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Daniele SANTI

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


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Pubblicazioni

2023 - Not only a matter of glucose: The andrological consequences of diabetes mellitus [Articolo su rivista]
Rastrelli, Giulia; Santi, Daniele
abstract


2022 - Accurate and time-saving, two-step intracavernosal injection procedure to diagnose psychological erectile dysfunction [Articolo su rivista]
Santi, Daniele; Spaggiari, Giorgia; Simoni, Manuela; Granata, Antonio R M
abstract

Background: The recognition of the erectile dysfunction pathogenesis is essential to identify the appropriate erectile dysfunction management. As vascular erectile dysfunction could be a manifestation of a systemic arterial damage, the watershed in the erectile dysfunction diagnostic framework is the discrimination between psychological erectile dysfunction and vascular erectile dysfunction. However, reliable tools to directly diagnose psychological erectile dysfunction are currently lacking. Objective: To identify which parameters could predict psychological erectile dysfunction. Moreover, we suggest a new intracavernosal injection procedure to optimize the erectile dysfunction diagnostic workup. Materials and methods: A retrospective, real-world analysis was carried out including all men who underwent intracavernosal injection procedure at the Modena Andrology Unit from 2018 to 2021. A first intracavernosal injection procedure with 5 µg of prostaglandin E-1 (PGE-1) was performed. In the absence of a full drug-induced erection (immediate or delayed), an echo-color Doppler penile evaluation after administration of PGE-1 10 µg was conducted, measuring intracavernosal blood flows, to document a possible vascular etiology. Hormonal evaluations were performed. Results: Out of 179 enrolled patients, 70.4% showed psychological erectile dysfunction, 21.7% vascular erectile dysfunction, and 7.8% hormonal genesis. Multinomial logistic regression analysis identified absence of cardiovascular disease (p = 0.017), presence of spontaneous morning erections (p = 0.018), and normal penile erections with masturbation (p = 0.035) as predictors of psychological erectile dysfunction. Clinically, normal intracavernosal injection test response was detected in 86 patients and abnormal response in 93 subjects. Among the latter, 54 patients experienced a delayed response. The combination of intracavernosal injection test with late penile erections evaluation was able to diagnose psychological erectile dysfunction (sensitivity 97%, specificity 100%), avoiding unnecessary retesting. Discussion: We propose a two-step intracavernosal injection procedure that allows to recognize psychological erectile dysfunction with a high sensitivity/specificity, saving costs and time, and limiting adverse events. Moreover, the presence of spontaneous morning erections and valid penile erections after masturbation could guide the diagnostic workup, indirectly identifying those patients deserving of a deeper evaluation of vascular health.


2022 - Determinants of sexual function in men living with HIV younger than 50 years old: Focus on organic, relational, and psychological issues [Articolo su rivista]
De Vincentis, Sara; Decaroli, Maria Chiara; Milic, Jovana; Fanelli, Flaminia; Tartaro, Giulia; Diazzi, Chiara; Mezzullo, Marco; De Santis, Maria Cristina; Roli, Laura; Trenti, Tommaso; Santi, Daniele; Pagotto, Uberto; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

Background: Sexual dysfunctions, particularly erectile dysfunction, are common in men living with HIV, whose organic and psychological components remain to be clarified. The aim of the study is to investigate the impact of risk factors of sexual dysfunctions, including organic, relational, and psychological determinants of erectile function, in men living with HIV younger than 50 years old. Methods: A cross-sectional, observational study was conducted in men living with HIV < 50 years. The questionnaire International Index of Erectile Function-15 was used to assess the prevalence and degree of erectile dysfunction. The structured interview of erectile dysfunction was used to explore the organic (Scale 1), relational (Scale 2), and psychological (Scale 3) components of erectile dysfunction. Total testosterone, estradiol, and dihydrotestosterone were measured by liquid chromatography-tandem-mass spectrometry; free testosterone was calculated by the Vermeulen equation. Results: A total of 313 consecutive men living with HIV were prospectively enrolled (median age 47.0 years; median HIV-infection duration 16.2 years). 187 patients (59.7%) had erectile dysfunction, with a higher prevalence of non-heterosexual (138 out of 187, 73.8%) than heterosexual patients (p = 0.003). Patients with erectile dysfunction showed a worse score of structured interview of erectile dysfunction scale 3 compared to patients without erectile dysfunction (p = 0.025); the International Index of Erectile Function-15 was inversely related to structured interview of erectile dysfunction scale 3 (p = 0.042). No difference was found for sex steroids (total testosterone, estradiol, free testosterone, and dihydrotestosterone) between men living with HIV with and without erectile dysfunction. In the multivariate analysis sexual orientation, and lack of stable relationships were major determinants for erectile dysfunction. Only 35 of 187 patients with erectile dysfunction (18.7%) reported the use of erectile dysfunction medications. Conclusions: Within the multidimensional network of erectile dysfunction in men living with HIV, the psychological component is predominant, highlighting the contribution of peculiar factors related to HIV distress (e.g., fear of virus transmission, stigma) rather than gonadal status and other classical risk factors. In contrast to the high prevalence, only a few patients reported the use of erectile dysfunction medications suggesting a general under-management of such issues.


2022 - Diabetic Neuropathic Cachexia: A Clinical Case and Review of Literature [Articolo su rivista]
Bellelli, A.; Santi, D.; Simoni, M.; Greco, C.
abstract

A 46-year-old man was admitted to the surgical department because of abdominal pain and anemia, with the radiological finding of a perforated duodenal ulcer, and underwent laparoscopic surgical treatment. Type 2 diabetes mellitus (T2DM) had been diagnosed 5 years earlier and treated with diet. At clinical investigation, the patient was depressed and anorexic; moreover, he complained of lower extremity weakness and bilateral feet pain, burning in nature and accompanied by allodynia. This painful sensation had been preceded by an 8-month history of fatigue and anorexia with profound weight loss of 35 kg. After clinical evaluation and a nerve conduction study, diagnosis of diabetic cachectic neuropathy was made based on the rapid onset of severe neuropathic pain in the context of diabetic neuropathy, marked weight loss, and depressed mood. The therapy with pregabalin and duloxetine had scarce effect and was gradually discontinued. The patient, however, obtained progressive relief and amelioration of neuropathic lower-limb pain concomitant with weight gain. This clinical trend also confirmed the diagnosis of this rare form of diabetic neuropathy. A few cases of diabetic neuropathic cachexia have been reported in the literature and are briefly reviewed here.


2022 - Editorial: Follicle-stimulating hormone: Fertility and beyond-volume II [Articolo su rivista]
Simoni, M.; Huhtaniemi, I.; Casarini, L.; Santi, D.
abstract


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 - First Year Metabolic and Hormonal Behavior Define two Different Populations of SGA Newborn for Weight or Height [Articolo su rivista]
Guazzarotti, Laura; Mauri, Silvia; Santi, Daniele; Pogliani, Laura; Zuccotti, Gianvincenzo
abstract

Context: Small-for-gestational-age (SGA) children have a particular metabolic and hormonal pattern at birth that changes rapidly.Objective: To evaluate the linear and weight growth in the first year of life in SGA children.Design: Prospective, monocentric cohort study.Setting: Real-world data collected from April 2012 to January 2016.Patients: SGA newborns uniformly defined by either growth or length lower than -2 SDs for gestational age.Interventions: All children were evaluated for 1 year after birth, at 3 days of life, then 3, 6, and 12 months after birth.Main outcome measures: Anthropometric parameters and biochemical variables, such as blood glucose, insulin, leptin, IGF-1, IGF binding protein-3 (IGFBP-3), and homeostasis model assessment - insulin resistance (HOMA-IR) index.Results: A total of 133 SGA children were enrolled. Length significantly improved 1 month after birth, whereas weight significantly increased only at 3 months after birth. Biochemical variables increased during the first year of life, showing a prediction by IGFBP-3 and HOMA-IR index. Then, the variables were divided considering either weight, length, or both, showing a different incidence. The biochemical variable changes recorded in the first step were maintained considering SGA children for weight or length, whereas they disappeared when weight and length were considered together.Conclusions: Our study shows a specific catchup growth for weight and length in SGA children. Moreover, we highlight that weight and length should be considered as independent parameters in SGA children, defining 2 different metabolic-hormonal populations with different conceivable predictive role in early catchup growth and in later growth and metabolic status.


2022 - Follicle stimulating hormone effectiveness in male idiopathic infertility: what happens in daily practice? [Articolo su rivista]
Romeo, Marilina; Spaggiari, Giorgia; Nuzzo, Federico; Granata, Antonio R M; Simoni, Manuela; Santi, Daniele
abstract

To assess the effectiveness of follicle-stimulating hormone (FSH) administration in male idiopathic infertility in a clinical setting.


2022 - Human fertility and sleep disturbances: A narrative review [Articolo su rivista]
Spaggiari, Giorgia; Romeo, Marilina; Casarini, Livio; Granata, Antonio R M; Simoni, Manuela; Santi, Daniele
abstract

Introduction: Many factors may be hidden behind the global fertility decline observed in Western countries. Alongside the progressively increased age of infertile couples, environmental and behavioural factors, including non-optimal lifestyle habits, should be considered. Among these, sleep disorders have been suggested to be linked to human fertility. Methods: This is a narrative review, describing first sleep physiology, its disturbances, and the tools able to quantify sleep dysfunction. Then, we consider all available studies aimed at investigating the connection between sleep disorders and human fertility, providing a comprehensive view on this topic. Results: Forty-two studies investigating the relationship between sleep habits and human reproduction were included. All the published evidence was grouped according to the aspect of human fertility considered, i.e. i) female reproductive functions, ii) male reproductive functions, iii) natural conception and iv) assisted reproduction. For each of the sub-groups considered, the connection between sleep dysregulation and human fertility was classified according to specific sleep characteristics, such as sleep duration, quality, and habits. In addition, possible physio-pathological mechanisms proposed to support the link between sleep and fertility were summarized. Conclusion: This review summarizes the most relevant findings about the intricate and still largely unknown network of molecular pathways involved in the regulation of circadian homeostasis, to which sleep contributes, essential for reproductive physiology. Thus, many mechanisms seem correlate sleep disorders to reproductive health, such as adrenal activation, circadian dysregulation, and genetic influences. This review highlights the need to properly designed trials on the topic.


2022 - Ketogenic state improves testosterone serum levels-results from a systematic review and meta-analysis [Articolo su rivista]
Furini, Chiara; Spaggiari, Giorgia; Simoni, Manuela; Greco, Carla; Santi, Daniele
abstract

It is widely demonstrated that obesity and hypogonadism are bi-directionally correlated, since the hypogonadism prevalence is higher in obese population, while weight loss increases testosterone serum levels. Several approaches are available to contrast weight excess, from simple dietary regimens to more complex surgical procedures. Ketogenic diets (KD) fit in this context and their application is growing year after year, aiming to improve the metabolic and weight patterns in obese patients. However, KD influence on testosterone levels is still poorly investigated.


2022 - Neither rationale nor scientific evidence exist to support that double stimulation is potentially unsafe [Articolo su rivista]
Casarini, Livio; Vaiarelli, Alberto; Cimadomo, Danilo; Santi, Daniele; Simoni, Manuela; Garcìa-Velasco, Juan Antonio; Alviggi, Carlo; La Marca, Antonio; Rienzi, Laura; Ubaldi, Filippo Maria
abstract


2022 - Phosphodiesterase (PDE) 5 inhibitors sildenafil, tadalafil and vardenafil impact cAMP-specific PDE8 isoforms-linked second messengers and steroid production in a mouse Leydig tumor cell line [Articolo su rivista]
Limoncella, S.; Lazzaretti, C.; Paradiso, E.; D'Alessandro, S.; Barbagallo, F.; Pacifico, S.; Guerrini, R.; Tagliavini, S.; Trenti, T.; Santi, D.; Simoni, M.; Sola, M.; Di Rocco, G.; Casarini, L.
abstract

Type 5 phosphodiesterase (PDE5) blockade by inhibitors (PDE5i) results in intracellular cyclic guanosine monophosphate (cGMP) increase and smooth muscle relaxation and are used for the treatment of men erectile dysfunction. Although they have high specificity for PDE5, these inhibitors are suspected to cross-interact also with cyclic adenosine monophosphate (cAMP)-specific PDEs, inducing the intracellular accumulation of this cyclic nucleotide and related testosterone increase, positively impacting male reproductive parameters. However, the link between the use of PDE5i and the activation of cAMP-mediated steroidogenesis is still unclear. We have investigated whether three PDE5i, sildenafil, tadalafil and vardenafil, cross-interacts with the high affinity cAMP-specific enzymes type 8A and 8B PDEs (PDE8A and PDE8B), in live, transfected mouse Leydig tumor (mLTC1) and human embryonic kidney (HEK293) cell lines in vitro. The PDE5i-induced production of cAMP-dependent testosterone and its precursor progesterone was evaluated as well. We have developed PDE8A/B biosensors and modified cyclic nucleotides confirming enzyme binding to cAMP, but not to cGMP, in our cell models. cAMP binding to PDE8A/B was displaced upon cell treatment with PDE5i, revealing that sildenafil, tadalafil and vardenafil have similar effectiveness in live cells, in vitro. The cross-interaction between PDE5i and PDE8A/B supports the gonadotropin-enhanced intracellular cAMP increase, occurring together with cGMP increase, as well as steroid synthesis. Indeed, we found that Leydig cell treatment by PDE5i increases progesterone and testosterone production triggered by gonadotropins. We demonstrated that PDE5i may interact with the cAMP-specific PDE8A and PDE8B, possibly inducing intracellular cAMP and sex steroid hormone increase. These findings support clinical data suggesting that PDE5i might increase testosterone levels in men.


2022 - Qualitative and quantitative analysis of doctor-patient interactions during andrological consultations [Articolo su rivista]
Santi, Daniele; Spaggiari, Giorgia; Romeo, Marilina; Ebert, Riccardo; Corradini, Federico; Baraldi, Claudio; Granata, Antonio R M; Rochira, Vincenzo; Simoni, Manuela; Gavioli, Laura; Niemants, Natacha S A
abstract

Although a trustworthy connection between doctor and patient is crucial in clinical practice, it could be hindered by different cultural and linguistic backgrounds. Moreover, an effective doctor-patient interaction could be even more challenging in andrological fields, in which psychological and social components are predominant.


2022 - Real-world evidence analysis of the follicle-stimulating hormone use in male idiopathic infertility [Articolo su rivista]
Santi, D.; Spaggiari, G.; Granata, A. R. M.; Simoni, M.
abstract

Male idiopathic infertility remains a therapeutic challenge in the couple infertility management. In this setting, an empirical treatment with follicle-stimulating hormone (FSH) is allowed, although not recommended. Twenty-one clinical trials and four meta-analyses highlighted an overall increased pregnancy rate in case of FSH administration, but the indiscriminate FSH prescription is still unsupported by clinical evidence in idiopathic infertility. This context could represent an example in which real-world data (RWD) could add useful information. From a nationwide clinical practice survey performed in Italy, emerged the clinicians’ attitude to prescribe FSH in the case of impaired semen with a significant improvement of semen parameters, identifying FSH treatment as a therapeutic card in the real-life management. Although more robust data are still needed to optimize FSH treatment in male idiopathic infertility, RWD should be included in the body of evidence considered in healthcare decision-making.


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.


2022 - Semen cryopreservation in men undergoing cancer treatment: a ten-year study [Articolo su rivista]
Melli, Beatrice; Morini, Daria; Daolio, Jessica; Nicoli, Alessia; Valli, Barbara; Capodanno, Francesco; Spaggiari, Giorgia; Aguzzoli, Lorenzo; Villani, Maria Teresa; Santi, Daniele; Sileo, Filomena G
abstract

Background: The advancement of Assisted Reproductive Technologies and the improvement in sperm freezing made male fertility preservation widely available. This study aims to evaluate the impact of cancer diseases on semen parameters before cryopreservation and the reproductive outcomes of patients who have thawed their semen samples. Methods: An observational, cohort study was conducted on cancer patients submitted to fertility preservation in AUSL-IRCCS of Reggio Emilia between 2007 and 2018. Semen samples were collected before cancer treatments, analysed and frozen by rapid freezing. On request, these samples were thawed for Assisted Reproductive Technologies procedures. Semen parameters were compared between testicular versus other cancers. Results: we included 329 patients with a successful cryopreservation in 94.5% of cases. Testicular cancer was associated with lower sperm volumes (p=0.041) and lower total sperm concentration (p=0.009) compared to other cancers. No difference was observed about sperm motility and morphology, while oligozoospermia was significantly more frequent in men with testicular cancer (p<0.001). In our cohort, the 8.4% of patients thawed their samples; the usage rate and the embryo transfer rate were significantly higher (p<0.05) among those with a testicular cancer, while pregnancy and livebirth rates did not differ. Conclusions: male fertility preservation is feasible, easy to be performed, non-invasive and does not delay cancer treatments. Men affected by testicular cancer had worse semen parameters at cryopreservation but pregnancy and livebirth rates were similar to those achieved by men with other cancers and similar to those achieved with fresh sperm.


2022 - Testosterone Serum Levels Are Related to Sperm DNA Fragmentation Index Reduction after FSH Administration in Males with Idiopathic Infertility [Articolo su rivista]
Lispi, Monica; Drakopoulos, Panagiotis; Spaggiari, Giorgia; Caprio, Francesca; Colacurci, Nicola; Simoni, Manuela; Santi, Daniele
abstract

Purpose: Although a robust physiological rationale supports follicle stimulating hormone (FSH) use in male idiopathic infertility, useful biomarkers to evaluate its efficacy are not available. Thus, the primary aim of the study was to evaluate if testosterone serum levels are related to sperm DNA fragmentation (sDF) index change after FSH administration. The secondary aim was to confirm sDF index validity as a biomarker of FSH administration effectiveness in male idiopathic infertility. Methods: A retrospective, post-hoc re-analysis was performed on prospectively collected raw data of clinical trials in which idiopathic infertile men were treated with FSH and both testosterone serum levels and sDF were reported. Results: Three trials were included, accounting for 251 patients. The comprehensive analysis confirmed FSH's beneficial effect on spermatogenesis detected in each trial. Indeed, an overall significant sDF decrease (p < 0.001) of 20.2% of baseline value was detected. Although sDF resulted to be unrelated to testosterone serum levels at baseline, a significant correlation was highlighted after three months of FSH treatment (p = 0.002). Moreover, testosterone serum levels and patients' age significantly correlated with sDF (p = 0.006). Dividing the cohort into responders/not responders to FSH treatment according to sDF change, the FSH effectiveness in terms of sDF improvement was related to testosterone and male age (p = 0.003). Conclusion: Exogenous FSH administration in male idiopathic infertility is efficient in reducing sDF basal levels by about 20%. In terms of sDF reduction, 59.2% of the patients treated were FSH-responders. After three months of FSH administration, a significant inverse correlation between sDF and testosterone was detected, suggesting an association between the FSH-administration-related sDF improvement and testosterone serum levels increase. These observations lead to the hypothesis that FSH may promote communications or interactions between Sertoli cells and Leydig cells.


2022 - The (decision) tree of fertility: an innovative decision-making algorithm in assisted reproduction technique [Articolo su rivista]
Villani, M. T.; Morini, D.; Spaggiari, G.; Furini, C.; Melli, B.; Nicoli, A.; Iannotti, F.; La Sala, G. B.; Simoni, M.; Aguzzoli, L.; Santi, D.
abstract

Purpose: Several mathematical models have been developed to estimate individualized chances of assisted reproduction techniques (ART) success, although with limited clinical application. Our study aimed to develop a decisional algorithm able to predict pregnancy and live birth rates after controlled ovarian stimulation (COS) phase, helping the physician to decide whether to perform oocytes pick-up continuing the ongoing ART path. Methods: A single-center retrospective analysis of real-world data was carried out including all fresh ART cycles performed in 1998–2020. Baseline characteristics, ART parameters and biochemical/clinical pregnancies and live birth rates were collected. A seven-steps systematic approach for model development, combining linear regression analyses and decision trees (DT), was applied for biochemical, clinical pregnancy, and live birth rates. Results: Of fresh ART cycles, 12,275 were included. Linear regression analyses highlighted a relationship between number of ovarian follicles > 17 mm detected at ultrasound before pick-up (OF17), embryos number and fertilization rate, and biochemical and clinical pregnancy rates (p < 0.001), but not live birth rate. DT were created for biochemical pregnancy (statistical power–SP:80.8%), clinical pregnancy (SP:85.4%), and live birth (SP:87.2%). Thresholds for OF17 entered in all DT, while sperm motility entered the biochemical pregnancy’s model, and female age entered the clinical pregnancy and live birth DT. In case of OF17 < 3, the chance of conceiving was < 6% for all DT. Conclusion: A systematic approach allows to identify OF17, female age, and sperm motility as pre-retrieval predictors of ART outcome, possibly reducing the socio-economic burden of ART failure, allowing the clinician to perform or not the oocytes pick-up.


2022 - The endocrine disruptor Benzo[a]Pyrene inhibits gonadotropin-mediated steroidogenesis in a mouse Leydig tumor cell line [Abstract in Atti di Convegno]
Sperduti, Samantha; Roy, Neena; Lazzaretti, Clara; Paradiso, Elia; D'Alessandro, Sara; Mascolo, Elisa; Baschieri, Lara; Santi, Daniele; Simoni, Manuela; Casarini, Livio
abstract


2022 - The impact of male factors and their correct and early diagnosis in the infertile couple's pathway: 2021 perspectives [Articolo su rivista]
Pallotti, F; Barbonetti, A; Rastrelli, G; Santi, D; Corona, G; Lombardo, F
abstract

Purpose: The current clinical practice in reproductive medicine should pose the couple at the centre of the diagnostic-therapeutic management of infertility and requires intense collaboration between the andrologist, the gynaecologist and the embryologist. The andrologist, in particular, to adequately support the infertile couple, must undertake important biological, psychological, economical and ethical task. Thus, this paper aims to provide a comprehensive overview of the multifaceted role of the andrologist in the study of male factor infertility. Methods: A comprehensive Medline, Embase and Cochrane search was performed including publications between 1969 and 2021. Results: Available evidence indicates that a careful medical history and physical examination, followed by semen analysis, always represent the basic starting points of the diagnostic work up in male partner of an infertile couple. Regarding treatment, gonadotropins are an effective treatment in case of hypogonadotropic hypogonadism and FSH may be used in men with idiopathic infertility, while evidence supporting other hormonal and nonhormonal treatments is either limited or conflicting. In the future, pharmacogenomics of FSHR and FSHB as well as innovative compounds may be considered to develop new therapeutic strategies in the management of infertility. Conclusion: To provide a high-level of care, the andrologist must face several critical diagnostical and therapeutical steps. Even though ART may be the final and decisive stage of this decisional network, neglecting to treat the male partner may ultimately increase the risks of negative outcome, as well as costs and psychological burden for the couple itself.


2022 - Very low-calorie ketogenic diet rapidly augments testosterone levels in non-diabetic obese subjects [Articolo su rivista]
Cignarelli, A.; Santi, D.; Genchi, V. A.; Conte, E.; Giordano, F.; Di Leo, S.; Natalicchio, A.; Laviola, L.; Giorgino, F.; Perrini, S.
abstract

BackgroundThe very low-calorie ketogenic diet (VLCKD) represents an opportunity to attain clinically relevant weight loss in obese patients. Functional hypogonadism represents a frequent hormonal disorder associated with obesity and visceral fat accumulation characterised by low testosterone levels and subnormal luteinising hormone (LH) levels. AimTo evaluate the early effects of VLCKD on serum total testosterone (TT) levels in non-diabetic obese patients.Methods: Twenty-two obese male patients (mean age 39.3 +/- 11.7 years, mean body mass index (BMI) 38.2 +/- 6.4 kg/m(2)) were enrolled and treated for 28 days with VLCKD. Anthropometric and hormonal variables were assessed before, during and after diet intervention. ResultsAfter 7 and 28 days on a VLCKD, a significant and persistent reduction in body weight, BMI, fat mass, blood glucose, insulin and homeostasis model assessment index was observed compared with baseline. TT significantly increased after 7 days (+35 +/- 64 ng/dl) and 28 days (+74 +/- 97 ng/dl) on a VLCKD. In addition to TT, a significant increase in serum sex hormone-binding globulin levels was observed after 7 (+2.1 +/- 4.1) and 28 days (+7.7 +/- 10.0). However, both calculated free testosterone and LH did not change after 7 or 28 days of VLCKD. Following cessation of VLCKD, hypogonadal subjects achieved a higher percentage of total weight loss (8.5% +/- 1.5%), a greater reduction in weight (-9.94 +/- 1.66 kg), fat mass (-7 +/- 2.1 kg) and waist circumference (-6.31 +/- 2.65 cm) and a greater improvement in glycaemia (-8.75 +/- 10.92 mg/dl) as compared with eugonadal subjects. Furthermore, hypogonadal subjects exhibited a trend of higher TT increase (+98.12 +/- 71.51 ng/dl) as compared with eugonadal subjects. ConclusionsVLCKD results in rapid improvements in TT levels associated with weight loss in male obese non-diabetic subjects, particularly in the presence of obesity-related hypogonadism.


2022 - Which sperm parameter limits could really guide the clinical decision in assisted reproduction? [Articolo su rivista]
Santi, Daniele; Spaggiari, Giorgia; Morini, Daria; Melli, Beatrice; Dalla Valentina, Leonardo; Aguzzoli, Lorenzo; Simoni, Manuela; Villani, Maria Teresa
abstract

Background The predictive role of sperm motility and morphology was recently detected in a large sample of more than 20000 assisted reproductive technology (ART) fresh cycles. However, the complete ART procedure consisted of both fresh and frozen-embryos transfers and only a comprehensive evaluation of the entire process could really confirm if these parameters really predict the ART success. The aim of the study was to evaluate which sperm parameter could predict the success of ART. Methods A retrospective, real-world data analysis was performed, enrolling all couples attending ART from 2008 to 2021, including both fresh and frozen cycles and both in vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI) procedures. Results Fresh cycles success (considering live birth rate) was predicted by female age (1.04 [1.02-1.06]), injected oocytes (0.96 [0.93-0.99]), embryo number (0.79 [0.75-0.83]) and progressive sperm motility (0.98 [0.97-0.99]). On the contrary, frozen cycle outcomes were predicted only by sperm motility (0.97 [0.95-0.99]). This prediction was confirmed in IVF but not in ICSI cycles. Conclusion Both female and male parameters predicted the ART success considering the entire path. However, frozen cycle success was predicted only by progressive sperm motility in IVF cycles, suggesting that the potential amelioration of this male parameter is relevant to improve ART success. Those couples expected to obtain the highest embryos after fertilization (low female age and better semen parameters) will have more attempts with frozen cycles and thus would benefit from a potential treatment focused to improve sperm parameters.


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


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 - Are sperm parameters able to predict the success of assisted reproductive technologies? A retrospective analysis of over 22000 ART cycles [Articolo su rivista]
Villani, M T; Morini, D; Spaggiari, G; Falbo, A I; Melli, B; La Sala, G B; Romeo, M; Simoni, M; Aguzzoli, L; Santi, D
abstract

An explosive increase in couples attending assisted reproductive technologies (ART) has been recently observed, despite an overall success rate about 20-30%. Considering the ART-related economic and psycho-social costs, the improvement of these percentages is extremely relevant. However, in the identification of predictive markers of ART success, male parameters are largely underestimated so far.


2021 - Association of nonalcoholic fatty liver disease (Nafld) with peripheral diabetic polyneuropathy: A systematic review and meta-analysis [Articolo su rivista]
Greco, C.; Nascimbeni, F.; Carubbi, F.; Andreone, P.; Simoni, M.; Santi, D.
abstract

Aims. The relationship between nonalcoholic fatty liver disease (NAFLD) and diabetic polyneuropathy (DPN) has been demonstrated in many studies, although results were conflicting. This meta-analysis aims to summarize available data and to estimate the DPN risk among NAFLD patients. Materials and methods. We performed a comprehensive literature review until 4 June 2021. Clinical trials analyzing the association between NAFLD and DPN were included. Results. Thirteen studies (9614 participants) were included. DPN prevalence was significantly higher in patients with NALFD, compared to patients without NAFLD (OR (95%CI) 2.48 (1.42–4.34), p = 0.001; I2 96%). This finding was confirmed in type 2 diabetes (OR (95%CI) 2.51 (1.33–4.74), p = 0.005; I2 97%), but not in type 1 diabetes (OR (95%CI) 2.44 (0.85–6.99), p = 0.100; I2 77%). Also, body mass index and diabetes duration were higher in NAFLD subjects compared to those without NAFLD (p < 0.001), considering both type 2 and type 1 diabetes. Conclusion. Despite a high heterogeneity among studies, a significantly increased DPN prevalence among type 2 diabetes subjects with NAFLD was observed. This result was not found in type 1 diabetes, probably due to the longer duration of disease. Physicians should pay more attention to the early detection of DPN, especially in patients with NAFLD.


2021 - From subjective to objective: A pilot study on testicular radiomics analysis as a measure of gonadal function [Articolo su rivista]
De Santi, Bruno; Spaggiari, Giorgia; Granata, Antonio Rm; Romeo, Marilina; Molinari, Filippo; Simoni, Manuela; Santi, Daniele
abstract

Background: The connection between testicular ultrasound (US) parameters and testicular function, including both spermato- and steroidogenesis has been largely suggested, but their predictive properties are not routinely applied. Radiomics, a new engineering approach to radiological imaging, could overcome the visual limit of the sonographer. Objectives: This study is aimed at extracting objective testicular US features, correlating with testicular function, including both spermato- and steroidogenesis, using engineering approach, in order to overcome the operator-dependent subjectivity. Materials and methods: Prospective observational pilot study from December 2019 to December 2020 on normozoospermic subjects and patients with semen variables alterations, excluding azoospermia. All patients underwent conventional semen analysis, pituitary-gonadal hormones assessment and testicular US, performed by the same operator. US images were analysed by Biolab (Turin) throughout image segmentation, image pre-processing and texture features extraction. Results: 170 US testicular images were collected from 85 patients (age 38.6±9.1 years). A total of 44 first-order and advanced features were extracted. US inhomogeneity defined by radiomics significantly correlate with the andrologist definition, showing for the first time a mathematical quantification of a subjective US evaluation. 13 US texture features correlated with semen parameters, predicting sperm concentration, total sperm number, progressive motility, total motility and morphology, and with gonadotropins serum levels, but not with total testosterone serum levels. Classification analyses confirmed that US textural features predicted patients' classification according to semen parameters alterations. Conclusions: Radiomics texture features qualitatively describe the testicular parenchyma with objective and reliable quantitative parameters, reflecting both the testicular spermatogenic capability and the action of pituitary gonadotropins. This is an innovative model in which US texture features represent a mirror of the pituitary-gonadal homeostasis in terms of reproductive function. This article is protected by copyright. All rights reserved.


2021 - Gynecological malignancy mimicking a thyroid lymph node metastasis. [Articolo su rivista]
Pederzoli, S.; Spaggiari, G.; Bernardelli, G.; Mattioli, F.; Baldessari, C.; Maiorana, A.; Rochira, V.; Santi, D.
abstract

We present the case of a 69-year-old woman who attended the Endocrinology Unit of Modena for a suspicious lymph node in the left cervical compartment discovered during the follow-up of a recurrent gynecological malignancy. At neck ultrasonography, a thyroid goiter was detected, and the further cytological examination was inconclusive for thyroid nodule and compatible with a localization of an adenocarcinoma with papillary architecture for the lymph node. The histological examination after a left neck dissection confirmed the presence of an intracapsular metastasis of a papillary carcinoma immunohistochemically focally positive for thyroid transcription factor 1 and paired box 8 and negative for thyroglobulin. Subsequently, in the suspicion of a thyroid primitiveness, a total thyroidectomy was performed, revealing an intraparenchymal follicular variant of papillary thyroid carcinoma of 2 mm in the right lobe. During the follow-up, the appearance of a suspected cervical metastatic lesion led to another neck dissection, histologically compatible with a papillary carcinoma localization, immunohistochemically focally positive for thyroid transcription factor 1 and paired box 8, and negative for thyroglobulin. The histological revision of surgical specimens suggests the cervical recurrence of the prior gynecological cancer, rather than a thyroid carcinoma metastasis. The case described shows how carefully the cytological, histological and immunoistochemical results must be evaluated in oncological management, considering the whole patient’s history.


2021 - Hiv and sexual dysfunction in men [Articolo su rivista]
De Vincentis, S.; Tartaro, G.; Rochira, V.; Santi, D.
abstract

Sexual issues tend to go unaddressed in human immunodeficiency virus (HIV) man-agement, although overt sexual dysfunctions are more prevalent in people living with HIV than uninfected people. Erectile dysfunction is the most frequent sexual problem, with a prevalence of 30–50% even in men <40 years of age, but other issues such as loss of libido and ejaculatory disorders should not be overlooked. Peculiar factors related to HIV infection (e.g., fear of virus trans-mission, changes in body image, HIV-related comorbidities, HIV distress and stigma), alongside classical factors non-related to HIV, should be considered when approaching sexual problems in HIV patients. For this reason, the diagnostic and therapeutic workout of sexual dysfunction in the context of HIV requires a multidisciplinary approach, involving specialists in both infectious diseases and sexual medicine. This narrative review presents an overview of current knowledge on sexual dysfunction in HIV men, deepening the factors driving and taking part in these issues, providing advice for the clinical approach, and underlining the importance of caring for sexual health to improve the quality of life of HIV patients.


2021 - Improvement of sperm morphology after surgical varicocele repair [Articolo su rivista]
Morini, D.; Spaggiari, G.; Daolio, J.; Melli, B.; Nicoli, A.; De Feo, G.; Valli, B.; Viola, D.; Garganigo, S.; Magnani, E.; Pilia, A.; Polese, A.; Colla, R.; Simoni, M.; Aguzzoli, L.; Villani, M. T.; Santi, D.
abstract

Background: A causative relationship between varicocele and impairment of semen quality has been largely investigated in the context of male infertility, although its clinical benefit remains controversial. Objective: To investigate the effect of varicocele correction on detailed morphologic microscopic semen parameters in a large homogeneous cohort of patients and to evaluate which factors could predict semen improvement after the surgical treatment. Materials and methods: An observational, retrospective cohort study was carried out including all patients undergoing surgical treatment for varicocele from September 2011 to March 2020 in the same clinical centre. Enrolled males performed at least one semen analysis before and one after surgical varicocele correction. Primary outcome was the detailed morphologic microscopic sperm evaluation. Secondary outcomes were conventional semen analyses. Results: A total of 121 males (mean age 24.6 ± 6.1 years) were enrolled. Using detailed morphologic microscopic sperm evaluation, a significant morphological improvement was recorded, with a reduction in head and tail abnormalities. Moreover, a significant increase in sperm concentration (p = 0.015) and percentage of progressive and total motility (p = 0.022 and p = 0.039) were observed after surgery. The multivariate logistic analysis identified the ultrasonography varicocele degree before surgery as a main predictor of the sperm concentration improvement (p = 0.016), with the highest improvement for varicocele of I and II degree. Discussion: For the first time, the detailed morphologic microscopic sperm evaluation highlights a relevant reduction in sperm abnormalities after varicocele surgery, showing its potential application in clinical practice.


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 - Low testosterone predicts hypoxemic respiratory insufficiency and mortality in patients with COVID-19 disease: another piece in the COVID puzzle [Articolo su rivista]
Vena, W.; Pizzocaro, A.; Maida, G.; Amer, M.; Voza, A.; Di Pasquale, A.; Reggiani, F.; Ciccarelli, M.; Fedeli, C.; Santi, D.; Lavezzi, E.; Lania, A. G.; Mazziotti, G.
abstract

Purpose: Hypogonadism was described in high number of male subjects with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated whether low testosterone (T) values may influence the clinical presentation and outcome of SARS-CoV-2-related pneumonia in a large population of adult males with coronavirus disease 19 (COVID-19). Methods: Two hundred twenty one adult males hospitalized for COVID-19 at the IRCCS Humanitas Research Hospital, Rozzano-Milan (Italy) were consecutively evaluated for arterial partial pressure oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio, serum T and inflammatory parameters at study entry, need of ventilation during hospital stay and in-hospital mortality. Results: Subjects low T values (< 8 nmol/L; 176 cases) were significantly older (P = 0.001) and had higher serum interleukin-6 (P = 0.001), C-reactive protein (P < 0.001), lactate dehydrogenase (P < 0.001), ferritin (P = 0.012), lower P/F ratio (P = 0.001), increased prevalence of low T3 syndrome (P = 0.041), acute respiratory insufficiency (P < 0.001), more frequently need of ventilation (P < 0.001) and higher mortality rate (P = 0.009) compared to subjects with higher T values. In the multivariable regression analyses, T values maintained significant associations with acute respiratory insufficiency (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.79–0.94; P < 0.001 and in-hospital mortality (OR 0.80, 95% CI 0.69–0.95; P = 0.009), independently of age, comorbidities, thyroid function and inflammation. Conclusion: Low T levels values are associated with unfavorable outcome of COVID-19. Prospective studies are needed to evaluate the long-term outcomes of hypogonadism related to COVID-19 and the clinical impact of T replacement during and after acute illness.


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 - Psychotropic Drugs Levels in Seminal Fluid: A New Therapeutic Drug Monitoring Analysis? [Articolo su rivista]
Mazzilli, Rossella; Curto, Martina; De Bernardini, Donatella; Olana, Soraya; Capi, Matilde; Salerno, Gerardo; Cipolla, Fabiola; Zamponi, Virginia; Santi, Daniele; Mazzilli, Fernando; Simmaco, Maurizio; Lionetto, Luana
abstract

The aim of this observational study was to develop a new quantitative liquid chromatography-mass spectrometry (LC-MS/MS) method for Therapeutic-Drug-Monitoring (TDM) of psychotropic drugs in seminal fluid to investigate potential gonadotoxic effects in patients with reduced fertility. After the validation of the LC-MS/MS method for psychotropics' levels determination in seminal fluid, we included 20 male partners of infertile couples with idiopathic and/or unexplained male infertility, treated with psychotropic medications for more than 3 months and 10 untreated fertile controls. General and andrological clinical examination, semen analysis and seminal drugs, and metabolites levels determination were performed for each subject. Of the 20 patients included, 6 were treated with antidepressants; 4 with benzodiazepines and 10 with antipsychotics. Seminal drugs and metabolites levels were detectable in all samples. In particular, alprazolam, olanzapine, and levetiracetam showed seminal and serum similar concentrations, while fluoxetine, quetiapine, and aripiprazole were detectable, but seminal levels were significantly lower than the serum therapeutic range. Sperm progressive motility was significantly reduced in subjects treated with psychotropic drugs compared to the untreated controls (p = 0.03). Sperm concentration and progressive motility were significantly reduced in subjects treated with antipsychotics compared to the untreated controls and to the other classes of psychotropics (p < 0.05). In conclusion, this study reports a validated LC-MS/MS method for the detection of seminal psychotropic levels and preliminary data suggesting a potential correlation of seminal psychotropics with alterations of sperm concentration and motility. Pending larger studies, semen TDM might represent a new pivotal tool in the clinical management of reduced fertility in males treated with psychotropic medications.


2021 - Spontaneous pregnancies among infertile couples during assisted reproduction lockdown for COVID-19 pandemic [Articolo su rivista]
Villani, Maria Teresa; Morini, Daria; Spaggiari, Giorgia; Simoni, Manuela; Aguzzoli, Lorenzo; Santi, Daniele
abstract

The worldwide spread of the SARS-CoV-2 infection has profoundly affected all aspects of human life, with tangible consequences in several contexts, including reproduction. However, evidences on the inter-relation between psychological distress and reproductive medicine are still conflicting.


2021 - The prevalence of hypogonadism and the effectiveness of androgen administration on body composition in hiv‐infected men: A meta‐analysis [Articolo su rivista]
Santi, D.; Spaggiari, G.; Vena, W.; Pizzocaro, A.; Maggi, M.; Rochira, V.; Corona, G.
abstract

Background: Hypogonadism is a common comorbidity in human immunodeficiency virus (HIV)‐infected men, although the real prevalence is difficult to be estimated. Moreover, in HIV settings, the efficacy of exogenous testosterone (Te) administration at improving body composition remains unclear. Aim of the study: This review has a double aim. First, to estimate the prevalence of pituitary–testis axis abnormality in HIV‐infected patients compared to uninfected subjects. Second, to evaluate the effect of androgen administration on body composition in HIV‐infected men. Materials and Methods: A systematic review of the literature and meta‐analysis was carried out. Two separated literature searches were performed, the first to evaluate the prevalence of Te deficiency in HIV‐infected men and the second one to evaluate effects of androgen administration on body composition. Results: The overall prevalence of Te deficiency in HIV‐infected men was calculated from 41 studies, showing a 26% prevalence, which was even higher when free T (fT) levels, more than total T, were considered. Indeed, TT serum levels were similar between HIV patients and controls, although higher SHBG and lower fT were detected in HIV populations. When HIV‐infected men were treated with exogenous Te, a significant increase in body weight, lean body mass and fat free mass was detected. Conclusion: The systematic review confirms the high prevalence of Te deficiency in HIV‐infected men, particularly when fT has been considered. Moreover, chronic androgen supplementation improves body composition, affecting the lean mass compartment. However, considering the general frailty of HIV patients, a tailored indication for Te therapy should be advocated.


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 - An Update on Clinical and Surgical Interventions to Reduce Sperm DNA Fragmentation in Infertile Men [Articolo su rivista]
Esteves, Sandro C; Santi, Daniele; Simoni, Manuela
abstract

Sperm chromatin integrity is essential for normal embryo development and pregnancy outcome. Sperm DNA fragmentation (SDF) testing constitutes a diagnostic tool to measure the proportion of sperm with damaged chromatin in the ejaculate. SDF is associated with potentially treatable conditions, including varicocele, male accessory gland infections, inadequate lifestyle, and gonadotoxin exposure, thus prompting their treatment as a means of improving sperm DNA quality and the reproductive outcomes.


2020 - Eating Behavior after Bariatric Surgery (EBBS) Questionnaire: a New Validated Tool to Quantify the Patients' Compliance to Post-Bariatric Dietary and Lifestyle Suggestions [Articolo su rivista]
Spaggiari, Giorgia; Santi, Daniele; Budriesi, Giulia; Dondi, Paola; Cavedoni, Sonia; Leonardi, Laura; Delvecchio, Carolina; Valentini, Laura; Bondi, Mario; Miloro, Clelia; Toschi, Patrizia Federica
abstract

In the management of bariatric surgery follow-up, a multidisciplinary approach allows to evaluate the weight loss maintenance and the dietary and lifestyle changes adherence. The main aim of this study is to create and to validate a questionnaire (eating behavior after bariatric surgery (EBBS)) to objectivize the compliance to dietary/lifestyle suggestions after bariatric surgery.


2020 - Effect of treatment with testosterone on endothelial function in hypogonadal men: a systematic review and meta-analysis [Articolo su rivista]
Sansone, Andrea; Rastrelli, Giulia; Cignarelli, Angelo; de Rocco Ponce, Maurizio; Condorelli, Rosita Angela; Giannetta, Elisa; Maseroli, Elisa; Pinto, Sara; Salzano, Ciro; Santi, Daniele
abstract

Despite several studies showing an inverse correlation of total testosterone with endothelial damage, the effect of testosterone replacement therapy (TTh) on endothelial function has been scarcely investigated. In order to systematically assess the relationship between endothelial dysfunction and TTh, we performed a review and meta-analysis of available prospective and cross-sectional studies. A thorough research was performed on MEDLINE for hypogonadism and endothelial dysfunction. We retrieved 28 papers, among which 23 were excluded for different reasons: five papers accounting for six studies (two crossover randomized clinical trial (RCT), three observational, one placebo controlled RCT) were therefore included in analysis. Overall, 86 patients with hypogonadism were included in analysis (mean age 49.57 ± 8.85 years). Baseline total testosterone serum levels were 8.11 ± 2.42 nmol/L and significantly increased while undergoing TTh (standard mean difference (SMD) 2.93 nmol/L, 95% confidence interval (CI) 1.89:3.97, p < 0.001). Due to the paucity of studies available, flow-mediated dilation (FMD) was chosen as the best surrogate marker of endothelial dysfunction. FMD did not significantly change after testosterone administration (SMD -0.22, 95% CI -1.29:0.84, I2 = 90%); acute testosterone administration was associated with an increase in FMD, whereas a reduction in FMD emerged following chronic treatment, but statistical significance was not reached for both effects. This is the first meta-analysis study assessing the influence of TTh on endothelial function; however, results are far from conclusive, as proven by the high heterogeneity.


2020 - Effects of acute hCG stimulation on serum INSL3 and 25-OH vitamin D in Klinefelter syndrome. [Articolo su rivista]
Santi, D.; Ivell, R.; Anand-Ivell, R.; De Toni, L.; Fanelli, F.; Mezzullo, M.; Pelusi, C.; Pagotto, U.; Belli, S.; M: Granata, A. R.; Roli, L.; Rochira, V.; Trenti, T.; Ferlin, A.; Simoni, M.
abstract

Background: It has recently been suggested that the hypergonadotropic hypogonadism characterizing Klinefelter syndrome (KS) might not be due to a steroidogenic dysfunction per se, but mainly to an altered testosterone (T) secretion into the bloodstream. However, the Leydig cell functionality remains incompletely studied in KS, and new markers should be considered. Previous data indicated that chronic hCG stimulation influence the production of both Insulin-like peptide 3 (INSL3) and 25-hydroxy-vitamin D (25-VD) in eugonadal men. Aim of the study: To evaluate INSL3 and 25-VD serum levels, as markers of Leydig cell functionality, in association with sex steroids, after an acute hCG test in a group of KS patients and healthy volunteers. Methods: A retrospective analysis of a prospective, case-control, clinical trial was carried out. KS patients (n=11) and age-matched healthy controls(n=11) provided a basal blood sample (V0) immediately followed by a single intramuscular injection of hCG 5000 IU. Blood samples were taken in the following five days(V1-V5). Results: At baseline, INSL3 was lower in KS patients compared to controls (p=0.007). When adjusted for INSL3 levels, the production of steroids was similar between KS patients and controls. 25-VD was in the insufficient range both in KS patients and controls and was not different (p=0.064). Acute hCG stimulation increased neither INSL3 nor 25-VD in both KS patients and controls. In controls, an inverse correlation was detected between INSL3 levels and body mass index (p=0.020) and waist circumference (p=0.020). Conclusions: INSL3 secretion is independent from steroidogenesis and its production is mostly not influenced by acute hCG stimulation both in KS men and controls. INSL3 serum levels should be considered as a marker of Leydig cell differentiation and numbers rather than steroidogenesis. 25-VD serum levels are also not increased by a single acute hCG administration, which was not able to restore the normal concentrations of 25-VD.


2020 - Elevated levels of nitrous dioxide are associated with lower AMH levels: A real-world analysis [Articolo su rivista]
La Marca, A.; Spaggiari, G.; Domenici, D.; Grassi, R.; Casonati, A.; Baraldi, E.; Trenti, T.; Simoni, M.; Santi, D.
abstract

STUDY QUESTION: Are there any associations between environmental pollutants and ovarian reserve, expressed by anti-Mullerian hormone (AMH) serum levels? SUMMARY ANSWER: In this first real-world approach to demonstrate the relationship between air pollutants and serum AMH levels, adverse associations were observed for nitrogen dioxide (NO2) but not with particulate matter. WHAT IS KNOWN ALREADY: In recent years, air pollution has emerged as a potential disrupter to the homeostasis of physiological hormones, possibly affecting human reproduction. Although the influence of age and smoking on AMH levels is largely accepted, the relationship between AMH and the environment has not currently been established. STUDY DESIGN, SIZE, DURATION: A longitudinal, observational, retrospective, real-world study was carried out, including all AMH measurements performed in a single laboratory from January 2007 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH data were connected to patients' age and residential address, to include air pollution data after geo-localisation. The air pollution considered daily particulate matter (PM) and NO2 values. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1463 AMH measurements were collected (mean 1.94 ng/ml, median 0.90 ng/ml). AMH was inversely related to patients' age in women older than 25 years (adjusted R-squared 0.120, P < 0.001), but not in those younger than 25 years (adjusted R-squared 0.068, P = 0.055). AMH levels were inversely related to environmental pollutants, such as PM10 (Rho =-0.088, P = 0.001), PM2.5 (Rho =-0.062, P = 0.021) and NO2 (Rho =-0.111, P < 0.001). After subdividing the dataset into quartiles for PM10 and PM2.5, the influence of age on AMH serum levels was found to be a stronger influence than that exerted by PM (P = 0.833 and P = 0.370, respectively). On the contrary, considering NO2 quartiles, higher AMH levels were observed in third quartile compared to fourth quartile, even after adjustment for age (P = 0.028), indicating a stronger influence of NO2 exposure on AMH serum levels. Considering an AMH cut-off of 0.3 ng/ml, a significant higher frequency of women with severe ovarian reserve reduction in the fourth quartile was shown only for NO2 (P = 0.010). LIMITATIONS, REASONS FOR CAUTION: Several limitations should be underlined, such as the lack of information about work and life habits of each patient and the retrospective nature of the analysis performed on real-world data. WIDER IMPLICATIONS OF THE FINDINGS: Although the genetic component is highly predictive for defining the ovarian reserve at birth, potentially modifiable environmental factors could influence the rate of decline in AMH and ovarian reserve during adulthood. STUDY FUNDINGCOMPETING INTEREST(S): Authors have neither funding nor competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.


2020 - Endogenous transient doping: physical exercise acutely increases testosterone levels-results from a meta-analysis [Articolo su rivista]
D'Andrea, S; Spaggiari, G; Barbonetti, A; Santi, D
abstract

Although endogenous testosterone levels are demonstrated to be affected by both acute exercise and resistance training, the dynamic regulation of androgen production after physical activity is still a matter of debate. This meta-analysis was designed to assess whether physical exercise acutely affects testosterone levels in men.


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 - FSH Treatment of male idiopathic infertility: Time for a paradigm change [Articolo su rivista]
Simoni, Manuela; Santi, Daniele
abstract

Follicle-stimulating hormone (FSH) has been used in inconclusive clinical trials for male idiopathic infertility in the past. FSH is sometimes prescribed empirically for male idiopathic infertility, showing some improvement in sperm parameters in about half of the patients. In this opinion article we briefly analyze the pathophysiological evidences in favor of a more aggressive approach in planning future studies on pharmacological FSH use in male infertility, in analogy with the FSH use for multiple follicular growth in women undergoing ovarian stimulation for assisted reproduction. There is sufficient evidence that spermatogenesis does not run at its top in the primate and that some extra FSH can stimulate spermatogenesis over its baseline. Existing data suggest that the pharmacological regimens applied so far were insufficient, both in dosage and in duration, to elicit this response in about half of the patients. A paradigm change is needed now: we should move away from the classical, endocrinological approach, which simply applied the substitutive, therapeutic regimen used in hypogonadotropic hypogonadism, towards testing a "testicular hyperstimulation" scheme for a time sufficient to cover more than only one spermatogenic cycle, a concept to be verified in an appropriately controlled, prospective, randomized clinical trial.


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 - 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 - Health status is related to testosterone, estrone and body fat: moving to functional hypogonadism in adult men with HIV. [Articolo su rivista]
De Vincentis, S.; Decaroli, M. C.; Fanelli, F.; Diazzi, C.; Mezzullo, M.; Morini, F.; Bertani, D.; Milic, J.; Carli, F.; Cuomo, G.; Santi, D.; Tartaro, G.; Tagliavini, S.; De Santis, M. C.; Roli, L.; Trenti, T.; Pagotto, U.; Guaraldi, G.; Rochira, V.
abstract

Objective: Hypogonadism is common in HIV-infected men. The relationship between health status, sex steroids and body composition is poorly known in HIV. The aim was to investigate the association between health status (comorbidities/frailty), body composition, and gonadal function in young-to-middle-aged HIV-infected men. Design: Prospective, cross-sectional, observational study. Methods: HIV-infected men aged<50 years and ongoing Highly Active Antiretroviral Therapy were enrolled. Serum total testosterone (TT), estradiol (E2), estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, LH and FSH by immunoassay. Free testosterone (cFT) was calculated by Vermeulen equation. Body composition was assessed by dual-energy X-ray absorptiometry and abdominal CT scan. Multimorbidity (MM) and frailty were defined as ≥3 comorbidities and by a 37-item index, respectively. Results: A total of 316 HIV-infected men aged 45.3±5.3 years were enrolled. Body fat parameters were inversely related to cFT and TT, and directly related to E1 and E2/T ratio. Patients with MM had lower cFT (p<0.0001) and TT (p=0.036), and higher E1 (p<0.0001) and E2/T ratio (p=0.002). Frailty was inversely related to cFT (R2=0.057, p<0.0001) and TT (R2=0.013, p=0.043), and directly related to E1 (R2=0.171, p<0.0001), E2 (R2=0.041, p=0.004) and E2/T ratio (R2=0.104, p<0.0001). Conclusions: Lower TT and cFT, higher E1, E2/T ratio and visceral fat were independently associated to poor health status and frailty, being possible hallmarks of unhealthy conditions in adult HIV-infected men. Overall, MM, frailty and body fat mass are strictly associated to each other and to sex steroids, concurring together to functional male hypogonadism in HIV.


2020 - Hormonal profile of menopausal women receiving androgen replacement therapy: a meta-analysis [Articolo su rivista]
Marina, L; Sojat, A S; Maseroli, E; Spaggiari, G; Pandurevic, S; Santi, D
abstract

Ovarian and adrenal aging leads to a progressive decline in androgen levels and deleterious effects on the quality of life. Despite this, specific replacement is not routinely recommended in the management of women with a physiological or pathological decline in their production, mainly due to the lack of long-term follow-up safety data. The purpose of this paper was to meta-analyze and summarize the existing data about hormonal profile changes in menopausal women receiving androgen replacement treatments. Full-text articles published through May 30, 2018 were found via MEDLINE and Embase and selected according to the strict inclusion criteria.


2020 - Low Serum Testosterone (T) Is Associated with Poor Health Status in Young to Middle-Aged Human Immunodeficiency Virus (HIV)-Infected Men. [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C.; Morini, F.; Bertani, D.; Fanelli, F.; Mezzullo, M.; Santi, D.; Tartaro, G.; Baraldi, E.; Tagliavini, S.; Pagotto, U.; Guaraldi, G.; Rochira, V.
abstract

BACKGROUND: The relationship between health status, defined by frailty and comorbidities, and serum T levels has been widely demonstrated in general population, while only one previous retrospective study has explored it in HIV-infected men1. AIM: To investigate the association between frailty and go- nadal status by assessing serum total T (TT) with Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS) in a cohort of HIV-infected men. METHODS: Prospective, cross-sectional, observational study on HIV-infected men (age <50 years) with on- going Highly Active Antiretroviral Therapy. Serum TT was assessed by the gold standard ID-LC-MS/MS. Sex hormone-binding globulin (SHBG) was measured by chem- iluminescent immunoassay. Calculated free T (cFT) was obtained by Vermeulen equation. Multimorbidity was de- fined as at least 3 comorbid conditions, including: hyperten- sion, diabetes, cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, osteoporosis, chronic viral hepatitis and cancers. Frailty was calculated through the validated 37-item frailty index (FI)2. Patients with FI>0.21 were considered frail. Statistical ana- lysis: Mann-Whitney U test was used to compare contin- uous variables. Correlations were performed using linear regression models. RESULTS: 315 consecutive HIV-infected men were enrolled (mean age 45.3±5.3 years; average duration of HIV-infection 16.3±8.8 years). 128 patients (40.5%) were co- morbid and 207 (64.9%) were frail. Either cFT (p=0.001) or TT (p<0.001) were lower in comorbid patients than others. FT was inversely related to the number of comorbidities (p<0.001, R2=0.045). Accordingly, cFT (p=0.003) and TT (p<0.001) were significantly lower in frail patients.Frailty score was inversely correlated with cFT (p<0.001, R2=0.058), TT (p=0.041, R2=0.014) and SHBG (p=0.003, R2=0.029). However, after adjustment for age and duration of HIV-infection, cFT, TT and SHBG were excluded from the regression model. CONCLUSIONS: Low cFT and TT levels are associated with multimorbidity and poor health status in HIV infected men. The bidirectional nature of this relationship leads to the figuration of an intriguing vicious circle where T de- ficiency triggers the onset of comorbidities or, vice versa, poor health status induces hypogonadism. At the same time, notwithstanding the inverse relation between FT and frailty, it seems that other stronger predictive factors, and in particular the duration of infection, are involved in de- termining the health outcome in this clinical setting.


2020 - Multilevel approach to male fertility by machine learning highlights a hidden link between haematological and spermatogenetic cells [Articolo su rivista]
Santi, Daniele; Spaggiari, Giorgia; Casonati, Andrea; Casarini, Livio; Grassi, Roberto; Vecchi, Barbara; Roli, Laura; De Santis, Maria Cristina; Orlando, Giovanna; Gravotta, Enrica; Baraldi, Enrica; Setti, Monica; Trenti, Tommaso; Simoni, Manuela
abstract

Male infertility represents a complex clinical condition requiring an accurate multilevel assessment, in which machine learning (ML) technology, combining large data series in nonlinear and highly interactive ways, could be innovatively applied.


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 - Seasonal Changes of Serum Gonadotropins and Testosterone in Men Revealed by a Large Data Set of Real-World Observations Over Nine Years [Articolo su rivista]
Santi, D.; Spaggiari, G.; Granata, A. R. M.; Setti, M.; Tagliavini, S.; Trenti, T.; Simoni, M.
abstract

Environmental rhythmicity is able to affect the hypothalamic-pituitary-gonadal axis in several animals to achieve reproductive advantages. However, conflicting results were obtained when assessing the environmental-dependent rhythmicity on reproductive hormone secretion in humans. This study was designed to evaluate seasonal fluctuations of the main hormones involved in the hypothalamic-pituitary-gonadal axis in men, using a big data approach. An observational, retrospective, big data trial was carried out, including all testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) measurements performed in a single laboratory between January 2010 and January 2019 using Chemiluminescent Microparticle Immunoassay. Subjects presenting any factor interfering with the hypothalamic-pituitary-gonadal axis were excluded. The trend and seasonal distributions were analyzed using autoregressive integrated moving average (ARIMA) models. A total of 12,033 data, accounting for 7,491 men (mean age 47.46 ± 13.51 years, range 18–91 years) were included. Testosterone serum levels (mean 5.34 ± 2.06 ng/dL, range 1.70–15.80 ng/dL) showed a seasonal distribution with higher levels in summer and a direct correlation to environmental temperatures and daylight duration. LH levels (mean 4.64 ± 2.54 IU/L, range 1.00–15.00 IU/L) presented 2 peaks of secretion in autumn and spring, independently from environmental parameters. FSH levels (mean 5.51 ± 3.24 IU/L) did not show any seasonal distribution. A clear seasonal fluctuation of both LH and testosterone was demonstrated in a large cohort of adult men, although a circannual seasonality of hypothalamic-pituitary-gonadal hormones in humans could be not strictly evolutionarily required. Testosterone seasonality seems independent from LH fluctuations, which could be regulated by cyclic central genes expression, and more sensible to environmental temperatures and daylight duration.


2020 - Testicular ultrasound inhomogeneity is an informative parameter for fertility evaluation [Articolo su rivista]
Spaggiari, Giorgia; M Granata, Antonio R; Santi, Daniele
abstract

Testicular volume (TV) is proposed to be a positive predictor of male fertility status, because of the relation known between the TV and the seminiferous tubule content. Independently of the measurement methodology, the role of TV and testicular ultrasound (US) assessments is still debated in andrological clinical practice. In this retrospective cohort study, we evaluated TV and testis US role in the diagnostic workup of andrological patients. All consecutive outpatients undergoing single-operator testis US (Modena, Italy) from March 2012 to March 2018 were enrolled, matching sonographic, hormonal, and seminal data. A total of 302 men were referred and evaluated for gynecomastia, suspected hypogonadism, couple infertility (CI), or sexual dysfunction. In the hypogonadal group, TV was lower compared to that in other groups (P < 0.001), and a significant, direct correlation between TV and testosterone level was observed in nonandrogen-treated patients (R = 0.911, P < 0.001), suggesting that testicular size could be related to the testosterone-secreting compartment. In the CI group, normozoospermic patients showed higher TV compared to men with impaired semen quality (P = 0.003) and azoospermia (P = 0.003). However, TV was not able to discriminate between patients presenting normal and altered semen quality. On the contrary, testis US inhomogeneity was more frequent in patients with impaired sperm quality (55.0%; P = 0.007) and azoospermia (40.0%; P = 0.012), compared to patients with normozoospermia (5%), identifying thereby the sonographic pattern as an informative parameter of the fertility status. Therefore, in the CI workup, US evaluation seems to be more informative than the TV assessment alone.


2020 - Testosterone (T) is poorly related to sexual desire and Erectile Dysfunction (ED) in Young/Middle Aged Human immunodeficiency virus (HIV)-Infected Men [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C; Morini, F.; Bertani, D.; Fanelli, F.; Mezzullo, M.; Santi, D.; Tartaro, G.; Baraldi, E.; Tagliavini, S.; Pagotto, U.; Guaraldi, G.; Rochira, V.
abstract

Background ED is highly prevalent in HIV-infected men. T leads sexual behavior in men, but preliminary data suggests that ED is poorly related to serum T in HIV- infected men. Aim To explore the relationship between sexual function and gonadal function in young/middle-aged HIV-infected men. Methodology Prospective, cross-sectional, observational study on HIV-infected men (age <50 years). Serum TT was assessed by the gold standard LC-MS/MS. Sex hormone-binding globulin (SHBG) was measured by chemiluminescent im- munoassay and calculated free T (cFT) was obtained by Vermeulen equa- tion. Biochemical hypogonadism was defined as TT levels below 320ng/ dl and/or cFT levels below 64pg/ml. The validated International Index of Erectile Function (IIEF)-15 questionnaire was used to identify the presence of ED (score <25) and its degree. IIEF-5 was performed to check if it is reliable as IIEF-15 in this setting. Statistical analysis Continuous and categorical variables were compared using ANOVA univari- ate and Chi-Square test. Correlations were performed using linear regression models.Results 315 consecutive HIV-infected men were enrolled (mean age 45.3 ± 5.3 years; mean duration of HIV-infection 16.3 ± 8.8 years). A total of 187 patients (59.7%) had ED at IIEF-15; 59 patients (31.5%) presented a severe form of ED (score <10). Considering gonadal function, 35 patients (11.1%) had T deficiency. Scores of EF (P=0.039) and sexual desire (P=0.015) domains were higher in hypogonadal than eugonadal men. Accordingly, the prev- alence of ED raised to 71.4% among hypogonadal men. By considering ED severity, patients with severe ED showed a longer duration of infection (P = 0.039) and lower cFT levels (P = 0.041) than patients with mild ED. No difference was found for age (P = 0.224) and TT levels (P = 0.110). IIEF-15 score was inversely related to duration of infection (R2 = 0.030, beta = –0.173, P = 0.002) and patients’ age (R2 = 0.020, beta = –0.140, P = 0.013).No signif- icant correlation was found between IIEF-15 score and total T (P = 0.236) and cFT (P = 0.126). The erectile function domain at IIEF-15 directly cor- related with IIEF-5 score (R2 = 0.545, beta = 0.778, P < 0.001). Conclusions In our HIV-cohort of young/middle-aged men, the prevalence of ED and T deficiency were high being of 60% and 11%, respectively. Serum TT and cFT did not correlate with sexual function parameters, even though sexual desire was lower in men with hypogonadism. ED seems to be better predict- ed by other factors, such as the duration of infection in this clinical setting, rather than the gonadal status. Furthermore, IIEF-5 seems to be as reliable as IIEF-15 for ED diagnosis in HIV-infected men


2020 - The hypothalamic-pituitary-adrenal and -thyroid axes activation lasting one year after an earthquake swarm: results from a big data analysis [Articolo su rivista]
Spaggiari, G.; Setti, M.; Tagliavini, S.; Roli, L.; De Santis, M. C.; Trenti, T.; Rochira, V.; Santi, D.
abstract

Purpose: To cope physical and/or psychological threats, the human body activates multiple processes, mediated by a close interconnection among brain, endocrine and inflammatory systems. The aim of the study was to assess the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes involvement after an acute stressful event (Emilia Romagna earthquake swarm) with a big data approach. Methods: A retrospective, observational trial was performed, collecting all biochemical examinations regarding HPA and HPT axes performed in the same laboratory the year before and the year after the earthquake swarm (20-29 May 2012). Results: Comparing 2576 pre-earthquake to 3021 post-earthquake measurements, a cortisol serum level increase was observed (p < 0.001). Similar increase was evident for urinary free cortisol (p = 0.016), but not for adrenocorticotropic hormone (p = 0.222). The biochemical hypercortisolism incidence increased from 7.6 to 10.3% after earthquakes (p = 0.001). Comparing 68,456 pre-earthquake to 116,521 post-earthquake measurements, a reduction in thyroid-stimulating hormone (TSH) levels was evident (p = 0.018), together with an increase in free triiodothyronine and free thyroxine levels (p < 0.001 and p < 0.001). Moreover, a significant increase in altered TSH after earthquakes was registered considering the epicenter-nearest measurements (p < 0.001). No clinically relevant alterations were observed considering thyroid-specific autoantibodies. Conclusion: A long-term HPA axis activation in the inhabitants of the earthquake-affected areas was highlighted for the first time. Moreover, an increased incidence of biochemical hypercortisolism emerged after earthquakes. We confirmed a recruitment of HPT axis after stressful events, together with increased incidence of altered TSH in the. Our big data study allowed to increase knowledge about the connection between external stressors and endocrine regulation.


2020 - The physician's gender influences the results of the diagnostic workup for erectile dysfunction [Articolo su rivista]
Rastrelli, Giulia; Cipriani, Sarah; Craparo, Andrea; De Vincentis, Sara; Granata, Antonio Rm; Spaggiari, Giorgia; Simoni, Manuela; Maggi, Mario; Santi, Daniele
abstract

Despite the well-known influence of psychological and situational factors on erectile dysfunction (ED), the influence of the physician's gender on the andrological work-up has never been investigated so far.


2020 - To beer or not to beer: A meta-analysis of the effects of beer consumption on cardiovascular health [Articolo su rivista]
Spaggiari, Giorgia; Cignarelli, Angelo; Sansone, Andrea; Baldi, Matteo; Santi, Daniele
abstract

A moderate alcohol consumption is demonstrated to exert a protective action in terms of cardiovascular risk. Although this property seems not to be beverage-specific, the various composition of alcoholic compounds could mediate peculiar effects in vivo. The aim of this study was to evaluate potential beer-mediated effects on the cardiovascular health in humans, using a meta-analytic approach (trial registration number: CRD42018118387). The literature search, comprising all English articles published until November, 30th 2019 in EMBASE, PubMed and Cochrane database included all controlled clinical trials evaluating the cardiovascular effects of beer assumption compared to alcohol-free beer, water, abstinence or placebo. Both sexes and all beer preparations were considered eligible. Outcome parameters were those entering in the cardiovascular risk charts and those related to endothelial dysfunction. Twenty-six trials were included in the analysis. Total cholesterol was significantly higher in beer drinkers compared to controls (14 studies, 3.52 mg/dL, 1.71-5.32 mg/dL). Similar increased levels were observed in high-density lipoprotein (HDL) cholesterol (18 studies, 3.63 mg/dL, 2.00-5.26 mg/dL) and in apolipoprotein A1 (5 studies, 0.16 mg/dL, 0.11-0.21 mg/dL), while no differences were detected in low density lipoprotein (LDL) cholesterol (12 studies, -2.85 mg/dL, -5.96-0.26 mg/dL) and triglycerides (14 studies, 0.40 mg/dL, -5.00-5.80 mg/dL) levels. Flow mediated dilation (FMD) resulted significantly higher in beer-consumers compared to controls (4 studies, 0.65%, 0.07-1.23%), while blood pressure and other biochemical markers of inflammation did not differ. In conclusion, the specific beer effect on human cardiovascular health was meta-analysed for the first time, highlighting an improvement of the vascular elasticity, detected by the increase of FMD (after acute intake), and of the lipid profile with a significant increase of HDL and apolipoprotein A1 serum levels. Although the long-term effects of beer consumption are not still understood, a beneficial effect of beer on endothelial function should be supposed.


2020 - Use of follicle-stimulating hormone (FSH) for the male partner of idiopathic infertile couples in Italy: Results from a multicentre, observational, clinical practice survey [Articolo su rivista]
Santi, Daniele; De Vincentis, Sara; Alfano, Patrizia; Balercia, Giancarlo; Calogero, Aldo E; Cargnelutti, Francesco; Coccia, Maria Elisabetta; Condorelli, Rosita A; Dal Lago, Alessandro; De Angelis, Cristina; Gallo, Mariagrazia; Iannantuoni, Nicola; Lombardo, Francesco; Marino, Angelo; Mazzella, Marco; Pallotti, Francesco; Paoli, Donatella; Pivonello, Rosario; Rago, Rocco; Rampini, Mariarita; Salvio, Gianmaria; Simoni, Manuela
abstract

The management of male idiopathic infertility is heterogeneous. Although meta-analyses reported the effectiveness on pregnancy rate, the real clinical impact of follicle-stimulating hormone (FSH) was not evaluated so far. In Italy, FSH is approved by the national Medicines Agency (AIFA) for idiopathic infertile patients with FSH < 8 IU/L, independently of semen parameters.


2019 - Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: A pilot study [Articolo su rivista]
Melcangi, R. C.; Casarini, L.; Marino, M.; Santi, D.; Sperduti, Samantha; Giatti, S.; Diviccaro, S.; Grimoldi, M.; Caruso, D.; Cavaletti, G.; Simoni, M.
abstract

Context: Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. Objective: To study whether epigenetic modifications occur in PFS patients. Methods: Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. Results: SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. Conclusions: For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.


2019 - An Observational Retrospective Cohort Trial on 4,828 IVF Cycles Evaluating Different Low Prognosis Patients Following the POSEIDON Criteria [Articolo su rivista]
Levi-Setti, Paolo Emanuele; Zerbetto, Irene; Baggiani, Annamaria; Zannoni, Elena; Sacchi, Laura; Smeraldi, Antonella; Morenghi, Emanuela; De Cesare, Raffaella; Drovanti, Alessandra; Santi, Daniele
abstract

Objective: To study the actual controlled ovarian stimulation (COS) management in women with suboptimal response, comparing clinical outcomes to the gonadotropins consume, considering potential role of luteinizing hormone (LH) addition to follicle-stimulating hormone (FSH).Design: Monocentric, observational, retrospective, real-world, clinical trial on fresh intra-cytoplasmic sperm injection (ICSI) cycles retrieving from 1 to 9 oocytes, performed at Humanitas Fertility Center from January 1st, 2012 to December 31st, 2015.Methods: COS protocols provided gonadotropin releasing-hormone (GnRH) agonist long, flare-up, short and antagonist. Both recombinant and urinary FSH were used for COS and LH was added according to the clinical practice. ICSI outcomes considered were: gonadotropins dosages; total, mature, injected and frozen oocytes; cumulative, transferred and frozen embryos; implantation rate; pregnancy, delivery and miscarriage rates. Outcomes were compared according to the gonadotropin regimen used during COS.Results: Our cohort showed 20.8% of low responders, defined as 1-3 oocytes retrieved and 79.2% of "suboptimal" responders, defined as 4-9 oocytes retrieved. According to recent POSEIDON stratification, cycles were divided in group 1 (6.9%), 2 (19.8%), 3 (11.7%), and 4 (61.5%). The cohort was divided in 3 groups, according to the gonadotropin's regimen. Women treated with FSH plus LH showed worst prognostic factors, in terms of age, basal FSH, AMH, and AFC. This difference was evident in suboptimal responders, whereas only AMH and AFC were different among treatment groups in low responders. Although a different result, in terms of oocytes and embryos detected, major ICSI outcomes (i.e., pregnancy and delivery rates) were similar among groups of COS treatment. Outcomes were significantly different among Poseidon groups. Implantation, pregnancy and delivery rates were significantly higher in Poseidon group 1 and progressively declined in other POSEIDON groups, reaching the worst percentage in group 4.Conclusions: In clinical practice, women with worst prognosis factors are generally treated with a combination of LH and FSH. Despite low prognosis women showed a reduced number of oocytes retrieved, the final ICSI outcome, in terms of pregnancy, is similarly among treatment group. This result suggests that the LH addition to FSH during COS could improve the quality of oocytes retrieved, balancing those differences that are evident at baseline.


2019 - Diagnostic and Therapeutic Workup of Erectile Dysfunction: Results From a Delphi Consensus of Andrology Experts [Articolo su rivista]
Isidori, A. M.; Giammusso, B.; Corona, G.; Verze, P.; Albanesi, L.; Antomarchi, F.; Arcaniolo, D.; Balercia, G.; Barbonetti, A.; Barletta, D.; Barrese, F.; Bellastella, G.; Biggio, A.; Bitelli, M.; Botturi, A.; Brancato, T.; Branchina, A.; Cai, T.; Canale, D.; Capone, L.; Capone, M.; Carluccini, A.; Citarrella, R.; Cocci, A.; Corvese, F.; Cozza, P. P.; Creta, M.; D'Andrea, S.; Dalena, G.; Damiano, R.; Defeudis, G.; Del Grasso, A.; Delbarba, A.; Delle Rose, A.; Di Crosta, G.; Di, Filippo; Di Lena, S.; Di Martino, M.; Di Millo, F.; Di Palma, P.; Diazzi, D.; Dicuio, M.; Diosi, D.; Fabbri, A.; Fattorini, G.; Florio, M.; Formiconi, A.; Franco, G.; Galdiero, M.; Giambersio, A. M.; Gianfrilli, D.; Giovannone, R.; Granata, A. M.; Iafrate, M.; Iapicca, G.; Iatrino, G.; Ilacqua, N.; Innocenti, F.; Italiano, E.; Izzo, A.; Izzo, P.; Lamartina, M.; Ledda, A. F.; Lepri, L.; Lo, C. F.; Lombardo, F.; Luca, G.; Macchione, L.; Maga, T.; Matteo, M.; Malvestiti, G. M.; Marella, G.; Maretti, C.; Maturo, G.; Mazzaferro, D.; Mazzilli, R.; Migliorini, F.; Milardi, D.; Minardi, V.; Moiso, A.; Mondaini, N.; Moretti, M.; Motta, G.; Nerva, F.; Pastore, A. L.; Paulis, G.; Piazza, N.; Pili, M.; Pistone, A.; Pivonello, R.; Pizzocaro, A.; Polverini, M.; Provinzano, V.; Rastrelli, G.; Risi, O.; Rocchegiani, A.; Rolle, L.; Romanelli, F.; Romano, G.; Russo, G. I.; Salemi, G.; Salzano, C.; Sanna, F.; Sansone, A.; Santi, D.; Scalese, G. A.; Scarano, P.; Scroppo, F. I.; Serrao, M. F.; Sidoti, G.; Silvestre, G.; Simone, O.; Sorrentino, M.; Tallis, V.; Tammaro, R.; Ughi, G.; Vagnoni, V.; Vavallo, A.; Vecchio, D.; Vita, A.; Zicarelli, P.; Zucchi, A.
abstract

Introduction: Erectile dysfunction is a highly prevalent condition. Existing guidelines provide recommendations for diagnosis and treatment, but they are often disregarded in clinical practice in favor of a “patient-tailored” approach. Objectives: We planned a Delphi consensus method to bridge the gap between evidence-based medicine and the real-life approach in daily practice. Materials and Methods: The Advisory Board prepared 15 statements on debated topics in andrology, each including 4–6 items designed as a 5-point Likert scale. After a validation phase, the questionnaire was sent by e-mail to a panel of experts for a first round of voting; members of the panel were later invited to a second round of voting, preceded by discussion of the “hot topics” identified in the first round. Results: The first round of the Delphi consensus involved 101 experts; 71 (70%) also took part in the second round of voting. The Advisory Board deemed 22 items to be worthy of debate, and these underwent the second round of voting. “Real-life” results from the survey proved quite different from evidence-based recommendations. Conclusion: Although guidelines suggest the best approach for a “standard” patient, real-life settings require flexibility. Diagnostic and therapeutic approaches should be tailored to the patients’ needs. Phosphodiesterase type 5 inhibitors are recognized as the first-line therapy in both settings, including the newly introduced sildenafil orodispersible film. Indications from the panel might help close the gap between recommendations from guidelines and real-life practice in relation to the diagnosis and treatment of erectile dysfunction. Isidori AM, Giammusso B, Corona G, et al. Diagnostic and Therapeutic Workup of Erectile Dysfunction: Results From a Delphi Consensus of Andrology Experts. Sex Med 2019;7:292–302.


2019 - Editorial: Follicle-Stimulating Hormone: Fertility and Beyond [Articolo su rivista]
Simoni, Manuela; Huhtaniemi, Ilpo; Santi, Daniele; Casarini, Livio
abstract

Editorial on the Research Topic


2019 - Effectiveness of androgens administration on body composition in HIV-infected men: a meta-analysis [Abstract in Atti di Convegno]
Santi, D.; Spaggiari, G.; Corona, G.; Rochira, V.
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 - Free Testosterone (FT) is inversely related to frailty in Human Immunodeficiency Virus (HIV)-Infected Men [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C.; Morini, F.; Bertani, D.; Fanelli, F.; Mezzullo, M.; Santi, D.; Tartaro, G.; Baraldi, E.; Tagliavini, S.; Pagotto, U.; Guaraldi, G.; Rochira., V.
abstract


2019 - Free testosterone (FT) is inversely related to frailty in human immunodeficiency virus (HIV)-infected men. [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C.; Morini, F.; Bertani, D.; Fanelli, F.; Mezzullo, M.; Santi, D.; Tartaro, G.; Baraldi, E.; Tagliavini, S.; Pagotto, U.; Guaraldi, G.; Rochira., V.
abstract

BACKGROUND HIV-infection is associated to several age-related comorbidities, such as a premature decline of serum testosterone (T). There is evidence about the relationship between health status, represented by frailty and comorbidities, and serum T levels in general population, while only one previous retrospective study investigated it in HIV-infected men. AIM To investigate the association between frailty and gonadal status by assessing serum total T (TT) with Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS) in a cohort of HIV-infected men. METHODS Prospective, cross-sectional, observational study on HIV-infected men (age years) with ongoing Highly Active Antiretroviral Therapy (HAART). Serum TT was assessed by the gold standard ID- LC-MS/MS. Sex hormone-binding globulin (SHBG) was measured by chemiluminescent immunoassay. Free T (FT) was calculated by Vermeulen equation. Frailty was calculated through -items multimorbidity frailty index. Saca aa Parameters were not normally distributed and Mann- Whitney U test was used to compare continuous variables. Correlations were performed using linear regression models. RESULTS consecutive HIV-infected men were enrolled (mean age .. years; average duration of HIV-infection .. years). patients (.) had TT below ng/dL and patients (.) had calculated FT below pg/mL. Overall, patients (.) had T deficiency defined by low TT levels and/or low FT. patients (.) showed SHBG above the normal range (. nmol/L). Frailty score (p.), age (p.), duration of HIV-infection and of HAART (p.) significantly differed between eugonadic and hypogonadic patients, while no difference was found for BMI (p.). FT inversely correlated with frailty score (p., R.), while TT did not (p.). At stepwise multivariate regression analysis, FT showed an inverse relation with age (p.,R.), years of infection (-.,p.,R.) and years of HAART (-.,p.,R.), but not with frailty score and BMI of patients. CONCLUSIONS To the best of our knowledge, this is the first properly-designed prospective study aiming to investigate the relationship between general health status and gonadal function in a cohort of HIV-infected men. FT is inversely related to frailty score, suggesting an impairment of gonadal function in those patients affected by more multimorbidities in this setting as well as in general population. At the same time, the age of patient and the duration of HIV-infection seem to be more potent predictive factors for serum FT levels than frailty score. In clinical practice it is important to check for testosterone in these patients due to frequent alterations of SHBG.


2019 - Gonadal Function in Human Immunodeficiency Virus (HIV)-Infected Men Assessed by Isotopic Dilution-Liquid Chromatography-Tandem Mass Spectrometry (ID-LC-MS/MS) and Chemiluminescent Immunoassay. [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C.; Morini, F.; Bertani, D.; Fanelli, F.; Mezzullo, M.; Santi, D.; Baraldi, E.; Tagliavini, S.; Pagotto, U.; Guaraldi, G.; Rochira., V.
abstract


2019 - Gonadal Function in Human Immunodeficiency Virus (HIV)-Infected Men: comparison between Isotopic Dilution-Liquid Chromatography- Tandem Mass Spectrometry (ID-LC-MS/MS) and Chemiluminescent Immunoassay (CI). [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Fanelli, F.; Mezzullo, M.; Diazzi, C.; Morini, F.; Bertani, D.; Santi, D.; Baraldi, E.; Tagliavini, S.; Roli, L.; Trenti, T.; Pagotto, U.; Guaraldi, G.; Rochira., V.
abstract


2019 - Gonadal function in human immunodeficiency virus (HIV)-infected men: comparison between isotopic dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) and chemiluminescent immunoassay (CI) [Abstract in Atti di Convegno]
Decaroli, M. C.; De Vincentis, S.; Fanelli, F.; Mezzullo, M.; Diazzi, C.; Morini, F.; Bertani, D.; Santi, D.; Baraldi, E.; Tagliavini, S.; Roli, L.; Trenti, T.; Pagotto, U.; Guaraldi, G.; Rochira, V.
abstract


2019 - Identificazione ecografica di un nodulo sottocutaneo rilevato alla palpazione del collo e risultato un microcarcinoma papillare tiroideo persistente in sede sottocutanea atipica 25 anni dopo terapia chirurgica locale, tiroidectomia e linfadenectomia [Articolo su rivista]
Spaggiari, Giorgia; Piccinini, Francesca; Ansaloni, Anna; Madeo, Bruno; Zirilli, Lucia; Simoni, Manuela; Santi, Daniele
abstract

Descrizione di un caso clinico di particolare interesse


2019 - Multilevel approach to male infertility using machine learning [Abstract in Atti di Convegno]
Santi, D; Spaggiari, G; Michelangeli, M; Casarini, L; Grassi, R; Vecchi, B; Roli, L; De Santis, Mc; Baraldi, E; Setti, M; Trenti, T; Simoni., M
abstract


2019 - Polyphenol Health Effects on Cardiovascular and Neurodegenerative Disorders: A Review and Meta-Analysis [Articolo su rivista]
Potì, Francesco; Santi, Daniele; Spaggiari, Giorgia; Zimetti, Francesca; Zanotti, Ilaria
abstract

Several studies have demonstrated that polyphenol-enriched diets may have beneficial effects against the development of degenerative diseases, including atherosclerosis and disorders affecting the central nervous system. This activity has been associated not only with antioxidant and anti-inflammatory properties, but also with additional mechanisms, such as the modulation of lipid metabolism and gut microbiota function. However, long-term studies on humans provided controversial results, making the prediction of polyphenol impact on health uncertain. The aim of this review is to provide an overview and critical analysis of the literature related to the effects of the principal dietary polyphenols on cardiovascular and neurodegenerative disorders. We critically considered and meta-analyzed randomized controlled clinical trials involving subjects taking polyphenol-based supplements. Although some polyphenols might improve specific markers of cardiovascular risk and cognitive status, many inconsistent data are present in literature. Therefore, definitive recommendations for the use of these compounds in the prevention of cardiovascular disease and cognitive decline are currently not applicable. Once pivotal aspects for the definition of polyphenol bioactivity, such as the characterization of pharmacokinetics and safety, are addressed, it will be possible to have a clear picture of the realistic potential of polyphenols for disease prevention.


2019 - Polyphenol health effects on cardiovascular disorders: myth or truth? "Le basi farmacologiche dei nutraceutici" [Abstract in Atti di Convegno]
Potì, F; Zimetti, F; Spaggiari, G; Santi, D; Zanotti, I
abstract


2019 - Relative hyperestrogenism in Klinefelter Syndrome: results from a meta-analysis. [Articolo su rivista]
Santi, D.; De Vincentis, S.; Scaltriti, S.; Rochira, Vincenzo
abstract

OBJECTIVE: Klinefelter Syndrome (KS) is classically described as characterized by hyperestrogenism, although solid evidence is lacking. This study aims to test the hypothesis that men with KS have higher serum estradiol than normal controls. DESIGN: Meta-analysis of all studies extracted by MEDLINE from 1942 to 31 January 2018. All studies reporting serum estradiol measurement were considered, among them only case-control studies were included in the meta-analysis. METHODS: Meta-analysis was conducted according to the PRISMA statement using RevMan. RESULTS: Out of 4120 articles, 23 case-control studies, 14 case series, and 19 case reports reported data on serum estradiol. A total of 707 KS and 1019 controls were included in the meta-analysis. Serum estradiol was slightly, but significantly higher in KS than controls (mean difference 4.25 pg/mL; CI: 0.41, 8.10 pg/mL; p = 0.030). This difference was lost considering only studies using estradiol assays with good accuracy (5.48 pg/mL, CI: -2.11, 13.07 pg/mL; p = 0.160). Serum testosterone and estradiol/testosterone ratio were significantly lower and higher in KS than controls, respectively. Data from KS case series and case reports confirmed that serum estradiol is within the normal ranges. CONCLUSIONS: Serum estradiol is not increased in KS although slightly higher than controls. However, the meta-analysis that included only studies using a serum estradiol assay with good accuracy showed no difference in serum estradiol between KS and controls. The traditional belief that KS is associated with elevated serum estradiol should be reconsidered. This meta-analysis shows that men with KS have relative hyperestrogenism (increased estradiol/testosterone ratio) compared to controls.


2019 - Risk behaviours and alcohol in adolescence are negatively associated with testicular volume: results from the Amico-Andrologo survey [Articolo su rivista]
Gianfrilli, D; Ferlin, A; Isidori, A M; Garolla, A; Maggi, M; Pivonello, R; Santi, D; Sansone, A; Balercia, G; Granata, A R M; Sinisi, A; Lanfranco, F; Pasqualetti, P; Foresta, C; Lenzi, A
abstract

Risk factors established during adolescence affect health outcomes in adulthood, although little is known about how adolescent health risk behaviours (HRBs) affect testicular development and reproductive health.


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 - Serum Sodium Is Inversely Related to Frailty and Bone Mineral Density (BMD) in Human Immunodeficiency Virus (HIV)-Infected Patients [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C.; Santi, D.; Carli, F.; Zona, S.; Guaraldi, G.; Rochira, V.
abstract


2019 - Thyroid function in Klinefelter syndrome: a multicentre study from KING group [Articolo su rivista]
Balercia, G.; Bonomi, M.; Giagulli, V. A.; Lanfranco, F.; Rochira, V.; Giambersio, A.; Accardo, G.; Esposito, D.; Allasia, S.; Cangiano, B.; De Vincentis, S.; Condorelli, R. A.; Calogero, A.; Pasquali, D.; Aversa, A.; Balercia, G.; Calogero, A.; Corona, G.; Giorgino, F.; Fabbri, A.; Ferlin, A.; Ferrante, E.; Francavilla, F.; Giagulli, V.; Jannini, E.; Lanfranco, F.; Maggi, M.; Pasquali, D.; Pivonello, R.; Pizzocaro, A.; Radicioni, A.; Rochira, V.; Vignozzi, L.; Barchi, M.; Condorelli, R. A.; Cordeschi, G.; D'Andrea, S.; Mambro, A. D.; Foresta, C.; Francavilla, S.; Garolla, A.; Giovannini, L.; Granata, A. R. M.; La Vignera, S.; Motta, G.; Negri, L.; Pelliccione, F.; Persani, L.; Salzano, C.; Santi, D.; Selice, R.; Simoni, M.; Tatone, C.; Tirabassi, G.; Tresoldi, A. S.; Vicari, E.
abstract

PURPOSE:The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. METHODS: This is a case-control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student's t test. Mann-Whitney test and Chi-square test. RESULTS: FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto's thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. CONCLUSIONS: We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype.


2018 - 'Spare' Luteinizing Hormone Receptors: Facts and Fiction. [Articolo su rivista]
Casarini, Livio; Santi, Daniele; Simoni, Manuela; Potì, Francesco.
abstract

It is common opinion that maximal activation of luteinizing hormone (LH)-dependent steroidogenic signal occurs at <1% of human LH/choriogonadotropin (hCG) receptor (LHCGR) occupancy. This effect would be a consequence of an excess of receptors expressed on the surface of theca cells, resulting in a pool of LHCGRs remaining unbound (spare). This concept was borrowed from historical pharmacological studies, when discrepancies between ligand-receptor binding and dose-response curves of cAMP were evaluated by treating mouse or rat Leydig cells with hCG in vitro. Recent findings demonstrated the specificity of LH- and hCG-dependent effects, receptor heterodimerization, and differing behaviors of rodent versus human gonadotropin-responsive cells, which may help to revise the 'spare' LHCGRs concept applied to human ovarian physiology and assisted reproduction.


2018 - An Italian survey of compliance with major guidelines for L-thyroxine of primary hypothyroidism [Articolo su rivista]
Vezzani, Silvia; Giannetta, Elisa; Altieri, Barbara; Barbonetti, Arcangelo; Bellastella, Giuseppe; Certo, Rosaria; Cignarelli, Angelo; Cinti, Francesca; D'Andrea, Settimio; Di Dalmazi, Giulia; Frara, Stefano; Garelli, Silvia; Giuffrida, Giuseppe; Maiorino, Maria Ida; Mele, Chiara; Mezza, Teresa; Pani, Maria Grazia; Samá, Maria Teresa; Satta, Chiara; Santi, Daniele
abstract

Objective: The adherence by endocrinologists to guideline regarding levothyroxine (LT4) therapy and the compliance of patients may impact the management of hypothyroidism. The aim of this study was to compare the adherence of Italian endocrinologists to the ATA/AACE and ETA guidelines on the management of newly diagnosed primary hypothyroidism and to validate the Italian version of the Morisky-Green Medical Adherence Scale-8 (MMAS-8) questionnaire as applied to the evaluation of the adherence of patients with hypothyroidism to LT4 treatment. Methods: This was an observational, longitudinal, multicenter, cohort study, involving 12 Italian Units of Endocrinology. Results: The study enrolled 1,039 consecutive outpatients (mean age 48 years; 855 women, 184 men). The concordance of Italian endocrinologists with American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) and European Thyroid Association (ETA) recommendations was comparable (77.1% and 71.7%) and increased (86.7 and 88.6%) after the recommendations on LT4 dose were excluded, considering only the remaining recommendations on diagnosis, therapy, and follow-up. The MMAS-8 was filled out by 293 patients. The mean score was 6.71 with 23.9% low (score &lt;6), 38.6% medium (6 to &lt;8), 37.5% highly (= 8) adherers; the internal validation coefficient was 0.613. Highly adherent patients were not more likely to have good control of hypothyroidism compared with either medium (69% versus 72%, P = .878) or low (69% versus 43%, P = .861) adherers. Conclusion: Clinical management of hypothyroidism in Italy demonstrated an observance of international guidelines by Italian endocrinologists. Validation of the Italian version of the MMAS-8 questionnaire provides clinicians with a reliable and simple tool for assessing the adherence of patients to LT4 treatment.


2018 - Approccio a multilivelli all’infertilità maschile utilizzando il machine learning. [Abstract in Atti di Convegno]
Santi, D; Spaggiari, G; Michelangeli, M; Casarini, L; Grassi, R; Vecchi, B; Roli, L; De Santis, Mc; Baraldi, E; Setti, M; Trenti, T; Simoni, M
abstract


2018 - Clinical relevance of genetic variants of gonadotrophins and their receptors in controlled ovarian stimulation: a systematic review and meta-analysis [Articolo su rivista]
Alviggi, Carlo; Conforti, Alessandro; Santi, Daniele; Esteves, Sandro C; Andersen, Claus Yding; Humaidan, Peter; Chiodini, Paolo; De Placido, Giuseppe; Simoni, Manuela
abstract

Genotype has been implicated in the outcome of ovarian stimulation. The analysis of patient-specific genotypes might lead to an individualized pharmacogenomic approach to controlled ovarian stimulation (COS). However, the validity of such an approach remains to be established.


2018 - Could chronic Vardenafil administration influence the cardiovascular risk in men with type 2 diabetes mellitus? [Articolo su rivista]
Santi, Daniele; Locaso, Michela; Granata, Antonio R; Trenti, Tommaso; Roli, Laura; Pacchioni, Chiara; Rochira, Vincenzo; Carani, Cesare; Simoni, Manuela
abstract

Introduction Appropriate algorithms for the prediction of cardiovascular risk are strongly suggested in clinical practice, although still controversial. In type 2 diabetes mellitus (T2DM), the benefi- cial effect of phosphodiesterase (PDE)-5 inhibitors is demonstrated on endothelial function but not on the estimation of cardiovascular risk. Aim To study whether the chronic Vardenafil administration to men with T2DM influences vari- ables correlated with the predicted long-term cardiovascular risk calculated by different vali- dated algorithms. Methods Per-protocol analysis of a longitudinal, prospective, randomized, placebo-controlled, dou- ble-blind, investigator-started, clinical trial. 54 male patients affected by T2DM were assigned to study (26patients) and control-group (28patients), respectively. The study included a treatment phase (24weeks) (Vardenafil/placebo 10mg twice-daily) and a follow- up phase (24weeks). Three time points were considered: baseline(V0), end of treatment (V1) and end of the study(V2). Parameters evaluated: endothelial health-related parameters and cardiovascular risk, assessed by calculating the Framingham (coronary hart disease [CHD], myocardial infarction [MI], stroke and cardiovascular disease [CVD]), ASSIGN and CUORE equations. Results Predicted cardiovascular risk at ten years resulted different using the three algorithms cho- sen, without differences between study and control groups and among visits. IL-6 was directly related to CHD, CVD and CUORE scores at V1 and with MI and STROKE at V2. Similarly, hs-CRP was directly related to CHD, MI, STROKE and CUORE only at V1 in the study group. Testosterone serum levels were inversely related to CHD and MI at V1 in study group. Discussion The predicted cardiovascular risk is different depending on the algorithm chosen. Despite no predictive risk reduction after six months of treatment, a possible effect of Vardenafil could be hypothesized through its action on inflammation markers reduction and through restoration of normal testosterone levels.


2018 - FSH (Follicle-Stimulating Hormone) [Capitolo/Saggio]
Santi, Daniele; Casarini, Livio; R Marshall, Gary; Simoni, Manuela
abstract

Follicle-stimulating hormone (FSH) is a glycoprotein regulating development and reproduction. In both adult fertile males and females, FSH mediates spermatogenesis and folliculogenesis, acting through its G-protein coupled receptor (FSHR). Mutations and single nucleotide polymorphisms occurring within the genes encoding the hormone beta subunit and FSHR may modulate or even impair the physiological function of FSH in both males and females. Synthesis and secretion of FSH are described in the chapter, with a specific overview on the pathways activated upon FSH-FSHR interaction and the physiology of the hormone.


2018 - Gonadal function in human immunodeficiency virus (HIV)-infected men assessed by isotopic dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) and chemiluminescent assay. [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C.; Morini, F.; Bertani, D.; Fanelli, F.; Mezzullo, M.; Santi, D.; Baraldi, E.; Tagliavini, S.; Pagotto, U.; Guaraldi, G.; Rochira, Vincenzo
abstract

BACKGROUND: HIV infection is associated to premature decline of serum T1,2. However, prevalence and biochemical characterization of hypogonadism in HIV-infected men are still to be well defined1,2. AIM OF THE STUDY: We evaluated the gonadal status in young to middle aged HIV-infected men in order to characterize hypogonadism by assessing circulating total T (TT) with either Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS) or chemiluminescent immunoassay. METHODS: Prospective, cross-sectional, observational study on 315 consecutive HIV-infected male patients with ongoing Highly Active Antiretroviral Therapy (HAART), attending the Metabolic Clinic of Infectious Diseases. Serum TT, gonadotropins and sex hormone-binding globulin (SHBG) were measured by chemiluminescent immunoassay. Serum TT was also assessed by the gold standard LC-MS/MS in 233 patients. Free T (FT) was calculated by using Vermeulen equation3. Hypogonadism was defined as serum TT levels below 320 ng/dL and/or free T levels below 64 pg/ml4. Statistical analysis: Categorical variables were compared using Chi-Square test, while correlations were performed using Spearman’s Rho coefficient and linear regression models. RESULTS: 315 HIV-infected patients were enrolled (mean age 45.56±5.61 years) with average duration of HIV-infection of 16.57±10.45 years. Considering serum total T levels assessed by LC-MS/MS and immunoassay, 11 patients out of 233 (4.8%) and 10 patients out of 315 (3.2%) had T deficiency, respectively. TT combined with luteinizing hormone (LH) levels was used to classify hypogonadism (Table 1). No difference was found among subgroups comparing the two methodologies used for TT measurement (p=0.914). 56 patients (17.8%) showed SHBG above the normal range (>71.4 nmol/L). Considering calculated FT, the incidence of hypogonadism raised to 6.9% using either immunoassay or LC-MS/MS, respectively (Table 1), with no difference between methodologies (p=0.895). Including compensated form oh hypogonadism, the prevalence raised to 13% for TT and to 15% for FT. Patients with low FT were older than eugonadal patients (p=0.005) and showed a significantly longer duration of HIV-infection (p<0.0001) and HAART (p=0.002), while they did not differ for body mass index (p=0.231). FT showed an inverse relation with age (-0.340, p<0.0001, R2=0.116), years of infection (-0.339, p<0.0001, R2=0.120) and years of HAART (-0.346, p<0.0001, R2=0.117), but not with BMI of patients. CONCLUSIONS: To the best of our knowledge, this is the first, properly-designed prospective study aiming to investigate the gonadal status of HIV-infected men with both LC-MS/MS and chemiluminescent assay. In HIV-infected patients a) the two methodologies have equivalent reliability in TT measurement; b) SHBG for calculated FT is essential for the detection of T deficiency, revealing the real prevalence of hypogonadism in this context; c) duration of HIV-infection and HAART seem to be potent predictive factors for serum FT levels, suggesting a concomitant negative effect of virus per se and antiretroviral drugs on gonadal function. References 1Rochira V et al. Premature decline of serum total testosterone in HIV-infected men in the HAART-era. PLoS One. 2011;6(12):e28512. 2Rochira V & Guaraldi G. Hypogonadism in the HIV-infected man. Endocrinol Metab Clin North Am. 2014 Sep;43(3):709-30. 3Vermeulen A et al. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84:3666–3672 4Bhasin S et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 May 1;103(5):1715-1744.


2018 - IL SODIO SIERICO È INVERSAMENTE CORRELATO ALLA FRAILTY E ALLA DENSITÀ MINERALE OSSEA (BMD) NEI PAZIENTI CON INFEZIONE DA HUMAN IMMUNODEFICIENCY VIRUS (HIV) [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, MARIA CHIARA; Diazzi, C.; Santi, D.; Menozzi, M.; Zona, S.; Guaraldi, G.; Rochira, V.
abstract

L'iponatriemia si associa alla frailty nei pazienti con infezione da HIV


2018 - LH (Luteinizing Hormone) [Capitolo/Saggio]
Casarini, Livio; Santi, Daniele; R Marshall, Gary; Simoni, Manuela
abstract

Luteinizing hormone (LH) is secreted by the pituitary gland as a heterodimeric glycoprotein acting on the gonads, regulating development and reproduction. In human of fertile age, it plays a central role in follicle development and spermatogenesis stimulating the production of steroid hormones and mediating proliferative signals. LH acts on a G-protein coupled receptor (LHCGR), shared together with the pregnancy hormone choriogonadotropin (hCG), which features specific intracellular signaling and physiological function. In this chapter, the role exerted by LH during fetal life and fertile age of humans is described.


2018 - La risposta degli steroidi allo stimolo con gonadotropina corionica (hCG) nei soggetti con sindrome di Klinefelter non cambia utilizzando gli immunodosaggi o la spettrometria di massa [Articolo su rivista]
Roli, L.; Santi, D.; Tagliavini, S.; Cavalieri, S.; De Santis, M. C.; Baraldi, E.; Fanelli, F.; Mezzullo, M.; Granata, A. R.; Pagotto, U.; Pasquali, R.; Rochira, V.; Carani, C.; Simoni, M.; Trenti, T.
abstract

Obiettivi. La cromatografia liquida associata alla spettrometria di massa tandem (LC-MS/MS) è stata sviluppata contemporaneamente agli immunodosaggi (IA) ed oggigiorno viene proposta come gold standard per il dosaggio degli steroidi. Le cellule del Leydig dei soggetti con sindrome di Klinefelter (KS) sono in grado di rispondere allo stimolo con gonadotropina corionica (hCG), anche se la produzione di testosterone (T) è difettosa. L'obiettivo dello studio è di valutare come i risultati ottenuti con gli IA e la LC-MS/MS possono differentemente impattare sui risultati di una ricerca clinica sulla steroidogenesi gonadica dopo stimolo con hCG. Metodi. E' stato condotto uno studio clinico longitudinale, prospettico, caso-controllo (clinicaltrial.gov NCT02788136), arruolando maschi con KS e controlli sani appaiati per età, sottoposti a stimolo con somministrazione di hCG. Gli steroidi sierici sono stati valutati in condizioni basali e per 5 giorni consecutivi ad una iniezione intramuscolare di 5000 IU di hCG utilizzando sia gli IA che la LC-MS/MS. Risultati. Sono stati arruolati 13 pazienti KS (36 ± 9 anni) non in terapia sostitutiva con T e 14 controlli sani (32 ± 8 anni). T, progesterone (P), cortisolo (C), 14-idrossi-progesterone (17OHP) e androstenedione (A) erano si- gnificativamente più elevati utilizzando di IA rispetto alla LC-MS/MS. I due metodi hanno dimostrato una relazione diretta sebbene con una costante sovrastima da parte degli IA. Entrambi i metodi hanno rilevato lo stesso profilo d'incremento di 17OHP e di T, con aree sotto la curva (AUC) equivalenti. Conclusioni. Sebbene sia stata dimostrata una relazione lineare tra IA e LC-MS/MS, quest'ultima è più sensibile ed accurata, mentre gli IA mostrano una costante sovrastima dei livelli di steroidi sierici. Questo risultato suggerisce la necessità di stabilire intervalli di riferimento metodo-specifici. La fondamentale differenza fra i due metodi apre una profonda riconsiderazione su cosa sia necessario per migliorare l'accuratezza dei dosaggi per gli steroidi.


2018 - Molecular basis of androgen action on human sexual desire [Articolo su rivista]
Santi, Daniele; Spaggiari, Giorgia; Gilioli, Lisa; Potì, Francesco; Simoni, Manuela; Casarini, Livio
abstract

Reproduction is a fundamental process for the species maintenance and the propagation of genetic information. The energy expenditure for mating is overtaken by motivational stimuli, such as orgasm, finely regulated by steroid hormones, gonadotropins, neurotransmitters and molecules acting in the brain and peripheral organs. These functions are often investigated using animal models and translated to humans, where the androgens action is mediated by nuclear and membrane receptors converging in the regulation of both long-term genomic and rapid non-genomic signals. In both sexes, testosterone is a central player of this game and is involved in the regulation of sexual desire and arousal, and, finally, in reproduction through cognitive and peripheral physiological mechanisms which may decline with aging and circadian disruption. Finally, genetic variations impact on reproductive behaviours, resulting in sex-specific effect and different reproductive strategies. In this review, androgen actions on sexual desire are evaluated, focusing on the molecular levels of interaction.


2018 - Pharmacogenetics of G-protein-coupled receptors variants: FSH receptor and infertility treatment [Articolo su rivista]
Santi, Daniele; Potì, Francesco; Simoni, Manuela; Casarini, Livio
abstract

Infertility treatment may represent a paradigmatic example of precision medicine. Follicle-stimulating hormone (FSH) has been proposed as a valuable therapeutic option both in males and in females, even if a standardized approach is far to be established. To date, several genetic mutations as well as polymorphisms have been demonstrated to significantly affect the pathophysiology of FSH-FSH receptor (FSHR) interaction, although the underlying molecular mechanisms remain unclear. This review aims to highlight possible aspects of FSH therapy that could benefit from a pharmacogenetic approach, providing an up-to-date overview of the variability of the response to FSH treatment in both sexes. Specific sections are dedicated to the clinical use of FSH in infertility and how FSHR polymorphisms may affect the therapeutic endpoints.


2018 - Response: Commentary: Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "Personalized" Medicine Era: A meta-analysis [Articolo su rivista]
Santi, Daniele; Casarini, Livio; Alviggi, Carlo; Simoni, Manuela
abstract

N/A


2018 - Seasonal variation of semen parameters correlates with environmental temperature and air pollution: A big data analysis over 6 years [Articolo su rivista]
Santi, Daniele; Magnani, Elisa; Michelangeli, Marco; Grassi, Roberto; Vecchi, Barbara; Pedroni, Gioia; Roli, Laura; De Santis, Maria Cristina; Baraldi, Enrica; Setti, Monica; Trenti, Tommaso; Simoni, Manuela
abstract

Male fertility is progressively declining in many developed countries, but the relationship between male infertility and environmental factors is still unclear.


2018 - Serum Calcium to Phosphorous (Ca/P) Ratio is a simple, inexpensive, and accurate tool in the diagnosis of primary hyperparathyroidism [Articolo su rivista]
Madeo, B.; Kara, E.; Cioni, K.; Vezzani, S.; Trenti, T.; Santi, D.; Simoni, M.; Rochira, V.
abstract

Primary hyperparathyroidism (PHPT) diagnosis is challenging and is based on serum calcium (Ca) and parathyroid hormone (PTH). Because serum Ca and phosphorous (P) are inversely related in PHPT, we investigated the diagnostic value of the serum Ca/P ratio in the diagnosis of PHPT. We report a single-center, case-controlled, retrospective study including 97 patients with documented PHPT and compared them with those of 96 controls (C). The main outcome measures were: serum PTH, 25-OH vitamin D, Ca, P, albumin, and creatinine. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the serum Ca/P ratio were calculated. The results were verified using an independent, anonymous set of data extracted from a laboratory database containing over 900 million entries. A total of 35 (36.1%) PHPT patients had normocalcemic PHPT (NCHPT). Ca and PTH were significantly higher in PHPT than in C (p < 0.0001). P was significantly lower in PHPT than in C (p < 0.0001). The Ca/P ratio was significantly higher in PHPT than in C (p < 0.0001). Receiver-operating characteristic (ROC) curves analyses identified a cutoff of 2.71 (3.5 if Ca and P are expressed in mg/dL) for Ca/P ratio with a sensitivity and specificity of 86% and 87%, respectively (p < 0.0001), confirmed by the independent, big data approach. In conclusion, Ca/P is a valuable tool for the diagnosis of PHPT and is of superior value compared to serum Ca alone, especially in NCPHT. Because Ca/P is simple, inexpensive, and easily accessible worldwide, this ratio is useful for PHPT diagnosis, especially in laboratory/medical settings relying on limited resources, such as low-income countries. © 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.


2018 - Serum sodium is inversely related to frailty and bone mineral density (BMD) in human immunodeficiency virus (HIV)-infected patients [Abstract in Rivista]
De Vincentis, S.; Decaroli, MARIA CHIARA; Diazzi, C.; Santi, D.; Carli, F.; Zona, S.; Guaraldi, G.; Rochira, V.
abstract

Background HIV-infected patients are predisposed to an increased risk of hyponatremia. In healthy population, low sodium is associated with impaired health status and reduced BMD, but less is known about this association in HIV-infection. Aim To investigate the relationship between serum sodium, frailty and BMD in a large cohort of HIV-infected patients. Methodology A retrospective, observational, cohort study on adult HIV-infected patients (age R18 years), attending the Multidisciplinary Metabolic Clinic of Modena, was carried out including all sodium examinations performed at the Modena lab from 2007 to 2017 available in a large database. Laboratory ranges of normality for sodium (136–146mEq/l) were used to subdivide records in hyponatremic (HypoNa), hypernatremic (HyperNa) and normonatremic (NormoNa) groups. BMD was measured at total body, lumbar spine (L1–L4) and total hip using a Hologic QDR-2000 densitometer (DXA). Frailty was calculated through 38-item multimorbidity frailty index. Statistical analysis Parameters were not normally distributed and Kruskal-Wallis test, followed by Dunn’s test, was used to compare continuous variables. Correlations were performed using linear regression models. Results 8101 records (5454 from males and 2647 from females) of serum sodium (mean 139.4G3.1 mEq/l) evaluated in HIV-infected patients (mean age 49.0G7.9 years) were considered. 617 (7.6%), HypoNa, 44 (0.5%) HyperNa and 7440 (91.8%) NormoNa were found. Frailty score was inversely related to serum sodium (rZK0.174, R2Z0.03, P!0.0001), even after the exclusion of HyperNa group (RZK0.191, R2Z0.036, P!0.0001). Frailty was significantly higher in HypoNa than NormoNa (P!0.001). Considering results at DXA examination, BMD was normal in 30.3% and reduced in 69.7% (54.8% osteopenia, 14.9% osteoporosis). Total body BMD, but not femoral nor lumbar, directly correlated with serum sodium (RZ0.049, P!0.001) and it was significantly lower in HypoNa compared to NormoNa (PZ0.029). Conclusions This study shows that serum sodium is inversely related to frailty, suggesting its potential role as reliable and cheap marker in the HIV-infection follow-up. Furthermore, we demonstrate a direct correlation between sodium and body BMD in HIV-infected patients, similarly to general population. DOI: 10.1530/endoabs.56.P745


2018 - Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management [Abstract in Rivista]
Santi, Daniele; Spaggiari, Giorgia; Simoni, Manuela
abstract

10.1530/endoabs.56.GP214


2018 - Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management – meta-analyses [Articolo su rivista]
Santi, Daniele; Spaggiari, Giorgia; Simoni, Manuela
abstract

Conventional semen analyses have limitations in male infertility diagnosis and prognosis. Assessment of sperm DNA fragmentation (sDF) has been proposed to discriminate fertile from infertile men and predict FSH treatment response in infertile men, although a comprehensive evaluation of this is not available. The aims of these meta-analyses were to assess the power of sDF in male infertility diagnosis and its role in predicting FSH therapy response in infertile men. Two literature searches were conducted in MEDLINE (PubMed), Embase, the Cochrane Library, Scopus and UpToDate. First, interventional/observational clinical trials comparing fertile to infertile/subfertile men were included. Second, interventional/observational clinical trials evaluating FSH-treated infertile men were assessed. sDF levels were significantly higher in infertile men considering 28 studies (P &lt; 0.001), independently of the sDF method applied. Receiver operator characteristics curves identified an sDF threshold of 20%, with sensitivity of 79% and specificity of 86%. Six studies showed significant sDF improvement of 4.24% (95% confidence interval: 0.24–8.25%) after 3 months of FSH treatment. These meta-analyses demonstrate the sDF relevance in male infertility, suggesting a higher accuracy in detecting sperm function than conventional semen parameters. Although larger prospective trials are needed, sDF represents a promising tool for clinical and research practice.


2018 - Testicular ultrasound inhomogeneity is more informative than testicular volume in fertility evaluation [Abstract in Atti di Convegno]
Spaggiari, G; Santi, D; Granata, Arm; Simoni, M.
abstract


2018 - Testosterone (T) and estradiol (E2) are poorly associated to the reduction of bone mineral density (BMD) in Young/Middle Aged Men with Human immunodeficiency virus (HIV). [Abstract in Atti di Convegno]
De Vincentis, S.; Decaroli, M. C.; Diazzi, C.; Morini, Federica; Bertani, D.; Fanelli, F.; Mezzullo, M.; Santi, D.; Pagotto, U.; Guaraldi, G.; Rochira, Vincenzo
abstract

Background: Osteopenia and osteoporosis, as well as hypogonadism, are common findings in men with HIV- infection and they occur at a younger age than healthy subjects. The reduction of BMD is due to both HIV-related and HIV-unrelated factors. Previous studies suggest that T deficiency is not or poorly associated with reduced BMD in HIV context. On the other hand, estrogens are consid- ered more important than androgens for bone health in general population, but data about their role in HIV- infected men are still scanty. Objective: To investigate the relationship between BMD and circulating sex steroids assessed by Liquid Chro- matography tandem Mass Spectrometry (LC-MS/MS) in a cohort of young/middle aged HIV-infected men. Methods: Prospective, cross-sectional, observational study on 233 consecutive HIV-infected male patients with ongo- ing Highly Active Antiretroviral Therapy (HAART), attend- ing the Multidisciplinary Metabolic Clinic of Modena. Body composition and BMD at total body, lumbar spine (L1 to L4) and total hip were measured using a Hologic QDR-2000 densitometer (DXA). LC-MS/MS was used for hormonal assays. Statistical analysis: The nonparametric Mann–Whitney U test was used for group comparisons because variables were not normally distributed at the Kolmogorov-Smirnov test. Correlations were performed using linear regression models. Results: Two hundred and thirty-three HIV-infected patients were enrolled (mean age 45.29 ! 5.33 years) with average duration of HIV-infection of 190.8 ! 102.8 months. Eight patients (3.4%) had hypogonadism, defined as total T serum levels below 300 ng/dL. Considering results at DXA examination, BMD was normal in 36.5% and reduced in 63.5% (55.8% osteopenia, 7.7% osteoporo- sis). Both total T and E2 did not significantly differ com- paring patients with normal BMD to patients with reduced BMD. Body and lumbar BMD did not show any significant difference between eugonadal patients and patients with low T and/or low E2, while both femoral BMD and femoral T-score were significantly higher in patients with E2 above 20 pg/mL than in those with E2 below 20 pg/mL (p = 0.043 and p = 0.033, respectively). At linear and step- wise multiple regression analyses, BMD was positively associated with total lean mass (R2 = 0.154, p < 0.0001); apart from it, neither T nor E2 correlated with BMD and T- score at any site. Conclusion: Classical factors associated to BMD as E2 and T seem to be less relevant in this model of male osteoporo- sis. Other specific HIV-related factors, such as changes in body composition and consequent lipodystrophy, could be more deeply involved than sex steroids as potential mecha- nisms in bone loss in this setting. Finally, we confirm the high prevalence of reduced BMD in young/middle aged HIV-infected men, representing one of the clinical hallmarks of the premature aging process related to HIV infection.


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 - Advances in Robotic Transaxillary Thyroidectomy in Europe [Articolo su rivista]
Piccoli, Micaela; Mullineris, Barbara; Santi, Daniele; Gozzo, Davide
abstract

The robotic surgical approach for minimally invasive thyroid surgery has been well described from the Korean surgeons and shows a wide spread diffusion in Asian area. This paper gives a systematic review aiming to pointed out the interest and the way of behaving of the European surgeons about the role of the robotic thyroidectomy (RT).


2017 - Biologia del desiderio sessuale [Capitolo/Saggio]
Santi, Daniele; Granata, A.; Zirilli, Lucia; Rochira, Vincenzo
abstract

The chapter of the book deals with the biological and hormonal issues concerning sexual desire. In particular, the effects of hormones on human sexuality in both men and women, with particular regard to androgens and their role on sexual desire/interest are extensively reviewed.


2017 - Calcium to phosphorous ratio (Ca/P) as helpful index to recognize primary hyperparathyroidism, but not primary hypoparathyroidism: a big-data approach. [Abstract in Atti di Convegno]
Santi, Daniele; De Vincentis, Sara; Rochira, Vincenzo; Setti, M.; Tagliavini, S.; Varani, M.; Trenti, T.; Simoni, Manuela; Madeo, Bruno
abstract

BACKGROUND: Primary hyperparathyroidism (HyperPT) and primary hypoparathyroidism (HypoPT) are often underdiagnosed. Several strategies have been investigated in the past in order to identify diagnostic parameters, although the diagnosis of both HyperPT and HypoPT remains challenging so far, especially in asymptomatic patients. Calcium (Ca) and phosphorus (P) are inversely related together, thus the Ca/P ratio could be an useful tool to define these conditions. Recently, we proposed for the first time a cut-off of 3.5 for Ca/P ratio for the diagnosis of HyperPT. AIM: to evaluate the diagnostic value of the Ca/P ratio for HyperPT and HypoPT through a big-data approach. METHODOLOGY: a retrospective, observational, case-control study on big-data was carried out. All examinations of parathyroid hormone (PTH), Ca and P performed at the laboratory of Modena Hospital from 2010 to 2016 were consecutively included. We considered only patients between 18 and 90 years of age. Laboratory ranges of normality for both PTH and Ca were used to divide records in HyperPT, HypoPT and controls. Statistical analysis: The diagnostic accuracy of Ca/P ratio was investigated using receiver operator characteristics (ROC) curves in order to define cut-off points, which show higher sensitivity and specificity for the identification of affected patients. RESULTS: 46597 records were considered. 576 HyperPT (1.2%), 323 HypoPT (0.7%) and 45698 controls (98.1%) were found. Ca/P ratio was significantly different among groups (p<0.001). In particular, Ca/P ratio was significantly higher in HyperPT than controls (p<0.001). For the diagnosis of HyperPT, the threshold of 3.17 for Ca/P ratio was obtained by means of the ROC curve analysis, with 85% of both sensitivity and specificity. HypoPT showed lower Ca/P ratio compared to controls (p<0.001), although no useful threshold for the diagnosis was found at ROC curve because of the low sensitivity. CONCLUSIONS: We confirm the high sensitivity and specificity of Ca/P ratio for the diagnosis of HyperPT using the largest cohort of patients available so far in the literature. On the contrary, Ca/P ratio does not contribute to identify patients with HypoPT and further researches are needed to better describe this condition. In conclusion, Ca/P ratio is a simple and inexpensive diagnostic tool to recognize HyperPT.


2017 - Calcium to phosphorous ratio (Ca/P) as helpful index to recognize primary hyperparathyroidism, but not primary hypoparathyroidism: a big-data approach. [Abstract in Rivista]
De Vincentis, Sara; Santi, Daniele; Rochira, Vincenzo; Setti, M.; Tagliavini, S.; Varani, M.; Trenti, T.; Simoni, Manuela; Madeo, Bruno
abstract

Background Primary hyperparathyroidism (HyperPT) and primary hypoparathyroidism (HypoPT) are often underdiagnosed. Several strategies have been investigated in the past in order to identify diagnostic parameters, although the diagnosis of both HyperPT and HypoPT remains challenging so far, especially in asymptomatic patients. Calcium (Ca) and phosphorus (P) are inversely related together, thus the Ca/P ratio could be an useful tool to define these conditions. Recently, we proposed for the first time a cut-off of 3.5 for Ca/P ratio for the diagnosis of HyperPT. Aim To evaluate the diagnostic value of the Ca/P ratio for HyperPT and HypoPT through a big-data approach. Methodology A retrospective, observational, case-control study on big-data was carried out. All examinations of parathyroid hormone (PTH), Ca and P performed at the laboratory of Modena Hospital from 2010 to 2016 were consecutively included. We considered only patients between 18 and 90 years of age. Laboratory ranges of normality for both PTH and Ca were used to divide records in HyperPT, HypoPT and controls. Statistical analysis The diagnostic accuracy of Ca/P ratio was investigated using receiver operator characteristics (ROC) curves in order to define cut-off points, which show higher sensitivity and specificity for the identification of affected patients. Results 46 597 records were considered. 576 HyperPT (1.2%), 323 HypoPT (0.7%) and 45 698 controls (98.1%) were found. Ca/P ratio was significantly different among groups (P!0.001). In particular, Ca/P ratio was significantly higher in HyperPT than controls (P!0.001). For the diagnosis of HyperPT, the threshold of 3.17 for Ca/P ratio was obtained by means of the ROC curve analysis, with 85% of both sensitivity and specificity. HypoPT showed lower Ca/P ratio compared to controls (P!0.001), although no useful threshold for the diagnosis was found at ROC curve because of the low sensitivity. Conclusions We confirm the high sensitivity and specificity of Ca/P ratio for the diagnosis of HyperPT using the largest cohort of patients available so far in the literature. On the contrary, Ca/P ratio does not contribute to identify patients with HypoPT and further researches are needed to better describe this condition. In conclusion, Ca/P ratio is a simple and inexpensive diagnostic tool to recognize HyperPT.


2017 - Central hypogonadism due to a giant, “silent” FSH-secreting, atypical pituitary adenoma: effects of adenoma dissection and short-term Leydig cell stimulation by luteinizing hormone (LH) and human chorionic gonadotropin (hCG) [Articolo su rivista]
Santi, Daniele; Spaggiari, Giorgia; Casarini, Livio; Fanelli, Flaminia; Mezzullo, Marco; Pagotto, Uberto; Granata, Antonio R. M; Carani, Cesare; Simoni, Manuela
abstract

We present a case report of an atypical giant pituitary adenoma secreting follicle-stimulating hormone (FSH). A 55-year-old patient presented for erectile dysfunction, loss of libido and fatigue. The biochemical evaluation showed very high FSH serum levels in the presence of central hypogonadism. Neither testicular enlargement nor increased sperm count was observed, thus a secretion of FSH with reduced biological activity was supposed. The histological examination after neuro-surgery showed an atypical pituitary adenoma with FSH-positive cells. Hypogonadism persisted and semen analyses impaired until azoospermia in conjunction with the reduction in FSH levels suggesting that, at least in part, this gonadotropin should be biologically active. Thus, we hypothesized a concomitant primary testicular insufficiency. The patient underwent short-term treatment trials with low doses of either recombinant luteinizing hormone (LH) or human chorionic gonadotropin (hCG) in three consecutive treatment schemes, showing an equal efficacy in stimulating testosterone (T) increase. This is the first case of atypical, giant FSH-secreting pituitary adenoma with high FSH serum levels without signs of testicular hyperstimulation, in presence of hypogonadism with plausible combined primary and secondary etiology. Hypophysectomized patients may represent a good model to assess both pharmacodynamics and effective dose of LH and hCG in the male.


2017 - Diagnosi precoce nella Sindrome di Klinefelter [Abstract in Rivista]
Fisher, A. D.; Corona, G.; Rochira, V.; Maggi, M.; Simoni, M.; Santi, D.
abstract

The diagnosis of Klinefelter Syndrome is needed to guarantee adequate management, treatment and follow-up of the disease and to prevent the occurrence of associated comorbidities. The early diagnosis has the advantage to plan a continuous monitoring of the patients through periodic visits of follow-up. This allows to identify on time changes of the clinical pattern and to tailor treatment and counselling.


2017 - Effects of chronic administration of the phosphodiesterase inhibitor vardenafil on serum levels of adrenal and testicular steroids in men with type 2 diabetes mellitus [Articolo su rivista]
Santi, Daniele; Granata, A. R.; Pignatti, Elisa; Trenti, T.; Roli, L.; Bozic, R.; Zaza, S.; Pacchioni, C.; Rochira, Vincenzo; Carani, Cesare; Simoni, Manuela
abstract

To investigate whether long-term, chronic treatment with the phosphodiesterase-5 inhibitor vardenafil affects adrenal and testicular steroidogenesis in diabetic men, using liquid chromatography-tandem mass spectrometry. A longitudinal, prospective, investigator-started, randomized, placebo-controlled, double-blind, clinical-trial was carried out, enrolling 54 male patients affected by type 2 diabetes mellitus diagnosed within the last 5 years. In total, 26 and 28 patients were followed for 1 year and assigned to the study and placebo group, respectively. Progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, corticosterone, 11-deoxycortisol and cortisol, were evaluated using liquid chromatography-tandem mass spectrometry. No differences were seen in sex testicular steroids between study and control group. As for the adrenal gland, steroids were considered according to the zona in which they are produced. No significant differences were seen in steroid produced in zona fasciculata. For the zona reticularis, dehydroepiandrosterone significantly decreased during treatment only in the study group (p = 0.007), with higher levels at visit 2 and 8 than other visits. The dehydroepiandrosterone sulfate/dehydroepiandrosterone ratio significantly increased during treatment only in the verum group. Considering the adrenal zona glomerulosa, corticosterone significantly changed among visits both in both groups (p < 0.001), with higher levels at visit 2 (p = 0.028), 8 (p = 0.003), and 10 (p = 0.044), i.e., in coincidence with the complete clinical and instrumental examination performed only at these visits according to the study protocol. Chronically administered vardenafil reduces dehydroepiandrosterone levels and increases dehydroepiandrosterone sulfate/dehydroepiandrosterone ratio as possible consequences of modulation of steroidogenic enzymes by tissue changes in cyclic adenosine monophosphate and cyclic guanosine monophosphate availability. A possibly stress-related increase in corticosterone is suggested for the first time.


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 - Efficacy of FSH alone, FSH + LH, hMG or FSH + hCG on ART outcomes in the 'personalized' medicine era: a meta-analysis [Abstract in Rivista]
Santi, Daniele; Casarini, Livio; Alviggi, Carlo; Simoni, Manuela
abstract

Background: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle stimulating hormone (FSH) as well as menopausal gonadotropins (hMG) in controlled ovarian stimulation (COS) is debated. Aim: To compare FSH+LH, or FSH+hCG or hMG vs FSH alone on COS outcomes. Design: A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded. Results: Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH+LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH+LH, FSH+hCG or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH+LH-treated group versus others. Only twelve studies reported live birth rate, not providing protocol-dependent differences. Patients’ stratification by age (median=32.5 years) and/or by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations. Conclusion: In COS, FSH alone results in higher oocyte number. However, hMG improves the collection of mature oocytes and embryos and increases implantation rate, although the final increased pregnancy rate is evident only in GnRH agonist protocol. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data.


2017 - Efficacy of follicle-stimulating hormone (FSH) alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "personalized" medicine era: A meta-analysis [Articolo su rivista]
Santi, Daniele; Casarini, Livio; Alviggi, Carlo; Simoni, Manuela
abstract

Setting: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle-stimulating hormone (FSH) as well as menopausal gonadotropins (human menopausal gonadotropin; hMG) in controlled ovarian stimulation (COS) is debated. Objective: To compare FSH + LH, or FSH + hCG or hMG vs. FSH alone on COS outcomes. Design: A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH alone or combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded (PROSPERO registration no. CRD42016048404). Results: Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH + LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH + LH, FSH + hCG, or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH + LH-treated group vs. others. Only 12 studies reported live birth rate, not providing protocol-dependent differences. Patients' stratification by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations. Conclusion: In COS, FSH alone results in higher oocyte number. HMG improves the collection of mature oocytes, embryos, and increases implantation rate. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data.


2017 - Environmental temperature and particulate matter are correlated with semen parameters: a big-data approach [Abstract in Rivista]
Santi, Daniele; Magnani, E; Granata, Ar; Roli, L; De Santis, Mc; Baraldi, E; Trenti, T; Setti, M; Simoni, M
abstract

Environmental temperature and particulate matter are correlated with semen parameters: a big-data approach


2017 - Gene Expression and Apoptosis Levels in Cumulus Cells of Patients with Polymorphisms of FSHR and LHB Undergoing in Vitro Fertilization Program [Articolo su rivista]
Bosco, Liana; Ruvolo, Giovanni; Luparello, Claudio; Ferrari, Stefania; Valerio, Domenico; Santi, Daniele; Piomboni, Paola; Sarcina, Elena; Lispi, Monica; Roccheri, Maria Carmela
abstract

Background/Aims: FSH receptor (FSHR) Ala307Thr and Asn680Ser and LHβ chain (LHB) Trp28Arg and Ile35Thr polymorphisms affect the response to pharmacological ovarian stimulation with r-FSH in women undergoing assisted reproductive treatment (ART). Here, we evaluated the expression level of selected genes involved in follicle maturation and the possible onset of apoptosis in cumulus cells of patients with single and double FSHR and LHB polymorphisms, as potential markers of oocyte competence. Methods: Cumulus cells from 36 stimulated patients were collected and SNP genotyping performed by PCR. Gene expression was evaluated through real-time PCR, and apoptosis estimated via TUNEL assay, and cleaved caspase-3 and pAKT immunostaining. Results: The cumulative data show significant correlations indicating that the genetic alteration of FSHR and/or LHB genes may lead to perturbations of the signaling network programmed to granulosa cell survival and follicle development. Notably, when double heterozygotes were compared to the rest of the patients, a higher level of apoptosis in terms of both DNA fragmentation index and amount of active caspase-3 was observed in cumulus cells. Conclusions: These results may help to define personalized stimulation protocols in ART programs, to increase the success rate of ICSI procedures in accordance with the polymorphic condition of the individual patient.


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 - Impairment of sperm DNA methylation in male infertility: a meta-analytic study [Articolo su rivista]
Santi, D.; De Vincentis, S.; Magnani, E.; Spaggiari, G.
abstract

Considering the widespread use of assisted reproductive techniques (ART), DNA methylation of specific genes involved in spermatogenesis achieves increasingly clinical relevance, representing a possible explanation of increased incidence of syndromes related to genomic imprinting in medically assisted pregnancies. Several trials suggested a relationship between male sub-fertility and sperm DNA methylation, although its weight on seminal parameters alteration is still a matter of debate. To evaluate whether aberrant sperm DNA methylation of imprinted genes is associated with impaired sperm parameters. Meta-analysis of controlled clinical trials evaluating imprinted genes sperm DNA methylation comparing men with idiopathic infertility to fertile controls. Twenty-four studies were included, allowing a meta-analytic evaluation for H19, MEST, SNRPN, and LINE-1. When a high heterogeneity of the results was demonstrated, the random effect model was used. H19 methylation levels resulted significantly lower in 879 infertile compared with 562 fertile men (7.53%, 95% CI: 5.14–9.93%, pÂ&nbsp;


2017 - Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism [Articolo su rivista]
Bonomi, M.; Rochira, V.; Pasquali, D.; Balercia, G.; Jannini, E. A.; Ferlin, A.; Calogero, A.; Corona, G.; Fabbri, A.; Francavilla, F.; Giagulli, V.; Lanfranco, F.; Maggi, M.; Pivonello, R.; Pizzocaro, A.; Radicioni, A.; Accardo, L.; Cangiano, B.; Condorelli, R. A.; Cordeschi, G.; D'Andrea, S.; Mambro, A. D.; Esposito, D.; Foresta, C.; Francavilla, S.; Galdiero, M.; Garolla, A.; Giovannini, L.; Balercia, A. R. M.; La Vignera, S.; Motta, G.; Luciano, L.; Pelliccione, F.; Persani, L.; Santi, D.; Selice, R.; Simoni, M.; Tatone, C.; Tirabassi, G.; Tresoldi, A. S.; Vicari, E.
abstract

Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. The relationship between clinical phenotype and genetic background has been partially disclosed; nevertheless, physicians are aware that several aspects concerning this issue are far to be fully understood. By improving our knowledge on the role of some genetic aspects as well as on the KS, patients' interindividual differences in terms of health status will result in a better management of this chromosomal disease. The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.


2017 - Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders [Articolo su rivista]
Calogero, A. E.; Giagulli, V. A.; Mongioi, L. M.; Triggiani, V.; Radicioni, A. F.; Jannini, E. A.; Pasquali, D.; Balercia, G.; Bonomi, M.; Corona, G.; Fabbri, A.; Ferlin, A.; Francavilla, F.; Giagulli, V.; Lanfranco, F.; Maggi, M.; Pivonello, R.; Pizzocaro, A.; Radicioni, A.; Rochira, V.; Vignozzi, L.; Accardo, G.; Cangiano, B.; Condorelli, R. A.; Cordeschi, G.; D'Andrea, S.; Di Mambro, A.; Esposito, D.; Foresta, C.; Francavilla, S.; Galdiero, M.; Garolla, A.; Giovannini, L.; Granata, A. R. M.; La Vignera, S.; Motta, G.; Negri, L.; Pelliccione, F.; Persani, L.; Salzano, C.; Santi, D.; Selice, R.; Simoni, M.; Tatone, C.; Tirabassi, G.; Tresoldi, A. S.; Vicari, E.
abstract

Klinefelter syndrome (KS) is one of the most common genetic causes of male infertility. This condition is associated with much comorbidity and with a lower life expectancy. The aim of this review is to explore more in depth cardiovascular and metabolic disorders associated to KS. KS patients have an increased risk of cerebrovascular disease (standardized mortality ratio, SMR, 2.2; 95% confidence interval, CI, 1.6–3.0), but it is not clear whether the cause of the death is of thrombotic or hemorrhagic nature. Cardiovascular congenital anomalies (SMR, 7.3; 95% CI, 2.4–17.1) and the development of thrombosis or leg ulcers (SMR, 7.9; 95% CI, 2.9–17.2) are also more frequent in these subjects. Moreover, cardiovascular abnormalities may be at least partially reversed by testosterone replacement therapy (TRT). KS patients have also an increased probability of endocrine and/or metabolic disease, especially obesity, metabolic syndrome and type 2 diabetes mellitus. The effects of TRT on these abnormalities are not entirely clear.


2017 - NEUROACTIVE STEROID LEVELS AND PSYCHIATRIC AND ANDROLOGICAL FEATURES IN POST-FINASTERIDE PATIENTS [Articolo su rivista]
Melcangi, Roberto Cosimo; Santi, Daniele; Spezzano, Roberto; Grimoldi, Maria; Tabacchi, Tommaso; Fusco, Maria Letizia; Diviccaro, Silvia; Giatti, Silvia; Carrà, Giuseppe; Caruso, Donatella; Simoni, Manuela; Cavaletti, Guido
abstract

Recent reports show that, in patients treated with finasteride for male pattern hair loss, persistent side effects including sexual side effects, depression, anxiety and cognitive complaints may occur. We here explored the psychiatric and andrological features of patients affected by post-finasteride syndrome (PFS) and verified whether the cerebrospinal fluid (CSF) and plasma levels of neuroactive steroids (i.e., important regulators of nervous function) are modified. We found that eight out of sixteen PFS male patients considered suffered from a DSM-IV major depressive disorder (MDD). In addition, all PFS patients showed erectile dysfunction (ED); in particular, ten patients showed a severe and six a mild-moderate ED. We also reported abnormal somatosensory evoked potentials of the pudendal nerve in PFS patients with severe ED, the first objective evidence of a neuropathy involving peripheral neurogenic control of erection. Testicular volume by ultrasonography was normal in PFS patients. Data obtained on neuroactive steroid levels also indicate interesting features. Indeed, decreased levels of pregnenolone, progesterone and its metabolite (i.e., dihydroprogesterone), dihydrotestosterone and 17beta-estradiol and increased levels of dehydroepiandrosterone, testosterone and 5alpha-androstane-3alpha,17beta-diol were observed in CSF of PFS patients. Neuroactive steroid levels were also altered in plasma of PFS patients, however these changes did not reflect exactly what occurs in CSF. Finally, finasteride did not only affect, as expected, the levels of 5alpha-reduced metabolites of progesterone and testosterone, but also the further metabolites and precursors suggesting that this drug has broad consequence on neuroactive steroid levels of PFS patients.


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 - Psychological rather than organic and/or relational components are involved in sexual dysfunction in Young/Middle aged human immunodeficiency virus (HIV)-Infected Men. [Abstract in Rivista]
Decaroli, MARIA CHIARA; De Vincentis, Sara; Diazzi, Chiara; Zona, Stefano; Guaraldi, Giovanni; Santi, Daniele; Rochira, Vincenzo
abstract

Background HIV-infection is associated to an increased prevalence of erectile dysfunction (ED). In HIV-infected men ED seems to be less related to serum Testosterone (T), depending from other factors. Aim To investigate the role of different components (organic, relational, psycho- logical) of erectile function by using validate questionnaires in HIV-infected men with normal serum T. Methodology Prospective, cross-sectional, observational study on eugonadal HIV-infected male patients with ongoing Highly Active Antiretroviral Therapy (HAART) attending the Clinic of Infectious Diseases. The International Index of Erectile Function (IIEF)-15, IIEF-5 and Structured Interview for Erectile Dysfunction (SIEDY) were used to assess sexual function. Sexual desire was further evaluated through a direct question during the visit. LC-MS/MS was used to assess gonadal status. Results 225 HIV-infected patients were enrolled (mean age 45.19G5.36 years). SIEDY scores at appendix and scale 3 were significantly higher in patients with ED at IIEF- 15 (nZ136, 60.4%) compared with those without ED (P!0.001 and PZ0.015, respectively). Conversely, scale 1 (PZ0.448) and 2 (PZ0.503) of SIEDY did not differ between patients with or without ED, suggesting a predominance of the psychological basis of ED in our cohort. The erectile function domain at IIEF-15 was directly correlated with IIEF-5 score (0.778, P!0.001). Similarly, the score at SIEDY appendix was significantly different among ED degrees at IIEF-15 (P!0.001). In particular, lower score was found in HIV-infected men without ED compared to those with mild, moderate and severe ED (P!0.001, PZ0.001, and P!0.001, respectively), confirming the reliability of these tools. Sexual desire was impaired in 73 patients (31.33%) at interview with a good correlation with the specific item of IIEF-15 (P!0.001). Conclusions The psychological component impacts in a significant manner on ED in HIV- infection context. Despite the high prevalence of comorbidities in these patients, the organic component does not affect erectile function. All the three validated questionnaires seem to be trustworthy in the diagnosis of ED in this setting.


2017 - Psychological rather than organic and/or relational components are involved in sexual dysfunction in young/middle aged human immunodeficiency virus (HIV)-infected men. [Abstract in Atti di Convegno]
Decaroli, MARIA CHIARA; De Vincentis, Sara; Diazzi, Chiara; Zona, Stefano; Guaraldi, Giovanni; Santi, Daniele; Rochira, Vincenzo
abstract

BACKGROUND: HIV-infection is associated to an increased prevalence of erectile dysfunction (ED). In HIV-infected men ED seems to be less related to serum Testosterone (T), depending from other factors. AIM: To investigate the role of different components (organic, relational, psychological) of erectile function by using validate questionnaires in HIV-infected men with normal serum T. METHODOLOGY: Prospective, cross-sectional, observational study on eugonadal HIV-infected male patients with ongoing Highly Active Antiretroviral Therapy (HAART) attending the Clinic of Infectious Diseases. The International Index of Erectile Function (IIEF)-15, IIEF-5 and Structured Interview for Erectile Dysfunction (SIEDY) were used to assess sexual function. Sexual desire was further evaluated through a direct question during the visit. LC-MS/MS was used to assess gonadal status. RESULTS: 225 HIV-infected patients were enrolled (mean age 45.19±5.36years). SIEDY scores at appendix and scale 3 were significantly higher in patients with ED at IIEF-15 (n=136, 60.4%) compared with those without ED (p<0.001 and p=0.015, respectively). Conversely, scale 1 (p=0.448) and 2 (p=0.503) of SIEDY did not differ between patients with or without ED, suggesting a predominance of the psychological basis of ED in our cohort. The erectile function domain at IIEF-15 was directly correlated with IIEF-5 score (0.778, p<0.001). Similarly, the score at SIEDY appendix was significantly different among ED degrees at IIEF-15 (p<0.001). In particular, lower score was found in HIV-infected men without ED compared to those with mild, moderate and severe ED (p<0.001, p=0.001, and p<0.001, respectively), confirming the reliability of these tools. Sexual desire was impaired in 73 patients (31.33%) at interview with a good correlation with the specific item of IIEF-15 (p<0.001). CONCLUSIONS: The psychological component impacts in a significant manner on ED in HIV-infection context. Despite the high prevalence of comorbidities in these patients, the organic component does not affect erectile function. All the three validated questionnaires seem to be trustworthy in the diagnosis of ED in this setting.


2017 - Sexual dysfunction in subjects treated with inhibitors of 5α-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis [Articolo su rivista]
Corona, G; Tirabassi, G; Santi, Daniele; Maseroli, E; Gacci, M; Dicuio, M; Sforza, A; Mannucci, E; Maggi, M.
abstract

Despite their efficacy in the treatment of benign prostatic hyperplasia, the popularity of inhibitors of 5α-reductase (5ARIs) is limited by their association with adverse sexual side effects. The aim of this study was to review and meta-analyze currently available randomized clinical trials evaluating the rate of sexual side effects in men treated with 5ARIs. An extensive Medline Embase and Cochrane search was performed including the following words: 'finasteride', 'dutasteride', 'benign prostatic hyperplasia'. Only placebo-controlled randomized clinical trials evaluating the effect of 5ARI in subjects with benign prostatic hyperplasia were considered. Of 383 retrieved articles, 17 were included in this study. Randomized clinical trials enrolled 24,463 in the active and 22,270 patients in the placebo arms, respectively, with a mean follow-up of 99&nbsp;weeks and mean age of 64.0&nbsp;years. No difference was observed between trials using finasteride or dutasteride as the active arm considering age, trial duration, prostate volume or International Prostatic Symptoms Score at enrollment. Overall, 5ARIs determined an increased risk of hypoactive sexual desire [OR&nbsp;=&nbsp;1.54 (1.29; 1.82); p&nbsp;&lt;&nbsp;0.0001] and erectile dysfunction [OR&nbsp;=&nbsp;1.47 (1.29; 1.68); p&nbsp;&lt;&nbsp;0.0001]. No difference between finasteride and dutasteride regarding the risk of hypoactive sexual desire and erectile dysfunction was observed. Meta-regression analysis showed that the risk of hypoactive sexual desire and erectile dysfunction was higher in subjects with lower Qmax at enrollment and decreased as a function of trial follow-up. Conversely, no effect of age, low urinary tract symptom or prostate volume at enrollment as well as Qmax at end-point was observed. In conclusion, present data show that the use of 5ARI significantly increases the risk of erectile dysfunction and hypoactive sexual desire in subjects with benign prostatic hyperplasia. Patients should be adequately informed before 5ARIs are prescribed.


2017 - Short term Leydig cell stimulation by LH and hCG in man with central hypogonadism [Abstract in Atti di Convegno]
Santi, Daniele; Spaggiari, G; Casarini, L; Fanelli, F; Mezzullo, M; Pagotto, U; Granata, Arm; Carani, C; Simoni, M
abstract

Short term Leydig cell stimulation by LH and hCG in man with central hypogonadism


2017 - Sperm recovery and ICSI outcomes in Klinefelter syndrome: A systematic review and meta-analysis [Articolo su rivista]
Corona, G.; Pizzocaro, A.; Lanfranco, F.; Garolla, A.; Pelliccione, F.; Vignozzi, L.; Ferlin, A.; Foresta, C.; Jannini, E. A.; Maggi, M.; Lenzi, A.; Pasquali, D.; Francavilla, S.; Balercia, G.; Bonomi, M.; Calogero, A.; Fabbri, A.; Francavilla, F.; Giagulli, V.; Pivonello, R.; Radicioni, A.; Rochira, V.; Accardo, G.; Cangiano, B.; Condorelli, R. A.; Cordeschi, G.; D'Andrea, S.; Di Mambro, A.; Esposito, D.; Galdiero, M.; Giovannini, L.; Granata, A. R. M.; La Vignera, S.; Motta, G.; Negri, L.; Persani, L.; Salzano, C.; Santi, D.; Selice, R.; Simoni, M.; Tatone, C.; Tirabassi, G.; Tresoldi, A. S.; Vicari, E.
abstract

BACKGROUND: Specific factors underlying successful surgical sperm retrieval rates (SRR) or pregnancy rates (PR) after testicular sperm extraction (TESE) in adult patients with Klinefelter syndrome (KS) have not been completely clarified. OBJECTIVE AND RATIONALE: The aim of this review was to meta-analyse the currently available data from subjects with KS regarding SRRs as the primary outcome. In addition, when available, PRs and live birth rates (LBRs) after the ICSI technique were also investigated as secondary outcomes. SEARCH METHODS: An extensive Medline, Embase and Cochrane search was performed. All trials reporting SRR for conventional- TESE (cTESE) or micro-TESE (mTESE) and its specific determinants without any arbitrary restriction were included OUTCOMES: Out of 139 studies, 37 trials were included in the study, enrolling a total of 1248 patients with a mean age of 30.9 ± 5.6 years. The majority of the studies (n = 18) applied mTESE, 13 applied cTESE and in one case testicular sperm aspiration (TESA) was used. Additionally, four studies used a mixed approach and in one study, the method applied for sperm retrieval was not specified. Overall, a SRR per TESE cycle of 44[39;48]% was detected. Similar results were observed when mTESE was compared to cTESE (SRR 43[35;50]% vs 45[38;52]% for cTESE vs micro-TESE, respectively; Q = 0.20, P = 0.65). Meta-regression analysis showed that none of the parameters tested, including age, testis volume and FSH, LH and testosterone (T) levels at enrollment, affected the final SRR. Similarly, no difference was observed when a bilateral procedure was compared to a unilateral approach. No sufficient data were available to evaluate the effect of previous T treatment on SRR. Information on fertility outcome after ICSI was available for 29 studies. Overall a total of 218 biochemical pregnancies after 410 ICSI cycles were observed (PR = 43[36;50]%). Similar results were observed when LBR was analyzed (LBR = 43[34;53]%). Similar to what was observed for SRR, no influence of KS age, mean testis volume, LH, FSH or total T levels on either PR and LBR was observed. No sufficient data were available to test the effect of the women's age or other female fertility problems on PR and LBR. Finally, no difference in PR or LBR was observed when the use of fresh sperm was compared to the utilization of cryopreserved sperm. WIDER IMPLICATIONS: The present data suggest that performing TESE/micro-TESE in subjects with KS results in SRRs of close to 50%, and then PRs and LBRs of close to 50%, with the results being independent of any clinical or biochemical parameters tested.


2017 - Testosterone (T) is poorly related to erectile dysfunction (ED) in young/middle aged human immunodeficiency virus (HIV)-infected men. [Abstract in Atti di Convegno]
De Vincentis, Sara; Santi, Daniele; Decaroli, MARIA CHIARA; Fanelli, F.; Mezzullo, M.; Fazzini, A.; Ansaloni, Anna; Pagotto, U.; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

BACKGROUND: HIV-infection is strongly associated to ED in men. Preliminary data suggests that ED is poorly associated with serum T in HIV+ men. AIM: To investigate in HIV-infected men the relationship between sexual function as assessed by the validated International Index of Erectile Function (IIEF-15) and T deficiency using Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS). METHODOLOGY: Prospective, cross-sectional, observational study on HIV-infected male patients with ongoing Highly Active Antiretroviral Therapy (HAART), attending the Clinic of Infectious Diseases. IIEF-15 and IIEF-5 questionnaires were used to define ED, while LC-MS/MS was used for hormonal assays. RESULTS: 233 consecutive HIV-infected patients were enrolled (mean age 45.29±5.33years). Eight patients (3.4%) had total T <300ng/dL, while 142 patients (61.5%) had ED (score ≤25). Age, hormonal data and duration of HIV-infection and HAART did not differ among groups of patients according to the degree of ED. The direct comparison of each ED cluster showed that months of infection were significantly higher in men with severe ED compared to mild ED (p=0.037). The erectile function domain at IIEF-15 was directly correlated with IIEF-5 score (0.778, p<0.001), as expected. Moreover, the IIEF-15 score was inversely related to months of infection (-0.147, p=0.026), but not to months of HAART therapy (-0.121, p=0.071). CONCLUSIONS: To the best of our knowledge, this is the first, properly-designed prospective study aiming to investigate the relationship between erectile function and serum T, assessed by LC-MS/MS in HIV-infected men. In our cohort, a) IIEF-5 is reliable as IIEF-15 for ED diagnosis, b) ED is not associated with serum T, c) erectile function is not influenced by T and HAART, but only by HIV-infection duration. In conclusion, several specific factors, such as the duration of HIV infection, are involved in erectile function in HIV-infected men and should be carefully considered in this setting, while hormonal status seems to be less important


2017 - Testosterone is poorly related to erectile dysfunction in young/middle aged human immunodeficiency virus-infected men. [Abstract in Rivista]
De Vincentis, Sara; Santi, Daniele; Decaroli, MARIA CHIARA; Fanelli, F.; Mezzullo, M.; Fazzini, A.; Ansaloni, Anna; Pagotto, U.; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

Background human immunodeficiency virus (HIV)-infection is strongly associated to erectile dysfunction (ED) in men. Preliminary data suggests that ED is poorly associated with serum T in HIVC men. Aim To investigate in HIV-infected men the relationship between sexual function as assessed by the validated International Index of Erectile Function (IIEF-15) and T deficiency using Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS). Methodology Prospective, cross-sectional, observational study on HIV-infected male patients with ongoing Highly Active Antiretroviral Therapy (HAART), attending the Clinic of Infectious Diseases. IIEF-15 and IIEF-5 questionnaires were used to define ED, while LC-MS/MS was used for hormonal assays. Results 233 consecutive HIV-infected patients were enrolled (mean age 45.29G5.33 years). Eight patients (3.4%) had total T !300 ng/dl, while 142 patients (61.5%) had ED (score %25). Age, hormonal data and duration of HIV-infection and HAART did not differ among groups of patients according to the degree of ED. The direct comparison of each ED cluster showed that months of infection were significantly higher in men with severe ED compared to mild ED (PZ0.037). The erectile function domain at IIEF-15 was directly correlated with IIEF-5 score (0.778, P!0.001), as expected. Moreover, the IIEF-15 score was inversely related to months of infection (K0.147, PZ0.026), but not to months of HAART therapy (K0.121, PZ0.071). Conclusions To the best of our knowledge, this is the first, properly-designed prospective study aiming to investigate the relationship between erectile function and serum T, assessed by LC-MS/MS in HIV-infected men. In our cohort, i) IIEF-5 is reliable as IIEF-15 for ED diagnosis, ii) ED is not associated with serum T, iii) erectilef unction is not influenced by T and HAART, but only by HIV-infection duration. In conclusion, several specific factors, such as the duration of HIV infection, are involved in erectile function in HIV-infected men and should be carefully considered in this setting, while hormonal status seems to be less important. DOI: 10.1530/endoabs.49.EP1166


2017 - The steroid response to human chorionic gonadotropin (hCG) stimulation in men with Klinefelter syndrome does not change using immunoassay or mass spectrometry [Articolo su rivista]
Roli, L.; Santi, D.; Belli, S.; Tagliavini, S.; Cavalieri, S.; De Santis, M. C.; Baraldi, E.; Fanelli, F.; Mezzullo, M.; Granata, A. R.; Pagotto, U.; Pasquali, R.; Rochira, V.; Carani, C.; Simoni, M.; Trenti, T.
abstract

Purpose: Liquid-chromatography tandem mass-spectrometry (LC-MS/MS) was developed in parallel to Immunoassays (IAs) and today is proposed as the “gold standard” for steroid assays. Leydig cells of men with Klinefelter syndrome (KS) are able to respond to human chorionic gonadotropin (hCG) stimulation, even if testosterone (T) production was impaired. The aim was to evaluate how results obtained by IAs and LC-MS/MS can differently impact on the outcome of a clinical research on gonadal steroidogenesis after hCG stimulation. Methods: A longitudinal, prospective, case-control clinical trial. (clinicaltrial.gov NCT02788136) was carried out, enrolling KS men and healthy age-matched controls, stimulated by hCG administration. Serum steroids were evaluated at baseline and for 5 days after intramuscular injection of 5000 IU hCG using both IAs and LC-MS/MS. Results: 13 KS patients (36 ± 9 years) not receiving T replacement therapy and 14 controls (32 ± 8 years) were enrolled. T, progesterone, cortisol, 17-hydroxy-progesterone (17OHP) and androstenedione, were significantly higher using IAs than LC-MS/MS. IAs and LC-MS/MS showed direct correlation for all five steroids, although the constant overestimation detected by IAs. Either methodology found the same 17OHP and T increasing profile after hCG stimulation, with equal areas under the curves (AUCs). Conclusions: Although a linearity between IA and LC-MS/MS is demonstrated, LC-MS/MS is more sensitive and accurate, whereas IA shows a constant overestimation of sex steroid levels. This result suggests the need of reference intervals built on the specific assay. This fundamental difference between these two methodologies opens a deep reconsideration of what is needed to improve the accuracy of steroid hormone assays.


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 - Effects of chronic administration of the phosphodiesterase inhibitor vardenafil on serum levels of adrenal and testicular steroids in men with type 2 diabetes mellitus [Abstract in Rivista]
Santi, Daniele; Granata, A. R. M.; Pignatti, Elisa; Trenti, T.; Roli, L.; Bozic, R.; Zaza, S.; Rochira, Vincenzo; Carani, Cesare; Magnani, Elisa; Simoni, Manuela
abstract

Background. Steroidogenesis is a complex enzymatic pro- cess in which cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play an important role. Phosphodiesterase-5 inhibitors(PDE5i) increase cGMP, improving NO availability. Objective. To investigate whether long-term, chronic treat- ment with the PDE5i Vardenafil affects adrenal and testicular steroidogenesis in diabetic men, using liquid chromatography- mass spectrometry (LC-MS/MS). Design. A longitudinal, prospective, investigator-started, randomized, placebo-controlled, double-blind, clinical-trial was carried out. Setting and participants. 54 male patients affected by T2DM diagnosed within the last 5 years were enrolled. 26 and 28 patients were assigned to the verum and placebo-group, re- spectively. Interventions. The study consisted of an enrolment phase, a treatment phase (24 weeks) (Vardenafil/placebo 10 mg twice- daily), and a follow-up phase (24 weeks). Outcome measurements. Progesterone (P), 17-hydroxy- progesterone (17OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), corticosterone, 11-deoxycortisol and cortisol (C), were evalu- ated using LC-MS/MS. Results. No differences were seen in sex testicular steroids between study and control group. For the adrenal gland, steroids were considered according to the zona in which they are pro- duced. Considering steroids produced in the zona fasciculata, no significant differences were seen in 11-deoxycortisol and C among visits, both in the study and in the control group. For the zona reticularis, DHEA significantly decreased during treatment only in the study group (p=0.007). At post-hoc test DHEA showed higher levels at visit 2 and 8 than in other visits. The DHEAS/DHEAS ratio significantly increased during treatment only in the verum group. Considering the adrenal zona glomeru- losa, corticosterone significantly changed among visits both in the study and in the control group (p&lt;0.001). At post-hoc test, in ПРОБЛЕМЫ ЭНДОКРИНОЛОГИИ, 5, 2016 both groups, corticosterone was significantly higher at visit 2 (p=0.028), 8 (p=0.003) and 10 (p=0.044), i.e. in coincidence with the complete clinical and instrumental examination per- formed only at these visits according to the study protocol. Conclusions. This is the first double-blind, placebo-con- trolled clinical-trial in which steroidogenesis is extensively in- vestigated by LC-MS/MS in T2DM men chronically treated with Vardenafil for 6 months, and followed-up for 6 months after therapy-withdrawal. Chronically administered Vardenafil reduces DHEA levels and increases DHEAS/DHEA ratio as possible consequences of modulation of steroidogenic enzymes by tissue changes in cGMP and/or cAMP availability. A possi- bly stress-related increase in corticosterone is suggested for the first time.


2016 - Erectile dysfunction is common among men with acromegaly and is associated with morbidities related to the disease [Abstract in Rivista]
Lotti, F.; Rochira, Vincenzo; Pivonello, R; Santi, Daniele; Galdiero, M; Maseroli, E; Balestrieri, A; Faustini Fustini, M; Peri, A; Sforza, A; Colao, A; Maggi, M; Corona, G
abstract

Background: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. Aim: To evaluate sexual function in men with acromegaly. Methods: Multicenter-based, retrospective analysis of a non-selected series of 57 acromegalic subjects (mean age: 52.7 14.2 years) was performed. Acromegalic subjects reporting ED (n = 24) were compared with matched ED- patients without acromegaly or pituitary disease (con- trols), selected from a cohort of more than 4000 subjects enrolled in the Flrence Sexual Medicine and Andrology Unit. Patients were interviewed using SIEDY structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile colour-Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. Results: ED was reported by 42.1% of acromegalic sub- jects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension, and more often reported an impairment of sleep-related erections and a longer smoking habit. Accordingly, acro- megaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No rela- tionship between ED and testosterone levels or other acro- megaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer dis- ease duration. In a case-control analysis, comparing acromegalic subjects with ED-matched-controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acrome- galic patients with ED had a higher prevalence of major adverse cardiovascular events (MACE) history at enrol- ment and lower PCDU parameters. Conclusions: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow- up.


2016 - Erectile dysfunction is common among men with acromegaly and is associated with morbidities related to the disease. [Abstract in Atti di Convegno]
Lotti, F.; Rochira, Vincenzo; Pivonello, R.; Santi, Daniele; Galdiero, M.; Maseroli, E.; Balestrieri, Antonio; Faustini Fustini, M.; Peri, A.; Sforza, A.; Colao, A.; Maggi, M.; Corona, G.
abstract

Introduction: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. This study was aimed at evaluating sexual function in men with acromegaly.Methods: Multicenter-based, retrospective analysis of a non-selected series of 57 acromegalic subjects (52.7±14.2 years). Acromegalic subjects reporting ED (n=24) were compared with matched ED-patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4000 subjects enrolled in the Florence Unit. Patients were interviewed using SIEDY structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile colour-Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. Results: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension, and more often reported an impairment of sleep-related erections and a longer smoking habit.Acromegaly-associated ED was characterized by a higher organic component (Scale 1) and worse PCDU. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration.In a case-control analysis, comparing acromegalic men with ED-matched-controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events (MACE) history at enrolment and lower PCDU parameters. Conclusions:Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up.


2016 - Estrogens and male reproduction [Capitolo/Saggio]
Rochira, Vincenzo; Madeo, Bruno; Diazzi, Chiara; Zirilli, Lucia; Santi, Daniele; Carani, Cesare
abstract

n males, estrogens exert pleiotropic effects by acting on several tissue and organs, including the male reproductive system. The action of estrogens is manifest from prenatal life during which the exposure to estrogen excess might influence the development of some structures of the male reproductive tract. Male fertility is under the control of estrogens, especially in rodents. The loss of function of estrogen receptor alpha and/or of the aromatase enzyme leads to infertility in mice. In men, estrogens are able to exert their actions at several levels through the reproductive tract and on several different reproductive cells. However, the regulation of human male reproduction is more complex and the role of estrogens is less clear compared to mice. During fetal and perinatal life, estrogen acts on the central nervous system by modulating the development of some areas within the brain that are committed to controlling male sexual behavior in terms of setting gender identity, sexual orientation development and the evolution of normal adult male sexual behavior. This organizational, central effect of estrogens is of particular significance in other species (especially rodents and rams), being probably less important in men where psychosocial factors become more determining. Other relevant, non-reproductive physiological events depend on estrogen in men and they involve bone maturation and mineralization as well as metabolic functions. In this chapter we provide an update of estrogen’s role in male reproductive function by reviewing the physiological actions of estrogen on male reproduction and the pathophysiology related to estrogen deficiency and estrogen excess. Phenotypes associated with estrogen deficiency and excess in rodents and in man have shed new light on the mechanisms involved in male reproduction, challenging the perception of the predominant importance of androgens in men. It is now clear that the imbalance between estrogen and androgen in men might affect male reproductive function even in presence of normal circulating androgens. Some uncertainties still remain, especially regarding the impact of abnormal serum estrogen levels on male health, particularly due to the fact that estrogen is not routinely measured in men in clinical practice. Advancements in methods to precisely measure estrogens in men, together with a reduction of their costs, should provide better evidence on this issue and inform clinical practice. New basic and clinical research is required to improve our knowledge on the role of estrogen in male reproductive function and men’s health in general. For complete coverage of all related areas of Endocrinology, please see our online FREE web-book, www.endotext.org.


2016 - Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography-tandem mass spectrometry [Articolo su rivista]
Belli, Serena; Santi, Daniele; Leoni, E; Dall'Olio, Enrico; Fanelli, F; Mezzullo, M; Pelusi, C; Roli, L; Tagliavini, Silvia; Trenti, T; Granata, A. R; Pagotto, U; Pasquali, R; Rochira, Vincenzo; Carani, Cesare; Simoni, Manuela
abstract

BACKGROUND: Men with Klinefelter syndrome (KS) show hypergonadotropic hypogonadism, but the pathogenesis of hypotestosteronemia remains unclear. Testicular steroidogenesis in KS men was evaluated over three decades ago after human chorionic gonadotropin (hCG) stimulation, but inconclusive results were obtained. Intriguingly, some recent studies show increased intratesticular testosterone concentrations in men with KS. OBJECTIVE: To analyze serum steroid profile, as a proxy of testicular steroidogenesis, after hCG stimulation in KS compared with control men. DESIGN: A prospective, longitudinal, case-control, clinical trial. METHODS: Thirteen KS patients (36±9 years) not receiving testosterone (TS) replacement therapy and 12 eugonadic controls (32±8 years) were enrolled. Serum steroids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and for five consecutive days after intramuscular injection of 5000IU hCG. RESULTS: Progesterone (P), 17-hydroxyprogesterone (17OHP), TS, and estradiol (E2) showed a significant increase (P<0.001) after hCG stimulation in both groups. On the contrary, androstenedione (AS) and dehydroepiandrosterone did not increase after hCG stimulation. The 17OHP/P ratio increased in both groups (P<0.001), the TS/AS ratio (17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) activity) did not increase after hCG in any group, and the E2/TS ratio (aromatase activity) increased significantly in both groups (P=0.009 in KS and P<0.001 in controls). Luteinizing hormone decreased after hCG in both groups (P=0.014 in KS and P<0.001 in controls), whereas follicle-stimulating hormone decreased only in control men (P<0.001). CONCLUSION: This study demonstrates for the first time using LC-MS/MS that Leydig cells of KS men are able to respond to hCG stimulation and that the first steps of steroidogenesis are fully functional. However, the TS production in KS men is impaired, possibly related to reduced hydroxysteroid deydrogenase activity due to an unfavorable intratesticular metabolic state.


2016 - Impact of polymorphisms of gonadotropins and their receptors on controlled ovarian stimulation: a prospective observational study [Abstract in Rivista]
Alviggi, C.; Conforti, A.; Cariati, F.; Alfano, S.; Strina, ; Huhtaniemi, I.; Santi, Daniele; De Placido, G.; Humaidan5, P.
abstract

Study question: Which effect do polymorphisms of gonadotropins and their re- ceptors have on stimulation outcomes in IVF patients co-treated with a GnRHa long down-regulation protocol? Summary answer: Allele C of FSHR-29, LHCGR-291 and FSHR-680 all resulted in a significantly increased cumulative r-FSH dose: total number of oocytes or mature oocytes ratio. What is known already: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing IVF/ICSI. Data regarding the pos- sible interactions of these polymorphisms are still scanty, especially as regards LHCG-R polymorphisms. Study design, size, duration: Prospective observational study in 100 normogo- nadotropic IVF/ICSI patients came from three public IVF Units. Participants/materials, setting, methods: Normogonadotropic Caucasian women fulfilling the following inclusion criteria were enrolled: age 20–34 years; BMI 20–27 kg/m2; basal FSH ≤ 10 IU/l; functional ovaries. Exclusion crite- ria were: uterine anomalies; endocrine, genetic or immunological disorders; PCOS; history of impaired ovarian response (≤ 4 oocytes retrieved) in at least one IVF/ICSI cycle. Patients underwent a GnRH long down-regulation protocol with a starting dose of 150 IU of recombinant FSH daily. Six polymorphisms were genotyped. Main results and the role of chance: The following polymorphisms were analyzed: FSHR-680 (rs6166); FSHR-min29 (rs1394205); LHCGR intronic (rs4073366); LHCGR-291 (rs 12470652); LHCGR-312 (rs2293275); FSHβ- 2623 (rs6169). Basal FSH levels were significantly lower in homozygotic carriers of FSHR-630 (T/T) than in heterozygotic C/T (p = 0.023). Lower basal estradiol levels were seen in homozygotic carriers of FSHR-29 promoter C/C compared to heterozygotic C/T (p = 0.045). Basal estradiol levels and number of fertil- ized and mature oocytes were lower in homozygotic carriers of LHCGR-291 (T/T) compared to heterozygotic C/T (p = 0.035 and p = 0.05 respectively). The presence of allele C on both FSHR-min29 and LHCGR-291 caused an in- creased ratio between the cumulative r-FSH consumption and the total number of oocytes as well as mature oocytes (RR: 5.47, CI 95%: 3.13–7.81, p < 0.001). This observation was also confirmed when polymorphisms of FSHR-680 were included in the analysis. Specifically, the presence of allele C on these three genes was related to an increased ratio between the cumulative FSH consump- tion and the total number of oocytes or mature oocytes (RR: 5.44, CI 95%: 3.18–7.71, p < 0.001). Limitations, reasons for caution: Although limited by the small size of the population, these findings confirm a possible interaction between multiple poly- morphisms in assisted reproductive technology. Wider implications of the findings: These data support the concept that the ovarian response to exogenous FSH seems to be determined by the in- teraction of specific genetic traits. Moreover, this study shows an involve- ment of the LHCGR-291 polymorphism in ovarian response to exogenous gonadotropins. Trial registration number: Not applicable.


2016 - Is Testosterone (T) treatment safe and effective in men with HIV infection? A meta-analysis [Abstract in Rivista]
Santi, Daniele; Guaraldi, Giovanni; Corona, Giovanni; Rochira, Vincenzo
abstract

Background Prevalence of hypogonadism is high (30%) in men with HIV. In these patients T treatment (TT) is currently used mainly to counteract wasting syndrome and/or HIV-related lipodystrophy, irrespective of patients’ serum T. However, its effect and safety in HIV-infected men is still not completely known. Aim To investigate both beneficial and adverse effects related to TT in HIV-infected men using a meta-analytic approach. Methods An extensive MEDLINE search was performed using ‘PubMed’ with the following key-words: ‘HIV’ and: ’hypogonadism’, ‘TT’, ‘T’, ’androgens’ or ‘sex steroids’ from 1946 to April 2015. Meta-analysis included 19 placebo-controlled- clinical trials evaluating TT in HIV patients and was conducted according to PRISMA statement using RevMan. Results All 19 trials evaluated the effect of TT on body weight on a total of 952 subjects (TT group: 557; placebo group: 395). Patients’ gonadal status was often not reported and most of patients were presumably eugonadal. All data are shown as standardized mean and Confidence Interval (CI). TT significantly improved total lean body mass (1.44 [0.82–2.07], P!0.001), total body weight (0.99 [0.25–1.72], PZ0.008) and fat free mass (1.48 [0.85–2.12], P!0.001). This improvement is characterized by higher heterogeneity (I 2Z84%, 88%, and 60%, respectively). Conversely, no beneficial effects were seen on total fat mass (K0.17 [K1.58–1.25], PZ0.820). TT was associated with an increased incidence of minor adverse events (ORZ1.50[1.11–2.01], PZ0.008) and increased mean serum PSA (0.10 ng/mL, [0.03–0.17], PZ0.007). No change in hemoglobin (0.39 g/dL, [K0.29–1.07], PZ0.260) was seen. Conclusions Our study suggests that TT in HIV-infected men is effective in improving body composition (increase in lean body mass), although the incidence of general adverse events is higher than in the placebo group. However, studies show a highest variability and the real benefits of TT in HIV-infected men remains still to be established.


2016 - Is serum estradiol (E2) really increased in patients with Klinefelter Syndrome (KS)? Results from a meta-analysis study. [Abstract in Atti di Convegno]
Santi, Daniele; Scaltriti, Sara; Simoni, Manuela; Rochira, Vincenzo
abstract

BACKGROUND: KS has been classically described as characterized by hyperestrogenism and elevated serum E2 together with increased gonadotropins and low-to-normal serum testosterone (T). In literature, data on increased serum E2 are not solid. The aim of this study is to meta- analyse data from studies evaluating serum E2 in both KS and healthy subjects (HS) in order to verify if E2 is increased in KS. METHODS: An extensive MEDLINE was performed using ‘PubMed’ with the following key words: ‘KS’ and ‘E2’ or ‘T’ or ‘sex steroids’ from 1946 to January 2015 (Current Contents-ISI was used for searching oldest studies). All studies (case-control, case-series, case-reports) reporting E2 measurement were considered. Controlled-studies were used for meta-analysis. Only serum E2 at baseline (no ongoing treatments) was included. Meta-analysis was conducted according to the PRISMA statement using RevMan. RESULTS: Out of 956 articles, 26 case-control studies, 15 case-series and 21 case-reports had data on serum E2. A total of 878 KS and 1000 HS were included in the meta-analysis. Serum E2 was significantly higher in HS than in KS, with a mean difference of 7,93 pg/mL (CI: 2,24,13,61;p=0,006), with a chi-squared=688,32 (I-square=97%) (Figure 1). Serum T was significantly lower in KS than in HS, with a mean difference of -2,79 ng/mL (CI:-3,46,-2,11;p<0,001), with a chi-squared=198,29 (I-square=89%). Data from case-series and case-reports confirmed that E2 is not above the normal range in KS.CONCLUSIONS: Serum E2 is not increased in KS and is significantly lower than in HS in this meta-analysis. The limits of this study are the heterogeneity of methods for steroids measurement and the lack of studies having the comparison of serum E2 between KS and HS as primary endpoint. The traditional belief that KS is associated to elevated E2 should be reconsidered together with some pathophysiological and clinical issues.


2016 - Is serum estradiol (E2) really increased in patients with Klinefelter Syndrome (KS)? Results from a meta-analysisi study. [Abstract in Atti di Convegno]
Santi, Daniele; Scaltriti, Sara; Simoni, Manuela; Rochira, Vincenzo
abstract

Results from a meta-analysis on E2 in men with Klinefelter Syndrome


2016 - Psychological, rather than organic and/or relational components are involved in sexual dysfunction in Young/Middle Aged Human immunodeficiency virus (HIV)-Infected Men. [Abstract in Atti di Convegno]
Decaroli, MARIA CHIARA; De Vincentis, Sara; Diazzi, Chiara; Zona, Stefano; Guaraldi, Giovanni; Santi, Daniele; Rochira, Vincenzo
abstract

BACKGROUND: HIV-infection is associated to an increased prevalence of erectile dysfunction (ED)1,2. In HIV- infected men ED seems to be less related to serum Testosterone (T)2-4, ED and sexual dysfunction mainly depending from other factors1,2. However, data on other components of sexual dysfunction in HIV are scanty2. AIM: To investigate the role of different components (organic, relational, psychological) of erectile function by using different validate questionnaire in HIV-infected men with normal serum T who are mainly homosexual (70%). METHODOLOGY: Prospective, cross-sectional, observational study on 225 eugonadal, HIV-infected male patients with ongoing Highly Active Antiretroviral Therapy (HAART) attending the Clinic of Infectious Diseases. The International Index of Erectile Function (IIEF)-15, IIEF-5 and Structured Interview for Erectile Dysfunction (SIEDY) were used for the evaluation of sexual function. Moreover, the sexual desire was further evaluated using a direct question during the visit. Statistical analysis: comparison of continue variables among groups was performed using Kruskal-Wallis test and Dunnet test for post-hoc analyses. RESULTS: 225 HIV-infected patients were enrolled (mean age 45.19±5.36 years) with average duration of HIV- infection and of HAART treatment of 187.62±101.71 and 156.38+89.81 months, respectively. Table 1 summarizes the score obtained in each item evaluated by questionnaires.The SIEDY scores obtained at appendix and scale 3 were significantly higher in patients with ED at IIEF-15 (n=136, 60.4%) compared with those without ED (appendix: 7.64+4.39 vs 4.35+3-14, p&lt;0.001) (scale 3: 2.72+4.39 vs 2.07+1.86, p=0.015). Conversely, scale 1 (2.76+2.16 vs 2.46+2.10, p=0.448) and 2 (0.53+1.02 vs 0.61+1.47, p=0.503) of SIEDY did not differ between patients with or without ED. This suggests that the psychological basis of ED was predominant in HIV-infected men. However, when patients were grouped according to the severity of ED at IIEF-15 all SIEDY items did not differ among the 3 groups (p&gt;0.05). The erectile function domain at IIEF-15 was directly correlated with IIEF-5 score (0.778, p&lt;0.001). Similarly, the score at SIEDY appendix was significantly different among the ED degree found at IIEF-15 (p&lt;0.001). In particular, lower score was found in HIV-infected men without ED compared to those with mild, moderate and severe ED (p&lt;0.001, p=0.001, and p&lt;0.001, respectively), confirming the reliability of these tools. Sexual desire was evaluated using IIEF-15 appropriate domain and during the interview through direct question performed by the clinician. Sexual desire was impaired in 73 patients (31.33%) at interview with a good correlation with the item of IIEF-15 on sexual desire (p&lt;0.001). CONCLUSIONS: The psychological component of ED impacts in a significant manner on ED in men with HIV. Despite the high prevalence of comorbidities in these patients the organic component does not affect erectile function. Similarly, the relational component seems to play a not significant role probably because of the high percentage of men not in a stable relationship. All the three validated questionnaires well describe the degree of erectile dysfunction, with a good correlation index, suggesting that they are all reliable and accurate for the diagnosis of ED in this peculiar population. REFERENCES 1Zona S et al. Erectile dysfunction is more common in young to middle-aged HIV-infected men than in HIV-uninfected men. J Sex Med. 2012 Jul;9(7):1923-30. 2Santi D et al. Male sexual dysfunction and HIV--a clinical perspective. Nat Rev Urol. 2014 Feb;11(2):99-109. 3Rochira V et al. Premature decline of serum total testosterone in HIV-infected men in the HAART-era. PLoS One. 2011;6(12):e28512. 4Rochira V &amp; Guaraldi G. Hypogonadism in the HIV-infected man. Endocrinol Metab Clin North Am. 2014 Sep;43(3):709-30.


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 - Sexual dysfunction in subjects treated with inhibitors of 5a-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis [Abstract in Rivista]
Corona, G.; Santi, Daniele; Maseroli, E; Gacci, M; Di Cuio, M; Maggi., M
abstract

Sexual dysfunction in subjects treated with inhibitors of 5a-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis


2016 - Six months of daily treatment with Vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial. [Articolo su rivista]
Santi, Daniele; Granata, Ar; Guidi, Alessandro; Pignatti, Elisa; Trenti, T; Roli, L; Bozic, R; Zaza, S; Pacchioni, C; Romano, S; Nofer, Jr; Rochira, Vincenzo; Carani, Cesare; Simoni, Manuela
abstract

Abstract OBJECTIVE: Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, characterized by a reduction of nitric oxide (NO)-mediated relaxation. Phosphodiesterase-5 inhibitors (PDE5i) improve NO levels. The aim of the study is to investigate whether long-term, chronic treatment with the PDE5i Vardenafil improves systemic endothelial function in diabetic men. DESIGN: Prospective, investigator-initiated, randomized, placebo-controlled, double-blind, clinical-trial. METHODS: 54 male patients affected by T2DM, diagnosed within the last 5 years, and erectile dysfunction were enrolled, regardless of testosterone (T) levels. 26 and 28 patients were assigned to verum and placebo-group, respectively. The study consisted of an enrolment phase, a treatment phase (24weeks) (Vardenafil/placebo 10mg twice-daily), and a follow-up phase (24weeks). Parameters evaluated: International Index of Erectile Function (IIEF)-15, flow mediated dilation (FMD), serum interleukin (IL)-6, endothelin (ET)-1, gonadotropins and T (measured by liquid-chromatography/tandem mass-spectrometry). RESULTS: IIEF-15 erectile function improved during treatment (p&lt;0.001). At the end of the treatment both FMD (p=0.040) and IL-6 (p=0.019) significantly improved. FMD correlated with serum T levels (R2=0.299, p&lt;0.001). T increased significantly under Vardenafil treatment and returned in the eugonadal range only in hypogonadal men (n=13), without changes in gonadotropins. Chronic Vardenafil treatment did not result in relevant side effects. CONCLUSIONS: This is the first double-blind, placebo-controlled clinical-trial designed to evaluate the effects of chronic treatment of Vardenafil on endothelial health-related parameters and sexual hormones in patients affected by a chronic disease. Chronically administered Vardenafil is effective and improves endothelial parameters in T2DM patient. Moreover, chronic Vardenafil therapy improves hypogonadism in diabetic, hypogonadal men.


2016 - Sperm quality and environment: A retrospective, cohort study in a Northern province of Italy [Articolo su rivista]
Santi, Daniele; Vezzani, Silvia; Granata, Antonio; Roli, Laura; De Santis, Maria Cristina; Ongaro, Chiara; Donati, Federica; Baraldi, Enrica; Trenti, Tommaso; Setti, Monica; Simoni, Manuela
abstract

Background: Several studies proposed a relationship between environmental factors and semen quality, as well as the negative effect of air pollution on spermatogenesis and gonadal function. No specific studies evaluated the environmental influence on semen quality in a specific geographical area. Aim: to evaluate the environmental influence on male sperm parameters in a Northern Italian population referred for semen analysis in the National Health System. The objective of the study is the assessment of the relationship of both air pollution and environmental parameters with quality-related sperm variables, during the coldest months of the year when air is usually most polluted, due to low ventilation and poor rainfall. Study design: A retrospective, observational, cohort study was carried out in the province of Modena, located in the Emilia-Romagna region of Northern Italy. Methods: Semen analyses (n=406), environmental temperature, air humidity and air particulate matter (PM) measurements from the 1st of November, 2014 to the 19th of February, 2015 were acquired to the first database. Since spermatogenesis lasts over two months, a second, wider database was arranged, evaluating environmental exposure in the 3 months before semen collection (from August 1st 2014). All data included in the database were registered by geo-coding the residential address of the patients and the site of registration of environmental factors. The geo-codification of parameters was performed using Fusion Tables of Google available at https://www.google.com/fusiontables/data?dsrcid=implicit, considering the exact time of measurement. Results: Average air temperature was inversely related to sperm concentration and to total sperm number (p&lt;0.001). Semen volume was inversely related only to the minimum (p&lt;0.001) and not to maximum recorded temperature (p=0.110). Air humidity was not related to sperm quantity and quality. PM2.5 was directly related to total sperm number (p&lt;0.001). PM10 was directly related to both semen volume (0&lt;0.001), and typical forms (p&lt;0.001), inversely related to atypical forms (p&lt;0.001), but related neither to sperm concentration (p=0.430) nor to sperm motility. The extended analyses considering environmental parameters in the 3 months before semen collection, confirmed the relationship between air temperature and sperm quantity, whereas no influence was found between PM and sperm quality. Conclusion: An influence of environmental temperature on semen quantity is suggested, without a clear effect of air pollution, as assessed through PM10 levels, on sperm parameter variations.


2016 - Testosterone (T) is poorly related to Erectile Dysfunction (ED) in Young/Middle Aged Human immunodeficiency virus (HIV)-Infected Men. [Abstract in Atti di Convegno]
De Vincentis, Sara; Santi, Daniele; Decaroli, MARIA CHIARA; Fanelli, F.; Mezzullo, M.; Ansaloni, Anna; Pagotto, U.; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

BACKGROUND: HIV infection is strongly associated to ED in men1,2. Preliminary data suggests that ED is poorly associated with serum T in HIV+ men1,3-4. AIM: To investigate the relationship between sexual function as assessed by the validated International Index of Erectile Function (IIEF-15) and T deficiency in HIV-infected men by assessing circulating T by Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS). METHODOLOGY: Prospective, cross-sectional, observational study on 233 consecutive HIV-infected male patients with ongoing Highly Active Antiretroviral Therapy (HAART), attending the Clinic of Infectious Diseases. IIEF-15 questionnaire was used to define patients having ED (score <25), IIEF-5 was performed to check if it is reliable as IIEF-15 in this setting, while LC-MS/MS was used for hormonal assays. Statistical analysis: Continuous and categorical variables were compared using ANOVA univariate and Chi-Square test, respectively. Correlations were performed using Spearman’s Rho coefficient. RESULTS: 233 HIV-infected patients were enrolled (mean age 45.29±5.33 years) with average duration of HIV-infection of 195.98±129.54 months. Eight patients (3.4%) had hypogonadism, defined as total T serum levels below 300 ng/dL. 142 patients (61.5%) had ED (EF score ≤25) (Table 1). Age, hormonal data and duration of HIV infection and HAART did not differ among groups of patients according to the degree of ED (Table 1). Although no differences were seen among categories, the direct comparison of each ED cluster showed that months of infection were significantly higher in men with severe ED compared to mild ED (p=0.037); moreover, men with severe ED had lower T levels than men with mild form (p=0.029). All hypogonadal men had erectile dysfunction (p=0.020). However, no differences were found among ED degree for hypogonadal men (p=0.151). The erectile function domain at IIEF-15 was directly correlated with IIEF-5 score (0.778, p<0.001), as expected. Moreover, the IIEF-15 score was inversely related to months of infection (-0.147, p=0.026) (Figure 1), but not to months of HAART therapy (-0.121, p=0.071). Total T showed an inverse relation with months of infection (-0.172, p=0.009) (Figure 1) and months of HAART (-0.173, p=0.010), but not with IIEF-15 score (0.039; p=0.559). CONCLUSIONS: To the best of our knowledge, this is the first, properly-designed prospective study aiming to investigate the relationship between erectile function and serum T, assessed using the LC-MS/MS in HIV-infected men. Similarly to the IIEF-15, the IIEF-5 recognize ED patients and the scores of both correlates each other. In our cohort, the prevalence of ED and hypogonadism was 61% and 3.4%, respectively. Thus, ED evaluated by IIEF-15 seems to be not directly related to serum total T, but it correlates with age and months of infection. In conclusion, in HIV-infected patients a) IIEF-5 is reliable as IIEF- 15 for ED diagnosis, b) ED is not associated with serum T, c) erectile function is not influenced by T and HAART, but only by HIV-infection duration. In conclusion, several specific factors, such as the duration of HIV infection, are involved in erectile function in HIV-infected men and should be carefully considered in this setting, while hormonal status seems to be less important.


2016 - The influence of environment on the sperm quality: a comprehensive, retrospective, cohort study. [Abstract in Rivista]
Santi, Daniele; Vezzani, S; Granata A., Roli L; De Santis, Mc; Baraldi, E; Trenti, T; Setti, M; Simoni, M.
abstract

influence of environment on the sperm quality: a comprehensive, retrospective, cohort study


2016 - Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: A pharmacogenetic study [Articolo su rivista]
Simoni, Manuela; Santi, Daniele; Negri, Luciano; Hoffmann, Ivan; Muratori, Monica; Baldi, Elisabetta; Cambi, Marta; Marcou, Marios; Greither, Thomas; Baraldi, Enrica; Tagliavini, Simonetta; Carra, Daniela; Lombardo, Francesco; Gandini, Loredana; Pallotti, Francesco; Krausz, Csilla; Rastrelli, Giulia; Ferlin, Alberto; Menegazzo, Massimo; Pignatti, Elisa; Linari, Francesca; Marino, Marco; Benaglia, Renzo; Levi Setti, Paolo E.; Behre, Hermann M.
abstract

Study question: Does the spermDNAfragmentation index (DFI) improve depending on the FSH receptor (FSHR) genotype as assessed by the nonsynonymous polymorphisms rs6166 (p.N680S) after 3 months of recombinant FSH treatment in men with idiopathic infertility? summary answer: FSH treatment significantly improves sperm DFI only in idiopathic infertile men with the p.N680S homozygous N FSHR. what is known already: FSH, fundamental for spermatogenesis, is empirically used to treat male idiopathic infertility and several studies suggest that DFI could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is known that the FSHR single nucleotide polymorphism (SNP) rs6166 (p.N680S) influences ovarian response in women and testicular volume in men. study design, size and duration: Amulticenter, longitudinal, prospective, open-label, two-arm clinical trial was performed. Subjects enrolled were idiopathic infertile men who received 150 IU recombinant human FSH s.c. every other day for 12 weeks and were followed-up for a further 12 weeks after FSH withdrawal. Patients were evaluated at baseline, at the end of treatment and at the end of follow-up. participants/materials, setting, methods: Eighty-nine men with idiopathic infertility carrier of the FSHR p.N680S homozygousNor S genotype, FSH ≤ 8 IU/l and DFI &gt;15%,were enrolled. A total of 66 patients had DFI analysis completed on at least two visits. DFI was evaluated in one laboratory by TUNEL/PI (propidium iodide) assay coupled to flow cytometry, resolving two different fractions of sperm, namely the 'brighter' and 'dimmer' sperm DFI fractions. main results and the roleof chance: Thirty-eightmen(57.6%)were carriers of the p.N680S homozygousNand 28 (42.4%) of the homozygous S FSHR. Sperm concentration/number was highly heterogeneous and both groups included men ranging from severe oligozoospermia to normozoospermia. Total DFI was significantly lower at the end of the study in homozygous carriers of the p.N680SNversus p.N680S S allele (P = 0.008). Total DFI decreased significantly from baseline to the end of the study (P = 0.021) only in carriers of the p.N680S homozygous N polymorphism, and this decrease involved the sperm population containing vital sperm (i.e. brighter sperm) (P = 0.008). The dimmer sperm DFI fraction, including only nonvital sperm, was significantly larger in p.N680S S homozygous patients than in homozygous N men (P = 0.018). Total DFIwas inversely related to total sperm number (P = 0.020) and progressive sperm motility (P = 0.014).Whenpatients were further stratified according to sperm concentration (normoozospermic versus oligozoospermic) or -211G&gt;T polymorphism in the FSHB gene (rs10835638) (homozygous Gversus others), the significant improvement of sperm DFI in FSHR p.N680S homozygousNmen was independent of sperm concentration and associated with the homozygous FSHB -211G&gt;T homozygous G genotype. limitations, reasons for caution: The statistical power of the study is 86.9% with alpha error 0.05. This is the first pharmacogenetic study suggesting that FSH treatment induces a significant improvement of total DFI in men carriers of the p.N680S homozygousNFSHR; however, the results need to be confirmed in larger studies using a personalized FSH dosage and treatment duration. wider implications of the findings: The evaluation of sperm DFI as a surrogate marker of sperm quality, and of the FSHR SNP rs6166 (p.N680S), might be useful to predict the response to FSH treatment in men with idiopathic infertility. study funding/competing interest(s): The study was supported by an unrestricted grant to M.S. and H.M.B. from Merck Serono that provided the drug used in the study. MS received additional grants from Merck Serono and IBSA as well as honoraria from Merck Serono. The remaining authors declare that no conflicts of interest are present. trial registration number: EudraCT number 2010-020240-35.


2016 - Will steroid measurements affect the outcomes of clinical trials? Comparison between immunoassayand mass spectrometry in men with Kinefelter Syndrome undergoing human corionic gonadotropin stimulation test. [Abstract in Atti di Convegno]
Santi, Daniele; Roli, L.; Belli, Serena; Tagliavini, Silvia; Cavalieri, Silvia; De Santis, M. C.; Baraldi, Enrica; Fanelli, F.; Mezzullo, M.; Granata, A. R.; Pagotto, U.; Pasquali, R.; Rochira, Vincenzo; Carani, Cesare; Trenti, T.; Simoni, Manuela
abstract

The abstract deal with the comparison between immunoassayand mass spectrometry in measuring sex steroids in men with Kinefelter Syndrome


2015 - Chronic, long-term administration of Vardenafil improves endothelial function and corrects hypogonadism in patients with type 2 diabetes mellitus. A longitudinal, prospective, randomized, placebo-controlled, double blind, clinical trial [Abstract in Rivista]
Santi, Daniele; Guidi, Alessandro; Granata, Antonio; Pignatti, Elisa; Bozic, Roberto; Zaza, Stefano; Roli, Laura; Trenti, Tommaso; Carani, Cesare; Simoni, Manuela
abstract

10.1530/endoabs.37.OC4.3


2015 - ERECTILE DYSFUNCTION IS COMMON AMONG MEN WITH ACROMEGALY AND IS ASSOCIATED WITH MORBIDITIES RELATED TO THE DISEASE [Abstract in Atti di Convegno]
Lotti, F.; Rochira, Vincenzo; Pivonello, R.; Santi, Daniele; Galdiero, M.; Maseroli, E.; Balestrieri, Antonio; FAUSTINI FUSTINI, Marco; Peri, A.; Sforza, A.; Colao, A.; Maggi, M.; Corona, G.
abstract

Introduction: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. The aim of this study is to evaluate sexual function in acromegalic men. Methods: Multicenter-based, retrospective analysis of a non-selected series of 57 acromegalic subjects (mean age: 52.7±14.2 years) was performed. Patients were interviewed using SIEDY structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile colour-Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. Acromegalic subjects reporting ED (n=24) were compared with matched ED-patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4000 subjects enrolled in the Florence Sexual Medicine and Andrology Unit. Results: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension and impairment of sleep-related erections and a longer smoking habit. Accordingly, acromegaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration. In a case- control analysis, comparing acromegalic subjects with ED-matched-controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events (MACE) history at enrolment and lower PCDU parameters. Conclusions: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up.


2015 - Efficacy of follicle-stimulating hormone treatment in male idiopathic infertility: a meta-analysis [Abstract in Atti di Convegno]
Santi, Daniele; Granata, Antonio; Simoni, Manuela
abstract

Study question: To comprehensively evaluate whether follicle stimulating hor- mone (FSH) administration to the male partner of idiopathic infertile couples improves pregnancy rate, both spontaneous and after assisted reproductive tech- nique (ART), using a meta-analytic approach and including controlled clinical trial. Summary answer: The administration of FSH to infertile men is reported in the literature since 1991, improving fertilisation and pregnancy rate. A significant increase in pregnancy rate after ART and male treatment with FSH was already shown in several studies, since FSH improves the sperm quality. FSH treatment could improve sperm quality and pregnancy rate in idiopathic infertile men. What is known already: The Cochrane Collaboration recently estimated the overall effect of FSH treatment of the man in couples attending ART, enrolled in randomised, controlled, clinical-trials. That meta-analysis demonstrated that FSH treatment significantly improves spontaneous pregnancy rate, whereas no improvement of pregnancy rate was observed after ART, using fixed and strict inclusion criteria. They excluded all trials in which the randomization was not provided leading to potential loss of useful information that could help clini- cians in their routinely practice. Study design, size, duration: We conducted a comprehensive literature search for controlled clinical trials in which FSH was administered for male idiopathic infertility, compared with placebo or no treatment. The randomization was not considered as inclusion criterion. We considered studies in which men with idiopathic infertility or subfertility were enrolled, chronicallty treated with any type of FSH, compared with placebo or no treatment. Participants/materials, setting, methods: We found 15 controlled clinical stud- ies. Concerning the type of FSH, eight studies included in the meta-analysis used recombinant FSH, whereas seven studies used purified FSH. Pregnancy rate, when evaluated, was considered spontaneous or after ART. Selected trials gave details about 1275 infertile-men, 614 treated with FSH and 661 not-treated. Main results and the role of chance: Among the 15 studies included, nine studies evaluated the spontaneous pregnancy rate, resulting in an overall im- provement of about 4.5 (CI 2.17–9.33 and I2 = 0%) (p < 0.001). Eight stud- ies evaluated pregnancy rate after ART, showing a significant improvement of about 1.60 (CI 1.08–2.37 and I2 = 43%) (p = 0.002). Sub-dividing studies ac- cording to the FSH preparations (purified or recombinant), the pregnancy rate improvement remained significant (p = 0.007 and p = 0.002, respectively). Elev- en studies considered sperm quality after FSH treatment, finding a significant improvement of sperm concentration (mean improvement of 2.66x106 millions/ mL, with CI 0.47–4.84, p = 0.02), but not of sperm motility (mean improvement of 1.22x106 millions/mL, with CI -0.07–2.52, p = 0.06). Finally, three trials evaluated testicular volume, showing a non-significant increase in men treated (mean increase of 1.35 mL, with CI -0.44–3.14, p = 0,14). Limitations, reason for caution: The heterogeneity of studies, together with the high risk of biases in this field of research could limit the strength of these results. Wider implications of the findings: The results of controlled clinical trials available in literature indicate an improvement of pregnancy rate after FSH ad- ministration to the male partner of infertile couples, both spontaneous and after ART. Study funding/competing interest(s): Funding by University(ies) – University of Modena and Reggio Emilia. Trial registration number: NA. Keywords: FSH, idiopathic male infertility, reproduction


2015 - Erectile dysfunction is common among men with acromegaly and is associated with morbidities related to the disease [Articolo su rivista]
Lotti, F; Rochira, Vincenzo; Pivonello, R; Santi, Daniele; Galdiero, M; Maseroli, E; Balestrieri, A; Faustini Fustini, M; Peri, A; Sforza, A; Colao, A; Maggi, M; Corona, G.
abstract

INTRODUCTION.The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. AIM: The aim of this study was to evaluate sexual function in men with acromegaly. METHODS: Multicenter-based, retrospective analysis of a nonselected series of 57 acromegalic subjects (mean age: 52.7 ± 14.2 years) was performed. Acromegalic subjects reporting ED (n = 24) were compared with matched ED patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4,000 subjects enrolled in the Florence Sexual Medicine and Andrology Unit. MAIN OUTCOME MEASURES: Patients were interviewed using Structured Interview on Erectile Dysfunction (SIEDY) structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile color Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. RESULTS: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension and more often reported an impairment of sleep-related erections and a longer smoking habit. Accordingly, acromegaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration. In a case-control analysis, comparing acromegalic subjects with ED-matched controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events history at enrollment and lower PCDU parameters. CONCLUSIONS: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up.


2015 - Erratum to: GLP-1: Benefits beyond pancreas [Articolo su rivista]
Muscogiuri, G.; Cignarelli, A.; Giorgino, F.; Prodam, F.; Santi, D.; Tirabassi, G.; Balercia, G.; Modica, R.; Faggiano, A.; Colao, A.
abstract


2015 - FSH treatment improves sperm DNA damage in men with idiopathic infertility carriers of the FSH receptor p.N680S homozygous N genotype: an interim analysis [Abstract in Atti di Convegno]
Simoni, M; Santi, D; Linari, F; Baldi, E; Cambi, M; Ferlin, A; Gandini, L; Garolla, A; Krausz, C; Levi Setti, Pe; Lombardo, F; Marino, M; Muratori, M; Negri, L; Pignatti, E; Rastrelli, G; and Behre, Hm
abstract

Study question: To assess whether in men with idiopathic infertility, the sperm DNA fragmentation (sDF) improves depending on the FSH receptor (FSHR) genotype as assessed by the non-synonymous polymorphisms (SNP) rs6166 (wild type or p.N680S). Summary answer: FSH treatment improves sDF in a subgroup of idiopathic infertile men, although 40% of these men do not show any significant improve- ment. The response of sDF, a surrogate marker of sperm quality, together with the evaluation of FSHR SNP p.N680S might be useful to predict the response to FSH treatment. What is known already: FSH is fundamental for spermatogenesis and is em- pirically used to treat male idiopathic infertility. Several studies suggest that sDF could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is widely accepted that the FSHR SNP p.N680S influences ovarian response in women and testicular volume in men. Study design, size, duration: Multicenter, longitudinal, prospective, open-la- bel, two-arms clinical trial. Subjects enrolled were idiopathic infertile men and received 150 IU of recombinant FSH (Gonal f®) every other day for 12 weeks and were then followed-up for further 12 weeks after FSH-withdrawal. Patients were evaluated at baseline and at the end of the two phases. Participants/materials, setting, methods: Eighty-eight men with idiopathic male infertility carrier of the homozygous FSHR p.N680S N or S genotype, FSH < 8 IU/L and sDF > 15%, were enrolled. 66 patients completed the sDF analysis. sDF was centrally evaluated by TUNEL/PI assay coupled to flow cy- tometry, resolving two different sperm populations, namely: PIbrighter and PIdimmer. Main results and the role of chance: Thirty-seven men (56%) were carriers of the p.N680S homozygous-N and 29 (44%) of the homozygous-S genotype, respectively. Total sDF (PIbrighter + PIdimmer) was significantly lower at the end of the study in patients carriers of the p.N680S-N allele than patients carri- ers of p.N680S-S allele (p = 0.008). Only in patients carriers of the p.N680S-N allele, total sDF decreased significantly from baseline to the end of the study (p = 0.021) and this decrease was entirely sustained by the sperm population containing vital sperms (i.e., PIbrighter fraction) (p = 0.008). PIdimmer frac- tion, including only non-vital sperms, was significantly higher in patients car- riers of the p.N680S-S allele than in carriers of N allele (p = 0.018). Total sDF was inversely related to total sperm number (p = 0.020) and progressive sperm motility (p = 0.014). Limitations, reason for caution: The statistical power of the results obtained so far is 86.9%, with alpha-error 0.05. This is an interim-analysis. Wider implications of the findings: The study suggests that FSH treatment induces a significant improvement of total sDF in men carriers of the p.N680S homozygous N allele. This sDF decrease awaits confirmation, since the study will be completed by June 2015. Study funding/competing interest(s): Funding by commercial/corporate company(ies) – The study was supported by unrestricted grant by Merck Serono. Trial registration number: EudraCT number 2010-020240-35. Keywords: FSH treatment, male infertility, Sperm-DNA fragmentation


2015 - FSH treatment of male idiopathic infertility improves pregnancy rate: a meta-analysis [Articolo su rivista]
Santi, Daniele; Granata, Ar; Simoni, Manuela
abstract

INTRODUCTION: The aim of this study is to comprehensively evaluate whether FSH administration to the male partner of infertile couples improves pregnancy rate, spontaneously and/or after assisted reproductive techniques (ART). METHODS: Meta-analysis of controlled clinical trials in which FSH was administered for male idiopathic infertility, compared with placebo or no treatment. Randomization was not considered as an inclusion criterion. RESULTS: We found 15 controlled clinical studies (614 men treated with FSH and 661 treated with placebo or untreated). Concerning the type of FSH, eight studies used recombinant FSH, whereas seven studies used purified FSH. Nine studies evaluated spontaneous pregnancy rate, resulting in an overall odds ratio (OR) of about 4.5 (CI: 2.17-9.33). Eight studies evaluated pregnancy rate after ART, showing a significant OR of 1.60 (CI: 1.08-2.37). Sub-dividing studies according to the FSH preparations (purified/recombinant), pregnancy rate improvement remained significant for each preparation. Eleven studies considered sperm quality after FSH treatment, finding a significant improvement of sperm concentration (2.66×10(6)/ml, CI: 0.47-4.84), but not of concentration of sperm with progressive motility (1.22×10(6)/ml, CI: -0.07 to 2.52). Three trials evaluated testicular volume, showing a non-significant increase in men treated (1.35 ml, CI: -0.44 to 3.14). CONCLUSION: The results of controlled clinical trials available in the literature indicate an improvement of pregnancy rate after FSH administration to the male partner of infertile couples, both spontaneously and after ART. However, the heterogeneity of studies, the high risk of bias and the lack of precise criteria to guide FSH administration limit the strength of these results. Future studies should be designed to identify the markers of FSH response which are helpful in the decision-making process. Meanwhile, the use of FSH in the treatment of male infertility should be cautious.


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

aa


2015 - IS SERUM ESTRADIOL (E2) REALLY INCREASED IN PATIENTS WITH KLINEFELER SYNDROME (KS)? RESULTS FROM A META-ANALYSIS STUDY [Abstract in Atti di Convegno]
Santi, Daniele; Scaltriti, Sara; Rochira, Vincenzo
abstract

INTRODUCTION: KS has been classically described as characterized by hyperestrogenism and elevated serum E2 together with increased gonadotropins and low-to-normal serum testosterone (T). In literature, data on increased serum E2 are not solid. AIM: The aim of this study is to meta-analyse data from studies evaluating serum E2 in both KS and healthy subjects (HS) in order to verify if E2 is increased in KS. METHODS: An extensive MEDLINE was performed using ‘PubMed’ with the following key words: ‘KS’ and ‘E2’ or ‘T’ or ‘sex steroids’ from 1946 to January 2015 (Current Contents-ISI was used for searching oldest studies). All studies (case-control, case- series, case-reports) reporting E2 measurement were considered. Controlled-studies were used for meta-analysis, the others only for reviews. Only serum E2 at baseline (no ongoing treatments) was included. Meta-analysis was conducted according to the PRISMA statement using RevMan. RESULTS: Out of 956 articles, 26 case-control studies, 15 case-series and 21 case- reports had data on serum E2. A total of 878 KS and 1000 HS were included in the meta-analysis. Serum E2 was significantly higher in HS than in KS, with a mean difference of 7,93 pg/mL (CI:2,24,13,61;p=0,006), with a chi-squared=688,32 (I- square=97%). Serum T was significantly lower in KS than in HS, with a mean difference of -2,79 ng/mL (CI:-3,46,-2,11;p<0,001), with a chi-squared=198,29 (I- square=89%). Data from case-series and case-reports confirmed that E2 is not above the normal range in KS. CONCLUSIONS: Serum E2 is not increased in KS and is significantly lower than in HS in this meta-analysis. The limits of this study are the heterogeneity of methods for steroids measurement and the lack of studies having the comparison of serum E2 between KS and HS as primary endpoint. The traditional belief that KS is associated to elevated E2 should be reconsidered together with some pathophysiological and clinical issues.


2015 - Impact of gene polymorphisms of gonadotropins and their receptors on human reproductive success [Articolo su rivista]
Casarini, L.; Santi, D.; Marino, M.
abstract

Gonadotropins and their receptors' genes carry several single-nucleotide polymorphisms resulting in endocrine genotypes modulating reproductive parameters, diseases, and lifespan leading to important implications for reproductive success and potential relevance during human evolution. Here we illustrate common genotypes of the gonadotropins and gonadotropin receptors' genes and their clinical implications in phenotypes relevant for reproduction such as ovarian cycle length, age of menopause, testosterone levels, polycystic ovary syndrome, and cancer. We then discuss their possible role in human reproduction and adaptation to the environment. Gonadotropins and their receptors' variants are differently distributed among human populations. Some hints suggest that they may be the result of natural selection that occurred in ancient times, increasing the individual chance of successful mating, pregnancy, and effective post-natal parental cares. The gender-related differences in the regulation of the reproductive endocrine systems imply that many of these genotypes may lead to sex-dependent effects, increasing the chance of mating and reproductive success in one sex at the expenses of the other sex. Also, we suggest that sexual conflicts within the FSH and LH-choriogonadotropin receptor genes contributed to maintain genotypes linked to subfertility among humans. Because the distribution of polymorphic markers results in a defined geographical pattern due to human migrations rather than natural selection, these polymorphisms may have had only a weak impact on reproductive success. On the contrary, such genotypes could acquire relevant consequences in the modern, developed societies in which parenthood attempts often occur at a later age, during a short, suboptimal reproductive window, making clinical fertility treatments necessary.


2015 - Impact of gene polymorphisms of gonadotropins and their receptors on human reproductive success [Articolo su rivista]
Casarini, Livio; Santi, Daniele; Marino, Marco
abstract

Gonadotropins and their receptors' genes carry several single-nucleotide polymorphisms resulting in endocrine genotypes modulating reproductive parameters, diseases, and lifespan leading to important implications for reproductive success and potential relevance during human evolution. Here we illustrate common genotypes of the gonadotropins and gonadotropin receptors' genes and their clinical implications in phenotypes relevant for reproduction such as ovarian cycle length, age of menopause, testosterone levels, polycystic ovary syndrome, and cancer. We then discuss their possible role in human reproduction and adaptation to the environment. Gonadotropins and their receptors' variants are differently distributed among human populations. Some hints suggest that they may be the result of natural selection that occurred in ancient times, increasing the individual chance of successful mating, pregnancy, and effective post-natal parental cares. The gender-related differences in the regulation of the reproductive endocrine systems imply that many of these genotypes may lead to sex-dependent effects, increasing the chance of mating and reproductive success in one sex at the expenses of the other sex. Also, we suggest that sexual conflicts within the FSH and LH-choriogonadotropin receptor genes contributed to maintain genotypes linked to subfertility among humans. Because the distribution of polymorphic markers results in a defined geographical pattern due to human migrations rather than natural selection, these polymorphisms may have had only a weak impact on reproductive success. On the contrary, such genotypes could acquire relevant consequences in the modern, developed societies in which parenthood attempts often occur at a later age, during a short, suboptimal reproductive window, making clinical fertility treatments necessary.


2015 - Is serum estradiol really increased in patients with Klinefeler syndrome? Results from a meta-analysis study. [Abstract in Rivista]
Santi, Daniele; Scaltriti, Sara; Rochira, Vincenzo
abstract

Background and aim KS has been classically described as characterized by hyperestrogenism and elevated serum E2 together with increased gonadotropins and low-to-normal serum testosterone (T). In literature, data on increased serum E2 are not solid. The aim of this study is to meta-analyse data from studies evaluating serum E2 in both KS and healthy subjects (HS) in order to verify if E2 is increased in KS. Methods An extensive MEDLINE was performed using ‘PubMed’ with the following key words: ‘KS’ and ‘E2’ or ‘T’ or ‘sex steroids’ from 1946 to January 2015 (current contents-ISI was used for searching oldest studies). All studies (case–control, case–series, case–reports) reporting E2 measurement were considered. Con- trolled–studies were used for meta-analysis, the others only for reviews. Only serum E2 at baseline (no ongoing treatments) was included. Meta-analysis was conducted according to the PRISMA statement using RevMan. Results Out of 956 articles, 26 case–control studies, 15 case–series and 21 case–reports had data on serum E2. A total of 878 KS and 1000 HS were included in the meta- analysis. Serum E2 was significantly higher in HS than in KS, with a mean difference of 7.93pg/ml (CI: 2.24, 13.61; PZ0.006), with a c2Z688.32 (I-squareZ97%). Serum T was significantly lower in KS than in HS, with a mean difference of K2.79 ng/ml (CI:K3,46,K2,11; P!0.001), with a c2Z198,29 (I-squareZ89%). Data from case–series and case–reports confirmed that E2 is not above the normal range in KS. Conclusions Serum E2 is not increased in KS and is significantly lower than in HS in this meta- analysis. The limits of this study are the heterogeneity of methods for steroids measurement and the lack of studies having the comparison of serum E2 between KS and HS as primary endpoint. The traditional belief that KS is associated to elevated E2 should be reconsidered together with some pathophysiological and clinical issues.


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 - Outcomes of androgen replacement therapy in adult male hypogonadism: Recommendations from the Italian Society of Endocrinology [Articolo su rivista]
Isidori, A. M.; Balercia, G.; Calogero, A. E.; Corona, G.; Ferlin, A.; Francavilla, S.; Santi, D.; Maggi, M.
abstract

Objective: We developed clinical practice guidelines to assess the individual risk-benefit profile of androgen replacement therapy in adult male hypogonadism (HG), defined by the presence of specific signs and symptoms and serum testosterone (T) below 12 nmol/L. Participants: The task force consisted of eight clinicians experienced in treating HG, selected by the Italian Society of Endocrinology (SIE). The authors received no corporate funding or remuneration. Consensus process: Consensus was guided by a systematic review of controlled trials conducted on men with a mean T &lt; 12 nmol/L and by interactive discussions. The guidelines were reviewed and sequentially approved by the SIE Guidelines Commission and Executive Committee. Conclusions: We recommend T supplementation (TS) for adult men with severely reduced T levels (T &lt; 8 nmol/L) to improve body composition and sexual function. We suggest that TS be offered to subjects with T &lt; 12 nmol/L to improve glycaemic control, lipid profile, sexual function, bone mineral density, muscle mass and depressive symptoms, once major contraindications have been ruled out. We suggest that lifestyle changes and other available interventions (e.g. for erectile dysfunction) be suggested prior to TS. We suggest that TS should be combined with currently available treatments for individuals at high risk for complications, such as those with osteoporosis and/or metabolic disorders. We recommend against using TS to improve cardiac outcome and limited mobility. We recommend against using TS in men with prostate cancer, unstable cardiovascular conditions or elevated haematocrit. The task force places a high value on the timely treatment of younger and middle-aged subjects to prevent the longterm consequences of hypoandrogenism.


2015 - Therapy of endocrine disease. Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis. [Articolo su rivista]
Santi, Daniele; Giannetta, Elisa; Isidori, Andrea M; Vitale, Cristiana; Aversa, Antonio; Simoni, Manuela
abstract

OBJECTIVE: Diabetes mellitus (DM) is associated with endothelial dysfunction, reducing nitric oxide-dependent vasodilation, and increasing production of pro-inflammatory factors, leading to an increased risk of long-term cardiovascular disease. As the effects of phosphodiesterase 5 inhibitors (PDE5i) on endothelial function have not been systematically investigated, we conducted a meta-analysis of available randomized clinical trials (RCTs). DESIGN: A thorough search of the literature was carried out. Relevant studies were considered according to RCT study design, enrollment of men with type 2 DM, chronic administration of PDE5i, and evaluation of endothelial function through both hemodynamic and endothelial inflammation-related parameters. RESULTS: Fifteen studies fulfilled the eligibility criteria but only six RCTs met the inclusion criteria and were analyzed for 476 diabetic men, 239 randomized to Sildenafil, and 237 to placebo respectively. Four RCTs evaluated flow-mediated dilation (FMD), demonstrating a weighted mean increase of 2.19% (95% CI 0.48 to 3.90). This result showed a high heterogeneity (I(2): 98%). Thus, a further sub-group meta-analysis was performed and this analysis confirmed a significant, Sildenafil-related FMD improvement. Sildenafil improved endothelin 1 and high sensitivity C-reactive protein by ∼-0.94 pg/ml and -0.36 mg/l, respectively, not reaching statistical significance (P=0.69 and P=0.22 respectively). Finally, Sildenafil administration significantly reduced serum levels of interleukin 6 (IL6, -0.82 pg/ml; 95% CI -1.58 to -0.07). CONCLUSION: This meta-analysis suggests a beneficial effect of chronic PDE5i administration on endothelial function. Chronic Sildenafil administration seems to improve hemodynamic (FMD) and serum pro-inflammatory makers (IL6) in diabetic men. Larger studies are needed to confirm the effects of chronic PDE5i on endothelial function.


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 - Biosimilar recombinant follicle stimulating hormones in infertility treatment [Articolo su rivista]
Santi, Daniele; Simoni, Manuela
abstract

Follicle stimulating hormone (FSH) is a glycoprotein hormone essential for reproduction both in females and males and it is physiologically produced by the anterior pituitary gland in several isoforms. This heterogeneity is typical also of FSH-containing compounds, both urinary-derived and recombinant products. These compounds are widely used in assisted reproductive technologies (ART), to induce multifollicular development. Recently, the increased cost pressure on healthcare systems and the patent expiration date of widely used biotechnology-derived, recombinant FSH, prompted the pharmaceutical interest in FSH biosimilars.


2014 - FSH treatment improves sperm DNA damage in men with idiopathic infertility carriers of the FSH receptor p.N680S homozygous N genotype: an interim analysis [Abstract in Atti di Convegno]
Santi, Daniele; Linari, Francesca; Baldi, E; Behre, Hm; Cambi, M; Ferlin, A; Gandini, L; Garolla, A; Krausz, C; Levi Setti, Pe; Lombardo, F; Marino, M; Muratori, M; Negri, L; Pignatti, E; Rastrelli, G; Simoni, Manuela
abstract

FSH treatment improves sperm DNA damage in men with idiopathic infertility carriers of the FSH receptor p.N680S homozygous N genotype: an interim analysis


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 - GLP-1: benefits beyond pancreas. [Articolo su rivista]
Muscogiuri, G; Cignarelli, A; Giorgino, F; Prodam, F; Santi, Daniele; Tirabassi, G; Balercia, G; Modica, R; Faggiano, A; Colao, A.
abstract

INTRODUCTION: Glucagon-like peptide 1 (GLP-1) is an intestinal hormone secreted after the ingestion of various nutrients. The main role of GLP-1 is to stimulate insulin secretion in a glucose-dependent manner. However, the expression of GLP-1 receptor was found to be expressed in a variety of tissues beyond pancreas such as lung, stomach, intestine, kidney, heart and brain. Beyond pancreas, a beneficial effect of GLP-1 on body weight reduction has been shown, suggesting its role for the treatment of obesity. In addition, GLP-1 has been demonstrated to reduce cardiovascular risk factors and to have a direct cardioprotective effect, fostering heart recovery after ischemic injury. Further, data from both experimental animal models and human studies have shown beneficial effect of GLP-1 on bone metabolism, either directly or indirectly on bone cells. MATERIALS AND METHODS: We review here the recent findings of the extra-pancreatic effects of GLP-1 focusing on both basic and clinical studies, thus opening future perspectives to the use of GLP-1 analogs for the treatment of disease beyond type 2 diabetes. CONCLUSION: Finally, the GLP-1 has been demonstrated to have a beneficial effect on both vascular, degenerative diseases of central nervous system and psoriasis.


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 - 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 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 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; 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]
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]
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


2012 - Erectile dysfunction is more common in young to middle-aged HIV-infected men than in HIV-uninfected men. [Articolo su rivista]
Zona, Stefano; Guaraldi, Giovanni; Luzi, Kety; M., Beggi; Santi, Daniele; Stentarelli, Chiara; Madeo, Bruno; Rochira, Vincenzo
abstract

Introduction. The penis has been compared to a barometer of endothelial health, erectile dysfunction (ED) being an early sign of endothelial dysfunction. Aim. The aim of the study was to investigate the extent of the association between ED and endothelial dysfunction in patients with human immunodeficiency virus (HIV) infection on antiretroviral therapy. Methods. In this observational cross-sectional study, we evaluated the prevalence and factors associated with ED in a cohort of 133 HIV-infected men. Main Outcome Measures. The International Index of Erectile Function, ultrasound assessment of brachial artery flow mediated dilatation (FMD), and multi-slice computed tomography for coronary artery calcifications (CAC) as surrogates of endothelial dysfunction, the Adult Treatment Panel III criteria to diagnose metabolic syndrome (MS), plasma total testosterone (hypogonadism), and a visual analogue scale (VAS) of aesthetic satisfaction of the face and of the body (psychological distress associated with lipodystrophy). Results. Thirty-nine (29.32%) patients had mild ED, 14 (10.52%) patients had moderate ED, and 26 (19.55%) patients had severe ED. Prevalence of ED ranged from 45% to 65%, respectively, in patients less than 40 and more than 60 years old. MS was present in 20 (25%) patients with ED and 13 (24%) patients without ED (P value = 0.87). Prevalence of ED neither appeared to be associated with MS as a single clinical pathological entity nor with the numbers of its diagnostic components. FMD < 7% was present in 25 (32%) patients with ED and 18 (33%) patients without ED (P value = 0.83), and CAC > 100 was present in 8 (10%) patients with ED and 5 (9%) patients without ED (P value = 0.87). A stepwise multivariable logistic regression analysis was used to find predictors of ED. Independent predictors were VAS face (odds ratio [OR] = 0.85, 95% confidence interval [CI] 0.73–0.99, P = 0.049) and age per 10 years of increase (OR = 1.73, 95% CI 1.02–2.94, P = 0.04). Conclusions. Age constituted the most important risk factor for ED, which was related to aesthetic dissatisfaction of the face leading to negative body image perception.


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


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 - Pathophysiology of estrogen action in men. [Capitolo/Saggio]
Rochira, Vincenzo; Santi, Daniele; Carani, Cesare
abstract

The chapter of this book deals with the physiological actions of estrogens on several organs and tissues in men. In addition, the effects of disturbances in estrogen action are described and reviewed.


2012 - Prevalence of Erectile Dysfunction Is Greater in Young Middle-Aged HIV-Infected Men Than in HIV-Uninfected Men [Abstract in Rivista]
Madeo, Bruno; Santi, Daniele; Zona, Stefano; Guaraldi, Giovanni; A., Granata; Carani, Cesare; Rochira, Vincenzo
abstract

Erectile dysfunction is more frequent in men living with HIV than in HIV-uninfected men. Erectile function is impaired in men with HIV even at a young age.


2012 - Prevalence of Erectile Dysfunction is greater in young middle-aged HIV-infected Men than in HIV-uninfected Men [Abstract in Rivista]
Madeo, Bruno; Santi, Daniele; Zona, Stefano; Guaraldi, Giovanni; Rochira, Vincenzo
abstract

The study investigates the prevalence of erectile dysfunction in men with HIV infection in comparison with normal healthy men. Erectile dysfunction seems to be more prevalent in HIV and seems to occur at a younger age.


2012 - Report: a “silent” FSH-secreting adenoma [Abstract in Rivista]
Santi, Daniele; A. R. M., Granata; Rochira, Vincenzo; Simoni, Manuela; Carani, Cesare
abstract

Case-Report on FSH-secreting pituitary adenoma


2012 - Steroidogenesis in men with Klinefelter Syndrome (KS). [Abstract in Rivista]
Belli, Serena; E., Dall’Olio; Santi, Daniele; Rochira, Vincenzo; A. R., Granata; Carani, Cesare; Simoni, Manuela
abstract

Basal and stimulated sex steroid measurements with liquid mass spectrometry in men with Klinefelter Syndrome


2011 - Bone mineral density and sex hormones in HIV-infected men [Abstract in Rivista]
Madeo, Bruno; Santi, Daniele; Orlando, Gabriella; Guaraldi, Giovanni; Fabio, Vescini; Simoni, Manuela; Carani, Cesare; Rochira, Vincenzo
abstract

In men with HIV bone mineral density depends on estrogens and not from testosterone as in non HIV-infected men.


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 - 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


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; 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]
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