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Giulia BRIGANTE

Ricercatore t.d. art. 24 c. 3 lett. A
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Medicina, Endocrinologia, Metabolismo e Geriatria


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Pubblicazioni

2022 - cGMP is not involved in thyroid cancer cell death [Abstract in Atti di Convegno]
D'Alessandro, Sara; Paradiso, Elia; Lazzaretti, Clara; Sperduti, Samantha; Baschieri, Lara; Mascolo, Elisa; Roy, Neena; Anzivino, Claudia; Righi, Sara; Santi, Daniele; Brigante, Giulia; Simoni, Manuela; Casarini, Livio
abstract


2022 - Changes in quality of life after thyroidectomy in subjects with thyroid cancer in relation to the dose of levothyroxine [Articolo su rivista]
Monzani, M. L.; Piccinini, F.; Boselli, G.; Corleto, R.; Margiotta, G.; Peeters, R. P.; Simoni, M.; Brigante, G.
abstract

Previous studies demonstrated decreased quality of life (QoL) in differentiated thyroid cancer (DTC) survivors and suggested QoL variability related to time from thyroidectomy and levothyroxine dosage. The aims of this study were to evaluate QoL in thyroidectomized subjects in different levothyroxine states and to evaluate the association between TSH and thyroid hormones and QoL.


2022 - Effect of the Glucagon-Like Peptide-1 Receptor Agonists on Autonomic Function in Subjects with Diabetes: A Systematic Review and Meta-Analysis [Articolo su rivista]
Greco, Carla; Santi, Daniele; Brigante, Giulia; Pacchioni, Chiara; Simoni, Manuela
abstract

Background: In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes. Methods: According to the Cochrane Collaboration and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in diabetic subjects chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs). Results: In the studies enrolled, HR significantly increased after treatment (P<0.001), whereas low frequency/high frequency ratio did not differ (P=0.410); no changes in other measures of HRV were detected. Considering CARTs, only the 30:15 value derived from lying-to-standing test was significantly lower after treatment (P=0.002), but only two studies reported this measurement. No differences in other CARTs outcome were observed. Conclusion: The meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function.


2022 - Genetic signature of differentiated thyroid carcinoma susceptibility: a machine learning approach [Articolo su rivista]
Brigante, Giulia; Lazzaretti, Clara; Paradiso, Elia; Nuzzo, Federico; Sitti, Martina; Tüttelmann, Frank; Moretti, Gabriele; Silvestri, Roberto; Gemignani, Federica; Försti, Asta; Hemminki, Kari; Elisei, Rossella; Romei, Cristina; Zizzi, Eric Adriano; Deriu, Marco Agostino; Simoni, Manuela; Landi, Stefano; Casarini, Livio
abstract

To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics and a machine learning (ML) classifier to describe cases and controls in three different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P < 0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a seven-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals, and ML allows a fair prediction of case or control status based solely on the individual genetic background.


2022 - Seasonal reproduction and gonadal function: a focus on humans starting from animal studies [Articolo su rivista]
Beltran-Frutos, E.; Casarini, L.; Santi, D.; Brigante, G.
abstract

Photoperiod impacts reproduction in many species of mammals. Mating occurs at specific seasons to achieve reproductive advantages, such as optimization of offspring survival. Light is the main regulator of these changes during the photoperiod. Seasonally breeding mammals detect and transduce light signals through extraocular photoreceptor, regulating downstream melatonin-dependent peripheral circadian events. In rodents, hormonal reduction and gonadal atrophy occur quickly and consensually with short-day periods. It remains unclear whether photoperiod influences human reproduction. Seasonal fluctuations of sex hormones have been described in humans, although they seem to not imply adaptative seasonal pattern in human gonads. This review discusses current knowledge about seasonal changes in the gonadal function of vertebrates, including humans. The photoperiod-dependent regulation of hypothalamic-pituitary-gonadal axis, as well as morphological and functional changes of the gonads is evaluated herein. Endocrine and morphological variations of reproductive functions, in response to photoperiod, are of interest as they may reflect the nature of past population selection for adaptative mechanisms that occurred during evolution.


2021 - A prospective, observational clinical trial on the impact of COVID-19-related national lockdown on thyroid hormone in young males [Articolo su rivista]
Brigante, Giulia; Spaggiari, Giorgia; Rossi, Barbara; Granata, Antonio; Simoni, Manuela; Santi, Daniele
abstract

Trying to manage the dramatic coronavirus disease 2019 (COVID-19) infection spread, many countries imposed national lockdown, radically changing the routinely life of humans worldwide. We hypothesized that both the pandemic per se and the consequent socio-psychological sequelae could constitute stressors for Italian population, potentially affecting the endocrine system. This study was designed to describe the effect of lockdown-related stress on the hypothalamic-pituitary-thyroid (HPT) axis in a cohort of young men. A prospective, observational clinical trial was carried out, including patients attending the male infertility outpatient clinic before and after the national lockdown for COVID-19 pandemic. The study provided a baseline visit performed before and a follow-up visit after the lockdown in 2020. During the follow-up visit, hormonal measurements, lifestyle habits and work management were recorded. Thirty-one male subjects were enrolled (mean age: 31.6±6.0years). TSH significantly decreased after lockdown (p=0.015), whereas no significant changes were observed in the testosterone, luteinising hormone, follicle-stimulating hormone, estradiol and prolactin serum levels. No patient showed TSH serum levels above or below reference ranges, neither before nor after lockdown. Interestingly, TSH variation after lockdown was dependent on the working habit change during lockdown (p=0.042). We described for the first time a TSH reduction after a stressful event in a prospective way, evaluating the HPT axis in the same population, before and after the national lockdown. This result reinforces the possible interconnection between psychological consequences of a stressful event and the endocrine regulation.


2021 - Chronic thyroiditis in lateral ectopic thyroid mimicking cervical metastasis of thyroid cancer [Articolo su rivista]
Pederzoli, S.; Salviato, T.; Mattioli, F.; Di Massa, G.; Brigante, G.
abstract

We present the case of a 45-year-old Caucasian woman who attended the Endocrinology Unit for a left cervical mass discovered during follow-up for autoimmune chronic thyroiditis. The ultrasound-guided fine-needle aspiration biopsy of the lesion was consistent with a metastasis of follicular thyroid carcinoma. The sonographic neck evaluation revealed no thyroid nodules but three markedly hypoechoic and highly vascularized areas, with irregular margins and hyperechoic spots. In the clinical suspicion of primary thyroid neoplasm, ultrasound-guided fine-needle aspiration biopsy of two of the three areas was performed, but both cytological reports were non-diagnostic, revealing only colloid and blood. Subsequently, the patient underwent surgical removal of the cervical mass, with the intra-operatory consultation with frozen section examination suggesting follicular-like neoplasia. For this reason, thyroidectomy with both central and lateral neck dissection was performed. Surprisingly, the final histologic examination revealed chronic thyroiditis in the thyroid specimen and no evidence of metastasis in the left neck mass. Consequently, the pathological revision of the frozen section assessment led to the final diagnosis of chronic thyroiditis on the lateral ectopic thyroid. This case represents an uncommon example of lateral ectopic thyroid tissue with coexisting normally located thyroid tissue both affected by chronic thyroiditis. Learning points: •• Ectopic thyroid must be considered in the diagnostic work-up of lateral neck mass. •• Even if rare, ectopic thyroid tissue can be found lateral to the carotid sheath and with coexisting normally located thyroid tissue. •• As the orthotopic tissue, lateral ectopic thyroid tissue can be affected by chronic thyroiditis, which may complicate the diagnosis both on ultrasound and cytology.


2021 - LH/hCG and the Receptor: A Single Receptor for Two Ligands [Capitolo/Saggio]
Casarini, L.; Santi, D.; Brigante, G.; Simoni, M.
abstract

Gonadotropins are glycoprotein hormones that regulate development and reproduction. They are a family of structurally similar hormones likely evolved from a common ancestral encoding gene and achieved relatively high complexity in humans. Two of these molecules are the luteinizing hormone (LH) and the choriogonadotropin (hCG). They are encoded by a common gene cluster and act on the same receptor (LHCGR), however, are produced in primates and specialized for regulating unique physiological functions, such as LH for gametogenesis and hCG for pregnancy. The action of the two hormones is differentiated by LHCGR, which mediates ligand-specific intracellular signals optimized for supporting LH and hCG physiological functions. Since the two hormones are used as drugs for the treatment of infertility, the knowledge of their mode of action should be helpful for interpreting gonadotropin-related pathological conditions and optimizing their clinical treatment.


2021 - L’ormone luteinizzante e la gonadotropina corionica umana: attività molecolari e cliniche mediate da un unico recettore [Articolo su rivista]
Sperduti, Samantha; Paradiso, Elia; Lazzaretti, Clara; Rochira, Vincenzo; Brigante, Giulia; Santi, Daniele; Simoni, Manuela; Casarini, Livio
abstract


2021 - Real-life use of BRAF-V600E mutation analysis in thyroid nodule fine needle aspiration: consequences on clinical decision-making [Articolo su rivista]
Brigante, G.; Craparo, A.; Pignatti, E.; Marino, M.; Monzani, M. L.; De Vincentis, S.; Casarini, L.; Sperduti, S.; Boselli, G.; Margiotta, G.; Ippolito, M.; Rochira, V.; Simoni, M.
abstract

Purpose: This study aimed to evaluate the real-life use of BRAF-V600E mutation analysis in washout liquid from thyroid nodule fine needle aspiration (FNA), and the consequences of genetic result on clinical decision-making. Methods: We retrospectively considered subjects tested for BRAF-V600E among those attending the Endocrinology Unit of Modena for FNA between 2014 and 2018. Washing fluid was collected together with cytological sample and stored at −20 °C. If the clinician deemed it necessary, the sample was thawed, DNA extracted, and genetic test performed by high-resolution melting technique. We collected data on cytology according to the Italian Consensus for the cytological classification of thyroid nodules, type of surgery (when performed), histology, and adverse events. Results: Out of 7112 subjects submitted to FNA, BRAF analysis was requested for 683 (9.6%). Overall, 896 nodules were analyzed: 74% were indeterminate at cytology, mainly TIR3A (low risk). Twenty-two nodules were mutant (BRAF+). Only 2% of indeterminate, mainly TIR3B, were BRAF+. Based on final histological diagnosis, BRAF test had high specificity (100%) but poor sensitivity (21%), also in indeterminate nodules. Mutant subjects underwent more extensive surgery compared to wild type (p = 0.000), with frequent prophylactic central lymph node dissection. One third had local metastases. Higher prevalence of hypoparathyroidism was found in BRAF+ compared to wild type (p = 0.018). Conclusions: The analysis of BRAF-V600E outside of gene panels has low sensitivity, especially in indeterminate nodules, and a positive result could lead to more extensive surgery with greater risk of hypoparathyroidism and questionable clinical utility.


2021 - Ruolo diagnostico del dosaggio della calcitonina su liquido di lavaggio da agoaspirato tiroideo nel carcinoma midollare della tiroide [Articolo su rivista]
Brigante, Giulia; Madeo, Bruno; Diazzi, Chiara; Simoni, Manuela; Rochira, Vincenzo
abstract


2021 - Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells [Articolo su rivista]
Paradiso, E.; Lazzaretti, C.; Sperduti, S.; Antoniani, F.; Fornari, G.; Brigante, G.; Di Rocco, G.; Tagliavini, S.; Trenti, T.; Morini, D.; Falbo, A. I.; Villani, M. T.; Nofer, J. -R.; Simoni, M.; Poti, F.; Casarini, L.
abstract

Background and aims: Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At nanomolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P1-5, modulating different signaling pathways. S1P1 and S1P3 are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PR-stimulation in this context. METHODS AND RESULTS. hGLC and hGL5 cells were treated with a fixed dose (0.1 μM) of S1P, or by S1P1- and S1P3-specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1P-dependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca2+ channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P2 or S1P3 with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions. Conclusions: This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P–S1PR axis may cooperate with gonadotropins in modulating follicle development.


2021 - The “hitchhiker’s guide to the galaxy” of endothelial dysfunction markers in human fertility [Articolo su rivista]
Santi, D.; Spaggiari, G.; Greco, C.; Lazzaretti, C.; Paradiso, E.; Casarini, L.; Poti, F.; Brigante, G.; Simoni, M.
abstract

Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and represents the first step in the pathogenesis of cardiovascular diseases. The evaluation of endothelial health is fundamental in clinical practice and several direct and indirect markers have been suggested so far to identify any alterations in endothelial homeostasis. Alongside the known endothelial role on vascular health, several pieces of evidence have demonstrated that proper endothelial functioning plays a key role in human fertility and reproduction. Therefore, this stateof‐the‐art review updates the endothelial health markers discriminating between those available for clinical practice or for research purposes and their application in human fertility. Moreover, new molecules potentially helpful to clarify the link between endothelial and reproductive health are evaluated herein.


2020 - Clinical practice survey on BRAF V600E role in the therapeutic deci- sion in indeterminate thyroid cytology [Abstract in Atti di Convegno]
Brigante, G.; Craparo, A.; Pignatti, E.; Marino, M.; Casarini, L.; Sperduti, S.; Boselli, G.; Margiotta, G.; Rochira, V.; Simoni, M.
abstract

Introduction The use of multigene panels in thyroid nodule diagnosis is still limited, due to high costs and need for ad hoc sampling. Since BRAF-V600E is the com- monest genetic alteration in differentiated thyroid cancer, this is the mostly tested genetic parameter in clinical practice. Aim To evaluate the use of BRAF mutation analysis in wash-out liquid from fine needle aspiration (FNA) in clinical practice, characterizing the cases in which it is requested, and the consequences of genetic test result on thera- peutic decisions. Methods We considered all the subjects tested for BRAF-V600E among those attend- ing the Endocrinology Unit of Modena for FNA between January 2014 and November 2018. After written informed consent, washing fluid was collected together with cytological sample and stored at –20°C. If the clinician deemed it necessary, the sample was thawed, DNA was extracted and genetic test was performed by the high-resolution melting protocol previously described1. We collected cytology of nodules according to the 2010 SIAPEC-IAP Italian Consensus, and when surgical treatment was performed, histology. Results Out of a total of 7112 subjects submitted to FNA, BRAF analysis was re- quested for 681 (9.6%), for a total of 898 nodules: 97% of nodules were indeterminate at cytology, mainly TIR3A (low risk); 2% suspicious or di- agnostic for cancer, and genetic test was requested to estimate prognosis; 1% were suspect nodules at ultrasonography with unsuspicious cytology. Only 22 nodules were mutant (BRAF+).Most of them were already high risk or suspicious lesions at cytology (64%). One third were TIR3A. Con- sidering the prevalence of BRAF mutation among cytological classes of the whole group, only 1% of TIR3A were BRAF+. Twenty BRAF+ patients were addressed to surgery (one lost at follow-up, one refused): 5% underwent hemithyroidectomy, 25% total thyroidectomy and 70% total thyroidectomy plus central lymph nodes dissection. They all had papillary thyroid cancer. Since 64% of BRAF+ were TIR3B-4-5 at cytology, they had surgical indica- tion even before the genetic test. Among the 14 subjects treated with central neck dissection, only 2 had suspect metastasis before surgery; among those who would have had no indication, one third had metastases (only 1 among TIR3A and 2 among TIR3B). Conclusions Despite the development of panels, single gene tests are still requested, mainly for nodules with indeterminate low risk cytology. BRAF mutation in TIR3A is rare and leads clinicians to more invasive surgery, with question- able clinical utility.


2020 - De novo Lesions Frequently Develop in Adult Normal Thyroid Over Almost Six Years [Articolo su rivista]
Brigante, Giulia; Monzani, Maria Laura; Locaso, Michela; Gnarini, Valentina Luisa; Graziadei, Luigi; Kaleci, Shaniko; De Santis, Maria Cristina; Tagliavini, Simonetta; Simoni, Manuela; Rochira, Vincenzo; Madeo, Bruno
abstract

Purpose: In order to understand how thyroid abnormalities emerge over time in adults, we evaluated incidence of thyroid diseases in healthy subjects, after almost 6 years from a previous negative ultrasound. Methods: Anamnestic and physical data were collected. Ultrasound neck evaluation was performed by an experienced endocrinologist, recording detailed thyroid and nodules characteristics. Nodules were classified according to American Thyroid Association classification for prediction of cancer risk. Serum samples were collected for subsequent evaluations (TSH, free thyroid hormones, calcitonin, anti-thyroid antibodies). Anamnestic, clinical, sonographic, and serological characteristics were analyzed with logistic regression analysis for subjects with nodules vs. those without. Results: One hundred and eleven subjects were enrolled (43M, 68F). Half of them developed nodules, mainly smaller than 1 cm and without suspicious characteristics. Ninety-seven percent were euthyroid. Only 4% had serological diagnosis of thyroiditis. Incidence of thyroid diseases was higher in women, especially nulliparous. Comparing clinical characteristics of subjects with and without nodules, the only statistically significant difference concerned thyroid volume adjusted for body weight or surface (p < 0.05), but not residual volume excluding nodules. Multivariate logistic regression analysis showed that female gender, higher BMI-adjusted thyroid volume and residual thyroid volume excluding nodules, nulliparity, age, and fT3 increase the risk of developing nodules. Conclusions: These results demonstrate that adult thyroid tissue undergoes changes that are already detectable by US after almost 6 years. Half of the enrolled subjects developed de novo nodules or colloid cysts of poor clinical relevance.


2020 - Early diagnosis of medullary thyroid cancer in case of low serum calcitonin: Role of calcitonin measurement in fine-needle aspiration washout fluid [Abstract in Atti di Convegno]
Greco, C.; Madeo, B.; Rochira, V.; De Santis, M. C.; Brigante, G.
abstract

Background Screening serum calcitonin (sCT) measurement in patients with thyroid nod- ules is still debated. Moreover, sCt cutoffs for medullary thyroid carcino- ma (MTC) are not univocally defined. Also, sensitivity of cytology by fine needle aspiration biopsy (FNAb) has been demonstrated to detect approx- imately half of MTCs. Ct measurement in fine-needle aspiration washout fluid (Ct-FNAb) has high sensitivity and specificity and is helpful in case of non-diagnostic cytology1. Recently, a series oflow sCt MTC has been collected2. Aim The objectives of this retrospective observational study were to define Ct- FNAb levels in subjects with low sCt (below cutoffs diagnostic for MTC) and to evaluate their clinical, ultrasonographic (US), cytological and histo- logical characteristics.Methods We selected subjects with sCt above local normal ranges but below one of the diagnostic cutoff proposed for MTC (26 pg/ml in females and 68 pg/ ml in males), subjected to FNAb with Ct-FNAb measurement and then thy- roidectomized. Results Surprisingly, 50% (8/16) had MTC at histology, 19% cellular C hyperplasia (CCH) and only 31% neither MTC nor CCH. Ct-FNAb was significantly higher in MTC compared to both no MTC no CCH (2001 vs 25.32±55.72 pg/ml; P = 0.013) and to CCH (2001 vs 195.56 ± 286.09 pg/ml; P = 0.008). Even if below the diagnostic cutoff, also sCt was higher in MTC compared to no CCH and no MTC group (19±7 vs 9±4 pg/ml; P=0.019) but was not able to discriminate MTC from CCH. US failed to identify suspicious nod- ules, since MTC differed only for being solid and not haloed. At cytology nearly 90% of MTC lesions were non-diagnostic or, mainly, indeterminate. At histology, 7/8 were low risk micro MTCs. Conclusion HighCt-FNAb despite sCt only slightly elevated suggests: i) early detection of MTC before the onset of high secretion of Ct, ii) a peculiar variant of MTC, able to produce Ct but not to secrete it in bloodstream because of intracellular secretory pathway alteration, iii) possible methodological in- terferences in the dosage of sCt. In conclusion, this study demonstrates the importance of Ct-FNAb to discover early stages of MTC with sCt below diagnostic cutoffs.


2020 - Evolutionary, structural, and physiological differences between hCG and LH [Capitolo/Saggio]
Casarini, Livio; Lazzaretti, Clara; Paradiso, Elia; Santi, Daniele; Brigante, Giulia; Simoni, Manuela
abstract


2020 - Follicle-stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles [Articolo su rivista]
Santi, Daniele; Crépieux, Pascale; Reiter, Eric; Spaggiari, Giorgia; Brigante, Giulia; Casarini, Livio; Rochira, Vincenzo; Simoni, Manuela
abstract

Background: Human reproduction is regulated by the combined action of the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH) on the gonads. Although FSH is largely used in female reproduction, in particular in women attending assisted reproductive techniques to stimulate multi-follicular growth, its efficacy in men with idiopathic infertility is not clearly demonstrated. Indeed, whether FSH administration improves fertility in patients with hypogonadotropic hypogonadism, the therapeutic benefit in men presenting alterations in sperm production despite normal FSH serum levels is still unclear. In the present review, we evaluate the potential pharmacological benefits of FSH administration in clinical practice. Methods: This is a narrative review, describing the FSH physiological role in spermatogenesis and its potential therapeutic action in men. Results: The FSH role on male fertility is reviewed starting from the physiological control of spermatogenesis, throughout its mechanism of action in Sertoli cells, the genetic regulation of its action on spermatogenesis, until the therapeutic options available to improve sperm production. Conclusion: FSH administration in infertile men has potential benefits, although its action should be considered by evaluating its synergic action with testosterone, and well-controlled, powerful trials are required. Prospective studies and new compounds could be developed in the near future.


2020 - FSH for the Treatment of Male Infertility [Articolo su rivista]
Casarini, L.; Crépieux, P.; Reiter, E.; Lazzaretti, C.; Paradiso, E.; Rochira, V.; Brigante, G.; Santi, D.; Simoni, M.
abstract

Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility.


2020 - Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival [Articolo su rivista]
Casarini, L.; Lazzaretti, C.; Paradiso, E.; Limoncella, S.; Riccetti, L.; Sperduti, S.; Melli, B.; Marcozzi, S.; Anzivino, C.; Sayers, N. S.; Czapinski, J.; Brigante, G.; Poti, F.; La Marca, A.; De Pascali, F.; Reiter, E.; Falbo, A.; Daolio, J.; Villani, M. T.; Lispi, M.; Orlando, G.; Klinger, F. G.; Fanelli, F.; Rivero-Muller, A.; Hanyaloglu, A. C.; Simoni, M.
abstract

Molecular Biology; Female Reproductive Endocrinology; Endocrine Regulation


2020 - Polygenic Susceptibility to Papillary Thyroid Cancer in Italian Subjects. [Abstract in Atti di Convegno]
Brigante, G.; Lazzaretti, C.; Paradiso, E.; Foersti, A.; Hemminki, K.; Elisei, R.; Romei, C.; Rochira, V.; Simoni, M.; Landi, S.; Casarini, L.
abstract

olygenic Susceptibility to Papillary Thyroid Cancer in Italian Subjects INTRODUCTION AND AIM. Thyroid cancer is the most common endocrine neoplasia, with an estimated age- standardized incidence rate of 6.7 per 100000 worldwide in 2018 [1]. This rate is rapidly increasing and papillary thy- roid carcinoma (PTC) is the main histotype. PTC suscepti- bility is the result of genetic predisposition, environmental factors and lifestyle. We studied the genetic combination that characterizes PTC affected subjects, differentiating them from healthy controls. METHODS AND RESULTS. We considered the genetic variants (SNPs) significantly associated with PTC on the PubMed database. 184 informative SNPs were selected, considering linkage disequilibrium. Then, SNPs data were extracted from the online 1000 Genomes database,comprising genome of 2504 unselected individuals col- lected worldwide. The combination of 184 SNPs associ- ated with PTC was used to group individuals in different risk-clusters according to their genetic structure, calcu- lated by Bayesian statistics, as previously performed for polycystic ovary syndrome [2]. Individuals were distrib- uted among 7 groups worldwide, indicating different de- gree of genetic predisposition to PTC. We then considered genetic data from about 1200 individuals (697 PTC versus 497 healthy controls) of Central/South Italian origin reg- istered in a GWAS, specific for PTC [3]. This first analysis was refined using the 33 SNPs reasonably most causa- tive of genetic clustering (26 with p<0.05 at trend test in GWAS and 7 with p<0.05 in the model of recessive inher- itance). At multivariate logistic regression analysis, PTC and healthy controls resulted genetically different (ODDS RATIO 188.6, 95%CI 64.35-552.8), revealing diverse pre- disposition to develop cancer. Afterwards, these results have been confirmed in an independent cohort of Italian subjects (234 PTC and 100 controls). Then, the genetic structure of each subject was indicated as a percentage of affinity to each risk-cluster and re-analyzed together with other risk factors: sex, body-mass index, area of origin and familiarity (quantified in a growing score as the degree of kinship increases). These data were analyzed together by principal component analysis and clustering of the two groups was even more pronounced. The most contributive factors to the diversity between PTC and healthy controls were genetics and familiarity. CONCLUSION. We demonstrated that PTC affected subjects are genetically different from healthy controls, and that the difference is identifiable in a peculiar combi- nation of genetic variants.


2020 - Prospects for FSH Treatment of Male Infertility [Articolo su rivista]
Simoni, Manuela; Brigante, Giulia; Rochira, Vincenzo; Santi, Daniele; Casarini, Livio
abstract

Context: Despite the new opportunities provided by assisted reproductive technology (ART), male infertility treatment is far from being optimized. One possibility, based on pathophysiological evidence, is to stimulate spermatogenesis with gonadotropins. Evidence Acquisition: We conducted a comprehensive systematic PubMed literature review, up to January 2020, of studies evaluating the genetic basis of follicle-stimulating hormone (FSH) action, the role of FSH in spermatogenesis, and the effects of its administration in male infertility. Manuscripts evaluating the role of genetic polymorphisms and FSH administration in women undergoing ART were considered whenever relevant. Evidence Synthesis: FSH treatment has been successfully used in hypogonadotropic hypogonadism, but with questionable results in idiopathic male infertility. A limitation of this approach is that treatment plans for male infertility have been borrowed from hypogonadism, without daring to overstimulate, as is done in women undergoing ART. FSH effectiveness depends not only on its serum levels, but also on individual genetic variants able to determine hormonal levels, activity, and receptor response. Single-nucleotide polymorphisms in the follicle- stimulating hormone subunit beta (FSHB) and follicle-stimulating hormone receptor (FSHR) genes have been described, with some of them affecting testicular volume and sperm output. The FSHR p.N680S and the FSHB –211G>T variants could be genetic markers to predict FSH response. Conclusions: FSH may be helpful to increase sperm production in infertile men, even if the evidence to recommend the use of FSH in this setting is weak. Placebo-controlled clinical trials, considering the FSHB-FSHR haplotype, are needed to define the most effective dosage, the best treatment length, and the criteria to select candidate responder patients.


2020 - Terapia sostitutiva tiroidea e risposta tissutale: quando il TSH non basta [Articolo su rivista]
Monzani, Maria Laura; Piccinini, Francesca; Simoni, Manuela; Brigante, Giulia
abstract


2020 - The added value of operator’s judgement in thyroid nodule ultrasound classification arising from histologically based comparison of different risk stratification systems. [Articolo su rivista]
Madeo, B.; Brigante, G.; Ansaloni, A.; Taliani, E.; Kaleci, S.; Monzani, M. L.; Simoni, M.; Rochira, V.
abstract

Objective: Several ultrasound classifications for thyroid nodules were proposed but their accuracy is still debated, since mainly estimated on cytology and not on histology. The aim of this study was to test the diagnostic accuracy and the inter-classification agreement of AACE/ACE-AME, American Thyroid Association (ATA), British Thyroid Association (BTA), and Modena Ultrasound Thyroid Classification (MUT) that stratifies malignancy risk considering also the clinician subjective impression. Methods: A prospective study collecting thyroid nodule features at ultrasound and histological diagnosis was conducted. Ultrasound features were collected following a preformed checklist in candidates for surgery because of indeterminate, suspicious, or malignant cytology. All the nodules, besides the cytologically suspicious one, were blinded analyzed. MUT score was applied prospectively, and the others retrospectively. Sensitivity, specificity, diagnostic cut-off value, and accuracy of each classification were calculated. The overall agreement between classifications was tested by Bland-Altman, and agreement between single nodule analysis by different classifications by Weighted Cohen's Kappa. Results: In classifying a total of 457 nodules, MUT has the highest accuracy (AUC 0.808) and specificity (89%), followed by ATA and BTA, and finally by AACE/ACE-AME. ATA, BTA, and MUT are highly interchangeable. Considering agreement between single nodule analyses, ATA and BTA had the best (κ = 0.723); AACE/ACE-AME showed slight agreement with BTA (κ = 0.177) and MUT (κ = 0.183), and fair agreement with ATA (κ = 0.282); MUT had fair agreement with both ATA (κ = 0.291) and BTA (κ = 0.271). Conclusion: Classifications have an acceptable overall diagnostic accuracy, improved using a less rigid system that takes into consideration operator subjective impression.


2019 - Abacavir, nevirapine, and ritonavir modulate intracellular calcium levels without affecting GHRH-mediated growth hormone secretion in somatotropic cells in vitro [Articolo su rivista]
Brigante, G; Riccetti, L; Lazzaretti, C; Rofrano, L; Sperduti, S; Potì, F; Diazzi, C; Prodam, F; Guaraldi, G; Lania, Ag; Rochira, V; Casarini, L
abstract

Growth Hormone (GH) deficiency is frequent in HIV-infected patients treated with antiretroviral therapy. We treated GH3 cells with antiretrovirals (nevirapine, ritonavir or abacavir sulfate; 100 pM-1 mM range), after transfection with human growth hormone releasing hormone (GHRH) receptor cDNA. Cells viability, intracellular cAMP, phosphorylation of CREB and calcium increase, GH production and secretion were evaluated both in basal condition and after GHRH, using MTT, bioluminescence resonance energy transfer, western blotting and ELISA. Antiretroviral treatment did not affect GHRH 50% effective dose (EC50) calculated for 30-min intracellular cAMP increase (Mann-Whitney's U test; p ≥ 0.05; n = 4) nor 15-min CREB phosphorylation. The kinetics of GHRH-mediated, rapid intracellular calcium increase was perturbed by pre-incubation with drugs, while GHRH failed to induce the ion increase in ritonavir pre-treated cells (ANOVA; p < 0.05; n = 3). Antiretrovirals did not impact 24-h intracellular and extracellular GH levels (ANOVA; p ≥ 0.05; n = 3). We demonstrated the association between antiretrovirals and intracellular calcium increase, without consequences on somatotrope cells viability and GH synthesis. Overall, these results suggest that antiretrovirals may not directly impact on GH axis in HIV-infected patients.


2019 - Classification of thyroid nodules by ultrasound in clinical practice: the added value of the judgement of the skilled endocrinologist [Abstract in Atti di Convegno]
Madeo, B.; Brigante, G.; Ansaloni, A.; Taliani, E.; Kaleci, S.; Monzani, M. L.; Simoni, M.; Rochira, V.
abstract


2019 - Classification of thyroid nodules by ultrasound in clinical practice: the added value of the judgment of the skilled endocrinologist [Abstract in Rivista]
Madeo, B.; Brigante, G.; Ansaloni, A.; Taliani, E.; Kaleci, S.; Monzani, M. L.; Simoni, M.; Rochira, V.
abstract


2019 - Concomitant medullary thyroid carcinoma with paraganglioma-like pattern and papillary thyroid carcinoma [Articolo su rivista]
Greco, C.; Brigante, G.; Taliani, E.; Corrado, S.; Simoni, M.; Madeo, B.
abstract

A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the left lobe, was inhomogeneously hypoechoic, with irregular margins, macrocalcifications and intranodular vascularization. Fine-needle aspiration biopsy (FNAB) was performed. The cytological diagnosis was TIR 2, benign, according to the 2013 Italian thyroid cytology classification system. Moderately high serum calcitonin (s-Ct) (61.5 pg/mL, n.r. 0–7.5) and normal CEA were detected. The Ct level in FNAB wash-out fluid (Ct-FNAB) was 1450 pg/mL. Based on s-Ct and Ct-FNAB levels, patient underwent total thyroidectomy. Macroscopically, a dominant circumscribed nodule of 2 ecm was described; the histological and immunohistochemical features identified medullary thyroid carcinoma (MTC) with paraganglioma (PG)-like pattern positive for Ct, CEA and chromogranin and negative for S-100 sustentacular cells (SC). Moreover, papillary carcinoma of 3 mm in the right lobe was also associated. No areas of hyperaccumulation of the tracer were documented at Ga68 PET/CT. No RET-proto-oncogene mutations were found. Post-surgery s-Ct levels were within normal range (4 pg/mL). Two years after thyroidectomy, the patient is still disease-free. We reported a case of sporadic and rare variant of MTC: this is the ninth described case of PG-like MTC. In this case, cytologically benign, the clinical suspicion arose from high Ct values at FNAB wash-out fluid. Even if clinical behavior of this variant seems indolent, additional studies are necessary to understand prognoses and predictive factors.


2019 - Diagnostic Accuracy of Different Thyroid Ultrasound Classification Systems and the Added Value of Operator Subjective Impression in Stratifying Nodule Risk [Abstract in Atti di Convegno]
Madeo, Bruno; Brigante, G.; Ansaloni, A.; Taliani, E.; Kaleci, S.; Monzani, M. L.; Simoni, M.; V. Rochira.,
abstract


2019 - Expression and clinicopathological role of miR146a in thyroid follicular carcinoma. [Articolo su rivista]
Pignatti, E.; Vighi, E.; Magnani, E.; Kara, E.; Roncati, L.; Maiorana, A.; Santi, D.; Madeo, B.; Cioni, K.; Carani, C.; Rochira, V.; Simoni, M.; Brigante, Giulia
abstract

PURPOSE: Dysregulation of microRNA expression has been involved in the development and progression of follicular thyroid carcinoma (FTC). The aim of this work was to study the expression of miRNA146a in FTC and the association with clinicopathological features of the disease. METHODS: Thirty-eight patients affected by FTC were included in the study. Twenty patients carrying follicular thyroid adenoma (FA) were also enroled as the benign counterpart of FTC. Total RNA including miRNA146a was extracted from formalin-fixed paraffin-embedded (FFPE) pairs of affected/unaffected tissue and its expression was assessed by real-time PCR. Two selected target genes, TRAF6 (tumour necrosis factor receptor-associated factor 6) and IRAK1 (Il-1 receptor-associated kinase 1/2), were also analysed. RESULTS: miR146a expression in FTC tissue was overall not downregulated in malignant versus unaffected tissue, but its expression was inversely correlated with clinicopathological features of FTCs at diagnosis. A decreased expression of miR146a became apparent in FTC thyroid tissue of widely compared to minimally invasive tumours. However, miR146a expression differences between contralateral unaffected tissue (extra-FTC) and FTC were not observed regardless of clinicopathological features. IRAK1, a known target for miR146a, was upregulated in FTC and the increase was mainly appreciable in Hurtle FTC variant. Unexpectedly, miR146a did not correlate with TRAF6 showing an inverse trend compared to IRAK1 although both genes regulate the activity of nuclear factor- kB (NF-kB). CONCLUSION: The results of this study indicate that downregulation of miR146a, inversely correlated with clinicopathological features of FTCs at diagnosis and suggest a possible involvement of miR146a in FTC development. IRAK1 over-expression in FTC may be related to tumour development/progression. In vitro experiments are needed to support this hypothesis.


2019 - Graves' Disease and the Post-partum Period: An Intriguing Relationship [Articolo su rivista]
Croce, L.; Di Dalmazi, G.; Orsolini, F.; Virili, C.; Brigante, G.; Gianetti, E.; Moleti, M.; Napolitano, G.; Tonacchera, M.; Rotondi, M.
abstract

The post-partum period is an immunologically peculiar period in a woman's life. Indeed, most of the pregnancy-related immune changes gradually revert in the 12 months following delivery. Although the post-partum period has long been identified as a period of aggravation of autoimmune thyroid diseases, most of the currently available studies took into account the relationship between post-partum and autoimmune thyroiditis. More recently, the potential repercussions of the post-partum period on Graves' disease were also taken into account. The present mini review will briefly overview the most recent advances in our knowledge of the immunology of the post-partum period in relation with the potential repercussions on the clinical course of Graves' disease. Moreover, some peculiar aspects of post-partum Graves' disease in terms of clinical and biochemical presentation, diagnostic challenges, and specific therapeutic considerations also taking into account the recommendation of the latest clinical guidelines on the management of thyroid diseases in pregnancy will be overviewed.


2019 - Inferring biallelism of two FSH receptor mutations associated with spontaneous ovarian hyperstimulation syndrome by evaluating FSH, LH and HCG cross-activity [Articolo su rivista]
Lazzaretti, C.; Riccetti, L.; Sperduti, S.; Anzivino, C.; Brigante, G.; De Pascali, F.; Poti, F.; Rovei, V.; Restagno, G.; Mari, C.; Lussiana, C.; Benedetto, C.; Revelli, A.; Casarini, L.
abstract

Research question: What is the cumulative effect of two follicle-stimulating hormone receptor (FSHR) mutations in spontaneous ovarian hyperstimulation syndrome (sOHSS) pathogenesis? Are these mutations in the mono- or biallelic state? Design: Two FSHR mutations were found in a pregnant patient affected by sOHSS with no predisposing conditions. While the p.Asn106His mutation is novel, the p.Ser128Tyr mutation has been associated with sOHSS previously. The patient's FSHR gene was analysed by Sanger sequencing, and FSHR cDNAs carrying a single or both point mutations were created by mutagenesis in vitro. cAMP activation by recombinant FSH, luteinizing hormone (LH), human chorionic gonadotropin (HCG) and thyroid-stimulating hormone (TSH) was evaluated in transfected HEK293 cells by bioluminescence resonance energy transfer. Results: All mutations decreased the 50% effective concentration of FSH calculated for cAMP (P < 0.05, n = 6), resulting in two- to 10-fold lower ligand potency. TSH failed to induce an FSHR-mediated increase in intracellular cAMP, while LH was approximately four-fold more potent than HCG in p.Ser128Tyr FSHR-expressing HEK293 cells despite lower cAMP plateau levels (P < 0.05, n = 5). The p.Ser128Tyr FSHR mutation was found to be responsible for an LH-/HCG-induced increase in cAMP when it was in the biallelic heterozygous state with p.Asn106His, but no increase in cAMP was induced in the monoallelic state. Conclusion: In-vitro data support that, in pregnant patients with sOHSS, the two FSHR mutations have an opposing effect on the pathogenesis of sOHSS and are in the biallelic heterozygous form, allowing HCG to induce a p.Ser128Tyr FSHR-mediated increase in cAMP.


2019 - Prevalence of thyroid disfunctions in a large cohort of Human Immunodeficiency Virus (HIV)-Infected Patients [Abstract in Atti di Convegno]
Tartaro, G.; De Vincentis, S.; Brigante, G.; Diazzi, C.; Malagoli, A.; Guaraldi, G.; Rochira, V.
abstract


2019 - Semi-annual seasonal pattern of serum thyrotropin in adults [Articolo su rivista]
Santi, D.; Spaggiari, G.; Brigante, G.; Setti, M.; Tagliavini, S.; Trenti, T.; Simoni, M.
abstract

Circannual rhythmicity in thyroid-stimulating hormone (TSH) secretion is proposed, whereas evidences on seasonal peripheral thyroid hormones' fluctuation are contradictory. This study was designed to evaluate hypothalamic-pituitary-thyroid (HPT) seasonal secretion pattern using a big data approach. An observational, retrospective, big data trial was carried out, including all TSH measurements performed in a single laboratory between January 2010 and December 2017. A large dataset was created matching TSH data with patients' age, gender, environmental temperature exposure, and free triiodothyronine (fT3) and free thyroxine (fT4) when available. The trend and seasonal distributions were analysed using autoregressive integrated moving average models. A total of 1,506,495 data were included in the final database with patients mean age of 59.00 +/- 18.44 years. The mean TSH serum levels were 2.08 +/- 1.57 microIU/mL, showing a seasonal distribution with higher levels in summer and winter seasons, independently from age, gender and environmental temperatures. Neither fT3 nor fT4 showed a seasonal trend. TSH seasonal changes occurred independently from peripheral thyroid hormone variations, gender, age and environmental temperatures. Although seasonal TSH fluctuation could represent a residual ancestral mechanism to maintain HPT homeostasis, the underlying physiological mechanism remains unclear and specific studies are needed to clarify its impacting role in humans.


2019 - Ultrasound Changes of Healthy Thyroides over Six Years in Adults [Abstract in Atti di Convegno]
Brigante, G.; Monzani, M. L.; Locaso, M.; Gnarini, V. L.; Graziadei, L.; Kaleci, S.; De Santis, M. C.; Tagliavini, S.; Simoni, M.; Rochira, V.; Madeo, B.
abstract


2019 - Ultrasound changes of healthy thyroides over six years in adults [Abstract in Atti di Convegno]
Brigante, G.; Monzani, M. L.; Locaso, M.; Gnarini, V. L.; Graziadei, L.; Kaleci, S.; De Santis, M. C.; Tagliavini, S.; Simoni, M.; Rochira, V.; Madeo, B.
abstract


2018 - Crosstalk between gonadotropins and thyroid axis [Articolo su rivista]
De Vincentis, Sara; Monzani, Maria L; Brigante, Giulia
abstract

Gonadotropins and thyroid hormones are essential, respectively, for reproduction and metabolism. The classical endocrinological approach is based on the detection of axes that start from the hypothalamus and arrive at the final effector organ, in this case gonads and thyroid. However, several clues suggest that these axes do not work in parallel, but they dialogue with each other. In this article, we review evidences demonstrating crosstalk between gonadotropins and thyroid axis. Firstly, there is an undeniable structural similarity of both hormones and receptors, maybe due to a common ancient origin. This structural similarity leads to possible interaction at the receptor level, explaining the influence of thyroid stimulating hormone on gonadal development and viceversa. Indeed, altered levels of thyroid hormones could lead to different disorders of gonadal development and function throughout entire life, especially during puberty and fertile life. We here report the current knowledge on this item both in males and in females. In particular, we deepen the interaction between thyroid and gonads in two situations in females: polycystic ovary syndrome, the most frequent cause of menstrual alteration, and pregnancy.


2018 - Serum microRNA profiles in athyroid patients on and off levothyroxine therapy [Articolo su rivista]
Massolt, Elske T; Chaker, Layal; Visser, Theo J; Gillis, Ad J M; Dorssers, Lambert C J; Beukhof, Carolien M; Kam, Boen L R; Franssen, Gaston J; Brigante, Giulia; van Ginhoven, Tessa M; Visser, W Edward; Looijenga, Leendert H J; Peeters, Robin P
abstract

BackgroundLevothyroxine replacement treatment in hypothyroidism is unable to restore physiological thyroxine and triiodothyronine concentrations in serum and tissues completely. Normal serum thyroid stimulating hormone (TSH) concentrations reflect only pituitary euthyroidism and, therefore, novel biomarkers representing tissue-specific thyroid state are needed. MicroRNAs (miRNAs), small non-coding regulatory RNAs, exhibit tissue-specific expression patterns and can be detectable in serum. Previous studies have demonstrated differential expression of (precursors of) miRNAs in tissues under the influence of thyroid hormone.ObjectiveTo study if serum miRNA profiles are changed in different thyroid states.Design and methodsWe studied 13 athyroid patients (6 males) during TSH suppressive therapy and after 4 weeks of thyroid hormone withdrawal. A magnetic bead capture system was used to isolate 384 defined miRNAs from serum. Subsequently, the TaqMan Array Card 3.0 platform was used for profiling after individual target amplification.ResultsMean age of the subjects was 44.0 years (range 20-61 years). Median TSH levels were 88.9 mU/I during levothyroxine withdrawal and 0.006 mU/I during LT4 treatment with a median dosage of 2.1 fag/kg. After normalization to allow inter-sample analysis, a paired analysis did not demonstrate a significant difference in expression of any of the 384 miRNAs analyzed on and off LT4 treatment.ConclusionAlthough we previously showed an up-regulation of pri-miRNAs 133b and 206 in hypothyroid state in skeletal muscle, the present study does not supply evidence that thyroid state also affects serum miRNAs in humans.


2018 - Thyroid State Regulates Gene Expression in Human Whole Blood [Articolo su rivista]
Massolt, Elske T; Meima, Marcel E; Swagemakers, Sigrid M A; Leeuwenburgh, Selmar; van den Hout-van Vroonhoven, Mirjam C G M; Brigante, Giulia; Kam, Boen L R; van der Spek, Peter J; van IJcken, Wilfred F J; Visser, Theo J; Peeters, Robin P; Visser, W Edward
abstract

Context: Despite the well-recognized clinical features resulting from insufficient or excessive thyroid hormone (TH) levels in humans, it is largely unknown which genes are regulated by TH in human tissues.Objective: To study the effect of TH on human gene expression profiles in whole blood, mainly consisting of T3 receptor (TR) alpha-expressing cells.Methods: We performed next-generation RNA sequencing on whole blood samples from eight athyroid patients (four females) on and after 4 weeks off levothyroxine replacement. Gene expression changes were analyzed through paired differential expression analysis and confirmed in a validation cohort. Weighted gene coexpression network analysis (WGCNA) was applied to identify thyroid state-related networks.Results: We detected 486 differentially expressed genes (fold-change >1.5; multiple testing corrected P value < 0.05), of which 76% were positively and 24% were negatively regulated. Gene ontology (GO) enrichment analysis revealed that three biological processes were significantly overrepresented, of which the process translational elongation showed the highest fold enrichment (7.3-fold, P = 1.8 x 10(-6)). WGCNA analysis independently identified various gene clusters that correlated with thyroid state. Further GO analysis suggested that thyroid state affects platelet function.Conclusions: Changes in thyroid state regulate numerous genes in human whole blood, predominantly TR alpha-expressing leukocytes. In addition, TH may regulate gene transcripts in platelets.


2018 - Thyroid ultrasound alterations occurrence in patients with previous negative examination: A 6-years observational follow-up trial [Abstract in Rivista]
Monzani, Maria Laura; Brigante, Giulia; Locaso, Michela; Santi, Daniele; Graziadei, Luigi; Gnarini, Valentina Luisa; Simoni, Manuela; Madeo, Bruno
abstract

10.1530/endoabs.56.P1051


2018 - Two hormones for one receptor: evolution, biochemistry, actions and pathophysiology of LH and hCG [Articolo su rivista]
Casarini, Livio; Santi, Daniele; Brigante, Giulia; Simoni, Manuela
abstract

Luteinizing hormone (LH) and chorionic gonadotropin (CG) are glycoproteins fundamental for sexual development and reproduction. Since they act on the same receptor (LHCGR), there is a general consensus that LH and hCG are equivalent. However, separate evolution of LHβ and hCGβ subunits occurred in primates, resulting in two molecules sharing ∼85% identity and regulating different physiological events. Pituitary, pulsatile LH production results in a ∼90 min half-life molecule targeting the gonads, to regulate gametogenesis and androgen synthesis. Trophoblast hCG, the "pregnancy hormone", exists in several isoforms and glycosylation variants with long half-lives (hours), angiogenic potential, and acts on luteinized ovarian cells as a progestational. The different molecular features of LH and hCG lead to hormone-specific LHCGR binding and intracellular signaling cascades. In ovarian cells, LH action is preferentially exerted through kinases, pERK1/2 and pAKT, resulting in irreplaceable proliferative/anti-apoptotic signals and partial agonism on progesterone production in vitro. In contrast, hCG displays notable cAMP/PKA-mediated steroidogenic and pro-apoptotic potential, which is masked by estrogen action in vivo. In vitro data are confirmed by large dataset from assisted reproduction, since the steroidogenic potential of hCG positively impacts on the number of retrieved oocytes, while LH impacts pregnancy rate (per oocyte number). Interestingly, Leydig cell in vitro exposure to hCG results in qualitatively similar cAMP/PKA and pERK1/2 activation as compared to LH, as well as testosterone. The supposed equivalence of LH and hCG is debunked by such data highlighting their sex-specific functions, thus deeming it an oversight caused by incomplete understanding of clinical data.


2017 - Effects of probiotics assumption on serum thyroid hormone and TSH levels in hypothyroid patients on levothyroxine treatment. [Abstract in Atti di Convegno]
Spaggiari, Giorgia; Brigante, Giulia; De Vincentis, Sara; Cattini, Umberto; Roli, L.; De Santis, M. C.; Baraldi, Enrica; Tagliavini, S.; Varani, M.; Trenti, T.; Rochira, Vincenzo; Simoni, Manuela; Santi, Daniele
abstract

Background. Probiotics are live microorganisms able to confer a health benefit to the host, when administered in adequate amounts. Despite the widespread use of probiotics, their pharmacological interference remains unclear. The relationship between probiotics and levothyroxine (LT4) requirement has not yet been investigated. Objective. To assess whether a mixture of highly charged Lactobacilli and Bifidobacteria (VSL#3®) is able to influence LT4 metabolism acting on the gut microbiota. Methods. A prospective, randomized, single-blind, controlled, investigator-started clinical trial was carried out. Patients with primary hypothyroidism were randomly assigned to the study (VSL#3®+ LT4) and the control group (LT4). A two months treatment phase was followed by two months of follow-up. Clinical examination, blood tests for thyroid function and for peripheral tissue markers of thyroid hormones effect were performed monthly for 4 months. LT4 dose adjustments were performed during the study when necessary. Results. Thirty-nine patients were enrolled in the study group and 41 in the control group. No difference in thyroid function (thyroid-stimulating hormone (TSH), free triiodothyronine (fT3) and free thyroxine (fT4)) and peripheral tissue markers was found between groups and among visits. FT3/fT4 ratio was directly correlated to TSH at each visit in the control and in the study group, with the exception of the first evaluation of subjects treated with probiotics. LT4 daily dose adjustments occurred 10 times in 8 patients, more frequently in the control than in the study group, despite no differences in the mean LT4 daily dose. Conclusions. VSL#3® does not directly alter thyroid functional compensation. A probiotics- mediated influence on thyroid hormones homeostasis is suggested since probiotics supplementation could be able to prevent serum hormonal fluctuations.


2017 - Genetics of gonadotropins and their receptors as markers of ovarian reserve and response in controlled ovarian stimulation [Articolo su rivista]
Riccetti, Laura; Pascali, Francesco De; Gilioli, Lisa; Santi, Daniele; Brigante, Giulia; Simoni, Manuela; Casarini, Livio
abstract

Several controlled ovarian stimulation (COS) protocols have been developed to increase the yield of mature oocytes retrieved in assisted reproductive techniques (ARTs). The ovarian reserve (OR) influences the COS response, and it represents the main parameter that helps clinicians in refining clinical treatments in the perspective of a "personalized" ART. This approach is even more needed in particular conditions such as poor OR or polycystic ovary syndrome. Follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin are currently used in COS at different combinations and with different efficacies, even if the best approach definition is controversial. Differences in individual-specific ovarian response to gonadotropin stimulation can be due to alterations of genes encoding for hormones or their receptors. In particular, FSHB c.-211G>T, FSHR p.Asn680Ser, and c.-29G>A SNP allelic combinations may be used as OR and COS response markers. The purpose of this review is to highlight the evidence-based relevance of mutations and polymorphisms in gonadotropins and their receptor genes as predictive markers of OR and COS response to achieve fine-tuned therapeutic regimens.


2017 - Gonadotropins beyond ART [Articolo su rivista]
De Vincentis, Sara; Casarini, Livio; Simoni, Manuela; Brigante, Giulia
abstract

Gonadotropins (LH, FSH and hCG) play a central role in controlling steroidogenesis and gametogenesis. For this reason, they are largely used in the treatment of infertility, especially in the setting of assisted reproductive technique. Beyond their important action in the regulation of reproduction, gona dotropins are also involved in other hormonal processes, closely interacting with other endocrine axes. Among them, the interaction between gonadal and thyroid axes is widely studied in the literature. There is evidence of an undeniable structural similarity of both hormones and receptors, maybe due to a common ancient origin. Indeed, altered levels of thyroid hormones could lead to different disorders of gonadal development and function throughout entire life, especially before and during pregnancy. Moreover, a complex interplay between insulin-like growth factors and gonadotropins has been described both at central and peripheral level. Finally, several tumors are able to produce gonadotropins or are regulated by them in their own growth. The role of gonadotropins in the regulation of cellular growth and apoptosis is evident by now, but still not fully understood.


2017 - Pituitary growth hormone (GH) secretion is partially rescued in HIV-infected patients with GH deficiency (GHD) compared to hypopituitary patients [Articolo su rivista]
Diazzi, Chiara; Brigante, Giulia; Ferrannini, G.; Ansaloni, Anna; Zirilli, Lucia; De Santis, M. C.; Zona, Stefano; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

Biochemical growth hormone deficiency is prevalent among human immunodeficiency virus-infected patients, but if this condition is clinically relevant remains challenging. The aim is to prospectively compare the growth hormone deficiency/insulin-like growth factor-1 status of 71 human immunodeficiency virus-infected patients with impaired growth hormone response to growth hormone releasing hormone + Arginine with that of 65 hypopituitary patients affected by a true growth hormone deficiency secondary to pituitary disease. The main outcomes were: basal serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein 3, growth hormone peak and area under the curve after growth hormone response to growth hormone releasing hormone + Arginine test, body mass index, waist and hip circumference, and body composition by dual energy X-ray absorptiometry. Insulin-like growth factor-1 binding protein 3, basal growth hormone (p < 0.005), growth hormone peak and area under the curve after growth hormone response to growth hormone releasing hormone + Arginine, waist to hip ratio, insulin-like growth factor-1, fasting glucose, insulin, and triglycerides (p < 0.0001) were lower in hypopituitary than human immunodeficiency virus-infected patients. Total and trunk fat mass by dual energy X-ray absorptiometry were higher in hypopituitary than in human immunodeficiency virus-infected patients (p < 0.0001). In all the patients total body fat was associated with both growth hormone peak and area under the curve at stepwise linear regression analysis. The degree of growth hormone deficiency is more severe in hypopituitary than in human immunodeficiency virus-infected patients, suggesting that the function of growth hormone/insulin-like growth factor-1 axis is partially rescued in the latter thanks to a preserved pituitary secretory reserve. Data from the current study suggest that human immunodeficiency virus-infected patients with peak growth hormone < 9 mg/L may have partial growth hormone deficiency and clinicians should be cautious before prescribing recombinant human growth hormone replacement treatment to patients living with human immunodeficiency virus.


2017 - Primary Leydig cells naturally expressing mouse LHR do not discriminate between LH- and hCGmediated signaling in vitro [Articolo su rivista]
Riccetti, Laura; Gilioli, Lisa; Brigante, Giulia; Simoni, Manuela; Casarini, Livio
abstract

Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) are glycoprotein hormones fundamental for development and reproduction. These hormones were considered biologically equivalent for decades due to structural similarities and binding to the same receptor (LHCGR), although they mediate different physiological roles. Previous reports demonstrated LH- and hCGspecific intracellular signaling mediated by LHCGR in human primary granulosa cells, but few studies using rodent receptor (Lhr) are available. We investigated the Lhr-mediated activation of the cAMP/PKA-pathway, ERK1/2 and CREB phosphorylation, gene expression and steroidogenesis, in murine Leydig cells treated with LH and hCG. We found that hCG is more potent than LH in inducing cAMP production, as well as downstream the pERK1/2 activation. However, similar levels of CREB phosphorylation, Stard1 gene expression and testosterone production occurred upon LH and hCG treatment in vitro. These findings revealed that rodent Lhr mediates quantitatively, but not qualitatively, different LH- and hCG-dependent signaling, which results in similar testosterone synthesis. These data suggest that in vivo bioassay using a model expressing rodent receptor, which rely on the evaluation of testosterone-dependent endpoints, may be not suitable to quantify gonadotropins activity for clinical purpose.


2017 - Probiotics ingestion does not directly affect thyroid hormonal parameters in hypothyroid patients on levothyroxine treatment [Articolo su rivista]
Spaggiari, Giorgia; Brigante, Giulia; Vincentis, Sara De; Cattini, Umberto; Roli, Laura; De Santis, Maria Cristina; Baraldi, Enrica; Tagliavini, Simonetta; Varani, Manuela; Trenti, Tommaso; Rochira, Vincenzo; Simoni, Manuela; Santi, Daniele
abstract

Purpose: The relationship between probiotics and levothyroxine (LT4) requirement has not yet been investigated. The aim of this study was to assess whether a mixture of highly charged Lactobacilli and Bifidobacteria (VSL#3®) is able to influence LT4metabolism acting on the gut microbiota. Methods: A prospective, randomized, single-blind, controlled, investigator-started clinical trial was carried out. Patients with primary hypothyroidism were randomly assigned to the study (VSL#3® + LT4) and the control group (LT4). A 2-month treatment phase was followed by 2 months of follow-up. Clinical examination, blood tests for thyroid function and for peripheral tissue markers of thyroid hormones (PTM) were performed monthly. LT4dose adjustments were performed when necessary. Results: Thirty-nine patients were enrolled in the study group and 41 in the control group. No difference in thyroid function [thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4)] and PTM was found between groups and among visits. FT3/fT4ratio was directly correlated to TSH at each visit in both groups, with the exception of the first evaluation of probiotics-treated subjects (rho = 0.287, p = 0.076). LT4daily dose adjustments occurred more frequently in the control than in the study group (p = 0.007), despite no differences in the mean LT4daily dose. In particular, LT4doses were increased six times in the control group and decreased four times in the study group. Conclusion: VSL#3® does not directly alter thyroid functional compensation. A probiotics-mediated influence on thyroid hormones homeostasis is suggested since probiotics supplementation could be able to prevent serum hormonal fluctuations.


2017 - Role of the bile acid transporter SLC10A1 in liver targeting of the lipid-lowering thyroid hormone analog eprotirome [Articolo su rivista]
Kersseboom, Simone; Van Gucht, Anja L. M.; Van Mullem, Alies; Brigante, Giulia; Farina, Stefania; Carlsson, Bo; Donkers, Joanne M.; Van De Graaf, Stan F. J.; Peeters, Robin P.; Visser, Theo J.
abstract

The thyroid hormone (TH) analog eprotirome (KB2115) was developed to lower cholesterol through selective activation of the TH receptor (TR) b1 in the liver. Interestingly, eprotirome shows low uptake in nonhepatic tissues, explaining its lipid-lowering action without adverse extrahepatic thyromimetic effects. Clinical trials have shown marked decreases in serum cholesterol levels. We explored the transport of eprotirome across the plasma membrane by members of three TH transporter families: monocarboxylate transporters MCT8 and MCT10; Na-independent organic anion transporters 1A2, 1B1, 1B3, 1C1, 2A1, and 2B1; and Na-dependent organic anion transporters SLC10A1 to SLC10A7. Cellular transport was studied in transfected COS1 cells using [14C]eprotirome and [125I]TH analogs. Of the 15 transporters tested initially, the liver-specific bile acid transporter SLC10A1 showed the highest eprotirome uptake (greater than a sevenfold induction after 60 minutes) as well as TRb1-mediated transcriptional activity. Uptake of eprotirome by SLC10A1 was Na+ dependent and saturable with a Michaelis constant of 8 mM. Eprotirome transport was inhibited by known substrates for SLC10A1 (e.g., cholate and taurocholate), and by TH analogs such as triiodothyropropionic acid and triiodothyroacetic acid. However, no significant SLC10A1-mediated transport was observed of these [125I]TH analogs. We also studied the plasma disappearance and biliary excretion of [14C]eprotirome injected in control and Slc10a1 knockout mice. Although eprotirome is also transported by mouse Slc10a1, the pharmacokinetics of eprotirome were not affected by Slc10a1 deficiency. In conclusion, we have demonstrated that the liver-specific bile acid transporter SLC10A1 effectively transports eprotirome. However, Slc10a1 does not appear to be critical for the liver targeting of this TH analog inmice. Therefore, the importance of SLC10A1 for liver uptake of eprotirome in humans remains to be elucidated. (Endocrinology 158: 3307-3318, 2017).


2017 - Thyroid nodules ultrasound classification and the importance of the endocrinologist clinical feeling. [Abstract in Rivista]
Madeo, Bruno; Brigante, Giulia; Ansaloni, Anna; Taliani, Erica; Simoni, Manuela; Rochira, Vincenzo
abstract

Background and aim of the study Several ultrasound (US) classifications for estimating thyroid nodules risk have been proposed. Since most of them are hardly applicable in clinical practice, we created a local tool, named Modena classification (MC), considering US characteristics and clinician subjective impression. The aim is to verify the diagnostic accuracy of MC and to compare it to US classifications of American Thyroid Association(ATA) (1) and British Thyroid Association(BTA) (2). Methods We prospectively enrolled 111 patients (33M, 78F; age 19–75; total 457 nodules) with an indeterminate, suspicious for malignancy or malignant cytology. All the patients underwent neck US before surgery and a score risk was assigned, according to MC: low (not certainly nodular or not suspect); intermediate (indeterminate); high (suspect or very suspect). Then, we retrospectively classified nodules according to ATA and BTA. The US pattern was related to hystology. Results All the classifications had low sensitivity and positive predictive value (PPV), and high specificity and negative predictive value (NPV) for low risk categories. For the intermediate risk category, BTA had the highest accuracy (68%). For higher risk categories, MC had good sensitivity (62%), high specificity (89%) and accuracy (81%); ATA had high sensitivity (83%), low specificity (48%), accuracy 58%; BTA had high sensitivity (88%), low specificity (44%), accuracy 57%. Conclusions A classification that considers the subjective impression of the clinician, in addition to the known US characteristics, has highest accuracy and specificity compared to guidelines classifications, particularly if the nodule has suspect US features. References (1) Haugen et al. Thyroid. 2016, 26: 1–133. (2) Perros et al. Clin Endocrinol (Oxf). 2014; 81 (Suppl 1):1–122. DOI: 10.1530/endoabs.49.EP1383


2017 - Use of l-Arginine with Growth Hormone-Releasing Hormone (GHRH) and the Endocrine Response [Capitolo/Saggio]
Brigante, Giulia; Rochira, Vincenzo
abstract

Arginine is one of the most common natural amino acids that takes part to the structure of the messenger ribonucleic acid (mRNA). In mammals l-arginine is a semiessential or an essential amino acid depending on age.


2016 - Clinical Applications of Gonadotropins in the Female: Assisted Reproduction and Beyond. [Articolo su rivista]
Casarini, Livio; Simoni, Manuela; Brigante, Giulia; Santi, Daniele
abstract

Gonadotropins (LH, FSH, and hCG) act in concert in the regulation of female reproductive system. Exploiting this influence, they are part of the assisted reproductive technique protocols. In this review we analyze the effectiveness of the different available gonadotropin formulations and the consequent adverse events. Moreover, different protocols for poor-responders and polycystic ovary syndrome affected women are explored. All these clinical different approaches have specific molecular bases, covered in this review starting from evolution and population genetics, getting to in vitro studies of gonadotropins action. Beyond their application in assisted reproductive technique, gonadotropins have also been largely studied for their intertwined network of interactions with other hormones, which all together contribute to the functioning of the reproductive system and other hormonal axes. In particular, there is both clinical and molecular evidence of interaction between thyroid hormones and insulin growth factors with gonadotropins. Finally, gonadotropins are widely studied for their role in the maintenance of the proper balance between cell proliferation and differentiation, and therefore in cancer.


2016 - Is polycystic ovary syndrome a sexual conflict? A review [Articolo su rivista]
Casarini, Livio; Simoni, Manuela; Brigante, Giulia
abstract

Several studies have attempted to explain the high overall prevalence of polycystic ovary syndrome among women worldwide (about 4-10%) despite its link to subfertile phenotypes. For this reason, it is considered an evolutionary paradox. In this review, we show that several genetic loci associated with the disease differently modulate the reproductive parameters of men and women. This observation suggests that such genetic variants lead to opposite effects in the two sexes in reproductive success. Intralocus sexual conflict as a cause of the persistence polycystic ovary syndrome genotypes among humans is supported.


2016 - Serum total estradiol, but not testosterone is associated with reduced bone mineral density (BMD) in HIV-infected men: a cross-sectional, observational study [Articolo su rivista]
Santi, Daniele; Madeo, Bruno; Carli, Federica; Zona, Stefano; Brigante, Giulia; Vescini, F.; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

By investigating the relationship between serum testosterone, estradiol, and bone mineral density (BMD) in a large cohort of HIV-infected men, estradiol was associated with BMD, relative estrogen deficiency being involved in bone loss in men with hypogonadism, in addition to all HIV-related factors. Increased aromatization in adipose tissue does not counteract HIV-related bone loss. INTRODUCTION: The purpose of this study is to evaluate the relationship between serum testosterone, estradiol, and BMD in a large cohort of HIV-infected men. METHODS: We investigated biochemical, hormonal parameters, and BMD in 1204 HIV-infected men (age 45.64 ± 7.33 years) participating in a cross-sectional, observational study. Among other parameters, the main outcome measures were serum total testosterone and estradiol, gonadotropins, 25-hydroxyvitamin D [25(OH)D], parathormone (PTH), calcium, phosphorous, femoral, and lumbar BMD. RESULTS: In men with HIV, the prevalence of osteoporosis and osteopenia is 15.1 and 63.2 % with 25(OH)D insufficiency being very common (60.1 %). After age adjustment, BMD is positively associated with estradiol, but not testosterone, at linear (p < 0.001) and stepwise (p < 0.05) multiple regression. Lumbar BMD significantly increases across the estradiol quartiles but not among testosterone quartiles. Femoral and lumbar BMD are significantly higher in men with estradiol ≥ 27 pg/mL than in those with estradiol <27 pg/mL. Apart from estradiol, only age, calcium, and BMI predict BMD at stepwise linear multiple regression, but the strength of this association is weak. CONCLUSIONS: Estradiol, but not testosterone, is associated with BMD in HIV-infected men and exerts a protective role on bone especially when it is above 27 pg/mL. Relative estrogen deficiency is a potential mechanism involved in bone loss in hypogonadal HIV-infected men, in addition to all HIV-related factors. Increased aromatization in adipose tissue does not counteract HIV-related bone loss. Finally, reduced BMD in young-to-middle-aged HIV-infected men might be considered a peculiar hallmark of HIV infection due to its relevant prevalence, representing one of the several pieces composing the complicated puzzle of premature aging related to HIV infection.


2016 - Thyroid Ultrasound Pitfalls: Esophageal Fibrovascular Polyp Mimicking Thyroid Nodule [Articolo su rivista]
Ansaloni, Anna; Brigante, G; Madeo, B
abstract

Background. Ultrasound (US) is the most accurate tool in the diagnosis of thyroid nodules if performed by expert physician. Misdiagnosis due to extrathyroidal lesions mimicking thyroid nodules is reported in literature. We describe the first case of an esophageal fibrovascular polyp misdiagnosed as a thyroid nodule on US examination. Patient Findings. A 54-year-old woman presented to emergency department for headache and underwent carotid Doppler extended to neck ultrasound with incidental finding of a nodule in the posterior side of the left thyroid lobe. A following thyroid US performed by an endocrinologist allowed the characterization of the lesion as an esophageal pathology, considering the extrathyroidal position, the typical peripheral hyperechoic spots and hypoechoic rim, the connection to the esophagus, and the swallowing connected movement. The patient was addressed to further investigations and finally to anterior pharyngotomy with histological diagnosis of esophageal fibrovascular polyp. Summary. Differential diagnosis between thyroid nodules and other neck lesions is important to prevent an unnecessary fine needle aspiration biopsy and to treat the extrathyroidal pathology. In this case, an US performed by an expert endocrinologist allowed detecting an esophageal fibrovascular polyp requiring surgical removal. In conclusion, the possibility of an esophageal pathology, and even fibrovascular polyp, should be considered during US thyroid examination.


2015 - BIOLOGICAL ACTIVITY OF NOVEL THYROID HORMONE ANALOGUES: ROLE OF Na+ TAUROCHOLATE COTRANSPORTING POLYPEPTIDE IN LIVER SELECTIVITY [Abstract in Atti di Convegno]
Brigante, Giulia; Carlsson, B; Kersseboom, S; Peeters, Rp; Visser, Tj
abstract

Background: The interest in the potential effect of thyromimetics in lowering serum cholesterol is growing. Thyroid hormone actions on lipid metabolism are exerted in the liver and mediated by the T3 receptor TRβ1. The creation of molecules transported into hepatocytes by liver-specific transporters can increase the liver selectivity of thyromimetics. Sodium taurocholate co-transporting polypeptide (NTCP), a solute carrier protein primarily expressed on the basolateral membrane of hepatocytes, is particularly interesting. Objectives: The role of NTCP in the liver preferential uptake of a series of new thyromimetics was analysed. Methods: The compounds to test (KB141, KB5588, KB6628, KB6823, KB3488, KB3493, KB3495, KB4933, KB4956, KB5035, KB5160, KB5359, KB5525, KB5526, KB5866, KB6594, KB8038) were synthesised at Karo Bio AB. To explore the effect of NTCP on the nuclear availability of each compound, COS1 cells were co-transfected with TRβ1, NTCP, a construct coding for a TRE-dependent luciferase reporter and a control renilla reporter. Two days after transfection, cells were incubated for 24 h with 0.1–1000 nM of each compound. Incubation with the same concentrations of T3 was added as a control. The luciferase/renilla ratio was the measure of the compound transcriptional activity. Results: Like T3, KB141, KB5588, KB3488 and KB6823 demonstrated no differences in transcriptional activity in the absence or presence of NTCP. KB6628, KB5035, KB5866, KB5160 and KB4956 showed a 1.5-fold higher activity in cells transfected with NTCP compared to cells transfected with empty pcDNA3 vector. KB3493, KB3495, KB5359, KB5525, KB5526, KB4933, KB6594 and KB8038 showed an even greater difference as they had no activity in the absence of NTCP and a fourfold higher activity in the presence of NTCP. Conclusions: NTCP is an attractive transporter to target thyromimetics to the liver.


2015 - Genetic markers of ovarian response. [Capitolo/Saggio]
Brigante, Giulia; Simoni, Manuela
abstract


2015 - High-Resolution Melting is a sensitive, cost-effective, time-saving technique for BRAF V600E detection in thyroid FNAB washing fluid: a prospective cohort study [Articolo su rivista]
Marino, Marco; Monzani, Maria Laura; Brigante, Giulia; Cioni, Katia; Madeo, Bruno; Santi, Daniele; Maiorana, Antonino; Bettelli, Stefania Raffaella; Moriondo, Valeria; Pignatti, Elisa; Bonacini, Lara; Carani, Cesare; Rochira, Vincenzo; Simoni, Manuela
abstract

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2015 - Low testosterone is associated with poor health status in men with human immunodeficiency virus infection: a retrospective study [Articolo su rivista]
Rochira, Vincenzo; Diazzi, Chiara; Santi, Daniele; Brigante, Giulia; Ansaloni, Anna; Decaroli, Maria Chiara; De Vincentis, Sara; Stentarelli, Chiara; Zona, Stefano; Guaraldi, Giovanni
abstract

Men with human immunodeficiency virus (HIV) infection are often hypogonadal and develop several HIV-associated non-acquired immunodeficiency syndrome (AIDS) (HANA) conditions that impair overall health status. No studies explored the relationship between health status and serum testosterone (T) in HIV-infected men. This study aims to investigate the association between total serum T and HANA, multimorbidity, and frailty in a large cohort of 1359 HIV-infected men and to explore the relationship between patients' overall health status and serum T. Among biochemical and hormonal measurement performed the main are serum total T, free triiodothyronine (fT3), and luteinizing hormone. Other outcome measurements include anthropometry, assessment of comorbidities and disabilities, overall health status defined as the number of HANA and by the 38-item multimorbidity frailty index, anthropometry, and bone mineral density. The cumulative relative risk of comorbidities is increased in HIV-infected men with hypogonadism (p < 0.001) and hypogonadism is associated with several comorbidities. The prevalence of hypogonadism increases progressively with the increase of the number of comorbidities. Frailty index is inversely related to serum total T (age-adjusted r = 0.298, r(2) = 0.089, p < 0.0001). Serum fT3 levels are significantly lower in hypogonadal than eugonadal men (p = 0.022). This suggests that low serum T could be considered a sensitive marker of frailty and poor health status and that the latter might induce hypogonadism. The more HIV-infected men are frail the more they are hypogonadal. This suggests that hypogonadism might be a naturally occurring condition in unhealthy HIV-infected men and raises concern about the safety of T treatment. In conclusion, low serum T is associated with multimorbidity, HANA, and frailty in HIV-infected men and this association seems to be bidirectional. Given the wide attitude to offer T treatment to HIV-infected men, caution is needed when prescribing T to HIV-infected male patients, especially if the patient is unhealthy or frail.


2015 - Response to letter by Azziz R., et al. [Articolo su rivista]
Casarini, Livio; Brigante, Giulia
abstract

Comment on The polycystic ovary syndrome evolutionary paradox: a genome-wide association studies-based, in silico, evolutionary explanation. [J Clin Endocrinol Metab. 2014] Letter to the editor re: Casarini and Brigante, 2014, from Azziz R., et al. [J Clin Endocrinol Metab. 2015]


2015 - Serum gonadotropins secretion is not reduced with advancing age in HIV-infected females: results of a case–control study in menopausal women. [Abstract in Rivista]
Diazzi, Chiara; Brigante, Giulia; Guaraldi, Giovanni; Simoni, Manuela; Rochira, Vincenzo
abstract

Introduction HIV infection treated with highly active antiretroviral therapy (HAART) seems to be associated with hypogonadism in men. Less is known in HIV-infected women gonadal status. The aim of this study is to investigate gonadal function, in menopausal HIV-infected women compared sex- and age-matched healthy subjects (HS). Methods We retrospectively compared 188 HIV-infected women with 192 HS selected reviewing record charts and laboratory database respectively. We considered only women older than 50 years and we grouped them according to their age (50–54; 55–59; and O60 years). Basal serum LH, FSH, estradiol, and testosterone were measured. The FSH cut-off of 40 UI/l for establishing menopausal status. Results The percentage of subjects with FSH levels O40 UI/l was higher in HIV-infected women (67.5%) than in healthy controls (59.4%). This difference was found also in the younger subgroup (38% vs 27%). FSH serum levels in HIV-infected women (54.08G31.47 mUI/ml) did not differ (PZ0.27) from HS (50.87G 31 mUI/ml). Accordingly, no significant differences were found in LH, estradiol, and testosterone levels. Conclusions Menopause seems to occur at a younger age than HS in HIV-infected women. Moreover, differently from what was documented in HIV-infected male counterpart, HIV-infected women seem to not develop hypogonadotropic hypogonadism, but have a tendency to higher serum FSH at a younger age (!54 years) suggesting premature hypergonadotropic hypogonadism. With this in view menopause may be considered an element of the process of premature aging associated with HIV infection and its comorbidities.


2014 - BRAF V600E mutation in washing liquid of thyroid fine-needle aspiration: a surprising tool in cytological benign nodules. [Abstract in Rivista]
Monzani, Maria Laura; Brigante, Giulia; Marino, Marco; L., Bonacini; Pignatti, Elisa; K., Cioni; Madeo, Bruno; Rochira, Vincenzo; Santi, Daniele; Maiorana, Antonino; Carani, Cesare; Simoni, Manuela
abstract

The good diagnostic value of a new method for BRAF V600E detection within the washing fluid of thyroid fine-needle aspiration biopsy has been demonstrated together with time and cost saving characteristics of this procedure.


2014 - Funzione gonadica e sessuale in uomini giovani/adulti con infezione da Human Immunodeficiency Virus (HIV) [Abstract in Atti di Convegno]
Santi, Daniele; Brigante, Giulia; C., Diazzi; S., De Vincentis; Zona, Stefano; Guaraldi, Giovanni; Simoni, Manuela; Rochira, Vincenzo
abstract

This study investigates male sexual function in men with HIV infection according with their gonadal status and circulating androgens


2014 - Gender differences in GH response to GHRH+ARG in lipodystrophic patients with HIV: a key role for body fat distribution [Articolo su rivista]
Brigante, Giulia; Diazzi, Chiara; Ansaloni, Anna; Zirilli, Lucia; Orlando, Gabriella; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

OBJECTIVE: Gender influence on GH secretion in human immunodeficiency virus (HIV)-infected patients is poorly known. DESIGN AND METHODS: To determine the effect of gender, we compared GH response to GH-releasing hormone plus arginine (GHRH+Arg), and body composition in 103 men and 97 women with HIV and lipodystrophy. The main outcomes were IGF1, basal GH, GH peak and area under the curve (AUC) after GHRH+Arg, body composition, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). RESULTS: Men had lower GH peak and AUC than women (P<0.001). Of the study population, 21% of women and 37% of men had biochemical GH deficiency (GHD; GH peak <7.5 μg/l). VAT-to-SAT ratio was higher in men than in women with GHD (P<0.05). Unlike women, VAT, SAT, and trunk fat were greater in men with GHD than in men without GHD. IGF1 was significantly lower in women with GHD than in women without GHD, but not in men. At univariate analysis, BMI, trunk fat mass, VAT, and total adipose tissue were associated with GH peak and AUC in both sexes (P<0.05). BMI was the most significant predictive factor of GH peak, and AUC at multiregression analysis. Overall, abdominal fat had a less pronounced effect on GH in females than in males. CONCLUSIONS: These data demonstrate that GH response to GHRH+Arg is significantly lower in HIV-infected males than females, resulting in a higher percentage of GHD in men. Adipose tissue distribution more than fat mass per se seems to account for GH gender differences and for the alteration of GH-IGF1 status in these patients.


2014 - GH deficiency in HIV-infected patients compared to hypoopituitary patients [Abstract in Rivista]
Diazzi, Chiara; Brigante, Giulia; G., Ferrannini; Guaraldi, Giovanni; Ansaloni, Anna; Simoni, Manuela; Rochira, Vincenzo
abstract

The difference between HIV-infected patients with growth hormone deficiency (GHD) and GHD patients with hypopituitarism is in higher values go GH peak after GHRH+Arginine and IGF-1 in men with HIV.


2014 - GH deficiency in HIV-infected patients compared to hypopituitary patients [Abstract in Rivista]
Brigante, Giulia; Diazzi, Chiara; G., Ferrannini; S., De Vincentis; Guaraldi, Giovanni; Ansaloni, Anna; Simoni, Manuela; Rochira, Vincenzo
abstract

Gh peak after GHR+Arginine and IGF-1 are lower in HIV-infected patients with biochemical growth hormone deficiency than in patients with hypopituitarism and GHD.


2014 - Gonadal and sexual function in young/middle aged human immunodeficiency virus (HIV)-infected men [Abstract in Rivista]
Santi, Daniele; Brigante, Giulia; Diazzi, Chiara; S., De Vincentis; Zona, Stefano; Guaraldi, Giovanni; Simoni, Manuela; Rochira, Vincenzo
abstract

The study investigated male sexual function in men with HIV infection according with their gonadal status.


2014 - I pazienti con infezione da HIV hanno un reale deficit di GH (GHD) ? Confronto tra pazienti HIV positivi con documentato GHD biochimico e pazienti ipopituitarici HIV negativi con GHD [Abstract in Atti di Convegno]
Brigante, Giulia; Diazzi, Chiara; G., Ferrannini; Guaraldi, Giovanni; Ansaloni, Anna; Simoni, Manuela; Rochira, Vincenzo
abstract

The response to GHRH+Arginine is higher in HIV-infected patients with GHD when compared to patients with GHD and hypopituitarism


2014 - Identificazione di BRAF V600E nel liquido di lavaggio dell’agoaspirato: un nuovo strumento nella diagnostica del nodulo tiroideo [Abstract in Atti di Convegno]
Monzani, Maria Laura; Brigante, Giulia; Marino, Marco; L., Bonacini; Pignatti, Elisa; K., Cioni; Madeo, Bruno; Rochira, Vincenzo; Santi, Daniele; Maiorana, Antonino; Carani, Cesare; Simoni, Manuela
abstract

This study investigates the diagnostic value of a new methodology for the detection of the BRAF mutation in samples of washing fluid of thyroid fine needle aspiration biopsies. The study demonstrates that this method is valid, and time and cost saving.


2014 - Il volume tiroideo è ridotto in pazienti adulti affetti da beta-talassemia rispetto ai controlli [Abstract in Atti di Convegno]
Ansaloni, Anna; Diazzi, Chiara; Santi, Daniele; Brigante, Giulia; Ferrara, Francesca; Pietrangelo, Antonello; Simoni, Manuela; Rochira, Vincenzo
abstract

This study demonstrates that thyroid volume in adult patients with beta-thalassemia is reduced when compared with that of matched control subjects


2014 - Male sexual dysfunction and HIV--a clinical perspective. [Articolo su rivista]
Santi, Daniele; Brigante, Giulia; Zona, Stefano; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

Sexual dysfunction in men with HIV is often overlooked by clinicians owing to many factors, including the taboo of sexuality. The improved life expectancy of patients with HIV requires physicians to consider their general wellbeing and sexual health with a renewed interest. However, data on sexual dysfunction in those with HIV are scarce. Erectile dysfunction (ED) is the most common sexual dysfunction in men, with a prevalence of ∼30-50% and is frequent even in men <40 years of age. HIV infection itself is the strongest predictor of ED, and many factors related to the infection-fear of virus transmission, changes in body image, HIV-related comorbidities, infection stigma, obligatory condom use-all impair erectile function. The diagnosis and treatment of sexual dysfunction is based on a multidisciplinary approach, which involves specialists in both infectious diseases and sexual medicine. Particular attention should be paid to the promotion of safer sex in these patients. This Review, describes the issues surrounding sexual dysfunction in men with HIV and aims to provide clinical advice for the physician treating these patients.


2014 - Relationship between testosterone and HIV-related comorbidities: secondary hypogonadism is associated with a poor health status in HIV-infected men [Abstract in Atti di Convegno]
Rochira, Vincenzo; Diazzi, Chiara; Brigante, Giulia; Santi, Daniele; Maria Chiara De, Caroli; Sara De, Vincentis; Simoni, Manuela; Carani, Cesare; Guaraldi, Giovanni
abstract

ABSTRACT INTRODUCTION: Testosterone (T) deficiency is very common in men with Human Immunodeficiency Virus (HIV), and it is more often associated with inappropriately low/normal luteinizing hormone (LH). However, the underlying causes remain poorly understood. Moreover, the role of HIV and/or HIV infection treatments, as well as the role of the general health status on the gonadal axis have been rarely investigated. AIM: The aim of this study is to evaluate the association between gonadal function and health status in men with HIV infection. METHODS: We performed a cross-sectional, observational study on 1359 consecutive HIV male outpatients. Morning serum Total T (TT), LH, estradiol, HIV parameters were measured. Frailty Index and number of comorbidities were extracted from the Clinical Database in which all patients data are recorded. TT<300 ng/dL was used as the threshold for biochemical T deficiency. RESULTS: T deficiency was found in 212 subjects (15.6%), and most of them (n=183; 13.4%) had secondary hypogonadism. TT resulted inversely related to Frailty Index in all patients (r=0.302, r2=0.091), this correlation being strengthened in HIV- infected men with secondary hypogonadism (r=0.403, r2=0.162). The percentage of HIVinfected men with TT <300 ng/dL increased progressively in accordance with the increase in the number of comorbidities (0.5%, 2.8%, 8.5%, 22.7%, 25.5%, 40% in men with 0, 1, 2, 3, 4, and >5 comorbidities, respectively). CONCLUSION: Poor health status in HIV-infected men might be involved in the pathogenesis of hypogonadism. This mechanism could reflect an adaptive response to illness in unhealthy patients similarly to what happens in other clinical conditions such as anorexia nervosa. Thus, low TT could be considered a biomarker of frailty and might confer an advantage for both the sick patients (in terms of sparing energy) and the species (preventing fatherhood). Furthermore, frailty related hypogonadism could be part of the process of premature aging already demonstrated in HIVinfected patients.


2014 - The polycystic ovary syndrome evolutionary paradox: a genome-wide association studies-based, in silico, evolutionary explanation. [Articolo su rivista]
Casarini, Livio; Brigante, Giulia
abstract

Objective: In this study we analyze the PCOS phenotype-genotype relationship in silico, using SNPs of representative genes for analysis of genetic clustering and distance, to evaluate the degree of genetic similarity. Data Source: 1000 Genomes, HapMap, and Human Genome Diversity Project databases were used as source of allele frequencies of the SNPs, using data from male and female individuals grouped according to their geographical ancestry. Setting and Design: Genetic clustering was calculated from SNPs data by Bayesian inference. The inferred ancestry of individuals was matched with PCOS phenotype data, extracted from a previous meta-analysis. The measure of genetic distance was plotted against the geographic distance between the populations. Results: The individuals were assigned to five genetic clusters, matching with different world regions (Kruskal-Wallis/Dunn's post test; P < .0001), and converging in two main PCOS phenotypes in different degrees of affinity. The overall genetic distance increased with the geographic distance among the populations (linear regression; R2 = 0.21; P < .0001), in a phenotype-unrelated manner. Conclusions: Phenotype-genotype correlations were demonstrated, suggesting that PCOS genetic gradient results from genetic drift due to a serial founder effect occurred during ancient human migrations. The overall prevalence of the disease supports intralocus sexual conflict as alternative to the natural selection of phenotypic traits in females.


2014 - The TRHR Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine [Articolo su rivista]
Brigante, Giulia; Spaggiari, Giorgia; Santi, Daniele; Cioni, Katia; Gnarini, Valentina; Diazzi, Chiara; Pignatti, Elisa; Casarini, Livio; Marino, Marco; Tüttelmann, Frank; Carani, Cesare; Simoni, Manuela
abstract

Thyroidectomized patients need variable doses of levothyroxine (LT4) to obtain target thyroid-stimulating hormone (TSH) levels. Individual feedback set-points have been hypothesized and the influence of several genes in the regulation of the pituitary-thyroid axis has been demonstrated.


2014 - Thyroid volume in adult beta-thalassemic patients is smaller than in controls [Abstract in Rivista]
Ansaloni, Anna; Diazzi, Chiara; Santi, Daniele; Brigante, Giulia; Ferrara, Francesca; Carani, Cesare; Pietrangelo, Antonello; Simoni, Manuela; Rochira, Vincenzo
abstract

Thyroid volume is significantly reduced in adult patients with beta-thalassemia than in matched controls


2014 - Thyroid volume in adult beta-thalassemic patients is smaller than in controls [Abstract in Rivista]
Ansaloni, Anna; Diazzi, Chiara; Santi, Daniele; Brigante, Giulia; F., Ferrara; Pietrangelo, Antonello; Rochira, Vincenzo
abstract

Patients with beta-thalassemia have lower thyroid volume estimated at ultrasound than matched controls.


2013 - Effects of gender and body composition on GH response to GHRH plus Arginine (GHRH+ARG) in HIV-lipodystrophic patients [Abstract in Rivista]
Brigante, Giulia; Diazzi, Chiara; G., Ferrannini; Ansaloni, Anna; Zirilli, Lucia; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

GH-deficiency is more frequent in men with HIV than in HIV-infected women.


2013 - Effects of gender and body composition on GH response to GHRH plus Arginine (GHRH+Arg) in HIV-lipodystrophic patients: higher rate of GH deficiency in men. [Abstract in Rivista]
Brigante, Giulia; Diazzi, Chiara; G., Ferrannini; Ansaloni, Anna; Zirilli, Lucia; Carani, Cesare; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

The study investigates gender differences in the rate of GH-deficiency among hIV-infected men.


2013 - Effects of gender and body composition on GH response to GHRH+Arg in HIV-lipodystrophic patients: higher rate of GH deficiency in men [Abstract in Rivista]
Brigante, Giulia; Diazzi, Chiara; Giulia, Ferrannini; Ansaloni, Anna; Zirilli, Lucia; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

The study investigated the gender difference in GH secretion after GHRH+Arg in patients with HIV-related lipodystrophy showing hoe men are at higher risk to fail to respond copmared to females. In this group of patients with HIV that are at higher risk of GH deficiency, men have higher risk of GH deficiency than women.


2013 - Effects of treatment for acromegaly on Bone Mineral Density (BMD): is Pegvisomant protective on lumbar BMD? [Abstract in Rivista]
Brigante, Giulia; Santi, Daniele; Diazzi, Chiara; S., De Vincentis; G., Ferrannini; Madeo, Bruno; Simoni, Manuela; Carani, Cesare; Rochira, Vincenzo
abstract

The abstract deals with the different effects of treatments for acromegaly on bone


2013 - Effects of treatment for acromegaly on bone mineral density (BMD): is pegvisomant protective on lumbar BMD? [Abstract in Rivista]
Brigante, Giulia; Santi, Daniele; Diazzi, Chiara; S., De Vincetis; G., Ferrannini; Madeo, Bruno; Simoni, Manuela; Rochira, Vincenzo; Carani, Cesare
abstract

The type of medical therapy for acromegaly may have different effects on bone mineral density


2013 - Effects of treatment for acromegaly on bone mineral density: is pegvisomant protective on lumbar BMD? [Abstract in Rivista]
Brigante, Giulia; Santi, Daniele; Diazzi, Chiara; Sara De, Vincentis; Giulia, Ferrannini; Madeo, Bruno; Carani, Cesare; Simoni, Manuela; Rochira, Vincenzo
abstract

The type of pharmacological treatment used for the control of acromegaly might have different effect in the prevention of bone loss.


2013 - Endoscopic transsphenoidal approach as a promising surgical option in the treatment of craniopharyngioma [Abstract in Rivista]
Faustini-Fustini, Marco; Zoli, Matteo; Mazzatenta, Diego; Santi, Daniele; Brigante, Giulia; Pasquini, Ernesto; Frank, Giorgio
abstract

10.1530/endoabs.32.P850


2013 - TSH-deficiency is associated with a lower thyroid gland volume in hypopituitaric patients compared to healthy volunteers: a cross-sectional study [Abstract in Rivista]
Santi, Daniele; Brigante, Giulia; Gnarini, Valentina; Madeo, Bruno; Sara De, Vincentis; Carani, Cesare; Marco Faustini, Fustini; Balestrieri, Antonio; Rochira, Vincenzo
abstract

The lack of TSH secretion due to hypopituitarism does not influence thyroid nodules volume and their respective progressive growth. Otherwise growth of normal thyroid tissue is under the control of TSH; when the latter is undetectable thyroid volume appears to be reduced compared to controlsonly if thyroid nodules are absent.


2013 - TSH-deficiency is associated with a lower thyroid gland volume in hypopituitaric patients compared to healthy volunteers: a cross-sectional study [Abstract in Rivista]
Santi, Daniele; Brigante, Giulia; Gnarini, Valentina; Madeo, Bruno; S., De Vincentis; Carani, Cesare; M., Faustini Fustini; Balestrieri, Antonio; Rochira, Vincenzo
abstract

TSH deficiency is related to a lower volume of the thyroid in the case of absent thyroid disease, but it has no effect on nodular thyroid disease.


2013 - TSH-deficiency is associated with a lower thyroid gland volume in hypopituitaric patients compared to healthy volunteers: a cross-sectional study. [Abstract in Rivista]
Rochira, Vincenzo; Santi, Daniele; Brigante, Giulia; Gnarini, Valentina; Madeo, Bruno; Sara De, Vincentis; Marco Faustini, Fustini; Balestrieri, Antonio; Carani, Cesare
abstract

The study investigated the effects of long-term TSH-deficiency on thyroid volume suggesting that only healthy thyroid tissue is TSH-dependent, while nodular thyroid tissue is less TSH-dependent


2013 - Very high prevalence of ultrasound thyroid scan abnormalities in healthy volunteers in Modena, Italy [Articolo su rivista]
Gnarini, Valentina; Brigante, Giulia; DELLA VALLE, Elisa; Diazzi, Chiara; Madeo, Bruno; Carani, Cesare; Rochira, Vincenzo; Simoni, Manuela
abstract

Background: Italy is characterized by high preva- lence of goiter. To date, only limited data about the preva- lence of goiter in the Italian adult population are available. Aim: To investigate the prevalence of thyroid ultrasound ab- normalities in adults unaware of any thyroid disease and eval- uate the rate of differentiated thyroid cancer (DTC) obtained by this intervention. Methods: Ultrasound (US) thyroid scan was performed in adult volunteers recruited by advertisement in Modena, Italy. One hundred and thirty-five women and 66 men (no.= 201), unaware of any thyroid disease (mean age of 46±10.7 yr) underwent their first thyroid US scan. Results: US thyroid abnormalities were found in 101 subjects (50.3%): 91 nodular goiters (45.2%) and 13 US-thyroiditis (6.5%) associ- ated with positive auto-antibodies in 11 of them. Seventeen subjects (18%) with nodules underwent US-fine needle aspiration biopsy with the following cytological class (C) outcome: 14 patients C2 (82%), 1 patient C3 (6%), 2 patients had C4 (12%), the latter received histological confirmation. Conclu- sions: The prevalence of thyroid abnormalities is very high in subjects unaware of any thyroid disease. DTC was found in 1% of subjects and in 2% of those affected by nodular goi- ter. Compared to the detection rate of the well-established screening programs for breast (0.45%) and colorectal (0.27%) cancer, the prevalence of DTC seems to be much higher. Thy- roid US screening could allow the detection of DTC in asymp- tomatic subjects and this diagnosis often includes DTC at an advanced stage. Thus, US screening not necessarily results in the over-diagnosis of clinically not relevant thyroid diseases.


2012 - GH response to GHRH plus Arginine in lipodistrophic patients with human immunodeficiency virus: gender differences [Abstract in Rivista]
Brigante, Giulia; Diazzi, Chiara; Guaraldi, Giovanni; M., De Santis; L., Roli; Rochira, Vincenzo; Baraldi, Enrica
abstract

GH deficiency is more frequent in men with HIV than in HIV-infected women


2012 - Nuovi scenari di disfunzione sessuale: il paziente HIV positivo [Relazione in Atti di Convegno]
Santi, Daniele; Brigante, Giulia; Rochira, Vincenzo
abstract

Il capitolo esamina la prevalenza delle disfunzioni sessuali maschili in pazienti con infezione da HIV. Inoltre le peculiarità riguardanti la clinica (diagnosi e terapia) delle disfunzioni sessuali in tale particolare contesto vengono analizzate in dettaglio


2012 - Nuovi scenari di disfunzione sessuale: il paziente HIV positivo [Capitolo/Saggio]
Santi, Daniele; Brigante, Giulia; Rochira, Vincenzo
abstract


2012 - Propylthiouracil-induced interstitial pneumonia in a caucasian woman with amiodarone-induced thyrotoxicosis [Articolo su rivista]
Diazzi, Chiara; Brigante, Giulia; Rossi, Giulio; Rochira, Vincenzo
abstract

Background: Propylthiouracil (PTU) therapy is associated with a variety of adverse reactions, among the most rare being interstitial pneumonia. To date, this has been reported in four Asian patients with autoimmune hyperthyroidism. Here we describe a Caucasian woman who developed a bronchiolitis obliterans organizing pneumonia (BOOP)-like interstitial pneumonia after PTU administration for amiodarone-induced thyrotoxicosis. Patient Findings: The patient was a 68-year-old woman who had been treated with amiodarone for chronic atrial fibrillation starting in May 2004. She had been a heavy smoker with a history of hypertension but no dust exposures. In October 2006, amiodarone was stopped after she developed thyrotoxicosis. In January 2007 serum thyroid-stimulating hormone (TSH) was 0.01 mIU/L (0.35-4.94) and free T4 was 17.5 pg/mL (7 to 15). She was initially started on methimazole and then changed to PTU after she developed pruritus. She developed severe dyspnea 9 months after starting PTU. At the time she was also taking warfarin, enalapril, and sotalol. Chest X-ray showed diffuse interstitial peripheral opacities and transbronchial lung biopsy revealed subacute lung injury with organizing pneumonia with hyperplasia of the alveolar type 2 pneumocytes, and characteristics of BOOP-like interstitial pneumonia. Signs and symptoms progressively improved after PTU discontinuation as confirmed at X-ray and computed tomography (CT) scan of the chest and by respiratory function tests. She has been recurrence free for 4 years after stopping PTU. Summary: This woman of Caucasian ancestral origin developed BOOP-like interstitial pneumonia after PTU treatment for apparent amiodarone-induced thyrotoxicosis, with resolution of her lung disease after stopping PTU. Tests for TSH receptor antibodies, thyroid peroxidase antibodies, and antinuclear cytoplasmic autoantibody were negative. Thyroid ultrasound was consistent with thyroiditis without nodules. Conclusions: PTU-associated interstitial pneumonia is not limited to patients of Asian origin or those with autoimmune thyroid disease. PTU must be withdrawn in the presence of respiratory symptoms and documented interstitial pneumonia. X-ray films, CT-scan, respiratory function tests, and lung biopsy are needed to diagnose PTU-induced interstitial pneumonia with certainty and to monitor the evolution of the disease after PTU discontinuation.


2012 - The TRHR gene is associated to hypothalamo-pituitary sensitivity to levothyroxine in thyroidectomized patients [Abstract in Atti di Convegno]
Brigante, Giulia; Spaggiari, Giorgia; Cioni, K; Gnarini, Valentina; Pignatti, Elisa; Casarini, Livio; Marino, Marco; Tüttelmann, F; Carani, Cesare; Simoni, Manuela
abstract

Background: Patients thyroidectomized for thyroid cancer need variable doses of levothyroxine (LT4) to obtain TSH suppression. A predetermined thyroid function set-point for each individual has been hypothesized, suggesting a genetic influence in the regulation of pituitary-thyroid axis. We hypothesized of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to the negative feedback of the thyroid hormones. Methods: We performed a case–control association study, enrolling 107 thyroidectomized patients, in follow-up for differentiated thyroid cancer, and 99 volunteer controls. Patients were evaluated first when TSH levels were suppressed (<0.1 mIU/l), by the lowest effective LT4 dose, and then when TSH was subsuppressed (0.1<TSH<0.5 mIU/l). We selected two SNPs of TRHR gene, rs3134105 and rs3110040, identified as informative markers, using the online database ‘HapMap’. We performed a frequency analysis of the mapped SNPs, followed by a linkage analysis using the HaploView software. Genotyping was performed using the High Resolution Melting technology. Results: The selected SNPs were in linkage disequilibrium. A significant difference between the three possible genotypes for rs3134105 was found for fT4/TSH ratio (P=0.03). Moreover, despite similar serum concentrations of fT3 and fT4 obtained by similar levothyroxine doses, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (P=0.04) as well as higher fT3/TSH (P=0.05) and fT4/TSH ratios (P=0.02). Conclusions: We demonstrated an association between TSH and discrete alleles of the TRHR gene identified by the markers SNPs rs3134105 and rs3110040 in totally thyroidectomized patients with diagnosis of thyroid cancer under subsuppressive LT4 therapy. The TRHR gene is a determinant of hypothalamo-pituitary sensitivity to levothyroxine in such patients.


2012 - Ultrasound (US) Features of Thyroid Nodules with Cytology Suspicious for Malignancy [Abstract in Rivista]
Rochira, Vincenzo; Taliani, Erica; Ansaloni, Anna; Diazzi, Chiara; Brigante, Giulia; Carani, Cesare; Madeo, Bruno
abstract

Several US features are associated with and predict thyroid malignancy


2011 - Erectile Dysfunction Does Not Mirror Endothelial Dysfunction in HIV-Infected Patients [Abstract in Rivista]
Santi, Daniele; Mattia, Beggi; Brigante, Giulia; Zona, Stefano; Kety, Luzy; Orlando, Gabriella; Rossi, Rosario; Pierre, Bouloux; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

Non classical risk factors are associated with HIV-related erectile dysfunction


2011 - Erectile dysfunction does not mirror endothelial dysfunction in hiv-infected patients [Abstract in Rivista]
Santi, Daniele; Mattia, Beggi; Brigante, Giulia; Zona, Stefano; Luzi, Kety; Orlando, Gabriella; Rossi, Rosario; Pierre, Bouloux; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

This study confirms that the classical predictors of erectile dysfunction are not associated to impaired erectile function, probably since other factor are more important in HIV , the latter mask the role of classic risk factors


2011 - Lateralization of calcitonin measurements in the wash-out fluid from thyroid fine-needle aspiration: a useful tool for the diagnosis of C-cell-hyperplasia? [Articolo su rivista]
Rochira, Vincenzo; Diazzi, Chiara; Brigante, Giulia; L., Persani; L., Fugazzola; Rossi, Giulio; Carani, Cesare
abstract

The measurement of calcitonin in the wash-out fluid from fine-needle aspiration seems to be a reliable method for the detection of C-cell hyperplasia when an evident difference in calcitonin levels between the two lobes of the thyroid is present.


2011 - Premature Decline of Serum Total Testosterone in HIV-Infected Men in the HAART-Era [Articolo su rivista]
Rochira, Vincenzo; Zirilli, Lucia; Orlando, Gabriella; Santi, Daniele; Brigante, Giulia; Diazzi, Chiara; Carli, Federica; Carani, Cesare; Guaraldi, Giovanni
abstract

BackgroundTestosterone (T) deficiency remains a poorly understood issue in men with Human Immunodeficiency Virus (HIV). We investigated the gonadal status in HIV-infected men in order to characterize T deficiency and to identify predictive factors for low serum T.Methodology/Principal FindingsWe performed a cross-sectional, observational study on 1325 consecutive HIV male outpatients, most of them having lipodystrophy. Serum total T<300 ng/dL was used as the threshold for biochemical T deficiency. Morning serum total T, luteinizing hormone (LH), estradiol, HIV parameters, and body composition parameters by CT-scan and Dual-Energy-X-ray-Absorptiometry were measured in each case. Sexual behavior was evaluated in a subset of 247 patients. T deficiency was found in 212 subjects, especially in the age range 40–59, but was frequent even in younger patients. T deficiency occurred mainly in association with low/normal serum LH. Adiposity was higher in subjects with T deficiency (p<0.0001) and both visceral adipose tissue and body mass index were the main negative predictors of serum total T. Osteoporosis and erectile dysfunction were present in a similar percentage in men with or without T deficiency.Conclusions/SignificancePremature decline of serum T is common (16%) among young/middle-aged HIV-infected men and is associated with inappropriately low/normal LH and increased visceral fat. T deficiency occurs at a young age and may be considered an element of the process of premature or accelerated aging known to be associated with HIV infection. The role of HIV and/or HIV infection treatments, as well as the role of the general health state on the gonadal axis, remains, in fact, to be elucidated. Due to the low specificity of signs and symptoms of hypogonadism in the context of HIV, caution is needed in the diagnosis of hypogonadism in HIV-infected men with biochemical low serum T levels.


2011 - Premature decline of serum total testosterone in human immunodeficiency virus (HIV) infected men with HIV-related lipodystrophy in the highly active antiretroviral therapy (HAART) era: a cross-sectional observational study [Abstract in Rivista]
Rochira, Vincenzo; Zirilli, Lucia; Orlando, Gabriella; Santi, Daniele; Brigante, Giulia; Diazzi, Chiara; Carli, Federica; Zona, Stefano; Carani, Cesare; Guaraldi, Giovanni
abstract

Hypogonadism is common in HIV-infected men with HAART. The causes are both testicular failure and pituitary insufficiency, these two cause often coexist in a mixed form of hypogonadism.


2011 - Prevalence of secondary, primary, and compensated hypogonadism in HIV infected men in HAART era: a cross-sectional observational study [Abstract in Rivista]
Brigante, Giulia; Santi, Daniele; Zirilli, Lucia; Diazzi, Chiara; Orlando, Gabriella; Simoni, Manuela; Carani, Cesare; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

The study investigates the prevalence of male hypogonadism among patients with HIV infection paying particular attention to the different types of hypogonadism


2011 - Sex steroids and HIV-related osteoporosis in men: low circulating estrogens are associated with impaired bone mineral density (BMD) [Abstract in Rivista]
Santi, Daniele; Brigante, Giulia; Orlando, Gabriella; Ciccarese, Michela; Diazzi, Chiara; Guaraldi, Giovanni; Carani, Cesare; Rochira, Vincenzo; Madeo, Bruno
abstract

The study investigates the role of sex steroids on HIV-related osteoporosis, suggesting that relative estrogen deficiency might play a role even in this particular type of bone demineralization.


2011 - Testosterone Changes over Time in Men with Human Immunodeficiency Virus Infection: Preliminary Results [Abstract in Rivista]
Brigante, Giulia; Santi, Daniele; Zirilli, Lucia; Diazzi, Chiara; Orlando, Gabriella; Gnarini, Valentina; Carani, Cesare; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

The study explored the changes overtime of circulating testosterone


2011 - Testosterone changes over time in men with human immunodeficiency virus infection: preliminary results [Abstract in Rivista]
Brigante, Giulia; Santi, Daniele; Zirilli, Lucia; Diazzi, Chiara; Orlando, Gabriella; Gnarini, Valentina; Carani, Cesare; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

The study investigates the changes in circulating testosterone overtime in order to establish if hypogonadism in men with HIV is a reversal condition or not


2011 - Ultrasound mirror artifact of a thyroid nodule by trachea mimicking a tracheal mass [Articolo su rivista]
Diazzi, Chiara; Gnarini, Valentina; Brigante, Giulia; Rochira, Vincenzo
abstract

The article show how a mirror artifact generated by a thyroid nodule could mimic a tracheal mass, thus leading if not recognized to unnecessary further clinical examinations.


2010 - Prevalence and characterization of hypogonadism among men with human immunodeficiency virus infection: preliminary results [Abstract in Rivista]
Rochira, Vincenzo; Santi, Daniele; Brigante, Giulia; Zirilli, Lucia; Diazzi, Chiara; Orlando, Gabriella; Carani, Cesare; Guaraldi, Giovanni
abstract

Preliminary results on the prevalence of male hypogonadism in HIV-infected men


2010 - Prevalence and characterization of hypogonadism among men with human immunodeficiency virus infection: preliminary results [Abstract in Rivista]
Brigante, Giulia; Santi, Daniele; Zirilli, Lucia; Diazzi, Chiara; G., Orlando; Simoni, Manuela; Guaraldi, Giovanni; Carani, Cesare; Rochira, Vincenzo
abstract

Preliminary data on the prevalence and type of male hypogonadism in men with HIV infection


2010 - Prevalence and characterization of hypogonadism among men with human immunodeficiency virus infection: preliminary results. [Abstract in Rivista]
Rochira, Vincenzo; Brigante, Giulia; Santi, Daniele; Zirilli, Lucia; Diazzi, Chiara; Orlando, Gabriella; Carani, Cesare; Guaraldi, Giovanni
abstract

According to the preliminary results of the study HIV-infected men present a higher prevalence of hypogonadism, at a younger age than general population


2010 - Sex steroids and HIV-related osteoporosis in men: low circulating estrogens are associated with impaired bone mineral density (BMD) [Abstract in Rivista]
Santi, Daniele; Brigante, Giulia; Orlando, Gabriella; Ciccarese, Michela; Diazzi, Chiara; Guaraldi, Giovanni; Carani, Cesare; Rochira, Vincenzo; Madeo, Bruno
abstract

Preliminary data on the effects of sex steroids on bone max in men with HIV


2009 - Deficit di GH in pazienti affetti da lipodistrofia HIV-correlata: dati preliminari sugli effetti del trattamento con r-hGH sulla composizione corporea [Abstract in Atti di Convegno]
Diazzi, Chiara; Brigante, Giulia; Orlando, Gabriella; Squillace, Nicola; Guaraldi, Giovanni; Carani, Cesare; Rochira, Vincenzo; Simoni, Manuela; Zirilli, Lucia
abstract

r-hGH treatment in HIV-infected patients with documented GH deficiency seems to improve fat distribution


2009 - GH deficiency in HIV-infected patients with lipodystrophy: preliminary data on the effects of r-hGH treatment on body composition [Abstract in Rivista]
Zirilli, Lucia; Orlando, Gabriella; Brigante, Giulia; Squillace, Nicola; Diazzi, Chiara; Carani, Cesare; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

Evaluation of GH deficiency in HIV-infected patients with lipodystrophy,with particular concern to preliminary data on the effects of r-hGH treatment on body composition


2009 - Reversible Pegvisomant-related lypohypertrophy and its possible recurrence at the new site of injection: a clinical and radiological outcome in two acromegalic women [Abstract in Atti di Convegno]
Rochira, Vincenzo; Zirilli, Lucia; Romano, Stefania; Brigante, Giulia; Carani, Cesare
abstract

Case series of two acromegalic women with reversible pegvisomant-related lypodistrophy documented at MRI before and after changing the site of drug injunction