'Intracytoplasmic sperm injection (ICSI) paradox' and 'andrological ignorance': AI in the era of fourth industrial revolution to navigate the blind spots.

The quandary known as the Intracytoplasmic Sperm Injection (ICSI) paradox is found at the juncture of Assisted Reproductive Technology (ART) and 'andrological ignorance' - a term coined to denote the undervalued treatment and comprehension of male infertility. The prevalent use of ICSI as a solution for severe male infertility, despite its potential to propagate genetically defective sperm, consequently posing a threat to progeny health, illuminates this paradox. We posit that the meteoric rise in Industrial Revolution 4.0 (IR 4.0) and Artificial Intelligence (AI) technologies holds the potential for a transformative shift in addressing male infertility, specifically by mitigating the limitations engendered by 'andrological ignorance.' We advocate for the urgent need to transcend andrological ignorance, envisaging AI as a cornerstone in the precise diagnosis and treatment of the root causes of male infertility. This approach also incorporates the identification of potential genetic defects in descendants, the establishment of knowledge platforms dedicated to male reproductive health, and the optimization of therapeutic outcomes. Our hypothesis suggests that the assimilation of AI could streamline ICSI implementation, leading to an overall enhancement in the realm of male fertility treatments. However, it is essential to conduct further investigations to substantiate the efficacy of AI applications in a clinical setting. This article emphasizes the significance of harnessing AI technologies to optimize patient outcomes in the fast-paced domain of reproductive medicine, thereby fostering the well-being of upcoming generations.

Environmental and Genetic Traffic in the Journey from Sperm to Offspring.

Recent advancements in the understanding of how sperm develop into offspring have shown complex interactions between environmental influences and genetic factors. The past decade, marked by a research surge, has not only highlighted the profound impact of paternal contributions on fertility and reproductive outcomes but also revolutionized our comprehension by unveiling how parental factors sculpt traits in successive generations through mechanisms that extend beyond traditional inheritance patterns. Studies have shown that offspring are more susceptible to environmental factors, especially during critical phases of growth. While these factors are broadly detrimental to health, their effects are especially acute during these periods. Moving beyond the immutable nature of the genome, the epigenetic profile of cells emerges as a dynamic architecture. This flexibility renders it susceptible to environmental disruptions. The primary objective of this review is to shed light on the diverse processes through which environmental agents affect male reproductive capacity. Additionally, it explores the consequences of paternal environmental interactions, demonstrating how interactions can reverberate in the offspring. It encompasses direct genetic changes as well as a broad spectrum of epigenetic adaptations. By consolidating current empirically supported research, it offers an exhaustive perspective on the interwoven trajectories of the environment, genetics, and epigenetics in the elaborate transition from sperm to offspring.

Astaxanthin Supplementation Augments the Benefits of CrossFit Workouts on Semaphorin 3C and Other Adipokines in Males with Obesity.

Regular physical activity and the use of nutritional supplements, including antioxidants, are recognized as efficacious approaches for the prevention and mitigation of obesity-related complications. This study investigated the effects of 12 weeks of CrossFit training combined with astaxanthin (ASX) supplementation on some plasma adipokines in males with obesity. Sixty-eight males with obesity (BMI: 33.6 ± 1.4 kg·m-2) were randomly assigned into four groups: the control group (CG; n = 11), ASX supplementation group (SG; n = 11), CrossFit group (TG; n = 11), and training plus supplement group (TSG; n = 11). Participants underwent 12 weeks of supplementation with ASX or placebo (20 mg/day capsule daily), CrossFit training, or a combination of both interventions. Plasma levels of semaphorin 3C (SEMA3C), apelin, chemerin, omentin1, visfatin, resistin, adiponectin, leptin, vaspin, and RBP4 were measured 72 h before the first training session and after the last training session. The plasma levels of all measured adipokines were significantly altered in SG, TG, and TSG groups (p < 0.05). The reduction of resistin was significantly higher in TSG than in SG (p < 0.05). The plasma levels of omentin1 were significantly higher in both training groups of TG and TSG than SG (p < 0.05), although such a meaningful difference was not observed between both training groups (p > 0.05). Significant differences were found in the reductions of plasma levels of vaspin, visfatin, apelin, RBP4, chemerin, and SEMA3C between the SG and TSG groups (p < 0.05). The study found that a 12-week intervention using ASX supplementation and CrossFit exercises resulted in significant improvements in several adipokines among male individuals with obesity. Notably, the combined approach of supplementation and training had the most pronounced results. The findings presented in this study indicate that the supplementation of ASX and participation in CrossFit exercise have the potential to be effective therapies in mitigating complications associated with obesity and enhancing metabolic health.

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction.

Confluence of environmental, genetic, and lifestyle variables is responsible for deterioration of human fecundity. Endocrine disruptors or endocrine disrupting chemicals (EDCs) may be found in a variety of foods, water, air, beverages, and tobacco smoke. It has been demonstrated in experimental investigations that a wide range of endocrine disrupting chemicals have negative effects on human reproductive function. However, evidence on the reproductive consequences of human exposure to endocrine disrupting chemicals is sparse and/or conflicting in the scientific literature. The combined toxicological assessment is a practical method for assessing the hazards of cocktails of chemicals, co-existing in the environment. The current review provides a comprehensive overview of studies emphasizing the combined toxicity of endocrine disrupting chemicals on human reproduction. Endocrine disrupting chemicals interact with each other to disrupt the different endocrine axes, resulting in severe gonadal dysfunctions. Transgenerational epigenetic effects have also been induced in germ cells, mostly through DNA methylation and epimutations. Similarly, after acute or chronic exposure to endocrine disrupting chemicals combinations, increased oxidative stress (OS), elevated antioxidant enzymatic activity, disrupted reproductive cycle, and reduced steroidogenesis are often reported consequences. The article also discusses the concentration addition (CA) and independent action (IA) prediction models, which reveal the importance of various synergistic actions of endocrine disrupting chemicals mixtures. More crucially, this evidence-based study addresses the research limitations and information gaps, as well as particularly presents the future research views on combined endocrine disrupting chemicals toxicity on human reproduction.

Effectiveness of exercise interventions in animal models of multiple sclerosis.

Multiple sclerosis (MS) is associated with an impaired immune system that severely affects the spinal cord and brain, and which is marked by progressive inflammatory demyelination. Patients with MS may benefit from exercise training as a suggested course of treatment. The most commonly used animal models of studies on MS are experimental autoimmune/allergic encephalomyelitis (EAE) models. The present review intends to concisely discuss the interventions using EAE models to understand the effectiveness of exercise as treatment for MS patients and thereby provide clear perspective for future research and MS management. For the present literature review, relevant published articles on EAE animal models that reported the impacts of exercise on MS, were extracted from various databases. Existing literature support the concept that an exercise regimen can reduce the severity of some of the clinical manifestations of EAE, including neurological signs, motor function, pain, and cognitive deficits. Further results demonstrate the mechanisms of EAE suppression with information relating to the immune system, demyelination, regeneration, and exercise in EAE. The role for neurotrophic factors has also been investigated. Analyzing the existing reports, this literature review infers that EAE is a suitable animal model that can help researchers develop further understanding and treatments for MS. Besides, findings from previous animal studies supports the contention that exercise assists in ameliorating MS progression.

COVID-19 and hypogonadism: secondary immune responses rule-over endocrine mechanisms.

Men show higher vulnerability to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (COVID-19) and present with depleted testosterone levels. Reports pertaining to high luteinizing hormone (LH), while diminished levels of in COVID-19 patients negate the hypothalamic-pituitary-testicular (HPT) axis mediated lowering of testosterone. Although not evidenced, high testicular expression of angiotensin-converting enzymes-2 (ACE2), that aids viral entry into cells, may suggest direct viral-testicular invasion. However, secondary inflammation and oxidative stress (OS), owing to SARS-CoV-2 infection, are more likely to impair steroidogenesis. Moreover, blockage of ACE2 aided angiotensin II into angiotensin (1-7) conversion may also affect testosterone synthesis. SARS-CoV-2, by mimicking adrenocorticotrophic (ACTH) hormones, may trigger host antibodies against the ACTH molecules to suppress host stress response. This commentary concisely presents the possible mechanisms by which SARS-CoV-2 infection may affect testosterone levels, which possibly result in compromised male reproductive health.

Optimization of estrogen dosage for uterine receptivity for implantation in post-coital bilaterally ovariectomized mice.

Estrogens and progesterone, in unison and/or separately, synchronize the distinct events of blastocyst development, uterine priming and receptivity induction for implantation. In contrast to high implantation failure rates, the mechanistic concepts regarding the uterine receptivity for implantation still remain elusive. The present study aims to define the minimum estradiol (E2) dose to induce uterine receptivity for successful implantation in post-coitus bilaterally ovariectomized (BLO) progesterone-primed uterus of mice. Post-coital sperm-positive adult female mice were divided into two groups. In both the groups, delayed implantation was induced by BLO on post-coitus Day 4 (D4). Group 1 received 2 mg of progesterone (P4) from D5 until sacrifice, and E2 injection of 3.0, 10.0, 25.0 and 50.0 ng on D7. On D8, all mice of this group were sacrificed except the mice that received second dose of 25.0 ng of E2 on D8 and were sacrificed on D9. Group 2 followed the same doses, but were given simultaneously on D4, and sacrificed on D5. The mice that received second doses of 25.0 ng E2 were sacrificed on D6. The minimum dose of E2 required to induce uterine receptivity for implantation is a single dose of 50.0 ng E2. The uterus remained refractory following short receptive period at E2 doses lower than 50.0 ng, which is just sufficient to establish desired uterine receptivity. However, repeated administration of sub-threshold doses of 25.0 ng of E2 could also not effectively sustain uterine receptivity towards successful implantation.

Impact of Varicocele Repair on Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis.

PURPOSE: Despite the significant role of varicocele in the pathogenesis of male infertility, the impact of varicocele repair (VR) on conventional semen parameters remains controversial. Only a few systematic reviews and meta-analyses (SRMAs) have evaluated the impact of VR on sperm concentration, total motility, and progressive motility, mostly using a before-after analytic approach. No SRMA to date has evaluated the change in conventional semen parameters after VR compared to untreated controls. This study aimed to evaluate the effect of VR on conventional semen parameters in infertile patients with clinical varicocele compared to untreated controls. MATERIALS AND METHODS: A literature search was performed using Scopus, PubMed, Embase, and Cochrane databases following the Population Intervention Comparison Outcome (PICOS) model (Population: infertile patients with clinical varicocele; Intervention: VR [any technique]; Comparison: infertile patients with clinical varicocele that were untreated; Outcome: sperm concentration, sperm total count, progressive sperm motility, total sperm motility, sperm morphology, and semen volume; Study type: randomized controlled trials and observational studies). RESULTS: A total of 1,632 abstracts were initially assessed for eligibility. Sixteen studies were finally included with a total of 2,420 infertile men with clinical varicocele (1,424 patients treated with VR vs. 996 untreated controls). The analysis showed significantly improved post-operative semen parameters in patients compared to controls with regards to sperm concentration (standardized mean difference [SMD] 1.739; 95% CI 1.129 to 2.349; p<0.001; I²=97.6%), total sperm count (SMD 1.894; 95% CI 0.566 to 3.222; p<0.05; I²=97.8%), progressive sperm motility (SMD 3.301; 95% CI 2.164 to 4.437; p<0.01; I²=98.5%), total sperm motility (SMD 0.887; 95% CI 0.036 to 1.738; p=0.04; I²=97.3%) and normal sperm morphology (SMD 1.673; 95% CI 0.876 to 2.470; p<0.05; I²=98.5%). All the outcomes showed a high inter-study heterogeneity, but the sensitivity analysis showed that no study was sensitive enough to change these results. Publication bias was present only in the analysis of the sperm concentration and progressive motility. No significant difference was found for the semen volume (SMD 0.313; 95% CI -0.242 to 0.868; I²=89.7%). CONCLUSIONS: This study provides a high level of evidence in favor of a positive effect of VR to improve conventional semen parameters in infertile men with clinical varicocele. To the best of our knowledge, this is the first SRMA to compare changes in conventional semen parameters after VR with changes in parameters of a control group over the same period. This is in contrast to other SRMAs which have compared semen parameters before and after VR, without reference to a control group. Our findings strengthen the available evidence and have a potential to upgrade professional societies' practice recommendations favoring VR to improve conventional semen parameters in infertile men.

Are sexually transmitted infections associated with male infertility? A systematic review and in-depth evaluation of the evidence and mechanisms of action of 11 pathogens.

Purpose: To systematically review the evidence on the association between sexually transmitted infections (STIs) and male infertility. We sought to answer two questions: Are STIs significantly associated with detrimental changes in semen parameters?; and, is the prevalence of STIs significantly higher in infertile than fertile men? Materials and methods: PubMed, Scopus and Google Scholar databases were searched (inceptionMarch 2023) following the PRISMA guidelines. Identified original studies in English on the association between STIs and male infertility were included. Data was tabulated/described by pathogen, mechanisms of action, number of studies and their level of evidence. Results: Seventy out of 903 originally retrieved articles were included in this review. For the detrimental changes in semen parameters (first question), the evidence seems equivocal based on the nearly equal number of studies and similar levels of evidence. The only exception was for Ureaplasma, where the number of studies and levels of evidence supported an association with male infertility. Pertaining to a significantly higher prevalence of STI among infertile compared to fertile men (second question), evidence was insufficient to support/deny a significant association. The two exceptions were Ureaplasma and Mycoplasma, where the number of studies and evidence levels were in favour of an association with male infertility. Conclusions: Generally, the relationship between STIs and male infertility remains to be uncovered. Our appraisal of the overall state of this relationship shows that the evidence base leaves much to be desired. The exceptions are Ureaplasma and Mycoplasma, where the evidence convincingly suggests their associations with infertility in men.

Polycystic Ovary Syndrome: An Updated Overview Foregrounding Impacts of Ethnicities and Geographic Variations.

Polycystic ovary syndrome (PCOS) is one of the most common heterogeneous conditions of the endocrine reproductive system in women of childbearing age. Hyperandrogenism and oligomenorrhea are the two core characteristics of PCOS, a complicated and multifaceted illness. The condition is also linked to several major side effects, which include type 2 diabetes, early atherosclerosis, infertility, and endometrial cancer. There are few facts and statistics available on PCOS prevalence internationally due to the significant degree of geographic and ethnic variance and inconsistency caused by different diagnosis standards. Limited (n = 179) explorations have been made in the context of the prevalence of this complicated illness so far, and out of these, only 55 studies have discussed its association with race and/or ethnicity. However, those studies remain restricted due to the small sample size, biased selection, and the lack of comparative studies. Variations in PCOS prevalence frequency also arise due to different diagnostic criteria, as well as racial and ethnic differences, associated lifestyle factors, and subsequent illnesses that affect the accuracy of the diagnosis. The main objective behind this systematic review is to provide comprehensive epidemiological data on PCOS that is organized geographically. This evidence-based study also provides an overview of the clinical management of PCOS to instigate further research on this complex endocrinological condition and the subsequent development of preventive treatment strategies.

Arsenic-Induced Sex Hormone Disruption: An Insight into Male Infertility.

Arsenic (As) is one of the most potent natural as well as anthropogenic metalloid toxicants that have various implications in the everyday life of humans. It is found in several chemical forms such as inorganic salt, organic salt, and arsine (gaseous form). Although it is mostly released via natural causes, there are many ways through which humans come in contact with As. Drinking water contamination by As is one of the major health concerns in various parts of the world. Arsenic exposure has the ability to induce adverse health effects including reproductive problems. Globally, around 15% of the couples are affected with infertility, of which about 20-30% are attributed to the male factor. Arsenic affects the normal development and function of sperm cells, tissue organization of the gonads, and also the sex hormone parameters. Stress induction is one of the implications of As exposure. Excessive stress leads to the release of glucocorticoids, which impact the oxidative balance in the body leading to overproduction of reactive oxygen species (ROS). This may in turn result in oxidative stress (OS) ultimately interfering with normal sperm and hormonal parameters. This study deals with As-induced OS and its association with sex hormone disruption as well as its effect on sperm and semen quality.

Reductive Stress and Male Infertility.

Male infertility research and clinical advances had vast progress in the last few decades. Strong research evidence underpinned the concepts of oxidative stress (OS)-mediated male reproductive disruptions, which bear answers to several cases of idiopathic male infertility. Antioxidant treatment held the prime solution for OS-mediated male infertility. But excess use of antioxidants is challenged by the research breakthrough that reductive stress also predisposes to male infertility, resolutely instituting that any biological extremes of the redox spectrum are deleterious to male fertility. Superfluity of reducing agents may hinder essential oxidation mechanisms, affecting physiological homeostasis. These mechanisms need to be explicated and updated time and again to identify the fine thread between OS-mediated male infertility treatment and induction of reductive stress. This chapter thus presents the evidence-based concepts pertaining to the antioxidants actions to combat OS-induced male infertility, the mechanism of induction of reductive stress and its impact on male reproduction.

Viral Infections and Male Infertility: A Comprehensive Review of the Role of Oxidative Stress.

Viral infections have been a part of human existence to date, though viruses have posed a huge threat with various outbreaks lately. These threats are associated with reproductive health challenges, especially male infertility. The prime focus of this review is to highlight the mechanisms associated with viral infection-induced male infertility/subfertility and identify new treatment strategies with the aim to preserve male fertility. The reviewed data showed that viral infections stimulate inflammatory responses, resulting in the release of proinflammatory cytokines, which induces oxidative stress. This oxido-inflammatory cycle could continue in a vicious cycle and threaten male fertility. Existing data from human and experimental studies show that viral infection-induced oxido-inflammatory response results in testicular damage, atrophy of the seminiferous tubules and Sertoli cells, and reduced Leydig cell mass. This is accompanied by reduced circulatory testosterone, impaired spermatogenesis, reduced sperm motility, lipid peroxidation, DNA fragmentation and apoptosis of the sperm cells. Based on the available pieces of evidence, antioxidant therapy, in vivo and in vitro, may be beneficial and protects against the potential risk of male infertility from viral infection. It is, however recommended that more clinical studies be conducted to demonstrate the possible protective roles of antioxidants used as adjuvant therapy in viral infections, and in the in vitro treatment of semen samples for those utilizing semen washing and artificial reproductive techniques.

A Comparative Cross-Platform Analysis to Identify Potential Biomarker Genes for Evaluation of Teratozoospermia and Azoospermia.

Male infertility is a global public health concern. Teratozoospermia is a qualitative anomaly of spermatozoa morphology, contributing significantly to male infertility, whereas azoospermia is the complete absence of spermatozoa in the ejaculate. Thus, there is a serious need for unveiling the common origin and/or connection between both of these diseases, if any. This study aims to identify common potential biomarker genes of these two diseases via an in silico approach using a meta-analysis of microarray data. In this study, a differential expression analysis of genes was performed on four publicly available RNA microarray datasets, two each from teratozoospermia (GSE6872 and GSE6967) and azoospermia (GSE145467 and GSE25518). From the analysis, 118 DEGs were found to be common to teratozoospermia and azoospermia, and, interestingly, sperm autoantigenic protein 17 (SPA17) was found to possess the highest fold change value among all the DEGs (9.471), while coiled-coil domain-containing 90B (CCDC90B) and coiled-coil domain-containing 91 (CCDC91) genes were found to be common among three of analyses, i.e., Network Analyst, ExAtlas, and GEO2R. This observation indicates that SPA17, CCDC90B, and CCDC91 genes might have significant roles to play as potential biomarkers for teratozoospermia and azoospermia. Thus, our study opens a new window of research in this area and can provide an important theoretical basis for the diagnosis and treatment of both these diseases.

Reactive Nitrogen Species and Male Reproduction: Physiological and Pathological Aspects.

Reactive nitrogen species (RNS), like reactive oxygen species (ROS), are useful for sustaining reproductive processes such as cell signaling, the regulation of hormonal biosynthesis, sperm capacitation, hyperactivation, and acrosome reaction. However, endogenous levels of RNS beyond physiological limits can impair fertility by disrupting testicular functions, reducing gonadotropin production, and compromising semen quality. Excessive RNS levels cause a variety of abnormalities in germ cells and gametes, particularly in the membranes and deoxyribonucleic acid (DNA), and severely impair the maturation and fertilization processes. Cell fragmentation and developmental blockage, usually at the two-cell stage, are also connected with imbalanced redox status of the embryo during its early developmental stage. Since high RNS levels are closely linked to male infertility and conventional semen analyses are not reliable predictors of the assisted reproductive technology (ART) outcomes for such infertility cases, it is critical to develop novel ways of assessing and treating oxidative and/or nitrosative stress-mediated male infertility. This review aims to explicate the physiological and pathological roles of RNS and their relationship with male reproduction.

Vulnerability of The Male Reproductive System to SARS-CoV-2 Invasion: Potential Role for The Endoplasmic Reticulum Chaperone Grp78/HSPA5/BiP.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may adversely affect male reproductive tissues and male
fertility. This concern is elicited by the higher susceptibility and mortality rate of men to the SARS-CoV-2 mediated coronavirus disease-19 (COVID-19), compared to the women. SARS-CoV-2 enters host cells after binding to a functional receptor named angiotensin-converting enzyme-2 (ACE2) and then replicates in the host cells and gets released into the plasma. SARS-CoVs use the endoplasmic reticulum (ER) as a site for viral protein synthesis and processing, as well as glucose-regulated protein 78 (Grp78) is a key ER chaperone involved in protein folding by preventing newly synthesized proteins from aggregation.
Therefore, we analyzed Grp78 expression in various human organs, particularly male reproductive organs, using Broad
Institute Cancer Cell Line Encyclopedia (CCLE), the Genotype-Tissue Expression (GTEx), and Human Protein Atlas online
datasets. Grp78 is expressed in male reproductive tissues such as the testis, epididymis, prostate, and seminal vesicle. It can facilitate the coronavirus entry into the male reproductive tract, providing an opportunity for its replication. This link between the SARS-CoV-2 and the Grp78 protein could become a therapeutic target to mitigate its harmful effects on male fertility.