Showing papers in "The World Journal of Men's Health in 2021"

Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections on Testis.

Abstract: Purpose To evaluate the presence and analyze the pathological changes within the testes of patients who died or recovered from severe acute respiratory syndrome coronavirus 2 (COVID-19) complications. Materials and methods Testis tissue was collected from autopsies of COVID-19 positive (n=6) and negative men (n=3). Formalin-fixed paraffin-embedded tissues were stained with hematoxylin and eosin (H&E) and subjected to immunofluorescence for angiotensin-converting enzyme 2 (ACE-2) expression. Fluorescent-labeled tissue slides were imaged on a quantitative pathology scope with various zoom levels allowing for qualitative and quantitative interpretation. Tissue from four COVID-19 positive autopsy cases and a live seroconverted patient was imaged with transmission electron microscopy (TEM). Results H&E histomorphology showed three of the six COVID-19 biopsies had normal spermatogenesis while the remaining three had impaired spermatogenesis. TEM showed the COVID-19 virus in testis tissue of one COVID-19 positive autopsy case and the live biopsy, H&E stain on the same autopsy case demonstrated interstitial macrophage and leukocyte infiltration. Immunofluorescent stained slides from six COVID-19 positive men demonstrated a direct association between increased quantitative ACE-2 levels and impairment of spermatogenesis. Conclusions The novel COVID-19 has an affinity for ACE-2 receptors. Since ACE-2 receptor expression is high in the testes, we hypothesized that COVID-19 is prevalent in testes tissue of infected patients. This study suggests the male reproductive tract, specifically the testes, may be targets of COVID-19 infection. We found an inverse association between ACE-2 receptor levels and spermatogenesis, suggesting a possible mechanism of how COVID-19 can cause infertility.

COVID-19 Endothelial Dysfunction Can Cause Erectile Dysfunction: Histopathological, Immunohistochemical, and Ultrastructural Study of the Human Penis.

Abstract: PURPOSE: A pilot study to describe histopathological features of penile tissue of patients who recovered from symptomatic COVID-19 infection and subsequently developed severe erectile dysfunction (ED). MATERIALS AND METHODS: Penile tissue was collected from patients undergoing surgery for penile prosthesis for severe ED. Specimens were obtained from two men with a history of COVID-19 infection and two men with no history of infection. Specimens were imaged with TEM and H&E staining. RT-PCR was performed from corpus cavernosum biopsies. The tissues collected were analyzed for endothelial Nitric Oxide Synthase (eNOS, a marker of endothelial function) and COVID-19 spike-protein expression. Endothelial progenitor cell (EPC) function was assessed from blood samples collected from COVID-19 (+) and COVID-19 (-) men. RESULTS: TEM showed extracellular viral particles ~100 nm in diameter with peplomers (spikes) near penile vascular endothelial cells of the COVID-19 (+) patients and absence of viral particles in controls. PCR showed presence of viral RNA in COVID-19 (+) specimens. eNOS expression in the corpus cavernosum of COVID-19 (+) men was decreased compared to COVID-19 (-) men. Mean EPC levels from the COVID-19 (+) patients were substantially lower compared to mean EPCs from men with severe ED and no history of COVID-19. CONCLUSIONS: Our study is the first to demonstrate the presence of the COVID-19 virus in the penis long after the initial infection in humans. Our results also suggest that widespread endothelial cell dysfunction from COVID-19 infection can contribute to ED. Future studies will evaluate novel molecular mechanisms of how COVID-19 infection leads to ED.

Anti-Obesity Drugs: Long-Term Efficacy and Safety: An Updated Review

Abstract: As a chronic and relapsing disease, obesity negatively impacts the health of men to a greater extent than that of women, with a higher risk of cardiovascular disease. Since lifestyle modifications alone are often challenging and limited for the maintenance of weight reduction, pharmacotherapy should be considered in a timely manner for obese men or overweight patients with weight-related comorbidities. Recent advances in anti-obesity drugs have enabled the potential of achieving clinically significant weight loss. Increasing evidence has shown that behavior-based interventions with one of these medications can result in greater weight loss than that elicited by usual care conditions. Data from most recent meta-analyses showed that the overall placebo-subtracted weight reduction (%) with the use of anti-obesity drugs for at least 12 months ranges from 2.9% to 6.8%; phentermine/topiramate (-6.8%) liraglutide (-5.4%), naltrexone/bupropion (-4.0%), lorcaserin (-3.1%), and orlistat (-2.9%). However, they have a high cost and may cause adverse outcomes depending on the individual. Very recently, on February 13, 2020, the US Food and Drug Administration requested withdrawal of lorcaserin from the market because a safety clinical trial showed an increased occurrence of cancer. Therefore the decision to initiate drug therapy in obese individuals should be made after the benefits and risks are considered. Thereafter, treatment should be tailored to specific patient subpopulations depending on their chronic conditions, comorbidities, and preferences. Herein, we provide an overview of the latest developments in weight loss medications, which may serve as one of the strategies for long-term obesity control.

Utility of Antioxidants in the Treatment of Male Infertility: Clinical Guidelines Based on a Systematic Review and Analysis of Evidence

Abstract: It is widely accepted that oxidative stress plays an important role in the pathophysiology of male infertility and that antioxidants could have a significant role in the treatment of male infertility. The main objectives of this study are: 1) to systematically review the current evidence for the utility of antioxidants in the treatment of male infertility; and 2) propose evidence-based clinical guidelines for the use of antioxidants in the treatment of male infertility. A systematic review of the available clinical evidence was performed, with articles published on Scopus being manually screened. Data extracted included the type of antioxidant used, the clinical conditions under investigation, the evaluation of semen parameters and reproductive outcomes. The adherence to the Cambridge Quality Checklist, Cochrane Risk of Bias for randomized controlled trials (RCTs), CONSORT guidelines and JADAD score were analyzed for each included study. Further, we provided a Strength Weakness Opportunity Threat (SWOT) analysis to analyze the current and future value of antioxidants in male infertility. Of the 1,978 articles identified, 97 articles were included in the study. Of these, 52 (53.6%) were uncontrolled (open label), 12 (12.4%) unblinded RCTs, and 33 (34.0%) blinded RCTs, whereas 44 (45.4%) articles tested individual antioxidants, 31 (32.0%) a combination of several products in variable dosages, and 22 (22.6%) registered antioxidant products. Based on the published evidence, we 1) critically examined the necessity of additional double-blind, randomized, placebo-controlled trials, and 2) proposed updated evidence-based clinical guidelines for antioxidant therapy in male infertility. The current systematic review on antioxidants and male infertility clearly shows that antioxidant supplementation improves semen parameters. In addition, it provides the indications for antioxidant treatment in specific clinical conditions, including varicocele, unexplained and idiopathic male infertility, as well as in cases of altered semen quality.

Evaluation of SARS-CoV-2 in Human Semen and Effect on Total Sperm Number: A Prospective Observational Study.

Abstract: PURPOSE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created a surge of research to help better understand the breadth of possible sequelae. However, little is known regarding the impact on semen parameters and fertility potential. We sought to investigate for presence of viral RNA in semen of men with SARS-CoV-2 infection and to evaluate its effect on semen parameters in ejaculate. MATERIALS AND METHODS: We prospectively recruited thirty men diagnosed with acute SARS-CoV-2 infection using real-time reverse transcriptase polymerase chain reaction (RT-PCR) of pharyngeal swab specimens. Semen samples were collected from each individual using mailed kits. Follow-up semen samples were done with mailed kits or in-person in office setting. Semen analysis and PCR was performed after samples were received. RESULTS: Thirty semen samples from recovered men were obtained 11-64 days after testing positive for SAR-CoV-2 infection. The median duration between positive SAR-CoV-2 test and semen collection was 37 days (interquartile range [IQR]=23). The median total sperm number (TSN) in ejaculate was 12.5 million (IQR=52.1). When compared with age-matched SARS-CoV-2(-) men, TSN was lower among SARS-CoV-2(+) men (p=0.0024). Five men completed a follow-up sperm analysis (median 3 months) and had a median TSN of 18 million (IQR=21.6). No RNA was detected by means of RT-PCR in the semen in 16 samples tested. CONCLUSIONS: SARS-CoV-2 infection, though not detected in semen of recovered men, can affect TSN in ejaculate in the acute setting. Whether SARS-CoV-2 can affect spermatogenic function long-term remains to be evaluated.

Coenzyme Q10 Improves Sperm Parameters, Oxidative Stress Markers and Sperm DNA Fragmentation in Infertile Patients with Idiopathic Oligoasthenozoospermia.

Abstract: PURPOSE Oxidative stress and sperm DNA fragmentation (SDF) are potential contributing factors for idiopathic male infertility. Coenzyme Q10 (CoQ10) have been reported to be effective in the treatment of idiopathic male infertility, in general, owing to its antioxidant properties. Thus, the present study intends to investigate the effects of CoQ10 therapy on semen parameters, oxidative stress markers and SDF in infertile men, specifically with idiopathic oligoasthenozoospermia (OA). MATERIALS AND METHODS In this case-control study, sixty-five infertile patients with idiopathic OA and forty fertile men (control) were included. All participants underwent semen analysis based on the World Health Organization guidelines (5th edition, 2010). Patients received CoQ10 at the dose of 200 mg/d orally for three months. Seminal plasma CoQ10, total antioxidant capacity (TAC), total reactive oxygen species (ROS), glutathione peroxidase (GPx), and SDF levels were measured in controls (baseline) and infertile patients pre- and post-CoQ10 treatment. RESULTS CoQ10 treatment for three months significantly improved sperm concentration (p<0.05), progressive motility (p<0.05), total motility (p<0.01), seminal fluid CoQ10 concentration (p<0.001), TAC (p<0.001), and GPx (p<0.001) levels in infertile men with OA. Further, ROS level (p<0.05) and SDF percentage (p<0.001) were reduced in OA patients as compared to the baseline. CoQ10 levels also correlated positively with sperm concentration (r=0.48, p=0.01) and total motility (r=0.59, p=0.003) while a negative correlation was recorded between SDF and sperm motility (r=-0.54, p=0.006). CONCLUSIONS CoQ10 supplementation for three months could improve semen parameters, oxidative stress markers and reduce SDF in infertile men with idiopathic OA.

Editorial Commentary on Draft of World Health Organization Sixth Edition Laboratory Manual for the Examination and Processing of Human Semen

Abstract: Semen examination is the cornerstone of the evaluation of male fertility potential. Despite its apparent simplicity, it is a complex series of assessments with highly variable results that are subject to interpretation. The semen analysis is used to gauge reproductive potential and guide the clinician in management of the infertile couple. Over the past 40 years, the World Health Organization (WHO) Infertility Task Force has attempted to standardize the methodology of semen examination so as to bring uniformity and relevance to the test. The 1st edition of the “Laboratory Manual for the Examination and Processing of Human Semen” was published in 1980. Since then, four more editions of the WHO manual have been published, each attempting to reflect global male population demographics, to address limitations from previous versions, and to incorporate technological and scientific evolution in the field of reproduction. Currently, the 5th edition of the WHO manual, published in 2010, is implemented worldwide, and is considered one of the most used, yet contested documents in the field of male infertility [1]. In March 2021, the WHO released a preliminary draft of the 6th edition of its manual for public review and suggestions (https://www.who.int/publications/i/item/9789241547789). Essentially, the new manual comprises three parts: semen examination; sperm preparation and cryopreservation; and quality control and assurance. The procedures for semen examination include basic (routine) examinations, extended examinations (which may be used by laboratories or clinicians in certain situations), and advanced tests (which are not currently recommended for routine use and are primarily for research purposes). The 6th edition has presented the basic examination in a step-by-step and temporal manner, so that it can be reproduced precisely in any laboratory with the required equipment and expertise. The sections on extended and advanced examinations have been completely revamped in concordance with current clinical practice, with many older tests being abandoned and new tests being adopted. The purpose of this mini review and commentary is to familiarize fertility specialists with the principal changes proposed in the anticipated 6th edition of the WHO manual for human semen analysis. The advantages, limitations and clinical implications of these changes are discussed. 1. Use of decision limits to identify abnormal ejaculates The most important change proposed in the 6th edition is the adoption of decision limits to differentiate normal from abnormal ejaculates. The editors of the 6th edition acknowledge that the reference ranges described in the 5th edition should be abandoned as they are of limited value in differentiating fertile from infertile men. The 5th edition WHO manual utilized a population of 1,800 fertile men to obtain the reference distributions for semen parameters [1]. The lower 5th percentile was used to define the reference values for normal semen parameters. While the 5th percentile is commonly utilized as a statistical approach to determine cut-off norms in medical tests, this resulted in much controversy when applied to male fertility [2]. It has been argued that the 5th percentile is not applicable to assign normality in this case and proves unable to discriminate between fertile and infertile patients [3]. Several studies reported a shift of fertility status from abnormal to normal in 15% to 44% of patients by just using the 5th edition norms instead of the 4th edition [4,5,6,7]. It was therefore proposed that WHO reference ranges did not adequately reflect fertility dynamics of the male partner, with several investigators and clinicians believing that normal values were above the lower 5th percentile. With these limitations in mind, the editors of the 6th edition suggested using different reference limits because the previous reference ranges fail to differentiate fertile from infertile men [8]. Decision limits were introduced by Guzick et al [9], who proposed a two-level reference range narrative by defining an intermediate group of values. According to their data the sub-fertile population demonstrated a sperm concentration below 13.5×106/mL, sperm motility less than 32% and typical forms below 9%. Yet, the normal fertile subgroup had a sperm concentration greater than 48×106/mL, sperm motility over 63%, and normal morphology above 12%. Values between these two levels were categorized as intermediate fertility [9]. The 5th edition has been criticized for neglecting the female factor as an important confounder [3] and for both over- and under-representation of various regions of the world [4]. The editors of the 6th edition have acknowledged these limitations (Appendix 8.1 of the manual) and stipulated that semen examination cannot strictly differentiate between pathological and normal samples. Moreover, they recognize that using the lower 5th percentile is not the correct approach to identify normal or abnormal semen samples, and that semen analysis alone cannot predict fertility as this depends on multiple variables, particularly, female factors. Hence, the “normal” reference values of the 5th edition have been replaced by “decision limits” in the 6th edition. These are classified as “normal”, “borderline”, and “pathological”. A “normal” concentration is ≥20×106/mL, “borderline” lies between 10 to 20×106/mL, and “pathological” is <10×106/mL. For motility “normal” is defined as ≥50% progressively motile sperm, “borderline” is 35% to 49% progressively motile, while a “pathological” sample is defined as <35% progressively motile sperm. Morphology has been categorized as “normal” when typical forms are ≥14%, “borderline” is between 4% and 13% and “pathological” morphology is below 4%. Additionally, the 6th edition states that sperm antibodies are not the sole cause of agglutination as this may be caused by different pathologies. Therefore, sperm antibody binding below 50% is considered “normal”; it is “borderline” between 50% to 79%, and “pathological” when ≥80%. The introduction of the “decision limits” concept is an attempt to emphasize that the purpose of the semen examination is not to label a man as fertile or infertile, but rather to decide next steps in terms of further evaluation and treatment. The current limits are still arbitrary and future studies with clinical outcomes in the various groups will help refine these limits. The creation of a “borderline” group will have significant clinical implications as many men whose sample would previously have been labeled as normal using the 5th edition criteria, will now be classified as “borderline” and be eligible for therapeutic interventions. Clinicians can still offer hope for natural pregnancy in these cases before opting to pursue ART. The impact of this classification shift will likely be significant in clinical practice. If we now apply the new criteria and deem men with parameters below the new “normal” threshold (“borderline”+“pathological”) as infertile, we will suddenly increase the number of infertile men in our practices. Interestingly, the upcoming manual presents revised reference values based on combined data of fertile men (with time to pregnancy less than 12 months) from the 2010 manual (5th edition) and by including released data from studies published until 2020. The 6th edition has included data from 5 additional studies (with 1,789 more male subjects) to those used in the 5th edition. The five new studies have incorporated data from two regions in Europe, one from Africa and two from Asia, although notably 1,200 out of 1,789 participants originate from China alone, therefore skewing the reference values towards normality of specific geolocations that do not necessarily apply in different populations.

An In-Depth Bibliometric Analysis and Current Perspective on Male infertility Research.

Abstract: PURPOSE Male infertility is emerging as a major, escalating global health problem that imposes the need to investigate research trends in male infertility. The purpose of this study is to analyze male infertility research trends in the past 20 years using the bibliometric database from Scopus. MATERIALS AND METHODS In order to perform an in-depth bibliometric analysis, we propose a 'Funnel Model', which includes several layers representing different sub-areas of male infertility research. Adopting this Funnel Model, using Scopus, we retrieved relevant bibliometric data (articles per year, authors, affiliations, journals, and countries) for various areas of male infertility research and performed descriptive statistics. RESULTS The bibliometric analysis showed an exponential increase in male infertility research in the last 20 years. USA dominated in research output, with Agarwal, A. as the most prolific researcher. Testicular cancer, obesity and metabolic syndrome, and azoospermia were found to dominate male infertility research, whereas erectile dysfunction and unexplained male infertility had lesser attention. Interestingly, prognostic/diagnostic and mechanistic studies have significantly increased in parallel over the last 20 years. Furthermore, our bibliometric analysis revealed fewer publications in proteomics, transcriptomics and metabolomics when compared to genomics. Also, an increasing trend in publication was seen in assisted reproductive technology (ART) research. CONCLUSIONS An integrated and steep escalation in the field of omics and ART research appears to be a prerequisite for further development of future diagnostic and therapeutic strategies for male infertility.

Novel Emerging Therapies for Erectile Dysfunction.

Abstract: Currently, several treatments exist for the improvement of erectile dysfunction (ED). These include medical therapies such as phosphodiesterase type 5 inhibitors (PDE5-Is), invasive methods such as intracavernosal injection therapy of vaso-active substances, vacuum erection devices, and penile prosthesis implants. However, the percentage of patients that are unresponsive to available treatments and who drop out from treatments remains high. Current evidence reveals that the pathogenesis of ED is related to multiple factors including underlying comorbidities, previous surgery, and psychological factors. Diverse approaches using novel molecular pathways or new technologies have been tested as potential therapeutic options for difficultto-treat ED populations. Melanocortin receptor agonist, a centrally acting agent, showed promising results by initiating erection without sexual stimulation in non-responders to PDE5-Is. Recent clinical and pre-clinical studies using human tissues suggested that new peripherally acting agents including the Max-K channel activator, guanylate cyclase activator, and nitric oxide donor could be potential therapies either as a monotherapy or in combination with PDE5-Is in ED patients. According to several clinical trials, regeneration therapy using stem cells showed favorable data in men with diabetic or post-prostatectomy ED. Low-intensity shock wave therapy also demonstrated promising results in patients with vasculogenic ED. There are growing evidences which suggest the efficacy of these emerging therapies, though most of the therapies still need to be validated by well-designed clinical trials. It is expected that, should their long-term safety and efficacy be proven, the emerging treatments can meet the needs of patients hitherto unresponsive to or unsatisfied by current therapies for ED.

Protein Fingerprinting of Seminal Plasma Reveals Dysregulation of Exosome-Associated Proteins in Infertile Men with Unilateral Varicocele.

Abstract: Purpose Aberrant expression of seminal plasma proteins are associated with altered homeostasis that may affect the fertilizing ability of spermatozoa. However, the precise roles of seminal exosomes on sperm function remain unclear. The objective of this study was to identify the differentially expressed proteins (DEPs) associated with varicocele-mediated infertility by comparing seminal plasma protein profile of unilateral varicocele patients with proven fertile donors. Materials and methods Semen samples were obtained from 10 proven fertile donors with normal semen parameters and 33 infertile patients with unilateral varicocele. For proteomic analysis, 5 samples from each group were pooled and run in triplicate. Key DEPs (ANXA2, TF, CD63, KIF5B, SEMG1) associated with the exosome function were selected by bioinformatic tools and validated using Western blotting. Results A total of 47 seminal plasma proteins were differentially expressed in unilateral varicocele patients compared to fertile donors. Validation of exosome-associated DEPs in unilateral varicocele patients (n=7) and fertile donors (n=7) revealed significant upregulation of ANXA2 (p=0.0016) and downregulation of KIF5B (p=0.009). The main upstream regulators of the DEPs in seminal plasma of unilateral varicocele group were androgen receptor, YB1 and NRF2. Conclusions This is the first report to identify DEPs in seminal plasma of unilateral varicocele patients compared to fertile donors. Based on the detection of DEPs associated with exosomal function, Western blotting was used to validate the presence of defective exosome machinery in seminal plasma of unilateral varicocele patients. KIF5B and ANXA2 can be utilized as potential biomarkers of infertility in unilateral varicocele patients.

Gender Differences in Osteoporosis: A Single-Center Observational Study

Abstract: PURPOSE Osteoporosis affects more than 200 million people worldwide: its prevalence increases with age and is actually growing due to the constant population aging. Women are at greater risk than men, but in recent years it has become increasingly evident that osteoporosis represents a significantly important problem also for men. However, osteoporosis in men is still poorly studied, underdiagnosed and inadequately treated. MATERIALS AND METHODS We conducted an observational study to identify any gender disparities in osteoporosis screening. For this purpose we observed people consecutively admitted at our Outpatient Service for the Diagnosis of Osteoporosis during the last 3 years. Patients underwent clinical and laboratory assessment and bone mineral density (BMD) measurements by dual-energy X-ray absorptiometry. Bone turnover serum markers have been evaluated and stratified according to gender. RESULTS Out of 3,752 patients, 2,376 subjects who met the inclusion criteria were identified. As expected, the great majority (94.5%) of the screened subjects were women and only 5.4% were men. Women exhibited lower BMD compared to men (T-score values: -2.33±1.14 vs. -1.31±1.55; p<0.001), whereas the prevalence of fractures in osteoporotic men was significantly higher (50% vs. 31%; p<0.001). Women had lower vitamin D and higher bone remodeling markers compared to men. Secondary osteoporosis was more frequent in men (66.67%) than in women (20.83%) and the calculated risk for hip fractures was higher in osteoporotic men compared to women (11.47±10.62 vs. 6.87±7.73; p<0.001). CONCLUSIONS Here we highlighted that men are under-screened for osteoporosis and exhibit secondary osteoporosis more frequently than women.

Oxidative Stress, Diet and Prostate Cancer.

Abstract: Prostate cancer has become the second leading cancer in men worldwide. Androgen plays an important role in normal functioning, development, and differentiation of the prostate, and thus is considered to be the most powerful candidate that mediates reactive oxygen species (ROS) balance in the prostate. The elevation of ROS has been associated with the progression and development of this disease. Conventional therapy has shown a high cure rate in patients with localized prostate cancer. Despite the patients respond favorably initially, this therapy fails to response in the advanced stage of the diseases even in the absence of androgens. Indeed, the onset and progression of prostate cancer could be prevented by changing dietary habits. Much information indicates that oxidative stress and prostate cancer can be modulated by dietary components rich in antioxidants. While there is substantial evidence to suggest an association between prostate cancer risk and ROS-mediated oxidative stress; therefore, the interactions and mechanisms of this phenomenon are worth to discuss further. This review aimed to discuss the mechanisms of action of oxidative stress involved in the progression of prostate cancer. We also highlighted how some of the vital dietary components dampen or exacerbate inflammation, oxidative stress, and prostate cancer. Overall, the reported information would provide a useful approach to the prevention of prostate cancer.

Clinical Practice Guideline Recommendation on the Use of Low Intensity Extracorporeal Shock Wave Therapy and Low Intensity Pulsed Ultrasound Shock Wave Therapy to Treat Erectile Dysfunction: The Asia-Pacific Society for Sexual Medicine Position Statement.

Abstract: Published literature shows low intensity extracorporeal shock wave therapy (LIESWT) and low intensity pulsed ultrasound (LIPUS) therapy to improve erectile function and penile hemodynamic by inducing neovascularisation and promoting tissue regeneration. Key opinion leaders across the Asia Pacific region attended the recent biennial meeting of the Asia Pacific Society for Sexual Medicine in Australia, and presented the current evidence on LIESWT and LIPUS for erectile dysfunction (ED). The clinical findings were internally discussed, and the quality of evidence was graded based on the Oxford Centre for Evidence-Based Medicine recommendations. Existing literature supports the use of LIESWT and LIPUS in men with ED, with many clinical studies reported encouraging results with improved erectile function, good safety profile and short-term durability. However, controversial exists due to sampling heterogeneity, non-standardised treatment protocol and lack of large multiinstitutional studies. There is a need to better define which subgroup of ED population is best-suited, and specific treatment protocol to optimise shock wave energy delivery. More stringent and larger multi-institutional randomised placebo-controlled trials are warranted before clinical adoption of LIESWT and LIPUS as the new standard of care for men with ED.

Proteomic Profiling of Seminal Plasma Proteins in Varicocele Patients

Abstract: Purpose Seminal plasma provides a nutritive and protective milieu for spermatozoa. It contains factors/proteins required for sperm maturation, hyperactivation, capacitation and acrosome reaction. Alteration in the expression levels of seminal plasma proteins affect the fertilization process. The main objective of this study is to compare the seminal plasma proteome of healthy fertile men (control group) with varicocele patients in order to identify the differentially expressed seminal plasma proteins. Materials and methods Pooled seminal plasma samples from control (n=5) and varicocele (unilateral: n=5 and bilateral: n=5) subjects were used for proteomic profiling and functional bioinformatic analysis. Key differentially expressed proteins (DEPs) associated with binding of zona pellucida (acrosin; ACR), protein folding (heat shock related 70 kDa protein 2; HSPA2), oxidative stress (peroxiredoxin 2; PRDX2), lipid peroxidation and DNA fragmentation (apolipoprotein A2; APOA2) were validated by Western blot. Statistical analysis was conducted using Mann-Whitney test. Results A total of 412 and 486 proteins were detected in seminal plasma of control group and varicocele patients respectively. Twenty-eight proteins were identified as DEPs between varicocele and control group. Validation of DEPs revealed downregulation of HSPA2 (p=0.0037) as well as APOA2 (p=0.0373), and upregulation of PRDX2 (p=0.0474). Conclusions The seminal plasma protein profile of varicocele patients differ from healthy fertile men. Aberrant expression of seminal plasma proteins serve as an indicator of sperm pathology in varicocele patients.

The Natural History of Peyronie's Disease

Abstract: Peyronie's disease (PD), a fibrotic disorder of the tunica albuginea fully described in 1793 by French physician Francois de la Peyronie, is characterized by pain, plaque formation, penile deformity, and ultimately sexual function decline. The epidemiological data on PD vary considerably across previous studies, with recent evidence reporting a prevalence of up to 9%. PD is generally divided into two different phases: active or acute and stable or chronic. Plaque formation generally occurs during the acute phase, while during chronic phase pain usually tends to complete resolution and penile deformity stabilizes. PD's pathophysiology is still subject of great discussion. Tunical mechanical stress and microvascular trauma are major contributory factors. However, better understanding of the molecular pathophysiology of this condition remains paramount towards an in-depth comprehension of the disorder and the development of newer and more effective disease-targeted interventions. In this review we provide a detailed overview of natural history of PD, specifically focusing on clinical manifestations and the underlying molecular regulation patterns.

Review of Vasectomy Complications and Safety Concerns

Abstract: Vasectomy is a simple, safe, effective, and economical method used worldwide for long-term male contraception. As a surgical operation, it has short-term and long-term complications such as hematoma formation, infection, sterilization failure, sperm granulomas, short-term postoperative pain (nodal pain, scrotal pain, and ejaculation pain), and chronic pain syndrome. Whether it increases the risk of autoimmune disease, cardiovascular disease, testicular cancer, or prostate cancer is still controversial. Changes in plasma concentrations of luteinizing hormone, follicle-stimulating hormone, and testosterone after vasectomy have also been studied, as well as the relation between vasectomy and sexual function. Sperm quality decreases very slowly after vasectomy, and vasovasostomy and intracytoplasmic sperm injection could help a couple achieve a pregnancy if they change their minds at any point. We include a follow-up strategy and suggestions for follow-up care at the end of this review.

Rehabilitation Nutrition and Exercise Therapy for Sarcopenia.

Abstract: Sarcopenia is an age-related loss of skeletal muscle associated with adverse outcomes such as falls, fractures, disability, and increased mortality in older people and hospitalized patients. About half of older male nursing home residents have sarcopenia. The diagnostic criteria by the European Working Group on Sarcopenia in Older People (EWGSOP) and the Asian Working Group for Sarcopenia (AWGS) have led to increased interest in sarcopenia. Exercise and nutritional management are crucial for the prevention and treatment of sarcopenia. Nutritional therapy for sarcopenia that includes 20 g of whey protein and 800 IU of vitamin D twice a day improves lower limb strength. Exercise therapy for sarcopenia, such as resistance training and 6 months of home exercises, improves muscle strength and physical function. Combination therapy that includes both nutritional and exercise therapy improves gait speed and knee extension strength more than either exercise alone or nutrition therapy alone. Excessive bedrest and mismanagement of nutrition in medical facilities can lead to iatrogenic sarcopenia. Iatrogenic sarcopenia is sarcopenia caused by the activities of health care workers in health care facilities. Appropriate nutritional management and exercise programs through rehabilitation nutrition are important for prevention and treatment of iatrogenic sarcopenia. Nutritional and exercise therapy should be started very early after admission and adjusted to the level of inflammation and disease status. Repeated assessment, diagnosis, goal setting, interventions, and monitoring using the rehabilitation nutrition care process is important to maximize treatment effectiveness and improve patients' functional recovery and quality of life.

Sperm DNA Fragmentation: A Critical Assessment of Clinical Practice Guidelines

Abstract: Sperm DNA fragmentation (SDF) is implicated in male infertility and adverse reproductive outcomes. With the publication of many studies regarding the etiologies and contributors to SDF, as well as the effects of SDF, guidelines are necessary to aid clinicians in the application of SDF for male fertility evaluation. Two recent clinical practice guidelines were published by Agarwal et al and Esteves et al. In this article, we have evaluated and compared both guidelines. We have found fairly similar recommendations between the two guidelines and have also highlighted the differences between them. Finally, we have summarized and combined the best practice recommendations from both guidelines.

Testosterone deficiency and risk of cognitive disorders in aging males

Abstract: Cognitive impairment and dementia are predicted to undergo a dramatic increase in the following years with more than 131.5 million people being affected by 2030. Although vascular diseases play the most important role in the pathogenesis of memory impairment in aging men, some pre-clinical and clinical evidence has suggested a possible contribution of the age-dependent reduction of testosterone (T). In this paper we have summarized and discussed all the information derived from available animal and experimental studies. In addition, we meta-analyzed data rising from all randomized placebo controlled trials (RCTs) published so far. Only limited preclinical and clinical evidence can support a possible contribution of T in the pathogenesis of the age-dependent impairment of cognitive functions. In addition, our meta-analysis did not support the use of T replacement therapy for the improvement of several cognitive domains analyzed including attention/working memory, executive function, language, verbal memory, visual memory, visuomotor ability, and visuospatial ability. However, it is important to recognize that the vast majority of available RCTs included mixed populations of subjects with eugonadism and hypogonadism preventing any final conclusion being drawn on these issues.

A Novel Approach to Improving the Reliability of Manual Semen Analysis: A Paradigm Shift in the Workup of Infertile Men

Abstract: Conventional semen analysis (SA) is an essential component of the male infertility workup, but requires laboratories to rigorously train and monitor technicians as well as regularly perform quality assurance assessments. Without such measures there is room for error and, consequently, unreliable results. Furthermore, clinicians often rely heavily on SA results when making diagnostic and treatment decisions, however conventional SA is only a surrogate marker of male fecundity and does not guarantee fertility. Considering these challenges, the last several decades have seen the development of many advances in SA methodology, including tests for sperm DNA fragmentation, acrosome reaction, and capacitation. While these new diagnostic tests have improved the scope of information available to clinicians, they are expensive, time-consuming, and require specialized training. The latest advance in laboratory diagnostics is the measurement of seminal oxidation-reduction potential (ORP). The measurement of ORP in an easy, reproducible manner using a new tool called the Male Infertility Oxidative Stress System (MiOXSYS) has demonstrated ORP's potential as a feasible adjunct test to conventional SA. Additionally, the measurement of ORP by this device has been shown to be predictive of both poor semen quality and male infertility. Assessing ORP is a novel approach to both validating manual SA results and identifying patients who may benefit from treatment of male oxidative stress infertility.

A Global Survey of Reproductive Specialists to Determine the Clinical Utility of Oxidative Stress Testing and Antioxidant Use in Male Infertility.

Abstract: 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.

Macrophage and Adipocyte Mitochondrial Dysfunction in Obesity-Induced Metabolic Diseases.

Abstract: Obesity is one of major health burdens of modern society as it contributes to the growing prevalence of its related comorbidities, such as diabetes, cardiovascular diseases, and some cancers. A series of innate immune cells, especially macrophages, and adipocytes have been implicated in the pathogenesis of obesity. Mitochondrial dysfunction, which is induced by obesity, are critical mediators in initiating inflammation in macrophages and adipocytes, and subsequent systemic insulin resistance. In this review, we discuss new findings on how obesity impairs mitochondrial function in macrophages and adipocytes and how this dysfunction contributes to obesity and its comorbidities. We also summarize drugs that treat metabolic diseases by targeting mitochondrial dysfunction.

Comparison of Intralesional Hyaluronic Acid vs . Verapamil for the Treatment of Acute Phase Peyronie’s Disease: A Prospective, Open-Label Non-Randomized Clinical Study

Abstract: PURPOSE To compare the efficacy and safety of intralesional hyaluronic acid (HA) as compared with verapamil injection in patients with Peyronie's disease (PD). MATERIALS AND METHODS Between January 2015 and December 2018, men in PD acute phase were prospectively recruited. This open-label, prospective study included 2 different protocols. Group A: 8-week cycle of weekly intraplaque injections with HA; Group B: 8-week cycle of weekly intraplaque injections with verapamil. Penile curvature, plaque size, International Index of Erectile Function (IIEF)-15 score and visual analogue scale (VAS) were assessed at baseline and after 3 months. RESULTS Two-hundred forty-four patients were enrolled. Of these, 125 received intralesional HA (Group A), 119 received intralesional verapamil (Group B). At enrollment, median age was 56.0 years (interquartile range [IQR]=47.0-63.0 years), median curvature 35.0° (IQR=25.0°-45.0°), median IIEF-15 score 19.0 (IQR=16.0-23.0), median VAS 4.0 (IQR=4.0-5.0). Median difference for IIEF-15 was 1.0 (95% confidence interval [CI]=1.12-1.94) in Group A and 0.0 (95% CI=-0.04-0.14) in Group B (p<0.05) and median difference for VAS score was -4.0 (95% CI=-4.11--3.65) in Group A and -1.0 (95% CI=-0.50-2.01) in Group B (p<0.05). Plaque size decreased by -1.50 mm (IQR=1.60-2.10 mm) in Group A and -1.20 in Group B (p=0.10), while penile curvature decreased by -9.50° (IQR=4.50°-13.00°) in group A and -4.50 (IQR=2.50-7.50) in Group B (p<0.01). CONCLUSIONS Intralesional HA injections could represent a reliable treatment option for the conservative management of patients with acute phase of PD.

How to Prevent and Manage Post-Prostatectomy Incontinence: A Review.

Abstract: Purpose To provide an overview of the currently available evidence relating to the prevention and management strategies of urinary incontinence (UI) after radical prostatectomy (RP). Materials and methods A comprehensive research was carried out on MEDLINE/PubMed database to identify pertinent studies concerning post-RP UI. The search strategy included these words: urinary continence; urinary continence recovery; urinary incontinence; radical prostatectomy; and prostate cancer. Results Post-RP UI still represents a challenging issue for both urologic patients and clinicians. A complete preoperative assessment of the risk factors associated with post-RP UI aids both in counseling those patients with a higher estimated likelihood of postoperative UI and in identifying those who would probably benefit from preventive strategies in the preoperative and in the intraoperative settings. Over the last decades different surgical strategies based on either the "preservation" or the "reconstruction" of the anatomical elements responsible for urinary continence (UC) led to an overall improvement of postoperative functional outcomes. Finally, several therapeutic strategies should be evaluated for the postoperative UI management. Artificial urinary sphincter implantation represents the gold standard for treatment, notwithstanding its wide adoption is limited due to high costs and significant risk of surgical revision. In this context, male sling positioning seems the most promising strategy, in particular in mild and moderate post-RP UI. Conclusions To enhance the likelihood of obtaining an optimal UC recovery after RP, it is here strongly suggested to intervene throughout the overall clinical management process thus including the pre-, intra- and postoperative settings.

Genomic Profiling of Prostate Cancer: An Updated Review.

Abstract: Understanding the genomic profiling of prostate cancer is crucial, owing to the emergence of precision medicine to guide therapeutic approaches. Over the last decade, integrative genomic profiling of prostate tumors has provided insights that improve the understanding and treatment of the disease. Minimally invasive liquid biopsy procedures have emerged to investigate cancer-related molecules with the advantage of detecting heterogeneity as well as acquired resistance in cancer. The metastatic castration-resistant prostate cancer (mCRPC) tumors have a highly complex genomic landscape compared to primary prostate tumors; a number of mCRPC harbor clinically actionable molecular alterations, including DNA damage repair (e.g., BRCA1/2 and ATM) and PTEN/phosphoinositide 3-kinase signaling. Heterogeneity in the genomic landscape of prostate cancer has become apparent and genomic alterations of TP53, RB1, AR, and cell cycle pathway are associated with poor clinical outcomes in patients. Prostate cancer with mutant SPOP shows a distinct pattern of genomic alterations, associating with better clinical outcomes. Several genomic profiling tests, which can be used in the clinic, are approved by the U.S. Food and Drug Administration, including MSK-IMPACT, FoundationOne CDx, and FoundationOne Liquid CDx. Here, we review emerging evidence for genomic profiling of prostate cancer, especially focusing on associations between genomic alteration and clinical outcome, liquid biopsy, and actionable molecular alterations.

Advanced Paternal Age and Sperm DNA Fragmentation: A Systematic Review.

Abstract: Purpose Male ageing is often associated with defective sperm DNA remodeling mechanisms that result in poorly packaged chromatin and a decreased ability to repair DNA strand breaks. However, the impact of advanced paternal age on DNA fragmentation remains inconclusive. The aim of the present systematic review was to investigate the impact of advancing paternal age (APA) on DNA fragmentation. Materials and methods We conducted a thorough search of listed publications in Scopus, PubMed, and EMBASE, in accordance with the PRISMA guidelines. Results We identified 3,120 articles, of which nineteen were selected for qualitative analysis, resulting in a sample of 40,668 men. Of the 19 articles evaluating the impact of APA on DFI% (DNA fragmentation Index) included, 4 were on Normozoospermic and subfertile men, 3 on normozoospermic, Oligoasthenoteratozoospermic and Teratozoospermic, 6 on fertile and infertile men, 4 on just infertile men, and 2 evaluated a general population. Seventeen of the ninrnteen studies demonstrated APA's effect and impact on DFI%. Conclusions Although there was no universal definition for APA, the present review suggests that older age is associated with increased DFI. In elderly men with normal semen parameters, further studies should be performed to assess the clinical implications of DFI, as a conventional semen analysis can often fail to detect an etiology for infertility.

Consequences of Anabolic-Androgenic Steroid Abuse in Males; Sexual and Reproductive Perspective.

Abstract: The real epidemiology and the possible consequences of anabolic-androgenic steroids (AAS) use still represent a very tricky task due to the difficulties in the quantification and detection of these drugs. Chronic use of AAS, frequently combined with other illicit substances, can induce tremendous negative effects on the reproductive system, but it is also associated with an increased overall and cardiovascular mortality risk. In the present review we summarize and discuss the available evidence regarding the negative impact of AAS on the male reproductive system, providing practical suggestions to manage these problems. For this purpose a meta-analysis evaluating the effects of AAS abusers vs. controls on several hormonal, reproductive and metabolic parameters was performed. In addition, in order to overcome possible limitations related to the combined use of different AAS preparations, we also retrospectively re-analyzed data on animal models treated with supraphysiological dosage of testosterone (T), performed in our laboratory. Available data clearly indicated that AAS negatively affect endogenous T production. In addition, increased T and estradiol circulating levels were also observed according to the type of preparations used. The latter leads to an impairment of sperm production and to the development of side effects such as acne, hair loss and gynecomastia. Furthermore, a worse metabolic profile, characterized by reduced high density lipoprotein and increased low density lipoprotein cholesterol levels along with an increased risk of hypertension has been also detected. Finally sexual dysfunctions, often observed upon doping, represent one the most probable unfavorable effects of AAS abuse.

Premature Ejaculation and Endocrine Disorders: A Literature Review.

Abstract: Premature ejaculation (PE) is the most common male sexual dysfunction, with 30% of men experiencing PE worldwide. According to the generally accepted classification, there are two types of PE: lifetime PE and acquired PE. Various biological and psychological causes are known to be involved in the etiology of PE. However, due to the incomplete definition and etiopathogenesis of PE, there is no effective treatment. Although clinical and animal studies indicate that hormones play a role in controlling the ejaculation process, the precise endocrine mechanisms are unclear. In addition, little is known about the role of endocrine disorders in PE etiology. However, there is evidence that diabetes mellitus (DM), obesity, metabolic syndrome (MetS), thyroid gland disorders, pituitary gland disorders, and vitamin D deficiency affect the prevalence of PE. Moreover, it has been reported that the prevalence of PE decreases with treatment of these endocrine disorders. In this review, the relationship between PE and DM, MetS, obesity, vitamin D deficiency, and thyroid and pituitary gland disorders is summarized.

Cardiovascular Risks of Androgen Deprivation Therapy for Prostate Cancer

Abstract: Androgen deprivation therapy (ADT) is the gold standard treatment in patients with locally advanced or metastatic prostate cancer (PC). Emerging evidence has documented a tight association between ADT and body composition, along with metabolic profile impairment. These alterations might underpin the observed ADT-related increase in cardiovascular (CV) and thromboembolic (venous thromboembolism, VTE) mortality and morbidity. However, the specific mechanisms underlying these associations have not yet been completely elucidated. In the present review we summarize and discussed the available evidence linking ADT to increased cardio-metabolic risk, using both preclinical and clinical data. When possible, meta-analytic studies were preferred. Preclinical evidence, using a rabbit model of gonadotrophin-releasing hormone analogue-induced hypogonadism, indicates that the induced condition is associated with a dramatic increase in visceral adiposity and with an impairment of acetylcholine induced vascular relaxation, along with an increased propensity towards fatty liver. This suggests a direct role of ADT in inducing a worsened metabolic profile. In contrast, available clinical data are not sufficient to clarify a direct pathogeniclink between reduced testosterone (T) and altered metabolism. In fact, although T deprivation is associated with an altered metabolism, it is possible that the association between ADT and CV or VTE risk could simply be the result of a selection bias, related to the poor health status of patients with advanced PC. Despite the aforementioned considerations, all patients who are candidatesfor ADT should be screened for CV risk factors at baseline and monitored during the therapy. Life-style modifications and physical exercise are strongly encouraged.

Energy Metabolism and Aging

Abstract: Aging is strongly related to energy metabolism, but the underlying processes and mechanisms are complex and incompletely understood. Restricting energy intake and reducing metabolic rate can slow the rate of aging and extend longevity, implying a reciprocal relationship between energy metabolism and life expectancy. However, increased energy expenditure has also been associated with improved health and longer life. In both experimental animals and humans, reduced body temperature has been related to extended longevity. However, recent findings on the function of thermogenic (brown or beige) adipose tissue produced intense interest in increasing the amount of energy expended for thermogenesis to prevent and/or treat obesity, improve metabolic health, and extend life. Evidence available to-date indicates that increasing adipose tissue thermogenesis by pharmacologic, environmental, or genetic interventions can indeed produce significant metabolic benefits, which are associated with improved chances for healthy aging and long life.