Taymour Mostafa

INTRODUCTION: The recent global outbreak of coronavirus disease 2019 (COVID-19) has become a pandemic with a lot of sufferers. Excessive inflammation, exaggerated immune response, with ultimate apoptosis contribute to COVID-19 pathology that progress to acute lung acute respiratory distress.

OBJECTIVE: To shed a light on the likely benefits of the oral phosphodiesterase 5 (PDE5) inhibitor adjuvant role in combating COVID-19 infection.

METHODS: A literature review was performed in the PubMed/Medline database, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases using the keywords COVID-19; phosphodiesterase-5 inhibitors; cytokine storm; respiratory distress.

RESULTS: Despite the worsening trends of COVID-19, still no drugs are validated to have significant clinical efficacy in the treatment of patients with COVID-19 in large-scale studies. While the progress toward a curative agent and/or vaccine is certainly hopeful, the principal limiting factor in such public health emergencies is always the time. Therefore, a preexisting licensed therapeutic(s) might offer a reprieve to the healthcare systems operating at the edge of capacity. In this context, the innovation of oral PDE5 inhibitors with their valuable effects on erection have provided a breakthrough in the treatment of erectile dysfunction and opened new fields of clinical application for this class of drugs. Oral PDE5 inhibitors have been demonstrated to possess many beneficial useful additional implications with acknowledged anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties have been elucidated through the nitric oxide/soluble guanylyl cyclase/cyclic guanylate monophosphate pathway in addition to the emerged hemeoxygenase-1 enzyme as well as hydrogen sulfide pathways. These properties could support repurposing oral PDE5 inhibitors' potential adjuvant use in targeting different aspects of COVID-19 infection.

CONCLUSION: Oral PDE5 inhibitors retain several acknowledged off-labeled useful implications with anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties may support repurposing oral PDE5 inhibitors' potential adjuvant use in the protocols combating COVID-19 manifestations. Mostafa T. Could Oral Phosphodiesterase 5 Inhibitors Have a Potential Adjuvant Role in Combating Coronavirus Disease 2019 Infection? Sex Med Rev 2021;9:15-22.

PURPOSE: The use of antioxidants is common practice in the management of infertile patients. However, there are no established guidelines by professional societies on antioxidant use for male infertility.

MATERIALS AND METHODS: Using an online survey, this study aimed to evaluate the practice pattern of reproductive specialists to determine the clinical utility of oxidative stress (OS) testing and antioxidant prescriptions to treat male infertility.

RESULTS: Responses from 1,327 participants representing 6 continents, showed the largest participant representation being from Asia (46.8%). The majority of participants were attending physicians (59.6%), with 61.3% having more than 10 years of experience in the field of male infertility. Approximately two-thirds of clinicians (65.7%) participated in this survey did not order any diagnostic tests for OS. Sperm DNA fragmentation was the most common infertility test beyond a semen analysis that was prescribed to study oxidative stress-related dysfunctions (53.4%). OS was mainly tested in the presence of lifestyle risk factors (24.6%) or sperm abnormalities (16.3%). Interestingly, antioxidants were prescribed by 85.6% of clinicians, for a duration of 3 (43.7%) or 3-6 months (38.6%). A large variety of antioxidants and dietary supplements were prescribed, and scientific evidence were mostly considered to be modest to support their clinical use. Results were not influenced by the physician's age, geographic origin, experience or training in male infertility.

CONCLUSIONS: This study is the largest online survey performed to date on this topic and demonstrates 1) a worldwide understanding of the importance of this therapeutic option, and 2) a widely prevalent use of antioxidants to treat male infertility. Finally, the necessity of evidence-based clinical practice guidelines from professional societies is highlighted.

Several studies attempted to explain the negative impact of varicocele on spermatogenesis and fertilisation processes. YKL-40 is a novel glycoprotein biomarker that had been associated with several diseases. This quasi-interventional study aimed to assess the seminal levels of YKL-40 in infertile men with varicocele before and after varicocelectomy. Overall, 50 men were included in this study divided into 20 healthy fertile men and 30 infertile oligoasthenoteratozoospermic (OAT) men with varicocele that underwent varicocelectomy. All participants were subjected to history taking, clinical examination and scrotal Doppler. Also, semen analysis and seminal YKL-40 assessment were carried out in the start and 6 months after varicocele surgical repair. The results showed a significant increase in the mean seminal YKL-40 level in infertile OAT men with varicocele compared with the healthy fertile men. Six months post-varicocelectomy, the mean seminal KYL-40 level exhibited significant decreases correlated with improved sperm parameters. Overall, seminal levels of YKL-40 showed significant negative correlations with sperm concentration, total sperm motility and sperm normal morphology. It could be concluded that seminal YKL-40 is elevated in infertile OAT men with varicocele where varicocelectomy induces decreased seminal YKL-40 levels correlated with improved semen parameters.

INTRODUCTION: Several treatment strategies are nowadays available for erectile dysfunction (ED) patients. Currently, oral phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line therapy for ED. However, they are effective in all treated cases with variable non-responsiveness. Many factors have been listed for this behavior, but the possibility of gene polymorphisms as an underlying cause has not been systematically investigated.

OBJECTIVES: This review aimed to assess the possible involvement of gene polymorphisms affecting the response to PDE5Is in men with ED.

METHODS: A systematic review was conducted based on a search of all relevant articles in various electronic sites such as PubMed, Medline Medical Subject Headings, Cochrane Library, Science Direct, Scopus, Embase, CINAHL, and Egyptian Knowledge Bank databases. Keywords used for relevant associations were sexual health, genes, variants, erectile dysfunction, polymorphisms, PDE5Is, and cavernous tissues.

RESULTS: Several studies have been carried out to determine the contribution of different encoded genes to ascertain the association between different genotypes and ED men who were non-responders for PDE5Is. 11 studies were selected for this review. In these studies, 6 investigated eNOS genetic polymorphism with variable outcomes. Only 1 study was carried out for each of the following genetic polymorphisms: phosphodiestrase 5A, G-protein β3 subunit, angiotensin converting enzyme, dimethylarginine dimethylaminohydrolase, arginase, and vascular endothelial growth factor with variable results.

CONCLUSION: Despite the relative shortage of available studies and the varied methodologies used, most of the research articles demonstrated a significant association between genetic polymorphism and the response to PDE5Is, especially for endothelial nitric oxide synthase polymorphism. The limited number of studies that investigated the possible effect of genetic polymorphism and the response to PDE5Is are challenged by many factors, particularly for the definition of responders and non-responders. This should be a motivating factor for researchers to perform further studies with a standardized methodology to address the influence of genetic variations on the response to PDE5Is. Mostafa T, Hassan A, Alghobary MF, et al. Effect of Genetic Polymorphism on the Response to PDE5 Inhibitors in Patients With Erectile Dysfunction: A Systematic Review and a Critical Appraisal. J Sex Med 2020;8:573-585.

INTRODUCTION: Erectile dysfunction (ED) is usually developed from psychological, neurological, hormonal, and vascular pathologies or a combination of these factors. However, the possible genetic polymorphisms that might underlie this disorder were not thoroughly investigated.

OBJECTIVES: This review article aimed to assess the possible involvement of gene polymorphisms in men with ED.

METHODS: A systematic review was conducted until January 2020 based on a search of all relevant articles in many electronic sites such as PubMed, Medline Medical Subject Headings, Science Direct, Scopus, Cochrane Library, EMBASE, CINAHL, and Egyptian Knowledge Bank databases with no language restriction. Keywords used to assess the outcome and estimates for relevant associations were sexual health, genes, erectile dysfunction, polymorphisms, and cavernous tissues.

RESULTS: Many genetic studies were carried out to inspect the contribution of different encoded genotypes and ED. Overall, 50 studies were reviewed and were classified as per the type of gene polymorphisms. These studies have investigated 10,174 men with ED compared with 6,891 healthy men as controls. 35 studies were case-controlled, 13 cross-sectional cohort studies, one retrospective study, and one genome-wide association study. So far, the most relevant gene polymorphisms linked with men with ED included endothelial nitric oxide synthase (eNOS), angiotensin-converting enzyme (ACE), androgen receptor (AR) CAG repeat, G-protein β3 (GNB3) subunit, methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF), TGFB1, proprotein convertase subtilisin/kexin type 9 (PCSK9), ARG1, DRD2, DRD4, DDAH, and HNF4A genes. Both PROGINS and IGFBP-3 polymorphisms were investigated in only one study each but with irrelevant significance.

CONCLUSIONS: Although several genetic studies exposed the association between different genotypes and men with ED with varied outcomes, such a relationship should not be overlooked. Therefore, more studies should be encouraged to elucidate the exact role, if any, for such association. Mostafa T, Taymour M. Gene Polymorphisms Affecting Erectile Dysfunction. Sex Med 2020;8:561-572.

INTRODUCTION: A growing number of genetic association studies have been performed to investigate the association between the genetic susceptibility alleles and the risk of premature ejaculation (PE); however, the results remain inconclusive.

OBJECTIVES: This systematic review aimed: (i) to determine whether an association exists between gene(s) or allelic variant(s) and PE; (ii) to assess whether the associations are consistent across studies in magnitude and direction, and (iii) to identify any limitation, gap, or shortcoming in the included studies.

METHODS: The literature search was conducted in PubMed, MEDLINE, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases.

RESULTS: Different gene variants associated with PE were assessed. 25 genetic association studies met the inclusion criteria that investigated 11 genes, 2,624 men with PE compared with 9,346 men as controls, twins, and siblings. 19 studies demonstrated a significant association with PE, whereas 4 studies denied such a relationship. SLC6A4 gene polymorphism was investigated in 11 studies (7 studies demonstrated a significant relationship with PE, and 4 studies denied such a relationship). Dopamine transporter gene (DAT1) polymorphism was investigated in 4 studies exhibiting a significant relationship. Androgen receptor gene polymorphisms were investigated in 2 studies, 1 with a significant relationship and the other with a non-significant relationship. Oxytocin gene polymorphisms and tryptophan hydroxylase 2 gene polymorphisms were investigated in 2 studies with a significant relationship.

CONCLUSION: While this review has highlighted several genes that may be potentially associated with PE such as SLC6A4, limitations such as variance in study methods, lack of robust findings, small sample sizes, lack of reproducibility, quality of reporting, and quality of assessment remain a major concern. Further efforts such as standardizing reporting, exploring complementary designs, and the use of genome-wide association studies technology are warranted to test the reproducibility of these early findings. Mostafa T, Abdel-Hamid IA, Taymour M, et al. Gene Variants in Premature Ejaculation: Systematic Review and Future Directions. Sex Med Rev 2020;8:586-602.

This trial aimed to assess the efficacy of on-demand oral dapoxetine versus topical lidocaine treatments for lifelong PE. Cases with lifelong PE were randomised to start treatment by oral dapoxetine 60 mg or topical lidocaine 10% spray. The intravaginal ejaculatory latency time (ILET), validated Arabic Index for PE (AIPE), Sexual Health Inventory for Men (SHIM) and frequency of intercourse/week were recorded at the baseline and after 12 weeks treatment period of the first medication before two weeks washout period and then crossing over to the other one for another 12 weeks. Results showed that both medications significantly increased both IELT and AIPE scores compared with the baseline being significantly better with topical lidocaine (63.44 s, 179.4 s versus 21.87 s, p < .05). Significant decrease of SHIM score was recorded with lidocaine but not with dapoxetine. Global Efficacy Question for the patient's assessment of the effectiveness of drugs showed that lidocaine was described as being effective by 43 cases and ineffective by 12 cases, oral dapoxetine was described as being effective by 16 cases and ineffective by 39 cases. From these accumulated data, it is concluded that topical lidocaine is more effective on-demand therapy for lifelong PE compared with oral dapoxetine.

This work assessed seminal SIRT1-oxidative stress (OS) relationship in infertile oligoasthenoteratozoospermic (OAT) men after varicocele repair. Overall, thirty OAT men with varicocele were investigated. Inclusion criteria were infertile males (males who were unable to initiate a pregnancy within 1 year of regular unprotected intercourse), confirmed OAT and normal female factor. These cases were subjected to history taking, clinical checkup and semen analysis. In their semen, seminal SIRT1, malondialdehyde (MDA) and glutathione peroxidase (GPx) levels were assessed. These men were subjected to varicocele surgical repair and were followed up for 3 months. Post-operatively, the mean seminal SIRT1, GPx levels showed significant increases and the mean MDA level showed significant decrease compared to the pre-operative levels linked to improved sperm parameters. The mean seminal SIRT1, GPx, MDA levels showed more significant improvement in grade III varicocele cases compared to grade II cases after surgical repair. Seminal SIRT1 levels showed significant positive correlations with sperm concentration, sperm motility, sperm normal morphology, seminal GPx levels and a significant negative correlation with seminal MDA levels. It could be concluded that seminal SIRT1 is significantly decreased in infertile OAT men with varicocele after its surgical repair linked to improved sperm parameters as well as seminal OS.