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.

Men with spinal cord injury have a smaller prostate volume than age-matched able-bodied men: a meta-analysis of case-control studies.

STUDY DESIGN: Meta-analysis OBJECTIVES: Denervation and androgen deficiency, peculiar to individuals with chronic spinal cord injury (SCI), could hinder, to some extent, both prostate growth and activity. To comprehensively assess the relationship between SCI and prostate volume, we carried out a meta-analysis of the available case-control studies. METHODS: A thorough search of MEDLINE, Scopus and Web of Science was carried out to identify studies comparing prostate volume in men with and without SCI. Quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS). Mean differences (MDs) in prostate volume were combined using a random effect model. Funnel plot was used to assess publication bias. RESULTS: Four studies met the inclusion criteria and provided information on 278 men with SCI and 1385 able-bodied controls. The overall difference in prostate volume between the two groups reached the statistical significance (pooled MD: -14.85 ml, 95% CI: -27.10 to -2.61, p = 0.02). In a subgroup analysis including only the studies with the highest NOS score, the pooled MD remained significant (pooled MD: -18.56, 95% CI: -33.14 to -3.99, p = 0.01). The shape of funnel plot did not allow to rule out a possible publication bias. CONCLUSIONS: This meta-analysis suggests that in men with SCI, prostate volume tends to be smaller than in age-matched able-bodied men. Longitudinal studies of men with long-lasting SCI in advanced age are warranted to clarify whether this condition is associated with a lower risk of age-related prostate proliferative diseases.

Crocetin Mitigates Irradiation Injury in an In Vitro Model of the Pubertal Testis: Focus on Biological Effects and Molecular Mechanisms.

Infertility is a potential side effect of radiotherapy and significantly affects the quality of life for adolescent cancer survivors. Very few studies have addressed in pubertal models the mechanistic events that could be targeted to provide protection from gonadotoxicity and data on potential radioprotective treatments in this peculiar period of life are elusive. In this study, we utilized an in vitro model of the mouse pubertal testis to investigate the efficacy of crocetin to counteract ionizing radiation (IR)-induced injury and potential underlying mechanisms. Present experiments provide evidence that exposure of testis fragments from pubertal mice to 2 Gy X-rays induced extensive structural and cellular damage associated with overexpression of PARP1, PCNA, SOD2 and HuR and decreased levels of SIRT1 and catalase. A twenty-four hr exposure to 50 µM crocetin pre- and post-IR significantly reduced testis injury and modulated the response to DNA damage and oxidative stress. Nevertheless, crocetin treatment did not counteract the radiation-induced changes in the expression of SIRT1, p62 and LC3II. These results increase the knowledge of mechanisms underlying radiation damage in pubertal testis and establish the use of crocetin as a fertoprotective agent against IR deleterious effects in pubertal period.

Polymorphic Cytosine-Adenine-Guanine Repeat Length of Androgen Receptor Gene and Gender Incongruence in Trans Women: A Systematic Review and Meta-Analysis of Case-Control Studies.

INTRODUCTION: It has been hypothesized that gender incongruence in transgender women could result from an antenatal impaired androgen activity on the developing brain. As the length of polymorphic cytosine-adenine-guanine (CAG) repeat sequences in the androgen receptor (AR) gene is inversely correlated with AR transcriptional activity, some studies explored a possible association between long CAG repeats and gender incongruence in trangender women. Yet results remain inconclusive. AIM: To systematically evaluate whether a difference exists in the length of AR CAG repeat sequences between trans women and men without gender incongruence. METHODS: A thorough search of Medline, Scopus, Cochrane Library, Web of Science, and CINAHL databases was carried out to identify suitable case-control studies. Methodological quality of the included articles was assessed using the Newcastle-Ottawa Scale. In the absence of between-studies heterogeneity, as assessed by the Cochrane's Q and I2 tests, standardized mean differences (SMDs) in the length of AR CAG repeats were combined using a fixed effect model. Funnel plot and trim-and-fill analysis were used to assess publication bias. MAIN OUTCOME MEASURE: The association of gender incongruence in transgender women with longer length of AR CAG repeat sequences was evaluated by calculating pooled standardized mean difference with 95% confidence interval (CI). RESULTS: 5 studies included in the quantitative analysis collectively provided information on 795 trans women and 1,355 control men. At the overall estimate, the MtF group exhibited a significantly longer length of AR CAG repeat sequences (pooled standardized mean difference: 0.13, 95% CI: 0.04 to 0.22; P = 0.005; I2 = 0%, Pfor heterogeneity = 0.51). Sensitivity analysis demonstrated the high stability of the result. Funnel plot revealed a possible publication bias, and the trim-and-fill test detected 2 putative missing studies. Nevertheless, the significant association persisted even when pooled estimate was adjusted for publication bias. CLINICAL IMPLICATIONS: These findings could suggest a contribution of a genetically mediated impairment in androgen signaling in development of gender incongruence for transgender women. STRENGTH & LIMITATIONS: This is the first meta-analysis exploring the relationship between AR CAG repeat polymorphism and gender incongruence. However, interactions with other functional genetic variants were not explored, and caution should be exercised when generalizing these results because of the possible variability in the distribution of CAG repeats among different populations and ethnic groups. CONCLUSION: Trans woman population exhibits significantly longer polymorphic CAG repeat sequences in the AR gene. Further studies are warranted to elucidate whether, how and to what extent multiple functional variants in sex hormone signaling genes could be associated with gender incongruence/dysphoria. D'Andrea S, Pallotti F, Senofonte G, et al. Polymorphic Cytosine-Adenine-Guanine Repeat Length of Androgen Receptor Gene and Gender Incongruence in Trans Women: A Systematic Review and Meta-Analysis of Case-Control Studies. J Sex Med 2020;17:543-550.

Independent Association of Erectile Dysfunction and Low Testosterone Levels With Life Dissatisfaction in Men With Chronic Spinal Cord Injury.

BACKGROUND: The loss of global functional independence, along with bladder, bowel, and sexual dysfunctions, may contribute to psychological distress and life dissatisfaction after spinal cord injury (SCI). AIM: To explore the relationship of erectile function and androgenic status with life satisfaction, independently from confounders recognizable in spinal cord-injured men. METHODS: 100 consecutive men (49 ± 17 years) admitted to a rehabilitation program because of chronic SCI (≥1 year) underwent clinical/biochemical evaluations, including the assessment of life and sexual satisfaction using the Life-Satisfaction Questionnaire-9 (LiSat-9), erectile function using the International Index of Erectile Function-5 (IIEF-5), global and bowel-bladder functional independence using the Spinal Cord Independence Measure (SCIM) and measurement of total testosterone (TT) levels. The free testosterone level was calculated using the Vermeulen formula. OUTCOMES: The outcomes include the relationship between sexual health and life satisfaction in men with SCI. RESULTS: A LiSat-9 score <4, suggestive for life dissatisfaction, was exhibited by 49% of men. When compared with the life-satisfied group, a significantly higher percentage of them had sexual dissatisfaction and erectile dysfunction (ED); they also exhibited significantly lower levels of TT and calculated free testosterone (cFT) and a more severe impairment of bowel-bladder function. The life satisfaction degree correlated with sexual satisfaction degree, IIEF-5 score, TT, cFT, and bowel-bladder function degree. At the logistic regression model, including sexual LiSat-9 subscore and bowel-bladder SCIM subscore, only the former exhibited a significant negative association with life dissatisfaction. In a further logistic regression model, including the putative key determinants of sexual satisfaction, erectile function, and cFT levels, a higher odd of life dissatisfaction was independently associated both with a lower IIEF-5 score (OR: 0.93; 95% CI: 0.88, 0.98) and lower cFT levels (OR: 0.98; 95% CI: 0.98, 0.99). CLINICAL IMPLICATIONS: In men with chronic SCI, assessment of erectile function and testosterone levels can help to predict life satisfaction. STRENGTHS & LIMITATIONS: This is the first demonstration of the independent association of androgen deficiency and ED with life satisfaction in men with SCI. Prospective studies are warranted to clarify the cause-effect relationships. CONCLUSIONS: In men with SCI, ED and low testosterone levels exhibit a significant independent association with life dissatisfaction; longitudinal intervention studies could explore possible effects of their treatment in improving sexual and life satisfaction in this population. D'Andrea S, Minaldi E, Castellini C, et al. Independent Association of Erectile Dysfunction and Low Testosterone Levels With Life Dissatisfaction in Men With Chronic Spinal Cord Injury. J Sex Med 2020;17:911-918.

Mortality in tocilizumab-treated patients with COVID-19: a systematic review and meta-analysis.

OBJECTIVES: People who are exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could develop a potentially fatal disease with lung involvement and severe cytokine storm syndrome (CSS) - coronavirus disease 2019 (hereafter, COVID-19). Tocilizumab (TCZ) was administered to these subjects, despite the lack of randomised clinical trial data. Hence, summarising data on the mortality rate and related risks factors may help physicians to correctly administer TCZ. METHODS: We performed a systematic review and meta-analysis on mortality rate in TCZ- treated patients with COVID-19 according to the PRISMA guidelines. The pooled mortality rate in TCZ-treated persons was calculated and meta-regressions were done to investigate associated factors. RESULTS: We included 22 studies and 1520 TCZ-treated patients (mean age: 61 years, 95% CI: 59-64; male: 71%, 95% CI: 64-78%). The mortality estimated pooled prevalence was 19% (95% CI: 13-25, I2=100%, p<0.00001) and improvement estimated pooled prevalence was 71% (95% CI: 62-81). Factors associated with the mortality are the number of patients in intensive care unit, the number of patients requiring invasive ventilation and the sera C-reactive protein value before TCZ administration. We observed a reduction in the odds of mortality in TCZ-treated patients when compared to those treated with other therapies (OR=0.47, 95% CI: 0.22-0.98, p=0.004). CONCLUSIONS: This study showed that the mortality pooled prevalence in TCZ-treated patients is lower than the overall mortality reported in patients with severe COVID-19.

Erectile Dysfunction and Premature Ejaculation in Homosexual and Heterosexual Men: A Systematic Review and Meta-Analysis of Comparative Studies.

INTRODUCTION: Comparative studies on differences in sexual function outcomes between homosexual and heterosexual men are sparse and inconclusive. AIM: To systematically evaluate whether, and to what extent, a statistically significant difference exists in the odds of erectile dysfunction (ED) and premature ejaculation (PE) between homosexual and heterosexual men. METHODS: A thorough search of Medline, SCOPUS, CINAHL, and Web of Science databases was carried out to identify case-control studies comparing the prevalence of ED and PE in homosexual and heterosexual men. Methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Odds ratios (ORs) of reporting ED and PE were combined using random effect models. The Cochrane Q and I2 tests were carried out to analyze the between-studies heterogeneity. Funnel plots and trim-and-fill analysis were used to assess publication bias. MAIN OUTCOME MEASURES: The relationship between sexual orientation and odds of ED and PE was assessed by calculating pooled ORs with a 95% CI. RESULTS: 4 studies included in the quantitative analysis collectively provided information on 1,807 homosexual and 4,055 heterosexual men. The pooled ORs indicated that homosexual orientation was associated with 1.5-fold higher odds of reporting ED (OR = 1.49, 95% CI = 1.03-2.16; P = .04) and 28.0% lower odds of reporting PE in comparison to the heterosexual orientation (OR = 0.72, 95% CI = 0.52-1.00; P = .05). However, a significant heterogeneity among the studies was observed. Funnel plots revealed a possible publication bias only for the ED analysis, where the trim-and-fill test detected a putative missing study. Nevertheless, even when the pooled estimate was adjusted for publication bias, there was a significantly higher risk of ED in the homosexual group (adjusted OR = 1.60, 95% CI = 1.10-2.30; P = .01). CLINICAL IMPLICATIONS: These findings can drive future studies on sexual needs and concerns of homosexual men, which might not exactly match those of heterosexual individuals. STRENGTH & LIMITATIONS: This is the first meta-analysis exploring the differences in the prevalence of ED and PE between homosexual and heterosexual men. However, the results should be interpreted with caution, because their generalization could be hindered by the non-probabilistic nature of the samples, and a measurement bias could result from the use of different non-standardized indicators of sexual dysfunctions. CONCLUSION: Homosexual orientation is associated with higher odds of ED and lower odds of PE compared with heterosexual orientation. Further studies are warranted to elucidate the clinical significance of these findings and whether they reflect differences in patterns of sexual lifestyle. Barbonetti A, D'Andrea S, Cavallo F, et al. Erectile Dysfunction and Premature Ejaculation in Homosexual and Heterosexual Men: A Systematic Review and Meta-Analysis of Comparative Studies. J Sex Med 2019;16:624-632.

Effect of prolonged treatment with phosphodiesterase-5-inhibitors on endothelial dysfunction in vascular diseases and vascular risk conditions: A systematic review analysis and meta-analysis of randomized double-blind placebo-controlled trials.

OBJECTIVE: To challenge the argument that continuous use of phosphodiesterase-5-selective inhibitors may reduce endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions. DESIGN: This study included systematic reviews and meta-analysis of randomized double-blind placebo-controlled trials dealing with the prolonged use of phosphodiesterase-5-selective inhibitors. The risk of bias and quality of trials were assessed by the Cochrane algorithm. Fixed or random effect models, standardised mean differences and heterogeneity were estimated in the study. DATA SOURCES: Systematic search for randomized double-blind placebo-controlled trials was done in PubMed, Scopus, CINAHL, Science direct and the Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized double-blind placebo-controlled trials reporting measures of endothelial cell dysfunction and/or endothelial cell activation were included. RESULTS: On the whole, 469 subjects were allocated to the phosphodiesterase-5-selective inhibitor group, while 463 were assigned to the placebo group in 13 randomized double-blind placebo-controlled trials. Flow-mediated dilation of the brachial artery was found to improve after the administration of phosphodiesterase-5-selective inhibitors (P < 0.0001). The results were questioned by the elevated and uncorrectable heterogeneity (I2  = 92%) and the asymmetry of the funnel plot suggested a publication bias. Phosphodiesterase-5-selective inhibitors have no effect on endothelial cell dysfunction, as assessed in the resistance vessels by digital arterial tonometry. The blood level of endothelin-1 was observed to be decreased in phosphodiesterase-5-selective inhibitors arm (P = 0.03), although the effect disappeared once the publication bias and heterogeneity were corrected. The effect of phosphodiesterase-5-selective inhibitors on biomarkers of endothelial cell activation was found to be inconsistent. CONCLUSIONS: The results on the benefits of a prolonged use of phosphodiesterase-5-selective inhibitors, with the objective of lowering endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions are not convincing. This is because of the overall low quality of evidence, giving an unclear scientific support to this treatment. Systematic review registration: PROSPERO registration: CRD42017055399.

AN ITALIAN SURVEY OF COMPLIANCE WITH MAJOR GUIDELINES FOR L-THYROXINE OF PRIMARY HYPOTHYROIDISM.

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 <6), 38.6% medium (6 to <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. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; EDIPO = Endotrial SIE: DIagnosis and clinical management of Primitive hypothyrOidism in Italy; eCRF = electronic case report form; ETA = European Thyroid Association; fT3 = free triiodothyronine; fT4 = free thyroxine; LT4 = levothyroxine; MMAS-8 = Morisky-Green Medical Adherence Scale-8; PH = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; US = ultrasonography.

Low vitamin D levels are independent predictors of 1-year worsening in physical function in people with chronic spinal cord injury: a longitudinal study.

STUDY DESIGN: Longitudinal cohort study. OBJECTIVE: To explore the longitudinal association of baseline vitamin D levels with 1-year change in physical function outcomes in people with chronic spinal cord injury (SCI). SETTING: Rehabilitation institute. METHODS: Sixty-seven patients (44 men and 23 women) with chronic SCI admitted to a rehabilitation program were included. Functional independence in daily living activities (as evaluated by the Spinal Cord Independence Measure version III, SCIM III) and leisure time physical activity (LTPA) were assessed as measures of physical function at the admission and re-assessed 1-year later. Comorbidity was scored by Charlson comorbidity index (CCI). RESULTS: A 1-year worsening in SCIM and LTPA were registered in 44 and 40 patients (66% and 60% of the study population), respectively. They exhibited significantly lower baseline 25(OH)D levels, higher CCI, and shorter distance from the injury. At the multiple linear regression analyses, lower baseline 25(OH)D levels exhibited a significant independent association with higher percentages of 1-year worsening in both SCIM and LTPA. At ROC analysis, baseline 25(OH)D levels <18.6 and <18.2 ng/mL discriminated individuals with 1-year worsening in SCIM and LTPA, respectively. According to these cut-off points, at the multiple logistic regression analysis, patients with low baseline 25(OH)D levels exhibited an OR of worsening in SCIM and LTPA engagement 2.8- and 2.6-fold higher, after adjustment for CCI, distance from injury, and post-follow-up 25(OH)D levels. CONCLUSIONS: In people with chronic SCI, a low 25(OH)D level may represent an independent predictor of worsening in physical function outcomes over time.

Reproductive hormones and sperm parameters after varicocele repair: An observational study.

Varicocele repair (VR) is associated with improved sperm parameters in subfertile patients. We examined the association of the levels of reproductive hormones, scrotal colour Doppler ultrasound (CDU) and seminal parameters in subfertile men, before and after VR. Fifty subfertile males, with left-side varicocele, were enrolled in this retrospective study. The serum levels of FSH, LH and total testosterone (TT), along with continuous left spermatic venous reflux (SVR) and testicular volumes at CDU were evaluated, before and six months after VR by a left-side retrograde internal spermatic vein sclero-embolisation (SVE). Left-side SVR was either no longer present or significantly reduced in all patients after VR (p < 0.0001). Sperm parameters, in particular, the total sperm motile count (TMC), were found significantly improved after VR (p < 0.0001). Post-VR, no differences were observed in the baseline values of the reproductive hormones. Only SVR change was seen to predict TMC change (p = 0.026) in the univariate analysis, while reproductive hormones change had no effect on TMC change (FSH:p = 0.85;LH:p = 0.44;TT:p = 0.76). In conclusion, the improved sperm parameters were associated with the disappearance or reduction in SVR and not with changes in the levels of reproductive hormones after SVE. Thus, SVR change at CDU was the only predictor of improved sperm quality after VR in subfertile males.

Lower Vitamin D Levels Are Associated With Depression in People With Chronic Spinal Cord Injury.

OBJECTIVES: To determine (1) whether the serum concentration of 25-hydroxy vitamin D (25(OH)D3) was associated with depression levels in people with chronic spinal cord injury (SCI) and (2) whether any observed association was independent of potential confounders. DESIGN: Cross-sectional study. SETTING: Rehabilitation institute. PARTICIPANTS: Patients with chronic SCI (N=100) recruited consecutively. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients underwent clinical and biochemical evaluations, including assessment of 25(OH)D3 levels and the presence and severity of depressive symptoms, by using the interviewer-assisted self-report Beck Depression Inventory-II (BDI-II). RESULTS: Depression (BDI-II score ≥14) was observed in 15 of 28 women (53.6%) and 18 of 72 men (25.0%) of the study population. They exhibited significantly lower 25(OH)D3 levels, lower functional independence degree in performing activities of daily living, poorer engagement in leisure time physical activity, and higher body mass index. Lower 25(OH)D3 levels were associated with higher BDI-II scores as well as with the occurrence of depression. These associations persisted after adjustment for all significant predictors of the BDI-II score that were selected, as possible confounders, by univariate analysis. In receiver operating characteristic analysis, a 25(OH)D3 level of <9.99ng/mL had the highest accuracy in discriminating patients with depression. CONCLUSIONS: In people with chronic SCI, an inverse association exists between serum 25(OH)D3 levels and depressive symptoms, widely independent of potential confounders, especially those, peculiar to this population, that can mediate the effects of depression on vitamin D levels.

Serum From Patients With Erectile Dysfunction and Vascular Risk Factors Triggered an Oxidative Stress-Dependent Mitochondrial Apoptotic Pathway in Ex Vivo Expanded Circulating Angiogenic Cells of Healthy Men.

INTRODUCTION: Serum from men with erectile dysfunction (ED) and vascular risk factors inhibits circulating mononuclear cells (MNCs) from expanding ex vivo and differentiating circulating angiogenic cells (CACs), which are putatively involved in the repair of endothelial damage. AIM: To explore the involvement of apoptosis in the inhibition of CAC differentiation from MNCs of healthy men exerted by serum from men with ED and vascular risk factors. METHODS: MNCs from healthy men were cultured in serum from 10 healthy men (median age = 45 years, 25th-75th quartiles = 38.5-48.5) and from 14 patients (median age = 58.0 years, 25th-75th quartiles = 52.5-62.0). CACs were identified by the uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled acetylated low-density lipoprotein (DiLDL) and concomitant Ulex europaeus agglutinin I binding assessed by fluorescence microscopy. MAIN OUTCOME MEASURES: Flow cytometric evaluation of mitochondrial membrane potential, assessed with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benimidazolyl carbocyanine iodide dye, and of activated caspase-8, -9, and -3 in DiLDL-positive cells. RESULTS: The number of CACs was significantly decreased by serum from patients compared with controls. This was associated with suppression of the mitochondrial membrane potential and activation of caspase-9 and -3 but not of caspase-8. This suggests an activation of the intrinsic (mitochondrial) pathway of apoptosis, whereas the death receptor activation of apoptosis was not involved. Activation of caspase-9 and -3 induced by serum from patients with ED was prevented by the exposure of MNCs to Trolox, a hydrophilic cell-permeable vitamin E analog with high antioxidant capacity. CONCLUSION: An oxidative stress-dependent mitochondrial dysfunction was triggered in ex vivo expanded CACs of healthy men by serum from men with vascular risk factors and ED, the only clinical correlate for diffuse vascular disease. The activation of apoptosis and inhibition of CAC differentiation might generate a defective mechanism of vascular repair.

Independent Association of Vitamin D With Physical Function in People With Chronic Spinal Cord Injury.

OBJECTIVE: To explore the relation between vitamin D and physical function outcomes in people with spinal cord injury (SCI). DESIGN: Cross-sectional study. SETTING: Rehabilitation institute. PARTICIPANTS: Consecutive patients (N=100; 72 men and 28 women) with chronic SCI admitted to a rehabilitation program. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional independence in activities of daily living (ADL) and leisure time physical activity (LTPA) were assessed as measures of physical function. RESULTS: Vitamin D deficiency (<20ng/mL) was found in 78 patients: they exhibited a significantly higher body mass index, lower functional independence in ADL, and were engaged in a significantly poorer weekly LTPA. At the linear multiple regression analysis, lower 25-hydroxyvitamin D levels showed significant independent associations with poorer functional independence in ADL (ß=.59; 95% confidence interval, .36-.82; P<.0001) and with poorer LTPA (ß=2.35; 95% confidence interval, 0.77-3.94; P=.004), after adjustment for other predictors of physical function outcomes selected by univariate analyses. CONCLUSIONS: In people with chronic SCI, a low vitamin D level represents an independent predictor of poor physical function.

Interstitial Lung Disease and Pulmonary Damage in Primary Sjögren's Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary lung involvement is the most common extra-glandular manifestation in patients with primary Sjögren's syndrome (pSS), leading to a worsening of the patient's prognosis. To date, different studies have assessed the prevalence of pulmonary involvement and interstitial lung disease (ILD) in pSS patients with different results. METHODS: We performed a systematic literature review and meta-analysis on ILD pooled prevalence in pSS according to the PRISMA and MOOSE guidelines. Furthermore, we explored the pooled prevalence of the two main presentations of pSS-ILD, nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). RESULTS: We analysed the pSS-ILD prevalence in 30 studies including 8255 pSS patients. The pSS-ILD pooled prevalence was 23% (95% CI: 16-30). For NSIP, we found a pooled prevalence of 52% (CI 41-64), and for UIP we found a pooled prevalence of 44% (CI: 32-55). Regarding the meta-regression analysis, male gender, DLco value, country, and HRCT seem to contribute to the ILD presence. CONCLUSIONS: At least 20% of pSS patients have a comorbid ILD, usually NSIP. Male gender and alteration in DLco value may be considered the most important independent factors supporting an active search of lung complications during the clinical history of pSS patients.

Erectile dysfunction in hyperuricemia: A prevalence meta-analysis and meta-regression study.

BACKGROUND: Whether and to what extent an association exists between hyperuricemia and erectile dysfunction (ED) has not yet been fully determined. OBJECTIVE: To define pooled prevalence estimates and correlates of erectile dysfunction in men with hyperuricemic disorders. MATERIALS AND METHODS: A thorough search of Medline, Scopus, and Cochrane Library databases was performed. Data were combined using random-effects models and the between-study heterogeneity was assessed by Cochrane's Q and I2 tests. A funnel plot was used to assess publication bias. RESULTS: Overall, 8 studies included gave information about 85,406 hyperuricemic men, of whom 5023 complained of erectile dysfunction, resulting in a pooled erectile dysfunction prevalence estimate of 33% (95% Confidence Interval: 13-52%; I² = 99.9%). The funnel plot suggested the presence of a publication bias. At the meta-regression analyses, among the available covariates that could affect estimates, only type 2 diabetes mellitus was significantly associated with a higher prevalence of erectile dysfunction (ß = 0.08; 95% Confidence Interval: 0.01, 0.15, p = 0.025). At the sub-group analysis, the pooled erectile dysfunction prevalence decreased to 4% (95% Confidence Interval: 0%-8%) when only the largest studies with the lowest prevalence of type 2 diabetes mellitus were included and increased up to 50% (95% Confidence Interval: 17%-84%) when the analysis was restricted to studies enrolling smaller series with higher prevalence of type 2 diabetes mellitus. CONCLUSIONS: A not negligible proportion of men with hyperuricemia can complain of erectile dysfunction. While a pathogenetic contribution of circulating uric acid in endothelial dysfunction cannot be ruled out, the evidence of a stronger association between hyperuricemia and erectile dysfunction in type 2 diabetes mellitus points to hyperuricemia as a marker of systemic dysmetabolic disorders adversely affecting erectile function.

Erectile Dysfunction Is the Main Correlate of Depression in Men with Chronic Spinal Cord Injury.

Depression is the most prevalent psychological issue after a spinal cord injury (SCI) and is associated with noticeable disability, mortality and health expenditure. As SCI mainly occurs in sexually active men at a young age, and can lead to them suffering from an organic neurogenic erectile dysfunction (ED), we supposed that ED could be a major correlate of depressive status in men with SCI. As documented by a Beck Depression Inventory-II (BDI-II) score ≥14, depression was reported in 17 out of 57 men with a chronic SCI (29.8%). They exhibited a significantly higher prevalence of ED and a more severe bowel and bladder dysfunction when compared to the group without depression. At the multiple logistic regression analysis, depression showed a significant independent association with ED (OR = 19.0, 95% CI: 3.1, 203.3; p = 0.004) and, to a lesser extent, with a severe impairment of bowel and bladder function (OR = 0.84; 95% CI: 0.72, 0.94; p = 0.01). Depression was observed in 43.7% of men with ED and only in 12.0% of those without ED (p = 0.002). In conclusion, healthcare providers should give the right level of importance to the management of ED in men with SCI, as this represents a major independent correlate of depression, which, in turn, might hinder physical rehabilitation and exacerbate physical health issues related to SCI.

Association Between Minor Salivary Gland Biopsy During SjÓ§gren's Syndrome and Serologic Biomarkers: A Systematic Review and Meta-Analysis.

Objective: Patients with primary Sjögren's syndrome (pSS) may develop a potentially severe disease with extra-glandular involvement and lymphoma insurgence. Minor salivary gland biopsy is routinely used in the disease diagnosis, but its potential role as a biomarker for clinical disease presentation and prognosis is still poorly understood. Methods: We performed a systematic review and meta-analysis on clinical presentation and prognosis in pSS patients who underwent minor salivary gland biopsy at diagnosis according to the PRISMA guidelines. Results: We included five retrospective studies and 589 pSS patients. Ectopic GCs presence was not associated with a significant increase in the odds ratio for the clinical variables explored such as salivary gland swelling, arthritis, and Raynaud's phenomenon. As far as serological features are concerned, ectopic GCs presence accounted for an increased ratio of antibodies anti-SSA (OR = 3.13, 95% CI: 1.25-7.85, p = 0.02, I2 = 79%), anti-SSB (OR = 3.94, 95% CI: 1.50-10.37, p = 0.0005, I2 = 80%), and RFs presence (OR = 3.12, 95% CI: 1.94-5.00, p < 0.00001, I2 = 0%). Conclusions: This study showed that the association between ectopic GC in salivary glands identifies a clinical subset characterized by autoantibodies presence, and probably pSS patients affected from a more severe disease.

Effects of bisphenol S and bisphenol F on human spermatozoa: An in vitro study.

Bisphenol A (BPA), the main chemical monomer of epoxy resins and polycarbonate plastics, has generated concerns about its endocrine disruptor properties, along with the reported possible links with several human health disorders. Accordingly, some restrictions on its use have been recommended. Bisphenol S (BPS) and bisphenol F (BPF) are the main replacements to BPA, with which they share homologies in chemical structure. However, to date, little is known about their possible adverse effects for human reproduction. As the in vitro exposure of human spermatozoa to BPA induces oxidative/pro-apoptotic effects, the aim of the present study was to verify whether BPS and BPF could represent safer compounds for human sperm functions. The exposure of motile sperm suspensions to scalar concentrations of BPS or BPF for 4 h did not significantly reduce sperm motility (as assessed by computer-aided semen analysis) and viability. At flow cytometry, no changes in mitochondrial membrane potential, or mitochondrial generation of reactive oxygen species were detected by using the JC-1 and MitoSOX red probes, respectively. Interestingly, it nor even the combination of both BPS and BPF at the highest concentrations impaired sperm mitochondrial functions. In conclusion, BPS and BPF seem to be safer alternatives to BPA for sperm biology, as they do not affect mitochondrial functions, sperm motility and viability. These findings could help regulatory agencies to identify more secure chemicals to replace BPA in industrial production of plastics.

Pathophysiology of Mitochondrial Dysfunction in Human Spermatozoa: Focus on Energetic Metabolism, Oxidative Stress and Apoptosis.

The dogma of mitochondria as the major source of energy in supporting sperm motility should be critically reconsidered in the light of several experimental data pointing to a major role of glycolysis in mammalian spermatozoa. In this light, the reported positive correlation between the mitochondrial membrane potential (ΔΨm) and motility of ejaculated spermatozoa cannot be explained convincingly by an impaired mitochondrial ATP generation only. Evidence has been produced suggesting that, in human sperm, dysfunctional mitochondria represent the main site of generation of reactive oxygen species (ROS). Furthermore, in these organelles, a complex bidirectional relationship could exist between ROS generation and apoptosis-like events that synergize with oxidative stress in impairing sperm biological integrity and functions. Despite the activity of enzymatic and non-enzymatic antioxidant factors, human spermatozoa are particularly vulnerable to oxidative stress, which plays a major role in male factor infertility. The purpose of this article is to provide an overview of metabolic, oxidative and apoptosis-like inter-linkages of mitochondrial dysfunction and their reflections on human sperm biology.