Relationship between male aging and semen quality: a retrospective study on over 2500 men.

PURPOSE: We aimed to evaluate whether and to what extent an association exists between male aging and worsening of semen parameters and to determine whether a threshold age can be identified above which the decline in semen quality becomes statistically significant. METHODS: 2612 men (age: 16-56 years) attending an andrology outpatient clinic for semen analysis and clinical evaluation were studied. Semen analyses were performed according to the ongoing WHO-recommended procedures. Total motile count (TMC) and total progressive motile count (TPMC) were calculated by multiplying total sperm number by total motility and progressive motility, respectively. RESULTS: Significant negative correlations were found between age and total motility (r = - 0.131, p < 0.0001), progressive motility (r = - 0.112, p < 0.0001), TPMC (r = - 0.042, p = 0.037), and normal sperm morphology (r = - 0.053, p = 0.007). All these associations persisted in multivariate regression models adjusted for abstinence time, smoking, history of male accessory gland infections, varicocele and the year in which semen analysis was performed. When comparisons were performed among quartiles of increasing age, the fourth quartile, corresponding to the age group > 40 years, was associated with a significant decrease in total and progressive motility. An earlier decline in the TPMC and percentage of normal forms was also observed. CONCLUSION: Advancing male age exhibits an independent association with a decrease in the percentage of motile and morphologically normal spermatozoa, with greater evidence from the age of > 40 years. Further studies are warranted to elucidate the mechanisms and clinical reflections of these associations.

Arachidonic Acid Pathways and Male Fertility: A Systematic Review.

Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE1 and PGE2), PGF2α, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE1 and PGE2. The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility.

Neurotensin Gene rs2234762 C>G Variant Associates with Reduced Circulating Pro-NT Levels and Predicts Lower Insulin Resistance in Overweight/Obese Children.

Neurotensin (NT) is a small protein implicated in the regulation of energy balance which acts as both a neurotransmitter in the central nervous system and as a gastrointestinal peptide. In the gut, NT is secreted after fat ingestion and promotes the absorption of fatty acids. The circulating levels of its precursor, pro-NT, predicts the presence and development of metabolic and cardiovascular diseases. Despite the extensive knowledge on the dynamic changes that occur to pro-NT = after fat load, the determinants of fasting pro-NT are unknown. The aim of this study was to determine the possible genetic regulation of plasma pro-NT. The NT gene (NTS) was sequenced for potential functional variants, evaluating its entire genomic and potentially regulatory regions, in DNA from 28 individuals, stratified by low and high pro-NT levels. The identified variant differently distributed in the two pro-NT subgroups was genotyped in a cohort of nine hundred and thirty-two overweight/obese children and adolescents. A total of seven sequence variations across the NTS gene, none of them located in coding regions, were identified. The rs2234762 polymorphism, sited in the NTS gene promoter, was statistically more frequent in the lowest pro-NTS level group. Carriers of the rs2234762 variant showed lower pro-NT levels, after adjusting for sex, age, BMI, triglycerides and the Tanner stage. Having NTS rs2234762 predicted less pronounced insulin resistance at the 6.5-year follow-up with OR: 0.46 (0.216-0.983), at the logistic regression analysis adjusted for age, sex and BMI. In conclusion, the NTS rs2234762 gene variant is a determinant of reduced circulating pro-NT levels in overweight and obese children, which predisposes this group to a more favorable metabolic profile and a reduced insulin resistance later in life, independently from metabolic confounders.

ACE2 Receptor and Its Isoform Short-ACE2 Are Expressed on Human Spermatozoa.

Angiotensin-converting enzyme 2 (ACE2) is a protein widely expressed in numerous cell types, with different biological roles mainly related to the renin-angiotensin system. Recently, ACE2 has been in the spotlight due to its involvement in the SARS-CoV-2 entry into cells. There are no data available regarding the expression of ACE2 and its short-ACE2 isoform at the protein level on human spermatozoa. Here, protein expression was demonstrated by western blot and the percentage of sperm displaying surface ACE2 was assessed by flow cytometry. Immunocytochemistry assays showed that full-length ACE2 was mainly expressed in sperm midpiece, while short ACE2 was preferentially distributed on the equatorial and post-acrosomal region of the sperm head. To our knowledge, this is the first study demonstrating the expression of protein ACE2 on spermatozoa. Further studies are warranted to determine the role of ACE2 isoforms in male reproduction.

Deep Resequencing of 9 Candidate Genes Identifies a Role for ARAP1 and IGF2BP2 in Modulating Insulin Secretion Adjusted for Insulin Resistance in Obese Southern Europeans.

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1-5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11-0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105-0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136-5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion.

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.

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.

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.

Effects of gender affirming hormone therapy with testosterone on coagulation and hematological parameters in transgender people assigned female at birth: A systematic review and meta-analysis.

BACKGROUND: Hormone replacement therapy is associated with an increased thromboembolic risk. The effects of testosterone (T) on coagulation markers in people assigned female at birth (AFAB) under gender affirming hormone therapy (GAHT) are not well described. METHODS: Systematic review and meta-analysis on English-language articles retrieved from PubMed, Scopus and Cochrane Library up to April 2023 investigating T therapy in AFAB people. Coagulation parameters included international normalized ratio (INR), fibrinogen, activated partial thromboplastin clotting time (aPTT), plasminogen activator inhibitor-1 (PAI-1); hematological variables included hemoglobin (Hb) and hematocrit (HCT). We also reported the rate of thromboembolic events. Data were combined as mean differences (MD) with a 95 % confidence interval (CI) of pre- vs post-follow-up values, using random-effects models. RESULTS: We included 7 studies (6 prospective and 1 retrospective) providing information on 312 subjects (mean age: 23 to 30 years) who underwent GAHT with variable T preparation. T therapy was associated with a significant increase in INR values [MD: 0.02, 95 % confidence interval (CI): 0.01-0.03; p = 0.0001], with negligible heterogeneity (I2 = 4 %). T therapy was associated with increased Hb (MD: 1.48 g/dL, 95%CI: 1.17 to 1.78; I2 = 9 %) and HCT (4.39 %, 95%CI: 3.52 to 5.26; I2 = 23 %) values. No effect on fibrinogen, aPTT and PAI-1 was found. None of the study reported thromboembolic events during the follow-up. CONCLUSION: Therapy with T increased blood viscosity in AFAB men. A slight increase in INR values was also found, but the clinical relevance and mechanism(s) of this finding needs to be clarified.

Which PDE5 inhibitor is the most effective in the treatment of erectile dysfunction in men with spinal cord injury? A systematic review and network meta-analysis.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5i) are the first-line drugs for erectile dysfunction (ED) but differences among available molecules should drive therapy personalization. Choosing one PDE5i over another is a challenge in men with spinal cord injury (SCI), as the evidence of efficacy for each molecule is derived from few studies and comparative "head-to-head" trials are lacking. OBJECTIVE: To assess the efficacy of the different PDE5i for SCI-related ED with a network meta-analysis (NMA) approach. MATERIALS AND METHODS: Databases from PubMed, Web of Science, Scopus, and Cochrane Library were checked for randomized controlled trials (RCTs) comparing any PDE5i to each other or placebo in men with traumatic SCI lasting ≥6 months. Data were incorporated in a random-effect NMA, where treatments' efficacy was ranked using the surface under the cumulative ranking curve (SUCRA). RESULTS: The 10 RCTs included provided information about 1,492 men with ED due to traumatic SCI. Intervention arms included sildenafil, tadalafil, and/or vardenafil. Overall, at the pairwise meta-analysis, PDE5i were four times more effective than placebo in improving erectile function (risk ratio: 4.13, 95% CI: 2.76, 6.19). The comparative analysis from NMA revealed that tadalafil was associated with the highest SUCRA value (81%), followed by vardenafil (68%) and sildenafil (49%). DISCUSSION AND CONCLUSION: Within the grading of comparison network, tadalafil appeared to be the best PDE5i in the treatment of SCI-related ED. Further focused studies are warranted to confirm these findings and define optimal doses and duration of therapy.

Analysis of evidence on nutraceutical interventions for Peyronie's disease: a guideline-based critical review.

INTRODUCTION: The management of Peyronie's disease (PD) is a challenge for the clinician. Despite the lack of etiologic therapy, different nonsurgical approaches have often been empirically proposed. The most used treatment is based on nutraceutical drugs with antioxidant activity, although such an intervention remains controversial. OBJECTIVES: We reviewed the evidence from the randomized controlled trials included in the recommendations of the American Urological Association (AUA), Canadian Urological Association (CUA), European Association of Urology, and International Society for Sexual Medicine. METHODS: We searched PubMed, Scopus, Web of Science, and Cochrane Library for randomized controlled trials, reviews, and guidelines on nutraceutical interventions for PD. RESULTS: Our analysis provides detailed information on potential interventions, underlying the inconsistent evidence. Acetyl esters of carnitine, although not recommended by any of the available guidelines, showed potential benefit in some selected studies. Omega-3 fatty acids are not recommended due to withdrawn study evidence. The CUA and AUA were the only societies to consider the use of coenzyme Q10. While the CUA suggested that it might be offered as a treatment option, the AUA refrained from taking a definitive stance due to insufficient evidence. Similarly, conflicting recommendations have been produced on potassium para-aminobenzoate. While the CUA considers potassium para-aminobenzoate potentially useful in slowing PD progression, the AUA deems the evidence insufficient. Conversely, both the International Society for Sexual Medicine and European Association of Urology do not recommend its use. CONCLUSION: This critical comparative analysis of the most recent guidelines produced by the leading scientific societies highlights some inconsistencies in the recommendations on nutraceutical intervention for PD, even within a background of overall ineffectiveness of this treatment approach.