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Giavoli C.,Endocrinology and Diabetology Unit | Giavoli C.,University of Milan | Profka E.,Endocrinology and Diabetology Unit | Profka E.,University of Milan | And 4 more authors.
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2017

The relationships between GH system and hypothalamic-pituitary-thyroid axis are complex and not yet fully understood. The reported effects of GH administration on thyroid status of GHD patients have been remarkably divergent.This review will focus on the main studies aimed to clarify the effects of GH on thyroid function, firstly going through the diagnosis of central hypothyroidism and its possible pitfalls, then elucidating the possible contexts in which GHD may develop and examining the proposed mechanisms at the basis of interactions between the GH-IGF-I system and the hypothalamic-pituitary-thyroid axis. © 2017 Elsevier Ltd.


Filopanti M.,Fondazione Instituto Of Ricerca E Cura A Carattere Scientifico Irccs Cagranda | Corbetta S.,University of Milan | Corbetta S.,Endocrinology and Diabetology Unit | Barbieri A.M.,University of Milan | And 2 more authors.
Clinical Cases in Mineral and Bone Metabolism | Year: 2013

Calcium sensing receptor (CASR) is a G-protein couple receptor which plays a key role in calcium homeostasis in vertebrates. Its extracellular domain is sensitive to divalent cations, aminoacids and polyamines. In parathyroid glands, CASR activation causes parathyroid hormone (PTH) reduction and subsequently a decrease in blood calcium concentration. In PTH-dependent disorders, e.g. primary and secondary hyperparathyroidism (HPT), the need for therapeutic options other than surgery led to the synthesis of various allosteric CASR agonists (calcimimetics), such as cinacalcet. Cinacalcet is the only calcimimetic approved for HPT secondary to chronic kidney disease (CDK), parathyroid carcinoma, and, in some countries, primary HPT. Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary HPT, lowering the risk of bone fractures, surgery, and cardiovascular complications in the former patients. Long-term safety and pharmacoeconomics have to be fully tested yet. Few both in vitro and in vivo studies showed an association between Arg990Gly-CASR polymorphism and cinacalcet sensitivity, though in patients with severe CASR inactivating mutations the drug substantially retained its positive clinical effects. Recently, a new class of allosteric antagonists of CASR, i.e. calcilytics, has been synthesized. Calcilytics are structurally similar to calcimimetics, but exert their effects acting on a different allosteric site. Infusion of calcilytics was followed by transient rise in PTH and calcium. One of these compounds, ronacaleret, was able to increase femur BMD in post menopausal women, but with induction of mild hyperparathyroidism. In the future, calcilytics may contribute to the osteoporosis treatment choice.


Passeri E.,Endocrinology and Diabetology Unit | Benedini S.,University of Milan | Costa E.,Clinical Laboratory | Corbetta S.,University of Milan
International Journal of Endocrinology | Year: 2015

Background. The RANKL/RANK/OPG signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis. The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation. Aim. To test whether systemic blockage of RANKL by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women. Study Design. This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test. Results. A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose, insulin, or HOMA-IR at both 4 and 12 weeks. No changes could be detected in glucose response to the glucose load, Matsuda Index, or insulinogenic index. Nonetheless, 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks. Conclusions. A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients. © 2015 Elena Passeri et al.


Filopanti M.,Endocrinology and Diabetology Unit | Olgiati L.,University of Milan | Mantovani G.,University of Milan | Corbetta S.,University of Milan | And 18 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

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. Copyright © 2012 by The Endocrine Society.


Eller-Vainicher C.,University of Milan | Filopanti M.,University of Milan | Palmieri S.,University of Milan | Ulivieri F.M.,University of Milan | And 10 more authors.
European Journal of Endocrinology | Year: 2013

Objective: In primary hyperparathyroidism (PHPT), vertebral fractures (VFx) occur regardless of bone mineral density (BMD) and may depend on decreased bone quality. Trabecular bone score (TBS) is a texture measurement acquired during a spinal dual-energy X-ray absorptiometry (DXA). Recently, TBS has been proposed as an index of bone micro-architecture. Design:We studied 92 PHPT patients (74 females, age 62.1±9.7 years) and 98 control subjects. In all patients at baseline, in 20 surgically treated patients and in 10 conservatively treated patients after 24 months, TBS, spinal (lumbar spine (LS)) and femoral (total hip (TH) and femoral neck (FN)) BMD were assessed by DXA and VFx by spinal radiograph. Results: PHPT patients had lower TBS (K2.39±1.8) and higher VFx prevalence (43.5%) than controls (K0.98±1.07 and 8.2% respectively, both P!0.0001). TBS was associated with VFx (odds ratio 1.4, 95% CI 1.1-1.9, PZ0.02), regardless of LS-BMD, age, BMI and gender, and showed a better compromise between sensitivity (75%) and specificity (61.5%) for detecting VFx than LS-BMD, TH-BMD and FN-BMD (31 and 75%, 72 and 44.2%, and 64 and 65% respectively). In surgically treated patients, TBS, LS-BMD, TH-BMD and FN-BMD increased (C47±44.8,C29.2 ±34.1,C49.4G48.7 and C30.2±39.3% respectively, all P!0.0001). Among patients treated conservatively, TBS decreased significantly in those (nZ3) with incident VFx (K1.3±0.3) compared with those without (K0.01±0.9, PZ0.048), while BMD changes were not statistically different (LS 0.3G1.2 vs K0.8G0.9 respectively, PZ0.19; TH 0.4G0.8 vs K0.8±1.4 respectively, PZ0.13 and FN 0.4±0.9 vs K0.8±1.4 respectively, PZ0.14). Conclusions: In PHPT, bone quality, as measured by TBS, is reduced and associated with VFx and improves after surgery. © 2013 European Society of Endocrinology.


PubMed | Endocrinology and Diabetology Unit
Type: Journal Article | Journal: European journal of endocrinology | Year: 2013

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 Gilberts syndrome.To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment.Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy.A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled.Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping.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.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.


PubMed | Endocrine Surgery Unit, IRCCS Instituto Clinico Humanitas, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico and University of Milan
Type: Journal Article | Journal: Histology and histopathology | Year: 2015

The four regulatory subunits (R1A, R1B, R2A, R2B) of protein kinase A (PKA) are differentially expressed in several cancer cell lines and exert distinct roles in both cell growth and cell differentiation control. Mutations of the PRKAR1A gene have been found in patients with Carney complex and in a minority of sporadic anaplastic thyroid carcinomas. The aim of the study was to retrospectively evaluate the expression of different PKA regulatory subunits in benign and non benign human thyroid tumours and to correlate their expression with clinical phenotype. Immunohistochemistry demonstrated a significant increase in PRKAR2B expression in both differentiated and undifferentiated (anaplastic) thyroid tumors in comparison with normal thyroid tissues. Conversely, a significant increase in PRKAR1A expression was only demonstrated in undifferentiated thyroid carcinomas in comparison with normal thyroid tissue and differentiated thyroid tumors. In thyroid cancers without lymph nodal metastases PRKAR1A expression was higher in tumours of more than 2 cm in size (T2 and T3) compared to smaller ones (T1). In conclusion, our data shows that an increased PRKAR1A expression is associated with aggressive and undifferentiated thyroid tumors.


PubMed | Endocrinology and Diabetology Unit, Clinical Laboratory and University of Milan
Type: | Journal: International journal of endocrinology | Year: 2015

Background. The RANKL/RANK/OPG signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis. The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation. Aim. To test whether systemic blockage of RANKL by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women. Study Design. This is a prospective study on the effect of a subcutaneously injected single 60mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test. Results. A single 60mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose, insulin, or HOMA-IR at both 4 and 12 weeks. No changes could be detected in glucose response to the glucose load, Matsuda Index, or insulinogenic index. Nonetheless, 60mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks. Conclusions. A single 60mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients.


PubMed | Endocrinology and Diabetology Unit
Type: Journal Article | Journal: Neuroendocrinology | Year: 2015

Non-functioning pituitary adenomas (NFPA) account for about 40% of pituitary tumors. Pituitary deficiencies are present at diagnosis in 60-80% of NFPA, and, classically, growth hormone (GH) secretion is lost first, while adrenocorticotropic hormone is expected to disappear last. The aim of this study was to evaluate the incidence of multiple or isolated pituitary deficiencies in a large series of NFPA.We retrospectively analyzed data on 218 NFPA cases (59% females, 59% with macroadenomas, average age: 50.2 17 years) followed up at our center from 1990 to 2013. At diagnosis all patients had a complete evaluation of pituitary function in basal conditions and provocative tests for the hypothalamic-pituitary-adrenal axis, while tests for GH deficiency (GHD) were carried out in 38%.52.3% of patients (65.6% of macroadenomas, 33.3% of microadenomas) presented at least 1 pituitary deficiency: isolated deficiency in 29.8%, multiple deficiencies in 30% and panhypopituitarism in 9%. Isolated deficiencies were hypogonadism in 11.5% of patients (8% in micro-, 14% in macroadenomas), hypoadrenalism in 10.1% (14% in micro-, 7% in macroadenomas) and GHD in 8.3% (8.9% in micro-, 7.8% in macroadenomas). About 30% of microadenomas had at least 1 pituitary deficiency at diagnosis, independently of tumor localization within the sellar region.The presence of isolated hypoadrenalism suggests that the order of appearance of hypopituitarism does not always follow the one expected. Given the relatively high prevalence of isolated hypoadrenalism even in microadenomas, we suggest a full assessment of basal and dynamic pituitary function in all NFPA regardless of tumor size.


Trivellin G.,U.S. National Institutes of Health | Daly A.F.,University of Liège | Faucz F.R.,U.S. National Institutes of Health | Faucz F.R.,Pontifical Catholic University of Parana | And 53 more authors.
New England Journal of Medicine | Year: 2014

Results: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.Conclusions: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly.Background: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.Methods: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. Copyright © 2014 Massachusetts Medical Society.

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