Causal associations between COVID-19 and erectile dysfunction: a Mendelian randomization study.

OBJECTIVE: In this study, we aimed to explore the potential association between COVID-19 infection, hospitalization, severe COVID-19, and erection dysfunction (ED) using the two-sample Mendelian randomization (MR) method. METHODS: Data pertaining to COVID-19 were extracted from the latest version of the COVID-19 Host Genetics Initiative genome-wide association study (GWAS) meta-analyses (Round 7, April 2022), and outcome data were obtained from the Open GWAS database. We applied various MR analysis methods, including the inverse variance weighted method, weighted median method, and MR-Egger regression. RESULTS: Our investigation revealed a negative causal association between COVID-19 hospitalization and ED (total testosterone levels: beta = -0.026; 95% confidence interval: -0.049 to -0.001). However, no evidence supported causal relationships between COVID-19 infection, hospitalization for COVID-19, or severe COVID-19 and other ED risk factors. CONCLUSION: The results of this comprehensive MR analysis suggest a negative causal link between COVID-19 hospitalization and total testosterone levels. Nonetheless, COVID-19 (comprising infection, hospitalization, and severe illness) may not directly correlate with an increased risk of ED. These findings imply that COVID-19 may exert a distinct impact on ED through indirect pathways.

Targeting Adenosine A2b Receptor Promotes Penile Rehabilitation of Refractory Erectile Dysfunction.

The mechanisms of adenosine and specific adenosine receptor subtypes in promoting penile rehabilitation remain unclear. Single-cell RNA sequencing of human corpus cavernosum,  adenosine deaminase (ADA) and adenosine receptors knock-out mice (ADA-/-, A1-/-, A2a-/-, A2b-/-, and A3-/-), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine-induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age-related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus-induced ED. In single-cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, A2b receptor knock-out abolishes adenosine-induced erection but not that of A1, A2a, or A3 receptor. Under hypoxic conditions in vitro, activating the A2b receptor increases HIF-1α and decreases PDE5 expression. In refractory ED models, activating the A2b receptor with Bay 60-6583 improves erectile function and down-regulates HIF-1α and TGF-ß. Administering Dipyridamole (40 mg Kg-1) to BCNC rats improve penile adenosine levels and erectile function. Our study reveals that the A2b receptor mediates adenosine-induced penile erection. Activating the A2b receptor promotes penile rehabilitation of refractory ED by alleviating hypoxia and fibrosis.

Alzheimer's disease increases the risk of erectile dysfunction independent of cardiovascular diseases: A mendelian randomization study.

BACKGROUND: Previous research has underscored the correlation between Alzheimer's disease (AD) and erectile dysfunction (ED). However, due to inherent limitations of observational studies, the causative relationship remains inconclusive. METHODS: Utilizing publicly available data from genome-wide association studies (GWAS) summary statistics, this study probed the potential causal association between AD and ED using univariate Mendelian randomization (MR). Further, the multivariable MR assessed the confounding effects of six cardiovascular diseases (CVDs). The primary approach employed was inverse variance weighted (IVW), supplemented by three additional methods. A series of sensitivity analyses were conducted to ensure the robustness of the results. RESULTS: In the forward MR analysis, the IVW method revealed causal evidence of genetically predicted AD being a risk factor for ED (OR = 1.077, 95% CI 1.007∼1.152, P = 0.031). Reverse analysis did not demonstrate any causal evidence linking ED to AD (OR = 1.018, 95% CI 0.974∼1.063, P = 0.430). Multivariable MR analysis showed that after adjusting for coronary heart disease (OR = 1.082, 95% CI 0.009∼1.160, P = 0.027), myocardial infarction (OR = 1.085, 95% CI 1.012∼1.163, P = 0.022), atrial fibrillation (OR = 1.076, 95% CI 1.002∼1.154, P = 0.043), heart failure (OR = 1.103, 95% CI 1.024∼1.188, P = 0.010), ischemic stroke (OR = 1.079, 95% CI 1.009∼1.154, P = 0.027), hypertension (OR = 1.092, 95% CI 1.011∼1.180, P = 0.025), and all models (OR = 1.115, 95% CI 1.024∼1.214, P = 0.012), the causal association between AD and ED persisted. Sensitivity analyses confirmed the absence of pleiotropy, heterogeneity, and outliers, validating the robustness of our results (P > 0.05). CONCLUSIONS: This MR study consistently evidences a causal effect of genetically predicted AD on the risk of ED, independent of certain CVDs, yet offers no evidence for a reverse effect from ED.

LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells and ameliorates erectile dysfunction via the miR-206/CDC42/PAK1/paxillin signalling axis.

BACKGROUND: Erectile dysfunction (ED) is a common male sexual dysfunction, with an increasing incidence, and the current treatment is often ineffective. METHODS: Vascular endothelial growth factor (VEGFA) was used to treat bone marrow-derived mesenchymal stem cells (BM-MSCs), and their cell migration rates were determined by Transwell assays. The expression of the von Willebrand Factor (vWF)VE-cadherin, and endothelial nitric oxide synthase(eNOS) endothelial markers was determined by qRT‒PCR and Western blot analyses. The MALAT1-induced differentiation of BM-MCs to ECs via the CDC42/PAK1/paxillin pathway was explored by transfecting VEGFA-induced BM-MSC with si-MALAT1 and overexpressing CDC42 and PAK1. The binding capacity between CDC42, PAK1, and paxillin in VEGFA-treated and non-VEGFA-treated BM-MSCs was examined by protein immunoprecipitation. MiR-206 was overexpressed in VEGFA-induced BM-MSC, and the binding sites of MALAT1, miR-206, and CDC42 were identified using a luciferase assay. Sixty male Sprague‒Dawley rats were divided into six groups (n = 10/group). DMED modelling was demonstrated by APO experiments and was assessed by measuring blood glucose levels. Erectile function was assessed by measuring the intracavernosa pressure (ICP) and mean arterial pressure (MAP). Penile erectile tissue was analysed by qRT‒PCR, Western blot analysis, and immunohistochemical staining. RESULTS: MALAT1 under VEGFA treatment conditions regulates the differentiation of BM-MSCs into ECs by modulating the CDC42/PAK1/paxillin axis. In vitro experiments demonstrated that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs. CDC42 binds to PAK1, and PAK1 binds to paxillin. In addition, CDC42 in the VEGFA group had a greater ability to bind to PAK1, whereas PAK1 in the VEGFA group had a greater ability to bind to paxillin. Overexpression of miR-206 in VEGFA-induced BM-MSCs demonstrated that MALAT1 competes with the CDC42 3'-UTR for binding to miR-206, which in turn is involved in the differentiation of BM-MSCs to ECs. Compared to the DMED model group, the ICP/MAP ratio was significantly greater in the three BM-MSCs treatment groups. CONCLUSIONS: MALAT1 facilitates BM-MSC differentiation into ECs by regulating the miR-206/CDC42/PAK1/paxillin axis to improve ED. The present findings revealed the vital role of MALAT1 in the repair of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSC-mediated repair of DMED.

Single-cell transcriptome analysis of cavernous tissues reveals the key roles of pericytes in diabetic erectile dysfunction.

Erectile dysfunction (ED) affects a significant proportion of men aged 40-70 and is caused by cavernous tissue dysfunction. Presently, the most common treatment for ED is phosphodiesterase 5 inhibitors; however, this is less effective in patients with severe vascular disease such as diabetic ED. Therefore, there is a need for development of new treatment, which requires a better understanding of the cavernous microenvironment and cell-cell communications under diabetic condition. Pericytes are vital in penile erection; however, their dysfunction due to diabetes remains unclear. In this study, we performed single-cell RNA sequencing to understand the cellular landscape of cavernous tissues and cell type-specific transcriptional changes in diabetic ED. We found a decreased expression of genes associated with collagen or extracellular matrix organization and angiogenesis in diabetic fibroblasts, chondrocytes, myofibroblasts, valve-related lymphatic endothelial cells, and pericytes. Moreover, the newly identified pericyte-specific marker, Limb Bud-Heart (Lbh), in mouse and human cavernous tissues, clearly distinguishing pericytes from smooth muscle cells. Cell-cell interaction analysis revealed that pericytes are involved in angiogenesis, adhesion, and migration by communicating with other cell types in the corpus cavernosum; however, these interactions were highly reduced under diabetic conditions. Lbh expression is low in diabetic pericytes, and overexpression of LBH prevents erectile function by regulating neurovascular regeneration. Furthermore, the LBH-interacting proteins (Crystallin Alpha B and Vimentin) were identified in mouse cavernous pericytes through LC-MS/MS analysis, indicating that their interactions were critical for maintaining pericyte function. Thus, our study reveals novel targets and insights into the pathogenesis of ED in patients with diabetes.

The indicative effects of apolipoproteins on organic erectile dysfunction: bridging Mendelian randomization and case-control study.

The existing research on the association between apolipoproteins (Apos) and erectile dysfunction (ED) primarily relies on observational studies and does not distinguish between organic and psychogenic causes when diagnosing ED. It is difficult to believe that Apos play a role in psychogenic ED. To address these issues, our study explored the causal relationship between lipoproteins and ED using Mendelian randomization (MR) analysis and differentiate between organic and psychogenic ED through the use of nocturnal penile tumescence and rigidity (NPTR) monitoring. Multivariate MR analysis revealed significant causal associations between high-density lipoprotein (HDL), Apo A1, and Apo B/A1 with ED (OR and 95% CI were 0.33 (0.14-0.78), 3.58 (1.52-8.43), and 0.30 (0.13-0.66)). we conducted statistical and analytical analyses on the data of 212 patients using multivariate analyses and receiver operating characteristic (ROC) curves. Patients with organic ED had significantly lower levels of HDL, Apo A1 and Apo A1/B, whereas patients with organic ED had considerably higher levels of Apo B and low-density lipoprotein (LDL). The diagnostic value of Apos in predicting the risk of organic ED was evaluated using ROC curves. The results indicated that Apo A1 and Apo A1/B demonstrated good predictive value. HDL, Apo A1, and Apo A1/B have been identified as risk factors for ED in our study. Furthermore, our research highlights the significance of Apo A1 and Apo A1/Apo B in the development of organic ED and suggests their potential use as indicators to assess the risks associated with organic ED.

Exosomes secreted by adipose mesenchymal stem cells overexpressing circPIP5K1C exert.

BACKGROUND: Erectile dysfunction (ED) seriously affects men's normal life, and obstructive sleep apnoea (OSA) has been diagnosed as a causative factor. Currently, exosomes secreted by adipose mesenchymal stem cells (ADSC) have been used in the non-clinical experimental treatment of ED disease with prominent efficacy due to the advantages of high stability and no immune exclusion. METHODS: In this study, chronic intermittent hypoxia (CIH) exposure was used to induce ED-corresponding phenotypes in Sprague Dawley (SD) rats as well as in cavernous smooth muscle cells (CCSMCs). ED symptoms were treated using exosomes secreted by ADSCs overexpressing circPIP5K1C (EXO-circ) injected into the rat corpus cavernosum. RESULTS: EXO-circ has the effect of ameliorating ED induced by CIH exposure in rats, the mechanism of which is to promote the expression of the downstream target gene SMURF1 after adsorption of miR-153-3p through the sponge so that SMURF1 and PFKFB3 occur protein-protein binding and ubiquitination degradation of PFKFB3 appears to inhibit the occurrence of spongiotic smooth muscle cells glycolysis, and to restore the function of the smooth muscle. CONCLUSIONS: These findings show that EXO-circ have a promising therapeutic potential in OSA-induced ED.

Gonadal dysfunction in a man with Noonan syndrome from the LZTR1 variant: case report and review of literature.

Noonan syndrome (NS) is a genetic disorder characterized by multiple congenital defects caused by mutations in the RAS/mitogen-activated protein kinase pathway. Male fertility has been reported to be impaired in NS, but only a few studies have focused on fertility status in NS patients and underlying mechanisms are still incompletely understood. We describe the case of a 35-year-old man who underwent an andrological evaluation due to erectile dysfunction and severe oligospermia. A syndromic facial appearance and reduced testis size were present on clinical examination. Hormonal evaluation showed normal total testosterone level, high FSH level, and low-normal AMH and inhibin B, compatible with primary Sertoli cell dysfunction. Genetic analysis demonstrated the pathogenetic heterozygous variant c.742G>A, p.(Gly248Arg) of the LZTR1 gene (NM_006767.3). This case report provides increased knowledge on primary gonadal dysfunction in men with NS and enriches the clinical spectrum of NS from a rare variant in the novel gene LZTR1.

Association between leucocyte telomere length and erectile dysfunction in US adults: a secondary study based on 2001-2002 NHANES data.

OBJECTIVE: We aimed to explore the association between the leucocyte telomere length (LTL) and erectile dysfunction (ED) among a nationally representative sample of US adults. DESIGN: Secondary population-based study. SETTING: The National Health and Nutrition Examination Survey (NHANES) (2001-2002). PARTICIPANTS: A total of 1694 male participants were extracted from the NHANES database for 2001-2002. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary focus of the study was to determine the association between the LTL and ED, using multivariate logistic regression and restricted cubic spline models for examination. The secondary outcome measures involved conducting stratified subgroup analyses to exclude interactions of different variables with the LTL. RESULTS: Participants with ED had shorter LTLs than those without ED (p<0.05). After adjusting for confounding factors, compared with the reference lowest LTL quartile, the ORs and 95% CIs for the second, third and fourth LTL quartiles were (OR 1.51; 95% CI 1.01 to 2.26), (OR 1.79; 95% CI 1.24 to 2.58) and (OR 1.25; 95% CI 0.74 to 2.11), respectively. In addition, restricted cubic splines showed an inverted J-curve relationship between the LTL and ED. At an LTL of 1.037, the curve showed an inflection point. The ORs (95% CI) of ED on the left and right sides of the inflection point were (OR 1.99; 95% CI 0.39 to 10.20; p=0.385) and (OR 0.17; 95% CI 0.03 to 0.90; p=0.039). CONCLUSION: Our results demonstrated an inverted J-curve relationship between the LTL and ED. When the LTL was ≥1.037, the incidence of ED decreased with increasing LTL.

MicroRNA-503-5p protects streptozotocin-induced erectile dysfunction in diabetic rats by downregulating SYDE2.

Plentiful studies have clarified miRNAs take on a key role in the sexual dysfunction of diabetic rats. This study aimed to figure out microRNA (miR)-503-5p/SYDE2 axis' latent mechanisms in streptozotocin-induced diabetic rat sexual dysfunction. A model of erectile dysfunction (ED) in diabetic rats was established by injecting streptozotocin. MiR-503-5p and SYDE2 in ED rats were altered by injection of miR-503-5p mimic or si/oe-SYDE2. The targeting link between miR-503-5p and SYDE2 was testified. ICP/MAP value was tested by pressure sensor; Penile capillary abundance was assessed; Penile cGMP and AGEs were detected; penile smooth muscle cell apoptosis was assessed; MiR-503-5p and SYDE2 were tested. In streptozotocin-induced ED rats, miR-503-5p was reduced and SYDE2 was elevated. Elevating miR-503-5p or silencing of SYDE2 can enhance penile erection rate, ICP/MAP value, capillary abundance, and cGMP but reduce AGEs and penile smooth muscle cell apoptosis rate in ED rats. Strengthening SYDE2 with elevating miR-503-5p turned around the accelerating effect of elevated miR-503-5p on penile erection in ED rats. SYDE2 was a downstream target gene of miR-503-5p. MiR-503-5p protects streptozotocin-induced sexual dysfunction in diabetic rats by targeting SYDE2.

Inflammatory cytokine profiles in erectile dysfunction: a bidirectional Mendelian randomization.

Objectives: Inflammatory cytokines (ICs) play an important role in erectile dysfunction (ED). Previous studies have demonstrated that most ED patients have high levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). The causality between 41 ICs and ED is investigated using the Mendelian randomization (MR) approach. Methods: Single nucleotide polymorphisms (SNPs) exposure data of 41 ICs came from a genome-wide association study (GWAS) of 8293 subjects. At the same time, the FINNGEN R9 database provided the ED outcome data containing 2205 ED patients and 164104 controls. MR-Egger (ME), inverse variance weighting (IVW), and weighted median (WM) were applied to conduct the MR study and IVW was taken as the main criterion. Results: From a genetic perspective, the increase of interferon-inducible protein-10 (IP-10) level significantly increased the risk of ED (P=0.043, odds ratio (OR)=1.269, 95% confidence interval (95%CI): 1.007-1.600), while the increase of interleukin-1 receptor antagonist (IL-1RA) markedly decreased the risk of ED (P=0.037, OR=0.768, 95%CI: 0.600-0.984). Meanwhile, IP-10 (p=0.099) and IL-1RA (p=0.135) failed to demonstrate causality in reverse MR analysis. Conclusions: Changes in ICs levels will significantly affect the risk of ED, especially IP-10 as a risk component for ED and IL-1RA as a protective component for ED. In the future, we can achieve targeted treatment and prevention of ED by intervening with specific inflammatory factors.

Cldn4 overexpression promotes penile cavernous smooth muscle cell fibrotic response via the JNK signaling pathway.

BACKGROUND: Erectile dysfunction (ED), defined as the inability to achieve or maintain a penile erection sufficient to satisfy sexual behavior, is prevalent worldwide. AIM: Using previous research, bioinformatics, and experimental confirmation, we aimed to discover genes that contribute to ED through regulating hypoxia in corpus cavernosum smooth muscle cells (CCSMCs). METHODS: We used the Gene Expression Omnibus to acquire the sequencing data of the corpus cavernosum transcriptome for diabetic ED and nerve injury type ED rats. We intersected the common differentially expressed genes. Further verification was performed using single cell sequencing. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate whether the differentially expressed genes are found in the corpus cavernosum. We used induced hypoxia to assess cell viability changes, and we developed a lentivirus overexpressing Cldn4 for in vitro and in vivo experiments to measure changes in JNK signaling, fibrosis, hypoxia, and erectile function. OUTCOMES: Our results indicate that targeting the JNK pathway and decreasing local hypoxia may be better options for therapeutic intervention to improve erectile function. RESULTS: We identified Cldn4 and found its expression increased in the corpora cavernosa of the 2 datasets. In addition, we found that hypoxia can increase the expression of Cldn4, activate the JNK signaling pathway, and exacerbate fibrosis in CCSMCs. Cldn4 overexpression in CCSMCs activated the JNK signaling pathway and increased fibrotic protein expression. Last, rat corpus cavernosum overexpressing Cldn4 activated the JNK signaling pathway, increased local fibrosis, and impaired erectile function. CLINICAL IMPLICATIONS: Through bioinformatics and in vitro and in vivo experiments, we found that Cldn4 has a negative effect on ED, and targeting Cldn4 may provide new ideas for ED treatment. STRENGTHS AND LIMITATIONS: Although we have identified Cldn4 as a potential target for ED treatment, we have only conducted preliminary validation on CCMSCs, and we still need to further validate in other cell lines. CONCLUSION: CCSMC hypoxia leads to increased Cldn4, in both nerve injury and diabetic ED rat models, and promotes fibrosis by activating the JNK signaling pathway.

Genetic association of lipid-lowering drug target genes with erectile dysfunction and male reproductive health.

Objective: The effect of hypolipidemic drugs on male erectile function is still controversial. This Mendelian randomization (MR) study aimed to explore the potential impact of lipid-lowering drug targets on ED. Methods: We collected seven genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, APOC3 and LPL) from published genome-wide association study (GWAS) statistics, and performed drug target MR analysis. The risk of ED was defined as the primary outcome, sex hormone levels and other diseases as the secondary outcomes. Mediation analyses were performed to explore potential mediating factors. Results: The results showed that LDLR, LPL agonists and APOC3 inhibitors were significantly associated with a reduced risk of ED occurrence. APOB inhibitors were associated with an increased risk of ED occurrence. In terms of sex hormone levels, LDLR and LPL agonists were significantly associated with increased TT levels, and HMGCR was associated with decreased TT and BT levels significantly. In terms of male-related disease, MR results showed that LDLR agonists and PCSK9 inhibitors were significantly associated with an elevated risk of PH; HMGCR, NPC1L1 inhibitors were associated with a reduced risk of PCa; and LDLR agonists were significantly associated with a reduced risk of AS and MI; in addition, HMGCR inhibitors were associated with a reduced risk of PCa. Conclusion: After performing drug-targeted MR analysis, we found that that there was a causal relationship between lipid-lowering drug targets and ED. APOC3, APOB, LDLR and LPL may be new candidate drug targets for the treatment of ED.

A Mendelian randomization study on causal effects of inflammatory bowel disease on the risk of erectile dysfunction.

This study aimed to evaluate the causal effects of inflammatory bowel disease (IBD) and erectile dysfunction (ED) using Mendelian randomization (MR). All datasets were obtained from the public genome-wide association study database. In the exposure group, 12,882 IBD patients and 21,770 controls were included. A total of 1154 ED patients and 94,024 controls were included in the outcome group. Two-sample MR was conducted to estimate the causal effect of IBD on ED. Furthermore, Crohn's disease (CD) and ulcerative colitis (UC) were exposure factors in subgroup analyses. Weighted median, MR-egger, Inverse-variant weighted (IVW), weighted mode, and simple mode methods were used in MR analysis. Horizontal pleiotropy test, heterogeneity test, and leave-one-out method were utilized to evaluate the sensitivity and stability of results. After analysis, 62, 52, and 36 single nucleotide polymorphisms (SNPs) that IBD-ED, CD-ED, and UC-ED were included, respectively. The incidence of ED was increased by IBD (IVW: OR = 1.110, 95% CI = 1.017-1.211, P = 0.019; P-heterogeneity > 0.05) and, in addition, ED was affected by CD (IVW: OR = 1.085, 95% CI = 1.015-1.160, P = 0.016; P-heterogeneity > 0.05). However, there was no causal effect of UC on ED (IVW: OR = 1.018, 95% CI = 0.917-1.129, P = 0.743; P-heterogeneity < 0.05). All SNPs showed no significant horizontal pleiotropy (P > 0.05). These results indicate that IBD and CD can cause ED; However, UC did not cause ED. Additional research was required to determine causality and potential mechanisms further.

Genetically proxied intestinal microbiota and risk of erectile dysfunction.

BACKGROUND: The interaction between intestinal microbiota and erectile dysfunction (ED) is less investigated. This study was performed to explore the association between intestinal microbiota and ED. METHODS: In this two-sample Mendelian randomization (MR) study, genetic variants of gut microbiota were obtained from MiBioGen consortium containing 18,340 individuals. Six methods including inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR robust adjusted profile score, and MR pleiotropy residual sum and outlier were used to investigate the causal links between intestinal microbiota and ED. Furthermore, reverse MR analysis was performed to exclude the causal impact of ED on gut microbiota. RESULTS: As revealed by the IVW estimator, the risks of ED were raised by genetically proxied Lachnospiraceae (OR: 1.27), Lachnospiraceae NC2004 group (OR: 1.17), Oscillibacter (OR: 1.20), Senegalimassilia (OR: 1.32) (All P < 0.05) and Tyzzerella-3 (OR: 1.14, P < 0.05). It was observed that Ruminococcaceae UCG013 exerted protective effect against ED (OR: 0.77, P < 0.05). These results were consistent with other estimators in sensitivity analyses. In reverse MR analyses, genetic liability to ED did not alter the abundances of Lachnospiraceae, Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella-3, and Ruminococcaceae UCG013 (All P > 0.05). No heterogeneity and pleiotropy were detected by Cochran's Q-test, MR-Egger, and global test (All P > 0.05). CONCLUSIONS: This study provided novel evidence that genetically proxied Lachnospiraceae, Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella-3, and Ruminococcaceae UCG013 had potentially causal effects on ED. Further studies are needed to clarify the biological mechanisms linking intestinal microbiota to ED.

Effects of obesity-related anthropometric indices and body composition on erectile dysfunction mediated by coronary artery disease: A Mendelian randomization study.

BACKGROUND: The causal relationship between obesity-related anthropometric indicators/body composition and erectile dysfunction has not been established in previous observational studies. METHOD: We screened single nucleotide polymorphisms significantly associated with exposure from genome-wide association studies as instrumental variables (p < 5.0 × 10-8 ). The summary statistics for erectile dysfunction were collected from a genome-wide association study with a sample size of 223,805. Exposure and outcome populations included are of European ancestry. We used univariate and multivariate Mendelian randomization (i) to investigate the causal relationship between genetically predicted obesity-related anthropometric indicators/body composition and erectile dysfunction and (ii) to examine the mediating role of coronary artery disease. Mendelian randomization analysis was conducted using an inverse variance weighted method. A series of sensitivity analyses validated the results of the Mendelian randomization analysis. Causal estimates are expressed as odds ratios with 95% confidence intervals. RESULTS: Obesity-related anthropometric indicators/body composition were associated with an increased risk of erectile dysfunction in univariate Mendelian randomization analyses. For the 1-SD increase in body mass index, the odds ratio was 1.841 (95% confidence interval: 1.049-1.355, p = 0.006). For the 1-SD increase in waist circumference and hip circumference, the odds ratios were 1.275 (95% confidence interval: 1.101-1.478, p = 0.001) and 1.156 (95% confidence interval: 1.015-1.317, p = 0.009), respectively. The odds ratio for the 1-SD increase in whole body fat mass was 1.221 (95% confidence interval: 1.047-1.388, p = 0.002). For the 1-SD increase in leg fat percentage (left and right), the odds ratios were 1.256 (95% confidence interval: 1.006-1.567, p = 0.044) and 1.285 (95% confidence interval: 1.027-1.608, p = 0.028), respectively. For the 1-SD increase in leg fat mass (left and right), the odds ratios were 1.308 (95% confidence interval: 1.108-1.544, p = 0.001) and 1.290 (95% confidence interval: 1.091-1.524, p = 0.003), respectively. For the 1-SD increase in arm fat mass (left and right), the odds ratios were 1.269 (95% confidence interval: 1.113-1.447, p < 0.001) and 1.254, respectively. Multivariate Mendelian randomization analysis showed that after adjusting for coronary artery disease, some genetic predispositions to obesity-related anthropometric indicators and body composition were still associated with an increased risk of erectile dysfunction. Significant associations were found for waist circumference-erectile dysfunction (odds ratio: 1.218, 95% confidence interval: 1.036-1.432), leg fat percentage (left)-erectile dysfunction (odds ratio: 1.245, 95% confidence interval: 1.035-1.497), leg fat mass (left)-erectile dysfunction (odds ratio: 1.264, 95% confidence interval: 1.051-1.521), arm fat mass (right)-erectile dysfunction (odds ratio: 1.186, 95% confidence interval: 1.024-1.373), and arm fat mass (left)-erectile dysfunction (odds ratio: 1.17, 95% confidence interval: 1.018-1.360). Meanwhile, coronary artery disease mediated the effects of fat on erectile dysfunction, and the proportion of coronary artery disease-mediated cases ranged from 10% to 22%. CONCLUSION: There is a potential causal relationship between obesity-related anthropometric indicators/body composition and erectile dysfunction. Higher waist circumference, leg fat percentage, and arm fat mass may increase the risk of erectile dysfunction, and coronary artery disease partly mediates this overall effect. Understanding the causal relationship between obesity and erectile dysfunction and the mediating role of coronary artery disease may provide more information for erectile dysfunction intervention and prevention strategies.

Erectile function and androgen and estrogen beta receptor gene polymorphisms in acromegalic men.

PURPOSE: Sexual dysfunctions are often experienced by male patients with acromegaly, due to a combination of hypogonadism and other comorbidities, but are a scarcely investigated complication. Erectile dysfunction is also closely related to cardiovascular diseases through endothelial dysfunction. Therefore, this project aimed to assess the prevalence of erectile dysfunction in a population of acromegalic men and evaluate its association with cardio-metabolic disorders, also exploring associations with androgen and estrogen receptor gene polymorphisms. METHODS: Sexually active men aged 18-65 with previous diagnosis of acromegaly were recruited. Clinical and laboratory data were retrospectively collected. Each patient also provided a blood sample for AR and ERß gene polymorphisms analyses and filled out the IIEF-15 questionnaire. RESULTS: Twenty men with previous diagnosis of acromegaly (mean age 48.4 ± 10.0 years) were recruited. 13/20 subjects (65%) had erectile dysfunction, but only four had a concurrent biochemical hypogonadism, with no significant correlation with IIEF-15 scores. Total testosterone negatively correlated with sexual intercourse satisfaction domain (ρ = - 0.595; p = 0.019) and general satisfaction domain (ρ = - 0.651; p = 0.009). IGF-1 levels negatively correlated with biochemical hypogonadism (ρ = - 0.585; p = 0.028). The number of CAG and CA repeats in AR and ERß receptors genes was not significantly associated with IIEF-15 scores or with GH/IGF-1 levels, but a negative correlation between CA repeats and the presence of cardiomyopathy (ρ = - 0.846; p = 0.002) was present. CONCLUSIONS: Men with acromegaly have a high prevalence of erectile dysfunction, but it does not appear to be correlated with treatments, testosterone levels and AR/ER-beta signaling. Nonetheless, a shorter CA polymorphic trait (ERbeta) is associated with the presence of cardiomyopathy. If confirmed, these data may suggest an association between an incorrect hormonal balance and increased cardiovascular risk in acromegaly subjects.

The association between lipid parameters and erectile dysfunction: a two-sample Mendelian randomization and case-control study.

PURPOSE: Lipid parameters have been shown to have significant predictive value for cardiovascular disease, but few studies have evaluated their correlation with erectile dysfunction (ED) in young men. METHODS: The case-control study encompassed 186 young ED patients (ages 20-40) and 186 healthy controls. Lipid parameters, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TC/HDL ratio, TG/HDL ratio, and LDL-C/HDL-C ratio, were assessed in all participants. The International Index of Erectile Function (IIEF-5) scores were collected for all participants to evaluate erectile status. Multivariate logistic regression analysis was utilized to appraise the association of lipid-related parameters with ED. Single-nucleotide polymorphisms (SNPs) significantly correlated with lipid parameters (TC, TG, LDL-C, HDL-C) were selected from genome-wide association studies (GWAS) as instrumental variables (IV) (P < 5.0 × 10-8). Summary data for ED was gathered from a GWAS with a sample size of (n = 17,353 cases/28,210 controls). The inverse variance weighted (IVW) method was employed as the primary mendelian randomization (MR) analysis method to assess causal effects. Causal estimates were represented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Results from the case-control study revealed that, when compared with the control group, levels of LDL-C, TG, UA, LDL-C/HDL-C, TG/HDL-C, and TC/HDL-C in the ED group were significantly elevated (P < 0.01), while HDL-C was significantly decreased (P < 0.01) in the ED group. Multivariate logistic regression analysis indicated LDL-C/HDL-C as a risk factor for both the incidence and severity of ED (P < 0.001). Two-sample MR analysis demonstrated no significant causal correlation between lipid parameters-LDL-C (OR, 0.98, 95% CI, 0.88-1.08, P = 0.616), HDL-C (OR, 1.07, 95% CI: 0.96-1.19, P = 0.249), TC (OR, 1.07, 95% CI, 0.96-1.18, P = 0.208), TG (OR, 0.98, 95% CI, 0.80-1.13, P = 0.579) -and an increased risk of ED (all P > 0.05). CONCLUSIONS: The case-control analysis ascertained a significant association between LDL-C, HDL-C, LDL-C/HDL-C, and ED and its severity. However, results from the MR study do not support a causal role of lipid parameters in ED.

Comprehensive analysis of biological landscape of oxidative stress-related genes in diabetic erectile dysfunction.

Oxidative stress plays a pivotal role in the pathogenesis of diabetic erectile dysfunction, while specific mechanisms have not been illuminated. The study aims to reveal the genetic expression patterns of oxidative stress in diabetic erectile dysfunction. Transcriptome data of diabetic erectile dysfunction and oxidative stress-related genes (OSRGs) in the Gene Expression Omnibus database were downloaded and analyzed based on differential expression. Functional enrichment analyses were conducted to clarify the biological functions. A protein interaction framework was established, and significant gene profiles were validated in the cavernous endothelial cells, clinical patients, and rat models. A miRNA-OSRGs network was predicted and validated. The results were analyzed using Student's t-test. The analysis screened 203 differentially expressed OSRGs (p < 0.05), which had a close association with oxidoreductase activities, glutathione metabolism, and autophagy. A four-gene signature comprised of EPS8L2 (p = 0.044), GSTA3 (p = 0.015), LOX (p < 0.001) and MGST1 (p = 0.002) was well validated and regarded as the hub OSRGs. Compared with the control group, notable increases and decreases were observed in the expressions of GSTA3 (3.683 ± 0.636 vs. 0.416 ± 0.507) and LOX (2.104 ± 1.895 vs. 18.804 ± 2.751) in the validated diabetic erectile dysfunction group. The hub OSRGs-related miRNAs participated in smooth muscle cell proliferation. Besides, miR-125a-3p (p = 0.034) and miR-138-2-3p (p = 0.012) were validated as promising oxidative stress-related miRNA biomarkers. Our findings revealed the genetic alternations of oxidative stress in diabetic erectile dysfunction. These results will be instructive to explore the molecular landscape and the potential treatment for diabetic erectile dysfunction.