Idiopathic 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.

9233 Sperm-carried IGF2: a Spark Contributing To Embryo Growth And Development

Abstract Disclosure: R. Cannarella: None. O.J. Rando: None. R.A. Condorelli: None. C. Sandrine: None. S. Romano: None. A. Guglielmino: None. Q. Yin: None. H. Gustafsson: None. F. Mancuso: None. C. Bellucci: None. G. Luca: None. S. La Vignera: None. A.E. Calogero: None. Background: Sperm RNAs can regulate early embryo development. A potential key regulator of growth is insulin-like growth factor 2 (IGF2), a highly conserved paternally-imprinted gene involved in cell growth and proliferation that is expressed in human spermatozoa. Animal research supports the positive impact of IGF2-supplemented cultures on embryo quality. However, the role of sperm-carried IGF2 in the early development of the human embryo is unknown. Objective: To study whether sperm-carried IGF2 mRNA influences the morphokinetics of the human embryo. Design: Prospective, uncontrolled, observational pilot study. Setting: University-affiliated fertility center. Subjects: We enrolled 16 patients undergoing assisted reproductive techniques (ART) for idiopathic or male factor infertility and 10 healthy fertile controls with proven paternity. Couples with female factor infertility due to reduced oocyte reserve were excluded, while those with tubal factor or anovulation were included. Main Outcome Measure(s): After clinical use, an aliquot of the sperm samples employed for ART was used to evaluate IGF2 mRNA levels. Embryo kinetics were recorded and correlated with the amount of IGF2 mRNA, correcting for female age, body mass index (BMI), anti-Müllerian hormone (AMH) levels, and oocyte quality. To provide mechanistic insights into the human data, a transcriptome analysis was performed of parthenotes obtained from twelve-week-old superovulated mice injected with Igf2 mRNA plus Gfp mRNA (experimental group, n=20) or Gfp mRNAs (control group, n=20). Pathway enrichment analysis was then performed using g:Profiler g:GOSt and EnrichR. Results: Sperm IGF2 mRNA negatively correlated with time to 2-cell stage (t2), t3, t4, t5, and time to expanded blastocyst (tEB), independently of maternal age, BMI, AMH, and oocyte quality. IGF2 mRNA index >4.9 predicted the ability of the embryo to reach the blastocyst stage at day 5, with a sensitivity of 100% and specificity of 71.6% (AUC 0.845; p<0.001). The distribution of sperm IGF2 levels differs significantly between morphologically good or poor embryos, with the lowest levels more frequently associated with morphologically poor embryos (61.9%) than with good ones (38.1%) (p=0.0091). Furthermore, sperm-derived IGF2 levels were significantly lower in subfertile men compared to fertile controls with proven paternity. Transcriptome analysis of Igf2-injected embryos demonstrated differential expression of 101 genes activating pathways regulating early embryo development. Conclusion: Sperm-carried IGF2 mRNA can support early embryo development, independently of female factors. Larger studies are needed to confirm this finding and to investigate its role as a clinical marker to predict the chances of obtaining blastocysts that can be implanted in infertile couples undergoing ART. Presentation: 6/1/2024

7110 Sperm-carried IGF2: a Spark Contributing To Embryo Growth And Development

Abstract Disclosure: R. Cannarella: None. O.J. Rando: None. R.A. Condorelli: None. C. Sandrine: None. S. Romano: None. A. Guglielmino: None. Q. Yin: None. H. Gustafsson: None. F. Mancuso: None. C. Bellucci: None. G. Luca: None. S. La Vignera: None. A.E. Calogero: None. Background: Sperm RNAs can regulate early embryo development. A potential key regulator of growth is insulin-like growth factor 2 (IGF2), a highly conserved paternally-imprinted gene involved in cell growth and proliferation that is expressed in human spermatozoa. Animal research supports the positive impact of IGF2-supplemented cultures on embryo quality. However, the role of sperm-carried IGF2 in the early development of the human embryo is unknown. Objective: To study whether sperm-carried IGF2 mRNA influences the morphokinetics of the human embryo. Design: Prospective, uncontrolled, observational pilot study. Setting: University-affiliated fertility center. Subjects: We enrolled 16 patients undergoing assisted reproductive techniques (ART) for idiopathic or male factor infertility and 10 healthy fertile controls with proven paternity. Couples with female factor infertility due to reduced oocyte reserve were excluded, while those with tubal factor or anovulation were included. Main Outcome Measure(s): After clinical use, an aliquot of the sperm samples employed for ART was used to evaluate IGF2 mRNA levels. Embryo kinetics were recorded and correlated with the amount of IGF2 mRNA, correcting for female age, body mass index (BMI), anti-Müllerian hormone (AMH) levels, and oocyte quality. To provide mechanistic insights into the human data, a transcriptome analysis was performed of parthenotes obtained from twelve-week-old superovulated mice injected with Igf2 mRNA plus Gfp mRNA (experimental group, n=20) or Gfp mRNAs (control group, n=20). Pathway enrichment analysis was then performed using g:Profiler g:GOSt and EnrichR. Results: Sperm IGF2 mRNA negatively correlated with time to 2-cell stage (t2), t3, t4, t5, and time to expanded blastocyst (tEB), independently of maternal age, BMI, AMH, and oocyte quality. IGF2 mRNA index >4.9 predicted the ability of the embryo to reach the blastocyst stage at day 5, with a sensitivity of 100% and specificity of 71.6% (AUC 0.845; p<0.001). The distribution of sperm IGF2 levels differs significantly between morphologically good or poor embryos, with the lowest levels more frequently associated with morphologically poor embryos (61.9%) than with good ones (38.1%) (p=0.0091). Furthermore, sperm-derived IGF2 levels were significantly lower in subfertile men compared to fertile controls with proven paternity. Transcriptome analysis of Igf2-injected embryos demonstrated differential expression of 101 genes activating pathways regulating early embryo development. Conclusion: Sperm-carried IGF2 mRNA can support early embryo development, independently of female factors. Larger studies are needed to confirm this finding and to investigate its role as a clinical marker to predict the chances of obtaining blastocysts that can be implanted in infertile couples undergoing ART. Presentation: 6/1/2024

7110 Sperm-carried IGF2: a Spark Contributing To Embryo Growth And Development

Abstract Disclosure: R. Cannarella: None. O.J. Rando: None. R.A. Condorelli: None. C. Sandrine: None. S. Romano: None. A. Guglielmino: None. Q. Yin: None. H. Gustafsson: None. F. Mancuso: None. C. Bellucci: None. G. Luca: None. S. La Vignera: None. A.E. Calogero: None. Background: Sperm RNAs can regulate early embryo development. A potential key regulator of growth is insulin-like growth factor 2 (IGF2), a highly conserved paternally-imprinted gene involved in cell growth and proliferation that is expressed in human spermatozoa. Animal research supports the positive impact of IGF2-supplemented cultures on embryo quality. However, the role of sperm-carried IGF2 in the early development of the human embryo is unknown. Objective: To study whether sperm-carried IGF2 mRNA influences the morphokinetics of the human embryo. Design: Prospective, uncontrolled, observational pilot study. Setting: University-affiliated fertility center. Subjects: We enrolled 16 patients undergoing assisted reproductive techniques (ART) for idiopathic or male factor infertility and 10 healthy fertile controls with proven paternity. Couples with female factor infertility due to reduced oocyte reserve were excluded, while those with tubal factor or anovulation were included. Main Outcome Measure(s): After clinical use, an aliquot of the sperm samples employed for ART was used to evaluate IGF2 mRNA levels. Embryo kinetics were recorded and correlated with the amount of IGF2 mRNA, correcting for female age, body mass index (BMI), anti-Müllerian hormone (AMH) levels, and oocyte quality. To provide mechanistic insights into the human data, a transcriptome analysis was performed of parthenotes obtained from twelve-week-old superovulated mice injected with Igf2 mRNA plus Gfp mRNA (experimental group, n=20) or Gfp mRNAs (control group, n=20). Pathway enrichment analysis was then performed using g:Profiler g:GOSt and EnrichR. Results: Sperm IGF2 mRNA negatively correlated with time to 2-cell stage (t2), t3, t4, t5, and time to expanded blastocyst (tEB), independently of maternal age, BMI, AMH, and oocyte quality. IGF2 mRNA index >4.9 predicted the ability of the embryo to reach the blastocyst stage at day 5, with a sensitivity of 100% and specificity of 71.6% (AUC 0.845; p<0.001). The distribution of sperm IGF2 levels differs significantly between morphologically good or poor embryos, with the lowest levels more frequently associated with morphologically poor embryos (61.9%) than with good ones (38.1%) (p=0.0091). Furthermore, sperm-derived IGF2 levels were significantly lower in subfertile men compared to fertile controls with proven paternity. Transcriptome analysis of Igf2-injected embryos demonstrated differential expression of 101 genes activating pathways regulating early embryo development. Conclusion: Sperm-carried IGF2 mRNA can support early embryo development, independently of female factors. Larger studies are needed to confirm this finding and to investigate its role as a clinical marker to predict the chances of obtaining blastocysts that can be implanted in infertile couples undergoing ART. Presentation: 6/1/2024

LHCGR gene variants are associated with ovarian response and miscarriage risk following fresh and frozen embryo transfer

Background: Currently, infertility is a widespread problem. Despite recent advances in assisted reproductive technologies, success rates still need to be improved. Understanding patients' variability and addressing it with personalized methods may increase the success rates. The aim of the study: The aim of the present study was to analyze the possibility of using variants rs12470652 and rs2293275 of the LHCGR gene to predict ovarian response or pregnancy outcome in assisted reproductive technologies, including the influence of cryopreservation factor. Materials and methods: The present study included 292 infertile women who underwent assisted reproductive technologies. Inclusion criteria were the first or second IVF/ICSI cycle, including women with tubal or/and male factor, anovulation, idiopathic infertility. Exclusion criteria were reduced FSH and/or AMH serum levels. Results: The frequency distribution for rs12470652 and rs2293275 gene variants was AA (94%), AG (6%) and AA (9%), AG (52%), GG (39%) respectively. rs2293275 G allele was found to be associated with low ovarian response. In total, frozen embryo transfer was found to be marginally more efficient, than fresh embryo transfer. In women who became pregnant after fresh embryo transfer, the rs2293275 G allele was statistically significantly found to be a risk factor for miscarriage. Accordingly, frozen embryo transfer hypothesized to be more preferred for rs2293275 G allele carriers to give live birth, than fresh embryo transfer. Meanwhile, fresh embryo transfer might be more effective for rs12470652 G allele carriers to give live birth. Chi-squared test confirmed the results; however, the odds ratio was not applied due to the limited sample size. Further studies and sample increase are required to confirm the results. Conclusion: The present study proposes that LHCGR rs12470652 and rs2293275 genetic variants may improve the prognosis of efficiency of fresh and frozen embryo transfer and might be considered as predictors when planning IVF/ICSI cycles.

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.

Study of the role of polymorphic variants G919A and A2039G of the follicle stimulating hormone receptor gene FSHR in the genesis of male infertility

Aim. To determine the distribution of genotypes of polymorphic variants G919A and A2039G of the gene FSHR (follicle-stimulating hormone receptor) among men with azoospermia. Methods. DNA from peripheral blood leukocytes was isolated and purification using a modified salting out method. Extracted DNA was amplified by Polymerase chain reaction (PCR). The PCR products were subsequently digested with the restriction enzyme for identify polymorphic variants of the follicle-stimulating hormone receptor gene FSHR. Electrophoresis of PCR products was performed in a 2 % agarose gel. Results. Given that idiopathic infertility is overwhelmingly caused by genetic factors, it seemed necessary to conduct a set of cytological and molecular genetic studies in a group of men with azoospermia. The genetic component was verified in 28 men with azoospermia, which is 40 % of all subjects. Molecular genetic studies were performed and the distribution of genotypes of polymorphic variants A919G and A2039G of the FSHR gene among men with azoospermia was determined. Conclusions. A slightly higher frequency of homozygous genotypes GG of polymorphic variants A919G and A2039G of the follicle stimulating hormone receptor gene FSHR was found among men with azoospermia compared to the group of fertile men.

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.

Expression of exosomal microRNAs miR-34a and miR-210 in male infertility: relationship with morphokinetic parameters and sperm DNA fragmentation

Introduction. Infertility affects tens of millions of men and women across the globe. In approximately half of cases, male factors are the cause of infertility. In recent decades, there has been a significant decline in the quality of male ejaculate, which is characterized by reduced sperm concentration and motility. The insufficient diagnostic and prognostic value of routine semen analysis results highlights the challenge of developing effective diagnostic tools and searching for reliable biomarkers of male infertility. One of the most promising approaches may be assessing sperm microRNA expression.Objective. To study the role of sperm exosomal microRNAs miR-34a and miR-210 in the development of male infertility.Materials &amp; methods. The retrospective study included 150 men aged 25 – 49 years; of these, 96 patients were diagnosed with idiopathic infertility. The comparison group consisted of 54 fertile men. To assess the structure and motility of sperm, the results of a standard ejaculate study (WHO, 2021) and computer data analysis using MMC Sperm (MMCSoft, St. Petersburg, Russia) software were used. The degree of DNA fragmentation was assessed using the TUNEL method. To analyze the expression of miR-34a and miR-210, quantitative real-time PCR was performed using the miRCURY LNA SYBR Green PCR Kit («Qiagen» GmbH, Hilden, Germany) and the Rotor-Gene Q PCR product detection system («Qiagen» GmbH, Hilden, Germany).Results. The study of ejaculate using the Computer Assisted Sperm Analysis System (CASA) method revealed a statistically significant relationship between the level of DNA fragmentation of sperm and indicators of the speed of their movement: rectilinear (VSL) (r = -0.522726; p &lt; 0.01), curvilinear (VCL) (r = -0.499096; p &lt; 0.01), along the middle path (VAP) (r = -0.429533; p &lt; 0.01), as well as with the amplitude of lateral head displacement (ALH) (r = -0.294779, p &lt; 0.01), the linearity of their curvilinear path (LIN) (r = -0.385796; p &lt; 0.01), the degree of straight-line movements (STR) (r = -0.268248; p &lt; 0.05) and their progressive mobility (r = -0.411547; p &lt; 0.01). A study of the level of microRNA expression in sperm exosomes revealed a statistically significant decrease in its miRNA-34a pool (p = 0.0116). According to the Chaddock scale, the strength of the correlation between miR-210 expression and the effectiveness of ART programs was moderate (0.437993). The inverse relationship between miR-34a expression and IVF and ICSI results was weak (0.135314).Conclusion. The analysis of exosomal microRNA-34a and microRNA-210, which are involved in the regulation of spermatogenesis, reveals a direct correlation between their variations and changes in the kinetic and morphological parameters of gametes. It also indicates a relationship with the state of DNA fragmentation. These findings suggest varying levels of gene expression among infertile patients, men with proven fertility, and those undergoing assisted reproductive technology (ART) treatments, both with successful and repeated unsuccessful outcomes.

Fecundability in couples with idiopathic primary infertility after endometrial scratching: a retrospective cohort study

Fecundability in couples with idiopathic primary infertility after endometrial scratching: a retrospective cohort study

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.

Immunological testing for female infertility: a modern view on the problem

Introduction. According to various estimates, in Russia 10 to 20 % of people of reproductive age are infertile. Changes in the immune system play a key role in the etiology and treatment of various infertility forms. The active introduction of immunological testing into clinical practice can potentially improve the results of infertility diagnostics and treatment.Aim: to analyze the current literature data on immunological testing in female infertility, as well as to assess its potential role in infertility diagnostics and treatment.Materials and Methods. There was conducted a search for publications in the electronic databases PubMed and eLibrary by using the following keywords and their combinations: "infertility", "immunology", "immune system", "immunological testing", "diagnostics", "treatment". The articles were evaluated in accordance with the PRISMA recommendations. Ultimately, 88 publications were included in the review.Results. Testing for antiphospholipid antibodies (APA) may be useful for women undergoing assisted reproductive technology (ART) therapy, as these antibodies increase the risk of pregnancy complications and thrombotic risks associated with ovarian stimulation, but studies assessing AFA effect on in vitro fertilization (IVF) outcomes have ambiguous results. The presence of antithyroid antibodies (ATA) may be associated with infertility, so their assessment is indeed important to determine treatment tactics. It has been suggested that antinuclear antibodies (ANA) may affect reproductive function by disrupting trophoblast cell development and interfering with RNA transcription, which may lead to lowered reproductive success. Studies have shown that patients with a positive ANA data have a lower incidence of pregnancy and a higher rate of miscarriages after IVF procedure. The human herpes virus type 6 (HHV-6) affects female fertility and is often the cause of spontaneous termination of pregnancy. B-cell lymphoma protein 6 (BCL-6) can serve as an important prognostic biomarker to identify individuals with endometriosis and related reproductive disorders, including idiopathic infertility. Evaluation of endometrial decidualization can be a useful tool to assess readiness for endometrial implantation and provide opportunities for targeted therapeutic interventions. The issue of testing for NK-cells in patients undergoing infertility screening remains controversial due to the difficulties of standardizing testing recommendations.Conclusion. To date, there is a limited number of reliable data on the role of various immunological tests in infertility diagnostics and treatment. With the exception of testing for AFA in patients with RPL, as well as for thyroid-stimulating hormone (TSH) and anti-thyroperoxidase antibodies (TPOAb) in patients undergoing therapy using various types of assisted reproductive technologies, the remaining immunological tests provide scant data to justify their routine use in clinical practice. The major limitations of existing studies are coupled to a small patient sample, as well as heterogeneity of inclusion criteria, patient groups and research methods.

Sperm DNA fragmentation and infertility: a narrative review.

The purpose of this narrative review is to provide a practical understanding of sperm DNA fragmentation (SDF) in the management of male infertility. A search for systematic reviews and meta-analyses (SRMA) on SDF between April 1st, 2018 and April 1st, 2023 was performed using PubMed and articles were selected as per their relevance to the topic. Guidelines from major societies were also reviewed. Three clinical cases are reported and discussed. The search initially identified 80 articles. We selected 13 SRMAs based on their relevance to the topic. Of the 13 SRMAs, 7 evaluated the effect of SDF on assisted reproductive technology (ART) outcomes and recurrent pregnancy loss, 3 studied the effect of varicocele repair on SDF, and 3 evaluated the role of SDF involving lifestyle and environmental health factors including body mass index and male factor treatment strategies. Evidence suggests that increased SDF has a negative impact on natural pregnancy and ART outcomes. SDF testing may be particularly important in the infertility evaluation of men with varicoceles, idiopathic or unexplained infertility, recurrent pregnancy loss, or previous ART failure. Further studies are needed on SDF testing and the implications it can have on male factor infertility and pregnancy outcomes as well as its implementation in the setting of ART.

Bioconcentration of polycyclic aromatic hydrocarbons in the adipose tissue of women with pelvic endometriosis and idiopathic infertility: A case-control study

PurposePolycyclic aromatic hydrocarbons (PAHs), present in air and food, generated during energy production and waste incineration, are known for health toxicity. PAHs may activate the aryl hydrocarbon receptor, which could in turn modify estrogen-dependent inflammatory pathways in endometriosis. The possible role of PAHs in the pathogenesis of endometriosis remains unclear. The study aimed to evaluate the potential link between exposure to PAHs and the occurrence of peritoneal and ovarian endometriosis. MethodsA prospective case-control tertiary-center study included 46 women aged 22–45 undergoing laparoscopy due to pelvic endometriosis (n ​= ​32; arm 1) and idiopathic infertility (n ​= ​14; arm 2). A sample of the greater omentum was collected intraoperatively for detection of 16 standard PAHs by gas chromatography-isotope dilution mass spectrometry method. PAHs concentrations were compared in both study arms. The associations between PAHs concentrations and selected variables were investigated. ResultsThere were no significant differences between both arms in terms of reference PAHs concentrations, nor correlations between PAHs concentrations and the stage of endometriosis. However, notable differences were observed in specific PAHs concentrations related to certain conditions. The concentrations of acenaphthene (p ​= ​0.016) and fluorene (p ​= ​0.013) were significantly lower in women with peritoneal adhesions, while the concentrations of benz[a]anthracene, benzo[k]fluoranthene and indeno[1,2,3-cd]pyrene [ng/g] were higher in cigarette smokers. ConclusionsThe study showed no differences in exposure to PAHs between women with and without pelvic endometriosis. Determining the toxicity of PAHs in endometriosis requires further research.