Idiopathic Male Infertility Research Articles

Pharmacological therapies for male infertility.

Male factor infertility is a multifaceted problem that affects approximately 50% of couples suffering from infertility. Causes of male infertility include endocrine disturbances, gonadotoxins, genetic abnormalities, varicocele, malignancies, infections, congenital or acquired urogenital abnormalities, iatrogenic factors, immunological factors, and idiopathic reasons. There are a variety of treatment options for male infertility, depending on the underlying cause(s). These can include surgical treatments, medical/hormonal therapies, and assisted reproductive techniques (ART), which can be combined with surgical sperm retrieval (SSR) if necessary. In this review article, the pharmacological therapies for male infertility are grouped by their underlying causes. Some of these therapies are targeted and specific, while others are used empirically to treat idiopathic male infertility. This will include treatments to optimize infertility in patients who have hypogonadism, ejaculatory dysfunction, infections, or idiopathic male infertility. Finally, we will provide an overview of the future directions of pharmacological therapies for male infertility. Significance Statement Male infertility is a significant worldwide problem. Detailed knowledge of the pharmacological therapies available will ensure the prescription of appropriate therapy and avoid the use of unnecessary or harmful treatments.

Semen static oxidation-reduction potential is not helpful in evaluating male fertility.

Infertility affects a significant percentage of couples worldwide, with male infertility contributing substantially in a considerable number of cases. Research indicates that oxidative stress is a critical factor impacting male fertility. To explore the relationship between semen static oxidation-reduction potential (sORP), sperm parameters, and validated biomarkers of oxidative stress in infertile men. This cross-sectional study involved 202 men diagnosed with idiopathic male factor infertility and male partners from couples with unexplained infertility. Multivariable linear regression to query the associations between sORP, sperm parameters, and oxidative aggression biomarkers (lipid peroxidation, mitochondrial membrane potential, annexin V, and sperm DNA fragmentation). SORP has no linear association with any semen analysis parameter. Furthermore, its relationship with validated biomarkers of oxidative stress was inconsistent. sORP was inversely related to lipid peroxidation (multivariable linear regression coefficient: -0.64), positively associated with sperm DNA fragmentation (multivariable linear regression coefficient: 3.20), and unrelated to mitochondrial membrane potential or annexin V. There is no clear or consistent relationship between sORP and validated oxidative aggression biomarkers or sperm parameters. Our findings suggest that sORP is unlikely to be helpful in the evaluation of a male with idiopathic infertility.

Single nucleotide polymorphisms of CFAP43 and TEX14 associated with idiopathic male infertility in a Vietnamese population.

Male infertility is a multifactorial disease due to spermatogenesis impairment, with etiology remaining unknown for roughly one-third of infertile cases. Several studies have demonstrated that genetic variants are male infertility risk factors. CFAP43 and TEX14 are involved in the spermatogenesis process. The present study aimed to assess the association between single-nucleotide polymorphisms (SNPs) in CFAP43 (rs17116635 and rs10883979) and TEX14 (rs79813370 and rs34818467) and idiopathic male infertility in a Vietnamese population. A cohort of 206 infertile men and 195 controls were recruited for the study. CFAP43 and TEX14 SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypes of randomly selected samples, accounting for 10% of the total, were confirmed using Sanger sequencing. The obtained data were analyzed using statistical methods. The results showed that 4 SNPs (rs17116635, rs10883979, rs79813370, and rs34818467) were in accordance with Hardy-Weinberg Equilibrium (HWE; P > .05). CFAP43 rs10883979 and TEX14 rs79813370 were associated with male infertility. For CFAP43 rs10883979, in the recessive model, the combination AA + AG was associated with male infertility when compared to the GG genotype (OR = 0.26; 95% CI: 0.06-0.85; P = .02). For TEX14 rs79813370, a protective effect against infertility risk was identified in the presence of the T allele of rs79813370 when compared to the G allele (OR = 0.48; 95% CI: 0.32-0.72; P < .001). Our results suggest that CFAP43 rs10883979 and TEX14 rs79813370 are likely associated with male infertility in the Vietnamese population, in which the G allele of rs79813370 may be a risk factor for male infertility.

Telomeric RNAs, TERRA, as a Potential Biomarker for Spermatozoa Quality.

Characterization of long non-coding telomeric repeat-containing RNAs in sperm of normozoospermic and oligoasthenozoospermic men as new biomarker of idiopathic male infertility. We conducted an observational prospective study with two groups of men with normal or orligoasthenozoospermic spermiogram, aged 40 and above. Fertility parameters were analyzed in men undergoing intracytoplasmic sperm injection with donor oocytes, to avoid the female factor. Telomeric RNAs and telomere length were measured by quantitative fluorescent in situ hybridization. Data from seminal parameters and in-vitro fertilization were assessed according to IVIRMA protocols. Patients with oligoasthenozoospermia, who had worse seminal parameters, also obtained embryos with lower inner-cell-mass quality (p = 0.04), despite using donor oocytes. While mean levels of telomeric RNAs were similar for both groups, the percentage of spermatozoa with more than 3 foci was higher in oligoasthenozoospermic men (p = 0.02). Regarding telomere length, oligoasthenozoospermic men had shorter mean, a higher accumulation of short telomeres (15th percentile; p = 0.03) and a lower percentage of very-long telomeres (85th percentile; p = 0.01). Finally, a positive correlation was found between telomeric-RNAs intensity and total progressive motility in the spermatozoa of normozoospermic patients (r = 0.5; p = 0.03). Telomeric parameters were altered in the spermatozoa of the oligoasthenozoospermic group, which also showed lower quality embryos. Interestingly, in the normozoospermic group, a correlation was found between progressive motility and telomeric RNA levels, suggesting that they could be a good biomarker of sperm quality. Further studies are required to confirm these results and translate them into the clinical practice.Trial registration number: 1711-MAD-109-CB, 07/07/2021.

Human sperm RNA in male infertility.

The function and value of specific sperm RNAs in apparently idiopathic male infertility are currently poorly understood. Whether differences exist in the sperm RNA profile between patients with infertility and fertile men needs clarification. Similarly, the utility of sperm RNAs in predicting successful sperm retrieval and assisted reproductive technique (ART) outcome is unknown. Patients with infertility and fertile individuals seem to have differences in the expression of non-coding RNAs that regulate genes controlling spermatogenesis. Several RNAs seem to influence embryo quality and development. Also, RNA types seem to predict successful sperm retrieval in patients with azoospermia. These findings suggest that sperm RNAs could influence decision-making during the management of patients with infertility. This evidence might help to identify possible therapeutic approaches aimed at modulating the expression of dysregulated genes in patients with infertility. Performing prospective studies with large sample sizes is necessary to investigate cost-effective panels consisting of proven molecular targets to ensure that this evidence can be translated to clinical practice.

Evaluation of daily supplementation of fertitonex on different semen parameters in idiopathic male infertility: a randomized double blind placebo controlled cross over study.

The study aimed to evaluate the effect of fertitonex containing L-carnitine L-tartrate together with other micronutrients on different semen parameters in idiopathic male infertility as well as male reproductive hormones. 100 randomized infertile patients were recruited from July 2023 to February 2024. They were randomized into two groups. Group (A) received fertitonex twice daily for the first 3months. Group (B) received placebo twice daily for the first 3months. Crossover was done after 1month wash-out period for additional 3months. Group (A) who started fertitonex first showed significant improvement in sperms concentration and motility and progressive motility as well as significant reduction in abnormal forms after 3months from beginning the study (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). Interestingly, these improvements continued for additional 3months after placebo intake (p < 0.001, p 0.005, p < 0.001, p < 0.001, respectively). Group (B) who started placebo first showed significant improvement in sperms concentration and motility and progressive motility as well as significant reduction in abnormal forms after 6months from beginning the study (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). LH level was significantly higher among group (A) compared to group (B) at baseline and 3months and 6months (p value 0.02, 0.032. 0.024, respectively). We finally concluded that fertitonex is an effective, tolerable and safe drug that can be used for treating idiopathic male infertility.

Association of Functional Genetic Variations in Uric Acid Transporters with the Risk of Idiopathic Male Infertility: A Genetic Association Study and Bioinformatic Analysis.

Uric acid plays an important role in sustaining and improving sperm morphology, viability, and motility. It is known that SLC2A9 and ABCG2 protein are the main urate transporter and genetic variations in these genes could be associated with the levels of serum uric acid. This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) SLC2A9-rs16890979, SLC2A9-rs3733591, ABCG2-rs2231142, and ABCG2-rs2231137 with male infertility. Additionally, the correlation of these SNPs with the uric acid level in seminal plasma of infertile men was examined. Subsequently, an in silico analysis was performed. In a case-control study, 193 infertile and 154 healthy controls were recruited. After semen sample collection, the uric acid level of seminal plasma was measured by a commercial kit. After genomic DNA extraction from sperm samples, SNPs genotyping was performed by PCR-RFLP method. Lastly, the effects of SNPs on the SLC2A9 and ABCG2 gene function were evaluated by bioinformatics tools. The genetic association study revealed that there are significant associations between rs16890979, rs3733591, rs2231142, and rs2231137 genetic variations and increased risk of male infertility. Also, these variations were associated with oligozoospermia and teratozoospermia, and sometimes with asthenozoospermia. Also, we found that four studied SNPs could be associated with a decreased level of uric acid of seminal plasma in teratozoospermia and asthenozoospermia. Bioinformatic analysis revealed that the mentioned polymorphisms could affect molecular aspects of SLC2A9 and ABCG2 genes. In this preliminary study, the rs16890979, rs3733591, rs2231142, and rs2231137 genetic variations could be considered as genetic risk factors for male infertility by interfering with the uric acid level of seminal plasma.

Cadmium exposure and its association with oxidative stress, MT1A methylation, and idiopathic male infertility in Egypt: A case-control study

Idiopathic male infertility, a significant health concern, lacks a clear etiology. Cadmium (Cd), a widespread environmental pollutant known to impact male reproductive health negatively, can accumulate in mussels, a common food source in Egypt. This study investigated the link between ecological Cd exposure, oxidative stress, MT1A methylation, and idiopathic male infertility in two regions of Alexandria. Thirty-three infertile men and 33 fertile controls were included. Cd levels were measured in mussels from the study sites and in participants' blood and semen. Biomarkers reflecting Cd exposure and its effects were assessed. Mussel Cd levels exceeded regulatory limits. Infertile men revealed significantly higher blood and semen Cd levels, reduced semen quality, increased oxidative stress, and elevated MT1A methylation compared to controls. MT1A methylation was inversely correlated with sperm count and is the strongest predictor of idiopathic male infertility, demonstrating the lowest p-value and considerable effect size. This study suggests that environmental Cd exposure, potentially through mussel consumption, may contribute to idiopathic male infertility in Egypt by increasing oxidative stress, inducing epigenetic modifications, and impairing semen quality. These findings underscore the need for further research into the mechanisms underlying Cd-induced male infertility and the development of preventative strategies.

FSH Therapy in Male Factor Infertility: Evidence and Factors Which Might Predict the Response.

Follicle-stimulating hormone (FSH) administration is applied in the management of subjects affected by hypogonadotropic hypogonadism. Whilst this application is widely recognized and established alone or in combination with human chorionic gonadotropin (hCG), a similar strategy is empirically advocated in idiopathic male factor infertility (MFI). In this setting, FSH therapy has been used to increase sperm quantity, quality, and pregnancy rate when FSH plasma concentrations are below 8 IU/L and when the seminal tract is not obstructed. In the literature, several studies suggested that giving FSH to patients with idiopathic MFI increases sperm count and motility, raising the overall pregnancy rate. However, this efficacy seems to be limited, and about 10-18 men should be treated to achieve one pregnancy. Thus, several papers suggest the need to move from a replacement approach to an overstimulating approach in the management of FSH therapy in idiopathic MFI. To this aim, it is imperative to determine some pharmacologic markers of FSH efficacy. Furthermore, it should be useful in clinical practice to distinguish, before starting the treatment, among patients who might respond or not to FSH treatment. Indeed, previous studies suggest that infertile men who have normal levels of gonadotropins in plasma might not respond to FSH treatment and about 50% of patients might be defined as "non-responders". For these reasons, identifying predictive markers of FSH action in spermatogenesis and clinical markers of response to FSH treatment is a fascinating area of study that might lead to new developments with the aim of achieving personalization of the treatment of male infertility. From this perspective, seminal parameters (i.e., spermatid count), testicular cytology, genetic assessment, and miRNA or protein markers in the future might be used to create a tailored FSH therapy plan. The personalization of FSH treatment is mandatory to minimize side effects, to avoid lost time with ineffective treatments, and to improve the efficacy, predicting the most efficient dose and the duration of the treatment. This narrative review's objective is to discuss the role of the different putative factors which have been proposed to predict the response to FSH treatment in idiopathic infertile men.

Idiopathic male infertility – what are we missing?

ABSTRACT Couple’s infertility is a rising issue worldwide affecting approximately 15% of couples. In 50% of the couples, a male factor infertility can be identified. Moreover, 30% of the men exhibit reduced sperm quality without any identifiable reason, thereby delineating the condition of idiopathic male infertility (IMI). Despite numerous improvements in the diagnosis and treatment of male infertility over the last decades, idiopathic forms are still the most challenging clinical dilemmas. The aim of this article is to describe the comprehensive diagnostic work-up that each idiopathic infertile man should follow. Moreover, potential new pathophysiological mechanisms and suggested treatment options are discussed. A detailed medical history and an extensive physical examination are mandatory to investigate potential treatable causes of MFI. Similarly, standard semen analysis has been proven to be limited in capturing the fecundability of the spermatozoa itself, therefore more advanced examinations, such as sperm DNA fragmentation (SDF) and oxidative stress measurement, are becoming important in clinical practice for IMI. In terms of diagnostic tools, imaging and genetic investigations are useful to classify idiopathic infertile men, however, epigenetic changes have demonstrated to have a role in sperm production and a prognostic value in fertility outcomes. Antioxidant treatment for IMI has been found to be a valid option to counteract ROS action, while gonadotropins are used to improve sperm quality and SDF. Artificial intelligence is promising to better manage idiopathic infertile men in terms of diagnosis and treatment options.

P-077 The role of glycosylation in the male reproduction revealed by omics technologies

Abstract Study question What is the current status of art and future perspective of glycosylation in the male reproduction using omics-based technology? Summary answer The precise site-specific glycoproteome of fertile human semen was generally established while the alteration in the pathogenic processes needed to be further investigated. What is known already The entire lifespan of human sperm concomitant with the glycosylation, which have been considered to be profoundly implicated in the male reproduction. In the past, only a few glycan patterns or glycoproteins in the male reproductive system were characterized due to technical limitations. Traditional strategies based on either glycomics or deglycosylated proteomics also are far from sufficient for fully understanding glycosylation in male reproduction. The development of the precise site-specific glycosylation of human semen was profiled, which laid a foundation on subsequently unveiling its role, while many challenging questions remain and require the assistance of advanced glycoproteomics. Study design, size, duration The original research and reviews in the PubMed and Web of Science databases were searched using terms regarding glycoproteome and male reproduction until September 2023. Participants/materials, setting, methods PubMed and Web of Science were used to search articles and reviews with the following main keywords pertaining to the glycoproteomics: “glycosylation”, “glycan”, “glycoprotein”, “glycome”, “glycoproteome”, “glycomics” and “glycoproteomics”, combined with “semen”, “spermatozoa”, “seminal plasma”, “epididymis”, “fertilization” and other key terms related to male reproduction. The search period included all publications until now (September 2023). The language was limited to English, and the species in most studies was limited to humans. Main results and the role of chance The precise site-specific glycoproteome of fertile human ejaculate spermatozoa and seminal plasma was generally established. Both are highly abundant in glycans and glycoproteins and share heavy fucosylation as the most significant feature. Their functions are mainly involved in immunomodulation, capacitation, and sperm-oocyte binding. Spatiotemporal regulation was found in glycosylation during male reproduction. Intracellular glycan synthesis occurs in testicular sperm, and a variety of glycan-modifying enzymes and extracellular vesicles are responsible for sperm maturation. Alterations in the semen glycoproteome were observed in male reproduction disorders and are associated with oligoasthenozoospermia, decreased sperm function, male accessory gland disease and immune dysregulation. Impaired glycosylation may be the result of genetic, endocrine, and oxidative stress and infection. Some idiopathic male infertility may be attributed to glycosylation abnormalities. Hence, glycoproteins have the potential to be biomarkers in male reproductive diseases and assisted reproductive technology. We point out that the mapping of the normal semen N-glycoproteome was the first step and there are many challenges such as the identification of the O-linked glycoproteome. Advanced glycoproteomic techniques developed recently have the potential to address them and promote the glycoproteome research in male reproduction. Limitations, reasons for caution There are no more than 20 articles regarding the glycomics or glycoproteomics of the semen and the samples processing is not ideal. Wider implications of the findings Our work hope to enlighten the biologists to depict the overall landscape of the male reproductive glycoproteome including spermatogenesis and maturation. Moreover, we provide adequate information for reproductive clinicians and technicians for the clinical translation of glyco-related biomarkers and therapeutic targets. Trial registration number not applicable

P-081 A first in class potentiating therapeutic antibody as a new male fertility treatment

Abstract Study question Can we improve spermatogenesis in male by increasing FSH activity with a potentiating antibody? Summary answer IGYXOS developed a first in class potentiating therapeutic antibody that is able to stimulate spermatogenesis better than gonadotropins only as demonstrated in animal models. What is known already Idiopathic male infertility, including oligozoospermia, oligoasthenoteratospermia (OATS) and azoospermia, accounts for at least 75% of infertile men population, and no treatment is available at the moment for them. IGYXOS developed a monoclonal antibody directed against human FSH. IGX12 is a humanized IgG4 and it is able to potentiate FSH activity in vitro and in vivo in several animal models. Study design, size, duration IGX12 was tested in azoospermic rat and mouse models. The first model was created by treating Wistar Han rats with a GnRH antagonist. Gonadotropin treatment started after full inhibition of spermatogenesis. Four rats per group were treated with FSH+hCG regimen alone or in combination with IGX12. The second model was hpg mice that are congenitally hypogonadal because of their inability to synthetize GnRH. Seven mice per group were treated with FSH only or FSH+IGX12. Participants/materials, setting, methods IGX12 was tested in vitro on HEK293 cells and in vivo in Steelman and Pohley bioassay. The potentiating effect was investigated in azoospermic rats, that were treated for 8 weeks with FSH+hCG or FSH+hCG+IGX12. Hpg mice were treated with Gonal-f or Gonal-f+IGX12 for 7 weeks, followed by a treatment with Menopur or Menopur+IGX12 for a further 7 weeks. At the end of treatment, sperm counts in the testes and in the epididymides were assessed. Main results and the role of chance In vitro on HEK 293 cells expressing the human FSH receptor, IGX12 combined to FSH improved both the potency (EC50) and the efficacy (Emax) of FSH by increasing the cyclic AMP production at all tested FSH concentrations. The potentiating activity was confirmed in vivo in the Steelman and Pohley bioassay. Ovaries weight of immature female rats was increased significantly in the group treated with hCG/FSH+IGX12 compared to hCG/FSH only. To further analyze the potential benefit of IGX12 on male fertility, its effect was investigated in azoospermic rodent models. In rats with acquired azoospermia, treatment with FSH+hCG reached ∼50% of spermatogenesis of wild-type (WT) animals. Doubling the dose of gonadotropins did not improve their effect, whereas the addition of IGX12 on top of FSH+hCG treatment during one spermatogenesis cycle only (8 weeks) significantly improved sperm count in the testes and in the epididymides, reaching the level of WT animals. In hpg mice with congenital azoospermia, sperm count in the testis was 3.6 times higher and the sperm count in the epididymides was 6 times higher in the group treated with IGX12+FSH compared with FSH only (p &amp;lt; 0.05). In conclusion, IGX12 combined to a standard treatment stimulated spermatogenesis better than standard gonadotropin treatment. Limitations, reasons for caution After several proofs of concept and regulatory safety and toxicology evaluation in different animal models, IGX12 safety and tolerability is now assessed in a randomized, double blinded clinical phase I study on healthy men and women volunteers. Wider implications of the findings This first in class potentiating antibody IGX12 represents an innovative and promising new therapy to treat male patients with idiopathic infertility, especially with oligozoospermia. Trial registration number not applicable

P-104 Cytoprotective effect of melatonin in prepubertal Sertoli cells: role in cadmium-induced idiopathic male infertility

Abstract Study question Melatonin (MLT) is a cytoprotective agent holding potential to prevent cadmium (Cd) toxicity and its impact in testicular function and fertility. Summary answer MLT produced a potent cytoprotective effect in Sertoli cells (SCs) exposed to Cd-toxicity, reducing its H2O2 generation and reductive stress effects by modulation Nrf2 activity. What is known already MLT a hormonal substance exhibiting strong antioxidative and antiapoptotic properties, has been proved to hold great potential as cytoprotec tive agent in a range of tissues and cell models exposed to Cd toxicity, including the rat bone, ovaries, human MSC, and even mammalian testes. However, cellular and mechanistic aspects of this effect of MLT in testes remain poorly understood. Cd is a pro-oxidant heavy metal reported to interfere with testicular function and fertility. Both the toxicity of Cd and the cytoprotective function of MLT involve redox-dependent mechanisms with the activity of Nrf2 transcription factor as key player on the cellular stress response. Study design, size, duration Porcine pre-pubertal SCs were maintained at 37 °C in a 5% CO2 humidified atmosphere in the absence (unexposed-control group) or presence of 5 or 10µM CdCl2 (Sigma Chemical Co.) and/or 50nM MLT (Sigma-Aldrich) for 48h in HAMF12 (Euroclone) supplemented with 0.166nM retinoic acid (Sigma-Aldrich Co.) and 5/500ml of Insulin-Transferrin-Selenium (ITS) + Premix (Cat. No. 354352; Corning). Participants/materials, setting, methods After treatment the parameters investigated in the study were: a) SCs viability (MTT test); b) SCs functionality parameters AMH and inhibin B. (real-time PCR and ELISA analysis); c) Intracellular and extracellular ROS production ( with Amplex Red and DCFH-DA fluorescent probe respectively); d) Catalase enzyme activity (spectrophotometric assay procedure); e) Nrf2 and other transcription factors (by semi-quantitative microplate confocal microscopy analysis); f) Intracellular and extracellular levels of GSH and other thiols (by HPLC); g) c-Jun and ERK1/2 (Immunoblot). Main results and the role of chance MLT co-treatment significantly prevented the effects of Cd on cell viability and abnormal ROS production. The reduction of H2O2 efflux was very important and combined with an increased CAT activity that was demonstrated upon MLT treatment significantly in SCs exposed to 5μMCd. The co-treatment with MLT compared to Cd treatment, showed a trend toward a significant recovery of AMH and inhibin B gene expression and secretion levels, respectively, demonstrating the cytoprotective effect of MLT in SCs exposed to Cd toxicity at the functional level. In Cd-treated cells, MLT significantly reduced the expression and nuclear translocation of Nrf2 protein, and decreased GSTP induction. However, MLT reduced Cys uptake and stimulated GSH efflux when the cells were treated with 10 µM Cd, suggesting a specific role for the Nrf2-GSTP axis in the cytoprotective response to MLT of Cd-treated SCs. Finally MLT induced MAPK-ERK1-2 pathway and c-Jun transcription factor when the cells were treated with Cd. MLT is a cytoprotective agent in SCs exposed to Cd toxicity capable to restore cell viability and function. Its activity is associated with the modulation of Nrf2 and other stress response genes important in the control of thiols and H2O2 metabolism of SCs, including cJun and MAPKs. Limitations, reasons for caution Other ROS-scavenging genes other than CAT may have a role in the antioxidant response to MLT of SCs, such as superoxide dismutase, glutathione peroxidases, and peroxyredoxins that are worth investigating further. Wider implications of the findings The aspects that emerged from our study and, described for the first time in these cells, warrant further preclinical and clinical investigation holding potential in the treatment of Cd-induced testicular damage and fertility problems. Trial registration number Not applicable

Melatonin as a natural anti-inflammatory and anti-oxidant therapy in the testis: a focus on infertility and aging†.

Melatonin is a pineal hormone that regulates testicular activity (i.e., steroidogenesis and spermatogenesis) through two complementary mechanisms, indirect effects exerted via the hypothalamic-adenohypophyseal axis and direct actions that take place on the different cell populations of the male gonad. The effects of increased age on the testis and the general mechanisms involved in testicular pathology leading to infertility are still only poorly understood. However, there is growing evidence that link testicular aging and idiopathic male infertility to local inflammatory and oxidative stress events. Because literature data strongly indicate that melatonin exhibits anti-inflammatory and anti-oxidant properties, this review focuses on the potential benefits exerted by this indoleamine at testicular level in male reproductive fertility and aging. Taking into account that the effects of melatonin supplementation on testicular function are currently being investigated, the overview covers not only promising prospects but also many questions concerning the future therapeutic value of this indoleamine as an anti-aging drug as well as in the management of cases of male infertility for which there are no medical treatments currently available.

Quantum sensing of free radicals in semen: Investigating the role of oxidative stress in idiopathic male infertility

Quantum sensing of free radicals in semen: Investigating the role of oxidative stress in idiopathic male infertility

A comprehensive analysis of spermatozoal RNA elements in idiopathic infertile males undergoing fertility treatment

Current approaches to diagnosing male infertility inadequately assess the complexity of the male gamete. Beyond the paternal haploid genome, spermatozoa also deliver coding and non-coding RNAs to the oocyte. While sperm-borne RNAs have demonstrated potential involvement in embryo development, the underlying mechanisms remain unclear. In this study, 47 sperm samples from normozoospermic males undergoing fertility treatment using donor oocytes were sequenced and analyzed to evaluate associations between sperm RNA elements (exon-sized sequences) and blastocyst progression. A total of 366 RNA elements (REs) were significantly associated with blastocyst rate (padj < 0.05), some of which were linked to genes related to critical developmental processes, including mitotic spindle formation and both ectoderm and mesoderm specification. Of note, 27 RE-associated RNAs are predicted targets of our previously reported list of developmentally significant miRNAs. Inverse RE-miRNA expression patterns were consistent with miRNA-mediated down-regulation. This study provides a comprehensive set of REs which differ by the patient’s ability to produce blastocysts. This knowledge can be leveraged to improve clinical screening of male infertility and ultimately reduce time to pregnancy.

Association between embryo morphokinetic development and intracytoplasmic sperm injection with epididymal sperm via time-lapse imaging.

The objective of this study was to investigate the impact of sperm source on embryo morphokinetics and the clinical outcomes of intracytoplasmic sperm injection (ICSI) cycles by considering the clustering of data (multiple embryos per patient that share a comparable developmental timing). This matched cohort study was performed at a private university-affiliated in vitro fertilization center. Women who underwent ICSI with epididymal sperm between January 2019 and December 2020 (the percutaneous epididymal sperm aspiration group, n = 32 cycles) were matched with women who underwent ICSI with ejaculated sperm because of idiopathic male factor infertility (the male factor infertility [MFI] group, n = 32 cycles) or female infertility (the control group, n = 32 cycles). Embryos were cultured in a time-lapse imaging incubator, and morphokinetic development was recorded and compared among the groups. Significantly slower divisions were observed in embryos derived from epididymal sperm than in those derived from the MFI and control groups. Embryos derived from epididymal sperm had a significantly lower KIDScore (3.1 ± 0.2) than did those derived from ejaculated spermatozoa from the MFI (5.4 ± 0.1) and control (5.6 ± 0.2, p < 0.001) groups. Epididymal sperm-derived embryos showed a significantly greater occurrence of multinucleation (23.2%) than did those derived from ejaculated sperm from the MFI and control groups (2.8% and 3.7%, p < 0.001, respectively). Epididymal sperm-derived embryos were significantly more likely to undergo direct or reverse cleavage (11.1%) than ejaculated sperm-derived embryos in the control group (4.3%, p = 0.001). In conclusion, delayed cell cleavage and increased incidences of blastomere multinucleation and abnormal cleavage patterns are observed when epididymal-derived sperm are used for ICSI.

The Association of Sperm DNA Fragmentation With Serum Lipid Profile Among Males With Abnormal Semen Parameters: An Analytical Cross-Sectional Study.

Through the ages, infertility, affecting 8% to 12% of couples worldwide, has been a perturbing clinical problem. Approximately 40% to 50% of all infertility cases are due to 'male factor' infertility. Semen analysis is crucial in routinely evaluating idiopathic male infertility. Studies support the idea that semen parameters are associated with serum lipids and sperm DNA fragmentation (SDF). Therefore, it is possible to evaluate male infertility by serum lipid levels, especially before assisted reproduction technology, and modify it by bringing about lifestyle modifications. This study aimed to measure the correlation of SDF with levels of total cholesterol (TC), triglycerides (TG),very low-density lipoprotein (VLDL),low-density lipoprotein (LDL), and high-density lipoprotein (HDL) among males with abnormal semen parameters. A cross-sectional analytical study was conducted in the infertility clinic of a tertiary care hospital. A total of 106 infertile males with abnormal semen analysis as per the WHO criteria (2010) were enrolled in the study. After routine semen analysis, SDF was studied using the comet assay. The serum fasting lipid profile was analyzed using the spectrophotometric kit in the autoanalyzer. The relationship of SDF with serum lipid profile parameters was analyzed. Out of 106 infertile men, 52% (n = 55) had severe SDF. A modest positive correlation was observed between SDF (percentage of DNA in comet tail) and serum lipid values (serum TG, serum LDL, and serum VLDL). Our study is novel in its research on the correlation between SDF and serum lipid values. Based on the findings of our study, it can be concluded that a significant level of SDF was observed in men with high levels of serum TG, LDL, and VLDL. This provokes a potential relationship between sperm DNA integrity and serum lipid profile, which warrants further research.

Male infertility: an overview of etiology, diagnosis and management

Male infertility, a multifaceted condition characterized by the inability to achieve pregnancy within a partner after a year of unprotected intercourse, affects approximately 7% of men globally. The etiology of male infertility is diverse, including genetic abnormalities, hormonal imbalances, physical obstructions, and lifestyle factors. This review synthesizes current knowledge on the causes, diagnostic methods, and therapeutic interventions for male infertility, with an emphasis on recent advances in genetic and assisted reproductive technologies (ART). The diagnostic approach to male infertility involves a comprehensive evaluation, including semen analysis, hormonal profiling, genetic testing, and imaging techniques, to identify underlying causes. Management strategies range from lifestyle modifications and pharmacological treatments to surgical interventions and ART, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Emerging technologies, including the use of artificial intelligence in semen analysis and the development of novel sperm retrieval techniques, promise to enhance diagnostic accuracy and treatment outcomes. Despite significant progress, challenges remain in improving access to care and addressing ethical considerations in the use of ART. This review highlights the importance of a multidisciplinary approach to the management of male infertility, integrating advances in medical science with considerations of patient well-being and ethical standards. Future research directions include elucidating the genetic basis of idiopathic male infertility, optimizing ART outcomes, and developing personalized treatment strategies. The ultimate goal is to improve the reproductive health and quality of life for affected individuals and couples.

Phase angle at bioelectric impedance analysis is associated with detrimental sperm quality in idiopathic male infertility: a preliminary clinical study.

In 2020, 38% of adults were affected by obesity, while infertility globally affected 1 in 6 people at some stage of their lives.Body mass index (BMI) provides an easy but occasionally inaccurate estimation of body composition. To achieve a more precise assessment, bioelectric impedance analysis serves as a validated tool that administers electrical energy through surface electrodes. Phase angle as a function of the relationship between tissues resistance and reactance, is a trustworthy predictor of body composition and cell membrane integrity. We aim to assess whether there is an association between phase angle and seminal parameters, as well as sperm DNA fragmentation percentage. Semen samples of 520 idiopathic infertile patients were analyzed according to 2021 World Health Organization guidelines and evaluated for sperm DNA fragmentation rate. Each participants underwent bioelectric impedance analysis. Median age was 40 years old, median BMI was 26.3 kg/m2, median phase angle was 6.2°. In the logistic regression analysis adjusted for age and total intracorporeal water, phase angle (continuous) was significantly associated with oligozoospermia (odds ratio [OR]:0.4; p<0.01) and sperm morphology (OR: 0.65; p=0.05) and slightly with sperm DNA fragmentation (OR: 0.98; p=0.07). In subgroup analysis, the logistic regression analysis adjusted for the mentioned parameters showed that a phase angle between 6.2 and 7 (°) (OR: 0.63; p=0.02) and >7 (°) (OR: 0.12; p<0.01) were associated with a reduced risk of oligozoospermia compared to values <6.2 (°). Similarly, a phase angle between 6.2 and 7 (°) (OR: 0.57; p< 0.01 and OR: 0.58; p= 0.01) and PA > 7 (°) (OR: 0.12; p= 0.03 and OR: 0.21; p< 0.01) were associated with a reduced risk of lower sperm concentration and lower total sperm count, respectively, compared to a phase angle < 6.2 (°). Our study suggests a negative association between phase angle and detrimental sperm parameters in male idiopathic infertility.