Effect of antioxidants on semen parameters in men with oligo-astheno-teratozoospermia: a network meta-analysis.

BACKGROUND: Although antioxidants are largely used in subfertile men with oligo-astheno-teratozoospermia (OAT), the choice among different molecules is challenged by the lack of comparative head-to-head studies. The network meta-analysis (NMA) can overcome limitations of pairwise meta-analyses, since it incorporates direct and indirect evidence into a single model generating an effectiveness hierarchy. OBJECTIVE: To assess with a NMA the effects of antioxidants in improving seminal parameters in idiopathic OAT. MATERIALS AND METHODS: PubMed, Scopus, Cinahl, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing any antioxidant treatment to each other or placebo in men with at least one idiopathic seminal abnormality. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). RESULTS: 29 RCTs provided information on 2045 men (mean age: 33.5 years) with idiopathic OAT and 19 antioxidant preparations. Compared to placebo, l-carnitine, especially in combination with l-acetyl-carnitine (LAC), had the highest SUCRA for sperm concentration, progressive motility, and morphology. Folate was the only other compound effective on sperm concentration. Vitamin E+selenium or zinc had the highest SUCRA for total motility. A contribution on progressive motility was revealed for pentoxifylline and vitamin E+CoQ10.

Testosterone therapy in diabetes and pre-diabetes.

BACKGROUND: Type 2 diabetes mellitus and pre-diabetes are associated with reduced circulating testosterone levels. However, the role of testosterone replacement therapy in these patients is still conflicting. OBJECTIVES: To summarize and critically analyze available data on the possible effect of testosterone administration in men with glucose abnormalities. MATERIALS AND METHODS: A comprehensive systematic review was performed. When available, meta-analytic data were preferred. To better analyze the relationship between testosterone and the pre-diabetes condition, a systematic analysis was performed and the data obtained with the latter search were used for a meta-analytic approach. Finally, clinical data derived from a consecutive series of 4682 patients seeking medical care for sexual dysfunction at the University of Florence were also considered. RESULTS: Patients with impaired fasting glucose were characterized by a 3 nmol/L lower level of total testosterone when compared to controls. Similarly, impaired fasting glucose was associated with a 1.8-fold increased risk of hypogonadism, when compared to subjects with normal glucose levels. Waist circumference and body mass index resulted as being the best predictors of reduced total testosterone levels. Secondary hypogonadism was two times higher in subjects with impaired fasting glucose when compared to rates observed in the general population. Testosterone replacement therapy was able to improve body composition, insulin resistance, and glucose profile both in impaired fasting glucose and type 2 diabetes mellitus whereas its role on body weight, lipid profile, and sexual function was less evident. DISCUSSION AND CONCLUSION: Weight loss and physical activities are able to improve both metabolic profile and testosterone levels. The combined approach of testosterone replacement therapy and lifestyle modifications could be suggested in symptomatic hypogonadal men to better motivate patients to perform physical activity which can eventually result in weight loss as well as metabolic profile and sexual function improvement. Whether or not these approaches can prevent the development of type 2 diabetes mellitus from pre-clinical conditions requires more studies.

Oncological diseases in Klinefelter Syndrome: an overview.

Epidemiological studies have highlighted a higher incidence of morbidity and mortality among individuals with Klinefelter's Syndrome (KS), however, the relative impact of oncological diseases on KS subjects is still uncertain. While some malignancies (e.g., hematological and lung cancers) may show an increased prevalence in the KS population, only a few rare tumors (i.e., extragonadal germ cell tumors [GCTs] and male breast cancer [MBC]) seem to follow this trend. Additionally, hormonal and genetic determinants may be involved in the pathogenesis of neoplasia in KS, even if subjects affected by this syndrome generally show lower incidence of prostate cancer along with lower disease-specific mortality despite testosterone replacement therapy (TRT). This review deals with the pathophysiological and clinical aspects of neoplastic diseases occurring in KS.

Low-intensity shockwave treatment (LISWT) improves penile rigidity in eugonadal subjects with erectile dysfunction: a pilot study.

BACKGROUND: Since low-intensity shockwave treatment (LISWT) has putative effects on penile hemodynamics remodeling, the aim of this study was to evaluate any improvement of penile vascular flows after LISWT treatment in patients with erectile dysfunction (ED) and poor response to PDE5i. METHODS: Twenty-one eugonadal patients with different ED severity underwent 6 weekly LISWT sessions (1500-4000 pulses) after 2 weeks withdrawal from PDE5i assumption. Once daily Tadalafil (2.5 mg daily) was reintroduced 4 weeks apart from LISWT termination and patients were evaluated at 1, 2 and 6 months follow-up (T1, T2, T6) by the International Index of Erectile Function-15 items questionnaire (IIEF-15) erectile function (EF) domain, Erection Hardness Score (EHS) and Global Assessment Questionnaires (GAQ). Basal Penile Color-Doppler Ultrasound parameters in the flaccid state (B-PCDU) were evaluated before, during and after interventional protocol. RESULTS: Mean EHS score improved in 35% of patients at T1, and in up to 50% of patients at T2 and T6 follow-up visits (P<0.05). We found 25% improvement of EF scores at T1 session, 43.75% at T2 and 62.5% at T6, respectively (P<0.05). No statistically significant differences in flow parameters, EF-domain and testosterone levels were found when baseline and last observation carried forward (LOCF) parameters were compared. The GAQ questionnaire scored higher satisfaction rates either at the end of the treatment (100%), or at LOCF (92.5%). CONCLUSIONS: Despite the study limitations with respect to B-PCDU in this setting, our results confirm a trend toward improvement of erectile questionnaire scores after LISWT with higher overall satisfaction rates among patients with ED. We conclude that LISWT may be an effective option in some difficult-to-treat patients with ED by improving the erectile response to PDE5i.

The Prevalence of Hypogonadism and the Effectiveness of Androgen Administration on Body Composition in HIV-Infected Men: A Meta-Analysis.

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.

Outcome of Sars-COV-2-related thyrotoxicosis in survivors of Covid-19: a prospective study.

PURPOSE: To evaluate the post- coronavirus disease-19 (COVID-19) outcome of thyroid function in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyrotoxicosis. METHODS: This was a single-center prospective study involving 29 patients (11 females, 18 males; median age 64 years, range: 43-85) with thyrotoxicosis diagnosed after hospitalization for COVID-19 and then followed-up for a median period of 90 days (range: 30-120) after hospital discharge. At follow-up, patients were evaluated for serum thyrotropin (TSH), free-thyroxine (FT4), free-triiodiothyronine (FT3), TSH receptor antibodies (TRAb), thyroglobulin antibodies (TgAb), thyroperoxidase antibodies (TPOAb) and ultrasonographic thyroid structure. RESULTS: After recovery of COVID-19, serum TSH values significantly increased (P < 0.001) and FT4 values significantly decreased (P = 0.001), without significant change in serum FT3 (P = 0.572). At follow-up, 28 subjects (96.6%) became euthyroid whereas overt hypothyroidism developed in one case. At the ultrasound evaluation of thyroid gland, hypoecogenicity was found in 10 patients (34.5%) and in these cases serum TSH values tended to be higher than those without thyroid hypoecogenity (P = 0.066). All subjects resulted to be negative for TgAb, TPOAb and TRAb. CONCLUSION: In a short-term follow-up, thyroid function spontaneously normalized in most subjects with SARS-CoV-2-related thyrotoxicosis. However, thyroid hypoecogenicity was found in a remarkable number of them and future longer-term studies are needed to clarify whether this ultrasonographic alteration may predispose to develop late-onset thyroid dysfunction.

Erectile Dysfunction and Decreased Libido in Klinefelter Syndrome: A Prevalence Meta-Analysis and Meta-Regression Study.

BACKGROUND: Only few studies have assessed sexual dysfunction in men with Klinefelter syndrome (KS). AIM: To define pooled prevalence estimates and correlates of erectile dysfunction (ED) and decreased libido (DL) in KS. METHODS: A thorough search of Medline, Embase and Web of Science was performed to identify suitable studies. Quality of the articles was scored using the Assessment Tool for Prevalence Studies. Data were combined using random effect models and the between-studies heterogeneity was assessed by the Cochrane's Q and I2. The sources of heterogeneity were investigated by meta-regression and sub-group analyses. Funnel plot, Begg's rank correlation and trim-and-fill test were used to assess publication bias. MAIN OUTCOME MEASURE: The pooled prevalence of ED and DL in KS as well as 95% confidence intervals (CIs) were estimated from the proportion of cases of sexual dysfunction and the sample size. Variables that could affect the estimates were identified by linear meta-regression models. RESULTS: Sixteen studies included collectively gave information about ED and DL in 482 and 368 KS men, respectively, resulting in a pooled prevalence of 28% (95% CI: 19%-36%) for ED and 51% (95% CI: 36%-66%) for DL, with a large heterogeneity. The trim-and-fill adjustment for publication bias produced a negligible effect on the pooled estimates. At the meta-regression analyses, a higher prevalence of ED was significantly associated with an older age but not with lower testosterone levels. In series with a mean age >35 years, the ED prevalence estimate increased up to 38% (95% CI: 31%-44%) with no heterogeneity (I2=0.0%, P=0.6). On the contrary, the prevalence of DL increased significantly as testosterone levels decreased, without a significant relationship with age. CLINICAL IMPLICATIONS: While DL would largely reflect an androgen deficiency, in older men with KS, erectile function should be assessed irrespective of testosterone levels. STRENGTH & LIMITATIONS: This is the first meta-analysis defining pooled prevalence estimates and correlates of ED and DL in KS. Nevertheless, caution is required when interpreting results, due to the high risk of bias in many studies, as well as the dearth of data about psychosocial and/or psychosexological variables and age at the diagnosis. CONCLUSIONS: ED and DL represent common clinical complaints in KS. While the prevalence of ED would increase with age, DL gets more common as serum testosterone decreases. Further studies are warranted to elucidate the pathogenetic mechanism(s) underlying the age-dependent increase in the prevalence of ED, apparently unrelated to the androgenic status. A Barbonetti, S D'Andrea, W Vena, et al. Erectile Dysfunction and Decreased Libido in Klinefelter Syndrome: A Prevalence Meta-Analysis and Meta-Regression Study. J Sex Med 2021;18:1054-1064.

Diabetes is most important cause for mortality in COVID-19 hospitalized patients: Systematic review and meta-analysis.

The presence of SARS-CoV-2 was officially documented in Europe at the end of February 2020. Despite many observations, the real impact of COVID-19 in the European Union (EU), its underlying factors and their contribution to mortality and morbidity outcomes were never systematically investigated. The aim of the present work is to provide an overview and a meta-analysis of main predictors and of country differences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-associated mortality rate (MR) in hospitalized patients. Out of 3714 retrieved articles, 87 studies were considered, including 35,486 patients (mean age 60.9 ± 8.2 years) and 5867 deaths. After adjustment for confounders, diabetes mellitus was the best predictors of MR in an age- and sex-dependent manner, followed by chronic pulmonary obstructive diseases and malignancies. In both the US and Europe, MR was higher than that reported in Asia (25[20;29] % and 20[17;23] % vs. 13[10;17]%; both p < 0.02). Among clinical parameters, dyspnea, fatigue and myalgia, along with respiratory rate, emerged as the best predictors of MR. Finally, reduced lymphocyte and platelet count, along with increased D-dimer levels, all significantly contributed to increased mortality. The optimization of glucose profile along with an adequate thrombotic complications preventive strategy must become routine practice in diseased SARS-CoV-2 infected patients.

Procoagulant Imbalance in Klinefelter Syndrome Assessed by Thrombin Generation Assay and Whole-Blood Thromboelastometry.

CONTEXT: Klinefelter syndrome (KS) is a condition at increased risk of thrombosis compared to 46,XY men. OBJECTIVE: This work aimed to investigate the coagulation balance of KS patients by thrombin generation assay (TGA) and thromboelastometry. METHODS: An observational, cross-sectional study was conducted at 3 tertiary endocrinological centers in Milan, Italy. Fifty-eight KS patients and 58 age-matched healthy controls were included. Anticoagulant or antiplatelet therapy and known coagulation disorders were exclusion criteria. TGA was performed in platelet-poor plasma (PPP) and platelet-rich plasma (PRP). Whole-blood thromboelastometry and activities of coagulation factors were assessed. Endogenous thrombin potential (ETP), the area under the thrombin generation curve, assessed with and without thrombomodulin (ETP-TM+ and ETP-TM-), and their ratio (ETP ratio), were considered as indexes of procoagulant imbalance. RESULTS: Patients with KS displayed higher PPP-ETP-TM+ (mean 1528 vs 0.1315 nM × min; P < .001), PPP-ETP ratio (0.78 vs 0.0.70; P < .001), factor (F)VIII (135% vs 0.107%; P = .001), fibrinogen (283 vs 0.241 mg/dL; P < .001), and FVIII/protein C ratio (1.21 vs 0.1.06; P < .05) compared to controls. Protein C was comparable in the 2 groups. Similar results were observed in PRP. The ETP ratio was positively associated with FVIII (ρ = 0.538, P < .001) in KS. Thromboelastometry parameters confirmed evidence of hypercoagulability in KS. CONCLUSION: Patients with KS display a procoagulant imbalance expressed by increased thrombin generation both in PPP and PRP, which is at least in part explained by increased FVIII levels. The procoagulant imbalance, which was confirmed by thromboelastometry, may be responsible for the thrombotic events observed in these patients. Further investigation on the benefit/risk ratio of antithrombotic prophylaxis is warranted.

Prevalence and determinants of radiological vertebral fractures in patients with Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (KS) may induce skeletal fragility, but the studies so far published on this topic were mainly focused on the evaluation of bone mineral density (BMD) and bone microstructure, whereas data on fracture risk are still lacking. OBJECTIVE: To evaluate the prevalence and determinants of vertebral fractures (VFs), that is, the hallmark of osteoporosis, in subjects with KS. MATERIALS AND METHODS: Eighty-seven patients with KS (median age 41 years, range 18-64) were consecutively evaluated for radiological VFs (by quantitative morphometry) and lumbar spine and femoral neck BMD (by DXA). Fifty-five patients with KS were also evaluated by the fracture risk assessment (FRAX) tool. RESULTS: Low BMD was found in 22/87 (25.3%) patients [12 with osteopenia, three with osteoporosis and seven with "low BMD per age" (subject < 50 years with Z-score ≤-2.0 SD)] and VFs in 13/87 (14.9%) patients. In patients with VFs, the median spine deformity index was 2 (range 1-9). Prevalence of VFs was similar between healthy and low-BMD patients (15.9% vs 13.6%; P = .80). Noteworthy, patients with VFs had significantly higher age at diagnosis of KS as compared to patients who did not fracture (P = .039), without significant differences in age at the time of observation (P = .162), body mass index (P = .234), testosterone replacement therapy (P = .432), duration of testosterone therapy (P = .409), vitamin D therapy (P = 681), and serum testosterone levels (P = .338). Moreover, patients with VFs were more likely to complain back pain in comparison with those without VFs (33.3% vs 7.4%; P = .047). In 55 cases evaluated by the FRAX® tool, no significant differences in 10-year risk of major fracture (P = .270) and hip fracture (P = .860) were found between fractured and non-fractured patients. CONCLUSIONS: This study provides first evidence that KS may be associated with risk of VFs in close relationship with delay in disease diagnosis but independently of BMD values and serum testosterone levels or testosterone therapy.

Sperm recovery and ICSI outcomes in men with non-obstructive azoospermia: a systematic review and meta-analysis.

BACKGROUND: Factor affecting sperm retrieval rate (SRR) or pregnancy rates (PR) after testicular sperm extraction (TESE) in patients with non-obstructive azoospermia (NOA) have not been systematically evaluated. In addition, although micro-TESE (mTESE) has been advocated as the gold standard for sperm retrieval in men with NOA, its superiority over conventional TESE (cTESE) remains conflicting. OBJECTIVE AND RATIONALE: The objective was to perform a meta-analysis of the currently available studies comparing the techniques of sperm retrieval and to identify clinical and biochemical factors predicting SRR in men with NOA. In addition, PRs and live birth rates (LBRs), as derived from subjects with NOA post-ICSI, were also analysed as secondary outcomes. SEARCH METHODS: An extensive Medline, Embase and Cochrane search was performed. All trials reporting SRR derived from cTESE or mTESE in patients with NOA and their specific determinants were included. Data derived from genetic causes of NOA or testicular sperm aspiration were excluded. OUTCOMES: Out of 1236 studies, 117 studies met the inclusion criteria for this study, enrolling 21 404 patients with a mean age (± SD) of 35.0 ± 2.7 years. cTESE and mTESE were used in 56 and 43 studies, respectively. In addition, 10 studies used a mixed approach and 8 studies compared cTESE with mTESE approach. Overall, a SRR per TESE procedure of 47[45;49]% (mean percentage [95% CI]) was found. No differences were observed when mTESE was compared to cTESE (46[43;49]% for cTESE versus 46[42;49]% for mTESE). Meta-regression analysis demonstrated that SRR per cycle was independent of age and hormonal parameters at enrolment. However, the SRR increased as a function of testis volume. In particular, by applying ROC curve analysis, a mean testis volume higher than 12.5 ml predicted SRR >60% with an accuracy of 86.2% ± 0.01. In addition, SRR decreased as a function of the number of Klinefelter's syndrome cases included (S = -0.02[-0.04;-0.01]; P < 0.01. I = 0.12[-0.05;0.29]; P = 0.16). Information on fertility outcomes after ICSI was available in 42 studies. Overall, a total of 1096 biochemical pregnancies were reported (cumulative PR = 29[25;32]% per ICSI cycle). A similar rate was observed when LBR was analysed (569 live births with a cumulative LBR = 24[20;28]% per ICSI cycle). No influence of male and female age, mean testis volume or hormonal parameters on both PR and LBR per ICSI cycle was observed. Finally, a higher PR per ICSI cycle was observed when the use of fresh sperm was compared to cryopreserved sperm (PR = 35[30;40]%, versus 20[13;29]% respectively): however, this result was not confirmed when cumulative LBR per ICSI cycle was analysed (LBR = 30[20;41]% for fresh versus 20[12;31]% for cryopreserved sperm). WIDER IMPLICATIONS: This analysis shows that cTESE/mTESE in subjects with NOA results in SRRs of up to 50%, with no differences when cTESE was compared to mTESE. Retrieved sperms resulted in a LBR of up to 28% ICSI cycle. Although no difference between techniques was found, to conclusively clarify if one technique is superior to the other, there is a need for a sufficiently powered and well-designed randomized controlled trial to compare mTESE to cTESE in men with NOA.

Levothyroxine supplementation on assisted reproduction technology (ART) outcomes in women with subtle hypothyroidism: a retrospective study.

The need for treating subclinical hypothyroidism (SCH) in women undergoing assisted reproduction technology (ART) is under debate. Moreover, it is known that controlled ovarian hyperstimulation (COH) protocols may impair the thyroidal axis. Therefore, we evaluated if levothyroxine (L-T4) supplementation in SCH women before undergoing ART positively affects the main reproductive outcomes. We retrospectively analyzed in vitro fertilization (IVF) data of 4147 women submitted to 6545 cycles in a tertiary care IVF Center (January 2009-December 2014). L-T4 (1.4-2.0 mcg/kg) treatment was offered to all women with a pre-cycle TSH >2.5 mIU/L before starting COH and main ART outcomes were compared in euthyroid and L-T4-treated women undergoing ART. Among 4147 women, 1074 (26%) were affected by SCH and were treated with L-T4 before COH was started. No statistically significant differences among L-T4-treated and euthyroid women group were observed regarding pregnancy rate, respectively, per cycle (27.67% vs 26.37%; p = .314) and per embryo transfer (30.13% vs 29.17%; p = .489), live birth rate, respectively, per cycle (21.58% vs 20.38%; p = .304) and per embryo transfer (23.49 vs 22.54%; p = .449) and the rest of primary and secondary efficacy endpoints. Early L-T4 treatment for infertile women with a subtle thyroid dysfunction may mitigate and protect from the negative effects of SCH in the setting of ART, and may preventively overcome also the negative impact of COH on thyroidal axis.

Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH).

OBJECTIVE: Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. DESIGN: Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. METHODS: We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). RESULTS: 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann's syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. CONCLUSIONS: Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.

Effect of superoxide dismutase supplementation on sperm DNA fragmentation.

BACKGROUND: antioxidants supplementation improves sperm quality, but few trials have analyzed the effects on sperm DNA fragmentation (SDF). This study compares the effectiveness of SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol in reducing SDF with other antioxidants without SOD, hydroxytyrosol, and carnosol. MATERIALS AND METHODS: men with high SDF at baseline were selected in our clinical database. The patients taken into account had a 2-month control. SDF was measured by Sperm Chromatin Dispersion test (SCD). Untreated men were used as a control group. The remaining subjects received some oral antioxidant supplements (12 different combinations of both hydrophilic and lipophilic antioxidants), with some of them receiving nutritional support with a SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol. RESULTS: 118 men were selected for a retrospective study. Mean age 39.3 ± 5.4 years. Fifteen had no treatment, 55 were treated with a SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol, and 48 took some antioxidant supplements for 2 months. Clinically, variations of at least 10% in baseline values of classic semen parameters and sperm DNA fragmentation were taken into consideration. Classic seminal parameters did not vary significantly in the three groups, with the exception of viability (p = 0.001). We assessed which of the active substances (no. 19) in different formulations were associated with variations in SDF. In the multivariable analysis of the 7 active substances that passed the univariable analysis, only the SOD molecule appeared to be linked to an improvement in SDF (< 0.0001). In detail, only one patient in the control group showed a spontaneous improvement in SDF (6%), compared to 16/48 (33%) of those taking various oral antioxidant supplements, and 31/55 (56%) of those taking a SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol. CONCLUSIONS: SOD-based antioxidant supplementation plus hydroxytyrosol and carnosol seems to provide a better chance of improving sperm DNA integrity than other classical antioxidant molecules.

Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis.

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.

Hypersexuality, Paraphilic Behaviors, and Gender Dysphoria in Individuals with Klinefelter's Syndrome.

INTRODUCTION: An increased risk of autistic traits in Klinefelter syndrome (KS) has been reported. In addition, some studies have shown an increased incidence of gender dysphoria (GD) and paraphilia in autism spectrum disorder. AIM: The aim of this study was to evaluate the presence of (i) paraphilic fantasies and behaviors; and (ii) GD symptomatology in KS. METHODS AND MAIN OUTCOMES MEASURES: A sample of 46 KS individuals and 43 healthy male controls (HC) were evaluated. Subjects were studied by means of several psychometric tests, such as Autism Spectrum Quotient (AQ) and Reading the Mind in the Eyes Revised (RME) to measure autistic traits, Gender Identity/GD questionnaire (GIDYQ-AA), and Sexual Addiction Screening Test (SAST). In addition, body uneasiness psychopathological symptoms were assessed using Symptom Checklist 90 Revised (SCL-90-R). The presence and frequency of any paraphilic fantasy and behavior was assessed by means of a clinical interview based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria. Finally, all individuals included were assessed by Wechsler Adult Intelligence Scale-Revised to evaluate intelligence quotient (IQ). Data from a subsample of a previous published series of male to female GD individuals, with the battery of psychological measures useful to provide a psychopathological explanation of GD in KS population available, was also considered. RESULTS: When compared with HC, KS reported significantly lower total, verbal and performance IQ scores and higher SCL-90 obsession-compulsive symptoms (all P < 0.001). In line with previously reported findings, KS showed higher autistic traits according with both RME and AQ tests (P < 0.001). With respect to sexuality, KS showed a significant higher frequency of voyeuristic fantasies during masturbation (52.2% vs. 25.6%) and higher SAST scores (P = 0.012). A mediation role of obsessive symptoms on the relationship between Klinefelter and SAST was confirmed (unstandardized estimate b = 2.75, standard error = 0.43 P < 0.001). Finally, KS individuals showed significantly higher gender dysphoric symptoms than HC (P = 0.004), which were mediated by the presence of autistic traits (Sobel's test; P < 0.05). CONCLUSIONS: KS is associated with hypersexuality, paraphilic behaviors, and GD, which were mediated by obsessive-compulsive and autistic traits.

Gonadal failure is associated with visceral adiposity in myotonic dystrophies.

BACKGROUND: Hypogonadism occurs in myotonic dystrophies type 1 (MD1) and type 2 (MD2). Sertoli and Leydig cell secretions, including insulin-like peptide-3 (INSL3), anti-Müllerian hormone (AMH) and inhibin B, were evaluated in male patients with MD. DESIGN: Academic settings. Forty-four male patients with MD [31 MD1, 13 MD2, aged 59 (50-64) years, median (interquartile range)], age-, sex- and BMI-matched non-MD hypogonadal patients (n = 14) and healthy controls (n = 32). Serum FSH, LH, inhibin B, AMH, testosterone (T) and INSL3 were measured; fat and muscle masses were evaluated by DEXA. RESULTS: Overt primary hypogonadism occurred in 29% of patients with MD1 and 46% of patients with MD2. Considering subclinical forms, the prevalence increased to 69% of MD1 and 100% of MD2. A half of patients with MD experienced symptoms. INSL3 levels were unaffected in most patients with MD. By contrast, AMH and inhibin B were reduced in most patients with MD and unrelated to age. Patients with MD showed increased body and visceral fat. Free T levels were negatively predicted by fat mass, and AMH and FSH levels were negatively correlated with waist/hip ratio and fat mass. AMH, inhibin B and FSH levels positively correlated with muscle strength and muscle mass. CONCLUSIONS: AMH and inhibin B secretion failures are common in male patients with MD and are more severe than Leydig cell hormones impairment. AMH and inhibin B measurements might provide clinical utility in evaluating fertility in patients with MD. Serum T, AMH and inhibin B productions are negatively influenced by increased fat mass, while AMH and inhibin B might be markers of muscle impairment.

US-elastography in the differential diagnosis of benign and malignant thyroid nodules.

BACKGROUND: Ultrasound (US)-elastography is a newly developed imaging technique for the reconstruction of tissue stiffness by measuring the degree of tissue's deformation in response to the application of an external force. This technique has previously been shown to be useful in the differential diagnosis between benign and malignant tumors. METHODS: The objective of this study was to assess the diagnostic accuracy of US-elastography in the differential diagnosis of thyroid cancer, using the cytologic/histopathologic analysis as the reference standard. A total of 67 consecutive patients with thyroid nodules who were referred to the Thyroid Unit at the Policlinico MultiMedica were enrolled in this prospective study between January and December 2006. Eighty-six nodules in these patients were examined by US B-mode, US color-power-Doppler, and US-elastography. Nodules were subjected to fine-needle aspiration biopsy and patients with a reading of malignant or indeterminate had thyroid surgery. The final diagnosis was based on the cytology reading in those who did not have surgery and the histopathology reading in those who had surgery. US-elastography scores were based on four classes of tissue stiffness (class 1 for soft nodules; class 2 and 3 for nodules with an intermediate degree of stiffness; class 4 for anelastic lesions). RESULTS: Seventeen nodules were malignant and 69 were benign. Sensitivity and specificity of the US-elastography for thyroid cancer diagnosis were 94.1% (16/17) and 81% (56/69), respectively. The positive and negative predictive values were 55.2% (16/29) and 98.2% (56/57), respectively. The accuracy of the technique was 83.7%. CONCLUSION: US-elastography is a promising technique that, combined with other US modalities, is easy and rapid to perform and can help to identify thyroid nodules that are likely to be malignant. An important limitation is probably lack of sensitivity for follicular thyroid carcinoma.

Psychobiological correlates of delayed ejaculation in male patients with sexual dysfunctions.

The pathogenesis of delayed ejaculation (DE) is rather unknown, though the contribution of various psychological, marital, hormonal, and neurological factors has been advocated. In this study we systematically investigated the relative relevance of the aforementioned factors in 1,632 men who were seeking medical help for sexual dysfunction. The severity of DE was classified according to Kaplan criteria. Mild and moderate forms of DE (MMDE) recognized different risk factors than the most severe ones (anejaculation or severe DE [ASDE]). ASDE was essentially coupled with the presence of neurological diseases or with the use of serotoninergic drugs. Serotoninergic drugs also significantly increase (by at least 10-fold) the risk for MMDE, which, however, was also coupled with other relational factors (eg, partner's impaired climax, patient's hypoactive sexual desire [HSD]) or intrapsychic factors (eg, stress at work). At multiple regression analysis, some organic pathological conditions (such as psychiatric disorders and hypogonadism) were also associated with MMDE. In particular, hypogonadism retained significance for DE even after adjustment for HSD (adjusted odds ratio = 2.08 [1.11-3.89]; P < .05), suggesting other effects of testosterone deficiency on the ejaculatory reflex besides reduced libido. In conclusion, the present study demonstrates that multiple psychobiological determinants are associated with DE, a still obscure condition that substantially impairs psychosexual equilibrium of the couple.