was observed in one patient, 3 months after the discontinuation of treatment.


We report for the first time that the combined intravenous and oral steroid therapy is effective in patients with AIT2. The treatment is well tolerated and leads to a rapid improvement of thyroid function, avoiding urgent total thyroidectomy and favoring a quick functional recovery and rehabilitation of cardiac patients.

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Germano Gaudenzi, Alessandra Dicitore, Silvia Carra, Davide Saronni, Carlotta Pozza, Elisa Giannetta, Luca Persani and Giovanni Vitale

Neuroendocrine neoplasms (NENs) are traditionally considered as a single group of rare malignancies that originate from the highly spread neuroendocrine system. The clinical management is complex due to the high heterogeneity of these neoplasms in terms of clinical aggressiveness and response to the therapy. Indeed, a multidisciplinary approach is required to reach a personalization of the therapy, including cancer rehabilitation. In this review, we discuss the possibility to adopt a precision medicine (PM) approach in the management of NENs. To this purpose, we summarize current knowledge and future perspectives about biomarkers and preclinical in vitro and in vivo platforms, potentially useful to inform clinicians about the prognosis and for tailoring therapy in patients with NENs. This approach may represent a breakthrough in the therapy and tertiary prevention of these tumors.

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Daniela Preziati, Luigi La Rosa, Giovanni Covini, Rosaria Marcelli, Stefania Rescalli, Luca Persani, Ersilio Del Ninno, Pier Luigi Meroni, Massimo Colombo and Paolo Beck-Peccoz

Preziati D, La Rosa L, Covini G, Marcelli R, Rescalli S, Persani L, Del Ninno E, Meroni PL, Colombo M, Beck-Peccoz P. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a. Eur J Endocrinol 1995;132:587–93. ISSN 0804–4643

The occurrence of thyroid abnormalities and the appearance of organ- and non-organ-specific autoantibodies during long-term recombinant interferon alpha-2a (IFN-α) therapy were studied in 86 and 51 consecutive outpatients with hepatitis C and B virus-related chronic active hepatitis (CAH-HCV and CAH-HBV), respectively. Most patients had longstanding community-acquired hepatitis. At baseline, 9.3% of CAH-HCV and 3.9% of CAH-HBV patients showed clinical and/or biochemical signs of thyroid dysfunction. The remaining patients were euthyroid, although anti-thyroid autoantibodies were found in 33/78 (42.3%) of CAH-HCV and in 5/49 (10.2%) of CAH-HBV patients. During IFN-α treatment, increased anti-thyroid autoantibody levels were seen in 40% of CAH-HCV initially negative patients, while they became detectable in no more than 10% of CAH-HBV patients. Interferon-α-induced hypo- or hyperthyroidism was recorded in 12 of 35 CAH-HCV patients treated for 12 months (34.3%). Only one CAH-HBV patient developed hyperthyroidism. High titers of anti-nuclear auto-antibodies (ANA) were recorded at enrolment in 5/36 (13.8%) of CAH-HCV and in 3/16 (18.7%) of CAH-HBV patients. Only one CAH-HCV patient displayed anti-parietal cell antibodies (PCA). After IFN-α treatment, ANA were found in 10/28 (35.7%) and PCA in 2/28 (7.1%) of CAH-HCV patients, while an additional CAH-HBV patient developed PCA, but not ANA. However, no signs of systemic autoimmune disease were recorded. In conclusion, more than half of the patients with chronic active hepatitis C, but only one-tenth of those with hepatitis B, displayed thyroid- and/or non-organ-specific autoantibodies prior to or during treatment with IFN-α. As most of the antibody-positive patients developed permanent thyroid disorders during IFN-α therapy, the risk of development of organ-specific autoimmunity should be assessed carefully and incorporated in the cost/effectiveness analysis in patients with longstanding hepatitis who are candidates for IFN-α treatment.

Paolo Beck-Peccoz, Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Padiglione Granelli, Via F. Sforza 35, 20122-Milano, Italy

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Marina Muzza, Daniela Cordella, Johny Bombled, Brigitte Bressac-de Paillerets, Fabiana Guizzardi, Zelia Francis, Paolo Beck-Peccoz, Martin Schlumberger, Luca Persani and Laura Fugazzola


Most germline-activating mutations of the RET proto-oncogene associated with inherited medullary thyroid cancer (MTC) are localized in exons 10, 11 and 13–15. Four novel RET variants, located in the extracellular domain (p.A510V, p.E511K and p.C531R) coded by exon 8 and in the intracellular juxtamembrane region (p.K666N) coded by exon 11, were identified on the leukocyte DNA from apparently sporadic cases.


Plasmids carrying Ret9-wild-type (Ret9-WT), Ret9-C634R and all Ret9 variants were transfected, and the phosphorylation levels of RET and ERK were evaluated by western blot analyses. The transforming potentials were assessed by the focus formation assay.


The p.A510V, p.E511K and p.C531R variants were found to generate RET and ERK phosphorylation levels and to have a transforming activity higher than that of Ret9-WT variant, but lower than that of Ret9-C634R variant. Differently, the p.K666N variant, located immediately downstream of the transmembrane domain, and involving a conserved residue, displayed high kinase and transforming activities. Computational analysis predicted non-conservative alterations in the mutant proteins consistent with putative modifications of the receptor conformation.


The molecular analyses revealed an oncogenic potential for all the novel germline RET variants. Therefore, the prevalence of exon 8 genomic variations with an oncogenic potential may be higher than previously thought, and the analysis of this exon should be considered after the exclusion of mutations in the classical hotspots. In addition, on the basis of these functional data, it is advisable to extend the genetic screening to all the first-degree relatives of the MTC patients, and to perform a strict follow-up of familial carriers.

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Silvia Dossena, Antonella Maccagni, Valeria Vezzoli, Claudia Bazzini, Maria Lisa Garavaglia, Giuliano Meyer, Johannes Fürst, Markus Ritter, Laura Fugazzola, Luca Persani, Patrick Zorowka, Carlo Storelli, Paolo Beck-Peccoz, Guido Bottà and Markus Paulmichl

Objective: The SLC26A4 protein (pendrin) seems to be involved in the exchange of chloride with other anions, therefore being responsible for iodide organification in the thyroid gland and the conditioning of the endolymphatic fluid in the inner ear. Malfunction of SLC26A4 leads to Pendred syndrome, characterized by mild thyroid dysfunction often associated with goiter and/or prelingual deafness. The precise function of the SLC26A4 protein, however, is still elusive. An open question is still whether the SLC26A4-induced ion exchange mechanism is electrogenic or electroneutral. Recently, it has been shown that human pendrin expressed in monkey cells leads to chloride currents.

Methods: We overexpressed the human SLC26A4 isoform in HEK293 Phoenix cells and measured cationic and anionic currents by the patch-clamp technique in whole cell configuration.

Results: Here we show that human pendrin expressed in human cells does not lead to the activation of chloride currents, but, in contrast, leads to an increase of cationic currents.

Conclusion: Our experiments suggest that the SLC26A4-induced chloride transport is electroneutral when expressed in human cellular systems.

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Cristina Romei, Stefano Mariotti, Laura Fugazzola, Augusto Taccaliti, Furio Pacini, Giuseppe Opocher, Caterina Mian, Maurizio Castellano, Ettore degli Uberti, Isabella Ceccherini, Nadia Cremonini, Ettore Seregni, Fabio Orlandi, Piero Ferolla, Efisio Puxeddu, Francesco Giorgino, Annamaria Colao, Paola Loli, Fabio Bondi, Barbara Cosci, Valeria Bottici, Antonello Cappai, Giovanni Pinna, Luca Persani, Verga Uberta, Marco Boscaro, Maria Grazia Castagna, Carlo Cappelli, Maria Chiara Zatelli, Antongiulio Faggiano, Giuseppe Francia, Maria Luisa Brandi, Alberto Falchetti, Aldo Pinchera, Rossella Elisei and The ItaMEN network


Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population.


We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres.

Results and conclusions

The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001).

Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.