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Purpose: There is several albeit not univocal evidence suggesting that ovarian reserve is not related to the chance of natural pregnancy, provided that the remnant follicular pool is sufficient to ensure regular menstrual cycles. Nevertheless, available studies have some methodological limitations, and the issue cannot be considered definitively ascertained. Methods: To further address this issue, we retrospectively selected infertile women whose infertility diagnostic work-up was unremarkable (unexplained infertility-cases) and matched them by age and study period to a group of infertile women who were diagnosed with severe male infertility (controls). If ovarian reserve impacts on natural fertility, one had to expect lower ovarian reserve among women with unexplained infertility. Tested biomarkers included AMH, AFC and day 2–3 serum FSH. The primary aim was the frequency of women with serum AMH < 0.7 ng/ml. Results: Two-hundred fifty-two women with unexplained infertility and 252 women with male infertility were included. All biomarkers of ovarian reserve did not differ between the study groups. AMH levels < 0.7 ng/mL were observed in 26 (10%) women with unexplained infertility and 35 (14%) women with male infertility (p = 0.28). The adjusted OR was 0.76 (95% CI: 0.44–1.33). Significant differences did not also emerge when repeating this dichotomous analysis using other biomarkers and other thresholds for the definition of low-ovarian reserve. Conclusion: This study confirms that ovarian reserve is unremarkable to natural conception. Physicians and patients should be aware of this concept to avoid inappropriate counseling and undue clinical decisions. [ABSTRACT FROM AUTHOR]

Objective: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and previous observational epidemiological studies have suggested an association between MS and male infertility; male infertility due to sperm abnormalities may result from a number of aetiological factors, such as genetics, autoimmune factors, etc., and there are currently no studies to assess whether MS is associated with sperm abnormalities in men. Therefore, we performed a Mendelian randomization (MR) analysis to assess the causal relationship between MS and abnormal spermatozoa. Methods: In this study, independent single nucleotide polymorphisms (SNPs) strongly associated with multiple sclerosis (MS) were identified by mining public genome-wide association study repositories and used as instrumental variables to explore causality. The causal effect of MS on sperm abnormalities was systematically assessed using two-sample Mendelian randomization (MR) techniques, and various analytical models such as inverse variance weighting (IVW), MR-Egger and MR-PRESSO were implemented to dissect the association. In addition, a wide range of sensitivity tests, including Cochran's Q test to detect heterogeneity, MR-Egger intercept analysis to assess bias, leave-one-out to test model robustness, and funnel plot analysis to detect potential publication bias, were implemented to ensure the robustness and reliability of the causal inference results. Results: There was a significant causal relationship between MS and abnormal sperm (OR 1.090, 95% CI [1.017–1.168], p = 0.014); The accuracy and robustness of the results were confirmed by sensitivity analysis. Conclusion: Here we show that there appears to be a causal relationship between multiple sclerosis and abnormal spermatozoa. MS as a chronic disease has a higher risk of concomitant sperm abnormalities in its male patients, and reproductive and fertility issues in men with MS should receive special attention from clinicians. [ABSTRACT FROM AUTHOR]

Advancements in the management of patients with chronic myeloid leukemia (CML) allowed them to achieve survival comparable with their healthy counterparts. Consequently, their care has widened with growing focus on quality of life, including parenting children. Although tyrosine kinase inhibitors (TKI) are contraindicated in pregnancy given their teratogenic effect, their effect on male fertility is less clear with contradictory results from animal studies and case reports/series. We compared the sperm analysis parameters, as the gold-standard assessment for male fertility, of 11 patients with CP- CML before and after TKI therapy. Median therapy duration was 5.1 years (range: 2.5–16.5). The sperm concentration, % progressive, and total motility before and after therapy were not significantly different (p = 0.376, 0.569, and 0.595, respectively). Our results suggest no impairment in fertility potential in male patients after TKI therapy. A larger sample size is crucial to support/refute our findings. [ABSTRACT FROM AUTHOR]

Background: Male factor infertility affect up to 50% of couples unable to conceive spontaneously. Several non-hormonal pharmacological treatments have been proposed to boost spermatogenesis and increase chances of conception in men with infertility. Still, no clear evidence exists on the most effective treatment strategy. Objective: We aimed to compare the effectiveness of non-hormonal pharmacological treatment options for men with infertility using a systematic review and network meta-analysis. Methods: We searched MEDLINE, EMBASE, and CENTRAL until October 2023 for randomised/quasi-randomised trials that evaluated any non-hormonal pharmacological treatment options for men with idiopathic semen abnormalities or those with hypogonadism. We performed pairwise and network meta-analyses using a random effect model. We assessed risk of bias, heterogeneity, and network inconsistency. We calculated the mean rank and the surface under the cumulative ranking curve (SUCRA) for each intervention the maximum likelihood to achieve each of reported outcomes. We reported primarily on sperm concentration and other important semen and biochemical outcomes using standardised mean difference (SMD) and 95% confidence-intervals(CI). Results: We included 14 randomised trials evaluating four treatments (Clomiphene citrate, Tamoxifen, Aromatase inhibitors, anti-oxidants) and their combinations in 1342 men. The overall quality of included trials was low. Sperm concentration improved with clomiphene compared to anti-oxidants (SMD 2.15, 95%CI 0.78–3.52), aromatase inhibitor (SMD 2.93, 95%CI 1.23–4.62), tamoxifen (SMD − 1.96, 95%CI -3.57; -0.36) but not compared to placebo (SMD − 1.53, 95%CI -3.52- 0.47). Clomiphene had the highest likelihood to achieve the maximum change in sperm concentration (SUCRA 97.4). All treatments showed similar effect for sperm motility, semen volume, and normal sperm morphology. FSH levels showed significant improvement with clomiphene vs.anti-oxidant (SMD 1.48, 95%CI 0.44–2.51) but not compared to placebo. The evidence networks for LH and testosterone suffered from significant inconsistency (p = 0.01) with similar trend of improvement with clomiphene compared to other treatments but not compared to placebo. Conclusion: There is insufficient evidence to support the routine use of Clomiphene, tamoxifen, and aromatase inhibitors to optimise semen parameters in men with infertility. Future randomised trials are needed to confirm the efficacy of clomiphene in improving fertility outcomes in men. PROSPERO: CRD42023430179. [ABSTRACT FROM AUTHOR]

Background: Evidence supports the benefits of hydroxyurea (HU) in adults with sickle cell disease (SCD), but reservations remain due to long-term concerns of fertility. Retrospective analysis of clinical records of SCD patients (haemoglobin SS genotype) have identified gender-related differences in disease progression. This could inform risk stratification during SCD at diagnosis with the possibility to guide therapeutic decisions. Methods: This systemic review and meta-analysis evaluated fertility parameters in both children (aged ≥ 6 years) and adults with SCD receiving HU therapy. Studies were sourced from PubMed and EMBASE from inception to July 2023. A total of 160 potentially relevant articles were identified. Results: Four studies were included that evaluated the effects of HU on sperm parameters in males. A further 4 studies assessed anti-mullerian hormone (AMH) levels and ovarian reserves in females. Differences from baseline values were used to identify compromised fertility. Amongst males, HU treatment negatively impacted the concentration of spermatozoa (MD = -15.48 million/mL; 95% CI: [-20.69, -10.26]; p< 0.001), which continued following treatment cessation (MD = -20.09 million/mL; 95% CI: [-38.78, -1.40]; P = 0.04). HU treatment also led to lower total sperm counts (MD = -105.87 million; 95% CI: [-140.61, -71.13]; P< 0.001) which persisted after treatment (MD = -53.05 million; 95% CI: [-104.96, -1.14]; P = 0.05). Sperm volume, initial forward motility and morphology were unaffected by HU treatment. In females, HU treatment decreased the mean AMH levels 1.83 (95% CI [1.42, 2.56]. A total of 18.2.% patients treated with HU showed reduced ovarian reserves. Interpretation & conclusions: This systemic review and meta-analysis suggest that the use of HU for SCD impacts seminal fluid parameters in males and can diminish AMH levels and ovarian reserves in females. [ABSTRACT FROM AUTHOR]

BACKGROUND The last decade has seen increased research on the relationship between diet and male fertility, but there are no clearly defined nutritional recommendations for men in the preconception period to support clinical fertility outcomes. OBJECTIVE AND RATIONALE The purpose of this scoping review is to examine the extent and range of research undertaken to evaluate the effect(s) of diet in the preconception period on male clinical fertility and reproductive outcomes. SEARCH METHODS Four electronic databases (MEDLINE and EMBASE via Ovid, CAB Direct, and CINAHL via EBSCO) were searched from inception to July 2023 for randomized controlled trials (RCTs) and observational studies (prospective/retrospective, case–control, and cross-sectional). Intervention studies in male participants or couples aiming to achieve dietary or nutritional change, or non-intervention studies examining dietary or nutritional components (whole diets, dietary patterns, food groups or individual foods) in the preconception period were included. Controls were defined as any comparison group for RCTs, and any/no comparison for observational studies. Primary outcomes of interest included the effect(s) of male preconception diet on clinical outcomes such as conception (natural or via ART), pregnancy rates and live birth rates. Secondary outcomes included time to conception and sperm parameters. OUTCOMES A total of 37 studies were eligible, including one RCT and 36 observational studies (prospective, cross-sectional, and case–control studies; four studies in non-ART populations) published between 2008 and 2023. Eight reported clinical outcomes, 26 reported on secondary outcomes, and three reported on both. The RCT did not assess clinical outcomes but found that tomato juice may benefit sperm motility. In observational studies, some evidence suggested that increasing fish or reducing sugar-sweetened beverages, processed meat or total fat may improve fecundability. Evidence for other clinical outcomes, such as pregnancy rates or live birth rates, showed no relationship with cereals, soy and dairy, and inconsistent relationships with consuming red meat or a 'healthy diet' pattern. For improved sperm parameters, limited evidence supported increasing fish, fats/fatty acids, carbohydrates and dairy, and reducing processed meat, while the evidence for fruits, vegetables, cereals, legumes, eggs, red meat and protein was inconsistent. Healthy diet patterns in general were shown to improve sperm health. WIDER IMPLICATIONS Specific dietary recommendations for improving male fertility are precluded by the lack of reporting on clinical pregnancy outcomes, heterogeneity of the available literature and the paucity of RCTs to determine causation or to rule out reverse causation. There may be some benefit from increasing fish, adopting a healthy dietary pattern, and reducing consumption of sugar-sweetened beverages and processed meat, but it is unclear whether these benefits extend beyond sperm parameters to improve clinical fertility. More studies exploring whole diets rather than singular foods or nutritional components in the context of male fertility are encouraged, particularly by means of RCTs where feasible. Further assessment of core fertility outcomes is warranted and requires careful planning in high-quality prospective studies and RCTs. These studies can lay the groundwork for targeted dietary guidelines and enhance the prospects of successful fertility outcomes for men in the preconception period. Systematic search of preconception diet suggests that increasing fish and reducing sugary drinks, processed meats and total fat may improve male fertility, while consuming healthy diets, fish, fats/fatty acids, carbohydrates and dairy and reducing processed meat can improve sperm health. [ABSTRACT FROM AUTHOR]

Objective: Triple A syndrome, caused by autosomal recessively inherited mutations in the AAAS gene is characterized by alacrima, achalasia, adrenal insufficiency, and neurological impairment. To the best of our knowledge, no patients of both sexes have been reported to have offspring. Our aim was to assess the causes of infertility in male patients with this multisystemic syndrome, and to present a female patient that spontaneously conceived a child. Design: Cross-sectional study. Methods: Six males aged 19-48 years were included. Gonadotropins, testosterone, DHEAS, androstenedione, inhibin B, anti-Mullerian hormone measurements and testicular ultrasound were performed. Results: All six male patients had impaired general health and neurological symptoms including erectile and ejaculatory dysfunction. None of them had an offspring. The only demonstrated cause of infertility in ourmale patients was erectile and ejaculatory dysfunction which precludes sexual intercourse. Our patients had normal libido but were sexually abstinent. Except for low adrenal androgen levels, the concentrations of all measured hormones as well as testicular ultrasound were normal which may indicate the possibility of spermatogenesis in male patients with triple A syndrome. Little is known about fertility in female patients, but based on our observations spontaneous pregnancies seem to be possible. Conclusion: Our results contribute to still scarce knowledge on fertility in patients with Triple A syndrome and as well represents a foundation for further research on causes of infertility and possible treatment options. [ABSTRACT FROM AUTHOR]

Testosterone is crucial in regulating several body functions in men, including metabolic, sexual, and cardiovascular functions, bone and muscle mass, and mental health. Therefore, optimizing testosterone levels in men is an important step to maintaining a healthy body and mind, especially as we age. However, traditional testosterone replacement therapy has been shown to lead to male infertility, caused by negative feedback in the hypothalamic–pituitary–gonadal (HPG) axis. Recent advances in research have led to the discovery of many new methods of administration, which can have more or less suppressive effects on the HPG axis. Also, the usage of ancillary medications instead of or after testosterone administration might help maintain fertility in hypogonadal patients. The goal of this narrative review is to summarize the newest methods for optimizing fertility parameters in patients undergoing treatment for hypogonadism and to provide the necessary information for healthcare providers to make the right treatment choices. [ABSTRACT FROM AUTHOR]

Non‐obstructive azoospermia (NOA) is the most severe form of human male infertility, and the genetic causes of NOA with meiotic arrest remain largely unclear. In this study, we identified novel compound heterozygous MEIOB variants (c.814C > T: p.R272X and c.976G > A: p.A326T) and a previously undescribed homozygous non‐canonical splicing variant of MEIOB (c.528 + 3A > C) in two NOA‐affected individuals from two irrelevant Chinese families. MEIOB missense variant (p.A326T) significantly reduced protein abundance and nonsense variant (p.R272X) produced a truncated protein. Both of two variants impaired the MEIOB‐SPATA22 interaction. The MEIOB non‐canonical splicing variant resulted in whole Exon 6 skipping by minigene assay, which was predicted to produce a frameshift truncated protein (p.S111Rfs*32). Histological and immunostaining analysis indicated that both patients exhibited a similar phenotype as we previously reported in Meiob mutant mice, that is, absence of spermatids in seminiferous tubules and meiotic arrest. Our study identified three novel pathogenic variants of MEIOB in NOA patients, extending the mutation spectrum of the MEIOB and highlighting the contribution of meiotic recombination related genes in human fertility. [ABSTRACT FROM AUTHOR]

Objective: Varicocele is the most frequently observed correctable cause of infertility in men. In this study, we aimed to evaluate the influence of age at the time of varicocelectomy on semen parameters and fertility. Methods: Infertile men who underwent microsurgical varicocelectomy between January 2012 and December 2019 were retrospectively evaluated. Patients were divided into 4 age groups as follows: group 1 including patients aged ≤25 years old, group 2 including patients aged ≥26 and ≤30 years old, group 3 including patients aged ≥31 and ≤35 years old, and group 4 including patients aged ≥36 years old. Results: A total of 138 infertile men were divided into 4 groups. There were 18 men in group 1, 58 men in group 2, 44 men in group 3, and 18 men in group 4. There were significant improvements in the mean sperm concentration, progressive motility, and total motile sperm count values in all groups after surgery. Significant improvement in sperm morphology was detected only in groups 1 and 2 (p=0.007 and p=0.005, respectively). There was no significant difference between the groups in terms of preoperative and postoperative sperm parameters. Total fertility rate and the number of patients having children with natural conception or assisted reproductive techniques were lower in group 4 but these differences were not statistically significant (p=0.083 and p=0.454, respectively). Conclusion: Varicocelectomy can be recommended for all infertile men regardless of age. There was no difference in postoperative semen parameters and fertility rates between the age groups. [ABSTRACT FROM AUTHOR]

Multiple morphological abnormalities of the flagella (MMAF) is a severe disease of male infertility, while the pathogenetic mechanisms of MMAF are still incompletely understood. Previously, we found that the deficiency of Ccdc38 might be associated with MMAF. To understand the underlying mechanism of this disease, we identified the potential partner of this protein and found that the coiled-coil domain containing 146 (CCDC146) can interact with CCDC38. It is predominantly expressed in the testes, and the knockout of this gene resulted in complete infertility in male mice but not in females. The knockout of Ccdc146 impaired spermiogenesis, mainly due to flagellum and manchette organization defects, finally led to MMAF-like phenotype. Furthermore, we demonstrated that CCDC146 could interact with both CCDC38 and CCDC42. It also interacts with intraflagellar transport (IFT) complexes IFT88 and IFT20. The knockout of this gene led to the decrease of ODF2, IFT88, and IFT20 protein levels, but did not affect CCDC38, CCDC42, or ODF1 expression. Additionally, we predicted and validated the detailed interactions between CCDC146 and CCDC38 or CCDC42, and built the interaction models at the atomic level. Our results suggest that the testis predominantly expressed gene Ccdc146 is essential for sperm flagellum biogenesis and male fertility, and its mutations might be associated with MMAF in some patients. [ABSTRACT FROM AUTHOR]

Reduced sperm motility and/or count are among the major causes of reduced fertility in men, and sperm membranes play an important role in the spermatogenesis and fertilization processes. However, the impact of sperm lipid composition on male fertility remains under-investigated. The aim of the present study was to perform a lipidomic analysis of human sperm membranes: we performed an untargeted analysis of membrane lipid composition in fertile (N = 33) and infertile subjects (N = 29). In parallel, we evaluated their serum lipid levels. Twenty-one lipids were identified by their mass/charge ratio and post-source decay spectra. Sulfogalactosylglycerolipid (SGG, seminolipid) was the most abundant lipid component in the membranes. In addition, we observed a significant proportion of PUFAs. Important differences have emerged between the fertile and infertile groups, leading to the identification of a lipid cluster that was associated with semen parameters. Among these, cholesterol sulfate, SGG, and PUFAs represented the most important predictors of semen quality. No association was found between the serum and sperm lipids. Dietary PUFAs and SGG have acknowledged antioxidant functions and could, therefore, represent sensitive markers of sperm quality and testicular function. Altogether, these results underline the important role of sperm membrane lipids, which act independently of serum lipids levels and may rather represent an independent marker of reproductive function. [ABSTRACT FROM AUTHOR]

Infertility affects a significant percentage of couples worldwide, and male factors contribute significantly to this problem. Traditional assessments of male fertility rely primarily on parameters such as sperm motility, morphology, viability, and concentration. However, these metrics often do not provide a comprehensive understanding of sperm function, which is critical not only for fertilization but also for successful embryo development. Herein, we used porcine spermatozoa as a model to investigate the potential of sperm RNA markers in assessing various aspects of sperm function from motility to fertility. Using artificial insemination, we evaluated male fertility based on the litter size of sows inseminated with sperm from 20 boars. In addition, we measured parameters such as weaning rate, death births, live births, and mummy births. Sperm functional parameters, including motility and kinematics, were assessed before and after in vitro capacitation. Finally, correlations between various sperm functional parameters and sperm RNA markers were explored. Our results revealed interesting relationships between sperm functional parameters. While motility and kinematics were correlated, they were not correlated with sperm capacitation status. Surprisingly, no significant correlations were found between these parameters and male fertility. However, specific parameters of sperm capacitation status after in vitro capacitation were correlated with weaning rate and live births, highlighting their importance in predicting successful fertilization. Further analysis of sperm RNA markers identified genes related to male fertility, including IZUMO1, known for its role in sperm-egg fusion. These genes showed correlations with motility, capacitation, and fertilization parameters, shedding light on their potential roles in sperm function. In conclusion, our study demonstrates that sperm RNA markers hold promise for the diagnosis and prognosis of various aspects of sperm function, providing valuable insights into male infertility. These markers may serve as diagnostic tools to improve our understanding of male fertility problems, ultimately benefiting couples struggling with infertility. [ABSTRACT FROM AUTHOR]

Background: Spermatogenesis is an essential process for human reproduction. Gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), folliclestimulating hormone (FSH), and testosterone play vital roles in the development and maturation of sperm. Growth hormone (GH) is thought to play a role in the reproductive system of both males and females. Growth Hormone deficiency can lead to reproductive problems. Aim: to assess predictors of fertility potentials and TESE outcomes among adult males. Methods: we enrolled 162 males and assessed FSH, LH, basal GH, clonidine (GH) stimulation test one time and insulin stimulation test in another time. We designed a predictive model to identify the fertility potentials, Fertility Score= 4.442 + (Basal GH*0.074) + (GH_CLON*0.035) - (FSH*0.021) (BMI*0.062)- (Smoker*0.429). The net result of this equation should be approximated to the nearest integer to predict the fertility status where, 1=TESE Negative, 2= TESE Positive, 3=Oligozoospermia, and 4= Fertile control. Results: multivariate analysis showed smoking status, testicular volume, BMI, Serum FSH, basal GH are not predictors for fertility potentials. GH after clonidine and after insulin stimulation GH after clonidine stimulation correlates positively with total motile count. Other semen parameters do not correlate with basal GH or GH after insulin or clonidine stimulation. Receiver Operator Characteristic (ROC) curve analysis is used to detect the cut off levels at which sperm recovery yield change. For the GH assessment only, the basal GH could be applied to predict the SRR in men with azoospermia, AUC=0.672 (95% CI: 0.499 to 0.844). Growth hormone after clonidine (AUC= 0.510) or Insulin stimulation (AUC=0.556) and therefore, cannot differentiate between TESE positive and TESE negative cases. Conclusion: Basal, post clonidine GH levels, has BMI and smoking are predictive factors for fertility potentials, our model have high sensitivity in predicting fertility potentials among positive TESE males. Basal GH can significantly predict TESE negative males. [ABSTRACT FROM AUTHOR]

To preserve male fertility after diagnosis of any kind of cancer, a prompt assessment of the semen quality and an appropriate semen cryopreservation must be performed before radio-chemotherapy starts. The present work aims to evaluate the semen parameters at diagnosis of different cancer patients before cryopreservation and after thawing. Testicular tumors and lymphomas are among the most common cancers in younger patients, and while chemotherapy significantly increases patients' survival, it can epigenetically alter the semen fluid, resulting in temporary or permanent infertility. We analyzed data from the database of the Gamete Cryopreservation Center (Annunziata Hospital, CS; Italy) in the period of 2011–2020 from a cohort of 254 cancer patients aged 18–56 years. The evaluation was performed in a blind manner and anonymously recovered; the main parameters referring to semen quality were assessed in accordance with the WHO guidelines and decision limits (6th edition; 2021). The cancer types were as follows: testis cancers (TC; n = 135; 53.1%), hematological cancers (HC; n = 76; 29.9%), and other types of cancer (OC; n = 43; 17%). Comparing TC vs. HC (P1) and vs. OC (P2), TC had the worst semen quality: sperm number/mL (P1 = 0.0014; P2 = 0.004), total motility (P1 = 0.02; P2 = 0.07), progressive motility (P1 = 0.04; P2 = 0.05), viability (P1 = 0.01; P2 = 0.02), and percentage of atypical morphology (P1 = 0.05; P2 = 0.03). After semen thawing, viability and progressive motility recovery lowered, accounting for 46.82% and 16.75%, respectively, in the whole cohort; similarly, in the subgroups ascribed to TC, they showed the lowest recovery. Strong correlation existed between pre- and post-cryopreservation viability and progressive motility in the whole cohort (p < 0.001) and in the TC subgroup (p < 0.05). All cancer subgroups, to significantly different extents, had semen findings below the WHO reference values, suggesting diverse sperm susceptibilities to different cancers and cryodamage. Cancer and associated treatments epigenetically affect patients' semen quality, meaning cryopreservation should be considered a useful personalized prerogative for any kind of cancer in a timely manner. [ABSTRACT FROM AUTHOR]

To study sperm parameters recovery and fertility outcomes in men with azoospermia or severe oligospermia caused by anabolic steroid use who underwent a standardized treatment regimen for spermatogenesis recovery. A retrospective analysis of a cohort of men with a prior history of anabolic steroid use and infertility complaints (between 2018 and 2022) was conducted. The standardized treatment approach involved discontinuing testosterone replacement therapy and administering a combination regimen of clomiphene citrate and human chorionic gonadotropin for a minimum of 3 to 6 months. The main outcome measures included changes in sperm parameters, predominantly sperm concentration, and subsequent pregnancy outcomes. A total of 45 men (median age 37 years, IQR 32–45) met the inclusion criteria for this analysis. Median duration of prior T use was 4 years (IQR 1.3–10), with the 2 most common modalities consisting of injection therapy (43.5%) and oral therapy (34.8%). The median initial sperm concentration was 0 million/cc (IQR 0–1.15), and 23 (51.1%) men initially presented with azoospermia. The median duration of combination human chorionic gonadotropin/clomid therapy was 5 months (IQR 3–12). In initially azoospermic men (N: 23), 5 were lost to follow-up, 6 (33.3%) progressed to severe oligospermia (<5 million/cc), 6 (33.3%) to oligospermia (<15 million/cc), 1 (5.6%) to normozoospermia (>15 million/cc), and 5 (27.8%) remained azoospermic after medical treatment for 6 months. Among the 24 couples who responded to the follow-up call, a total of 9 (37.5%) achieved a successful subsequent pregnancy. Of these, 33.3% (3 couples) used assisted reproductive technology, whereas 66.7% (6 couples) conceived naturally. On logistic regression analysis, no significant predictors for improved sperm parameters or successful pregnancy were identified. Despite appropriate treatment regimens, a significant proportion of men with a prior history of anabolic steroid use continue to exhibit severe oligospermia, with more than half showing limited improvement in semen parameters after 6 months of treatment. Only a fraction of men achieves normozoospermia after treatment. Further research is needed to explore predictors for improved sperm parameters and successful pregnancy outcomes in men with a history of anabolic steroid use. [ABSTRACT FROM AUTHOR]

Obesity prevalence worldwide is increasing significantly. Whilst maternal obesity has clear detrimental impacts on fertility, pregnancy and foetal outcomes, more recently there has been an increasing focus on the role of paternal obesity in human fertility. Recent meta‐analyses have indicated that obesity in men negatively affects basic sperm parameters such as sperm count, concentration and motility, increases the incidence of infertility and reduces the chances of conception. Sperm DNA damage, typically characterised by DNA strand breaks and oxidation of DNA nucleotides, is a specialised marker of sperm quality that has been independently associated with recurrent miscarriage, reduced assisted reproduction success and increased mutational loads in subsequent offspring. Whilst, there are still conflicting data in humans as to the association of obesity in men with sperm DNA damage, evidence from rodent models is clear, indicating that male obesity increases sperm DNA damage. Human data are often conflicting because of the large heterogeneity amongst studies, the use of body mass index as the indicator of obesity and the methods used for detection of sperm DNA damage. Furthermore, comorbidities of obesity (i.e., heat stress, adipokines, insulin resistance, changes in lipids, hypogonadism and obstructive sleep apnoea) are also independently associated with increased sperm DNA damage that is not always modified in men with obesity, and as such may provide a causative link to the discrepancies amongst human studies. In this review, we provide an update on the literature regarding the associations between obesity in men and fertility, basic sperm parameters and sperm DNA damage. We further discuss potential reasons for the discrepancies in the literature and outline possible direct and indirect mechanisms of increased sperm DNA damage resulting from obesity. Finally, we summarise intergenerational obesity through the paternal linage and how sperm DNA damage may contribute to the transmission. [ABSTRACT FROM AUTHOR]

Background: Although male factor accounts for 40%–50% of unintended childlessness, we are far from fully understanding the detailed causes. Usually, affected men cannot even be provided with a molecular diagnosis. Objectives: We aimed at a higher resolution of the human sperm proteome for better understanding of the molecular causes of male infertility. We were particularly interested in why reduced sperm count decreases fertility despite many normal‐looking spermatozoa and which proteins might be involved. Material and methods: Applying mass spectrometry analysis, we qualitatively and quantitatively examined the proteomic profiles of spermatozoa from 76 men differing in fertility. Infertile men had abnormal semen parameters and were involuntarily childless. Fertile subjects exhibited normozoospermia and had fathered children without medical assistance. Results: We discovered proteins from about 7000 coding genes in the human sperm proteome. These were mainly known for involvements in cellular motility, response to stimuli, adhesion, and reproduction. Numbers of sperm proteins showing at least threefold deviating abundances increased from oligozoospermia (N = 153) and oligoasthenozoospermia (N = 154) to oligoasthenoteratozoospermia (N = 368). Deregulated sperm proteins primarily engaged in flagellar assembly and sperm motility, fertilization, and male gametogenesis. Most of these participated in a larger network of male infertility genes and proteins. Discussion: We expose 31 sperm proteins displaying deviant abundances under infertility, which already were known before to have fertility relevance, including ACTL9, CCIN, CFAP47, CFAP65, CFAP251 (WDR66), DNAH1, and SPEM1. We propose 18 additional sperm proteins with at least eightfold differential abundance for further testing of their diagnostic potential, such as C2orf16, CYLC1, SPATA31E1, SPATA31D1, SPATA48, EFHB (CFAP21), and FAM161A. Conclusion: Our results shed light on the molecular background of the dysfunctionality of the fewer spermatozoa produced in oligozoospermia and syndromes including it. The male infertility network presented may prove useful in further elucidating the molecular mechanism of male infertility. [ABSTRACT FROM AUTHOR]

Na+/H+ exchangers (NHEs) are known to be important regulators of pH in multiple intracellular compartments of eukaryotic cells. Sperm function is especially dependent on changes in pH and thus it has been postulated that NHEs play important roles in regulating the intracellular pH of these cells. For example, in order to achieve fertilization, mature sperm must maintain a basal pH in the male reproductive tract and then alkalize in response to specific signals in the female reproductive tract during the capacitation process. Eight NHE isoforms are expressed in mammalian testis/sperm: NHE1, NHE3, NHE5, NHE8, NHA1, NHA2, NHE10, and NHE11. These NHE isoforms are expressed at varying times during spermatogenesis and localize to different subcellular structures in developing and mature sperm where they contribute to multiple aspects of sperm physiology and male fertility including proper sperm development/morphogenesis, motility, capacitation, and the acrosome reaction. Previous work has provided evidence for NHE3, NHE8, NHA1, NHA2, and NHE10 being critical for male fertility in mice and NHE10 has recently been shown to be essential for male fertility in humans. In this article we review what is known about each NHE isoform expressed in mammalian sperm and discuss the physiological significance of each NHE isoform with respect to male fertility. [ABSTRACT FROM AUTHOR]

Background: Infertility is a real public health issue because of its medical, socio-cultural, and financial impact. It does also have heavy psychological consequences on both partners. This study aimed to assess levels of anxiety and depression among men undergoing infertility investigation and to identify their associated factors. Methods: We conducted a cross-sectional study in the Laboratory of Cytogenetics and Reproductive Biology of Fattouma Bourguiba University Teaching Hospital (Monastir, Tunisia) between August 30th, 2020, and March 16th, 2021. Anxiety and depression levels were assessed using the valid Arab version of the Hospital Anxiety and Depression scale (HAD). Semen parameters were analyzed and interpreted according to 2021 World Health Organization (WHO) guidelines. Results: A total of 282 men were included in the current study. The mean HAD-D (depression) and HAD-A (anxiety) scores were of 6.56 ± 3.07 (IQR [4–8]) and 7.94 ± 3.73 (IQR[5–10]) respectively. Univariate analysis showed that patients having two or more comorbidities were nearly five times more likely to be anxious than those without or with only one comorbidity (ORc = 4.71; p = 0.007). Furthermore, single patients were about four times more anxious than those in couple having primary or secondary infertility (ORc = 3.85; p = 0.027). With regards to semen parameters, patients having hypospermia were more than two times anxious compared with those with normal semen volume (ORc = 2.33; p = 0.034). As for depression, we observed that patients with an infertility history lasting for a year or more have a nine times greater risk of depression (ORc = 9.848; p = 0.007). With regards to semen parameters, patients exhibiting two or more semen abnormalities, teratozoospermia and increased MAI were more depressed (ORc = 2.478; p = 0.036; ORc = 2.549: p = 0.023; ORc = 2.762; p = 0.036). Furthermore, we found a negative correlation between HAD-A scores and patient's age. Conclusions: We pointed out through the current study the associated factors with anxiety and depression in patients under fertility management to precociously identify those who need psychological counseling and hence to better manage infertility issues. [ABSTRACT FROM AUTHOR]

L-Carnitine, a natural antioxidant found in mammals, plays a crucial role in the transport of long-chain fatty acids across the inner mitochondrial membrane. It is used as a nutritional supplement by professional athletes, improving performance and post-exercise recovery. Additionally, its therapeutic applications, including those in male infertility, have been investigated, as it may act as a defense mechanism against the excessive production of reactive oxygen species (ROS) in the testis, a process that can lead to sperm damage. This effect is achieved by enhancing the expression and activity of enzymes with antioxidant properties. Nevertheless, the mechanisms underlying the benefits of L-Carnitine remain unknown. This review aims to consolidate the current knowledge about the potential benefits of L-Carnitine and its role in male (in)fertility. Considering in vitro studies with Sertoli cells, pre-clinical studies, and investigations involving infertile men, a comprehensive understanding of the effects of L-Carnitine has been established. In vitro studies suggest that L-Carnitine has a direct influence on somatic Sertoli cells, improving the development of germ cells. Overall, evidence supports that L-Carnitine can positively impact male fertility, even at a relatively low dose of 2 g/day. This supplementation enhances sperm parameters, regulates hormone levels, reduces ROS levels, and subsequently improves fertility rates. However, further research is needed to elucidate the underlying mechanisms and establish optimal doses. In conclusion, the role of L-Carnitine in the field of male reproductive health is highlighted, with the potential to improve sperm quality and fertility. [ABSTRACT FROM AUTHOR]

To study the effect of methotrexate on male fertility and subsequent effects on their children, for which data are scarce and contradictory. Nationwide multiregister cohort study. Not applicable. All children born alive in Sweden between 2006 and 2014 and their fathers. Three cohorts were defined: children to fathers with periconceptional methotrexate exposure (exposed cohort), children whose fathers stopped methotrexate intake ≥2 years before conception (previously exposed cohort), and children to fathers with no methotrexate exposure (control cohort). The father having at least one dispensed methotrexate prescription from pharmacies 0–3 months before conception, along with at least one more dispensed methotrexate prescription 0–12 months before conception (periconceptional exposure). Previously exposed cohort: the father having no dispensed methotrexate prescriptions in the 2 years before conception, but having at least two dispensed prescriptions before that. Congenital anomalies (major and any; primary outcomes), preterm birth (PTB) and being small for gestational age (SGA; secondary outcomes), as well as need of intracytoplasmic sperm injection (ICSI) to achieve pregnancy (primary outcome in exposed cohort vs. controls, exploratory outcome in previously exposed cohort vs. controls). Outcomes were analyzed using logistic regression. A total of 223 children to fathers with periconceptional methotrexate exposure were identified, along with 356 children whose fathers stopped methotrexate intake ≥2 years before conception and 809,706 not methotrexate-treated controls. In children with fathers periconceptionally exposed to methotrexate, the adjusted and unadjusted odds ratios (95% confidence intervals) for major congenital anomalies were 1.1 (0.4–2.6) and 1.1 (0.4–2.4), any congenital anomalies 1.3 (0.7–2.4) and 1.4 (0.7–2.3), PTB 1.0 (0.5–1.8) and 1.0 (0.5–1.8), SGA 1.1 (0.4–2.6) and 1.0 (0.4–2.2), and conception by use of ICSI 3.9 (2.2–7.1) and 4.6 (2.5–7.7). Use of ICSI was not increased among fathers who stopped methotrexate intake ≥2 years before conception, having adjusted and unadjusted odds ratios 0.9 (0.4–1.9) and 1.5 (0.6–2.9). This study suggests that paternal periconceptional methotrexate use does not increase risk of congenital anomalies, PTB, or SGA in the offspring but may temporarily reduce fertility. [ABSTRACT FROM AUTHOR]

The increasing frequency of general and particularly male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis antigens (CTA). The phylostratigraphy analysis of the human genome allowed us to link the early evolutionary origin of cancer via the reproductive life cycles of the unicellulars and early multicellulars, potentially driving soma-germ transition, female meiosis, and the parthenogenesis of polyploid giant cancer cells (PGCCs), with the expansion of the CTA multi-families, very late during their evolution. CTA adaptation was aided by retrovirus domestication in the unstable genomes of mammals, for protecting male fertility in stress conditions, particularly that of humans, as compensation for the energy consumption of a large complex brain which also exploited retrotransposition. We found that the early and late evolutionary branches of human cancer are united by the immunity-proto-placental network, which evolved in the Cambrian and shares stress regulators with the finely-tuned sex determination system. We further propose that social stress and endocrine disruption caused by environmental pollution with organic materials, which alter sex determination in male foetuses and further spermatogenesis in adults, bias the development of PGCC-parthenogenetic cancer by default. [ABSTRACT FROM AUTHOR]

Background: Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. Globozoospermia is an uncommon cause of male factor infertility, characterized by defects in sperm acrosome formation, leading to round‐headed spermatozoa. Objective: We generated Pdcl2 knockout mice to investigate the essential roles of PDCL2 in mammalian reproduction. Materials and methods: We used reverse transcription‐polymerase chain reaction to demonstrate that PDCL2 was expressed exclusively in the male reproductive tract in mice and humans. We created Pdcl2 knockout mice using the CRISPR‐Cas9 system and analyzed their fertility. Pdcl2 null spermatozoa underwent further evaluation using computer‐assisted sperm analysis, light microscopy, and ultrastructural microscopy. We used immunoblot analysis and immunofluorescence to elucidate relationships between PDCL2 and other acrosomal proteins. Results: The PDC family is highly conserved in eukaryotes. Mouse and human PDCL2 are testis enriched and localized to the testicular endoplasmic reticulum. Loss of the protein causes sterility because of abnormal acrosome biogenesis during spermiogenesis and immotility. Furthermore, Pdcl2 null spermatozoa have rounded heads, similar to globozoospermia in humans. Observation of the knockout testis shows a lack of acrosomal cap formation, aberrant localization of mitochondria in the sperm head, and misshapen nuclei. Conclusion: PDCL2 is essential for sperm acrosome development and male fertility in mice and is a putative contraceptive target in men. [ABSTRACT FROM AUTHOR]

Objective To explore the validity of speim telomere length in assessing semen quality and diagnosing male infertility. Methods A total of 55 infertile men aged 21 to 46 years, who visited our hospital between December 2021 and October 2022 as the infertility group, and 55 men of proven fertility during the same period as the controls were recruited in the study. Their semen specimens were collected and standard semen analysis was performed. Sperm telomere length was detected by a quantitative real-time fluorescence PCR (qRT-PCR), and the difference and correlation between sperm telomere length and semen quality parameters were assessed between the two groups. The diagnostic value of sperm telomere length for male infertility was evaluated by the receiver operating characteristic (ROC)curve・ Results Semen quality parameters and mean sperm telomere length were significantly lower in infertile men than those in fertile men (1.53 ±0. 82 憐.2.30 ±1.15, P <0・ 05). There was a significant positive linear correlation between telomere length and sperm motility (r = 0・ 324), percentage of forward moving sperm (a + b)% (r = 0. 334), sperm concentration (r = 0・ 245) and sperm count (r = 0.207). With a threshold of 2. 05, the area under the ROC curve [AUC] was 0. 799 (P V 0. 001) and the sensitivity and specificity of sperm telomere length fbrmale infertility were 90. 9% and 63, 6%. Conclusion Sperm telomere length shortening may be a sign

Simple Summary: This study focused on the relationship between microRNA-23a/b-3p and genes involved in human spermatogenesis, with the aim of understanding how this microRNA targets these genes and how it affects male fertility. Through computational prediction and experimental assays, we identified specific genes that are targeted by microRNA-23a/b-3p. By intentionally modifying the binding sites of microRNA-23a/b-3p in these genes, we confirmed the direct targeting. To validate their findings, we analyzed sperm samples from men with low sperm count and motility compared to a control group. The results revealed that the men with fertility issues had lower expression levels of the target genes. Furthermore, we found a positive correlation between basic semen parameters and the reduced expression levels of the target genes. This indicates that microRNA-23a/b-3p plays a significant role in spermatogenesis by regulating the expression of target genes associated with male fertility problems, and it also has an impact on basic semen parameters. Overall, this study provides important insights into the involvement of microRNA-23a/b-3p in spermatogenesis and its potential influence on male fertility. The expression levels of various genes involved in human spermatogenesis are influenced by microRNAs (miRNAs), specifically microRNA-23a/b-3p. While certain genes are essential for spermatogenesis and male germ cell function, the regulation of their expression remains unclear. This study aimed to investigate whether microRNA-23a/b-3p targets genes involved in spermatogenesis and the impact of this targeting on the expression levels of these genes in males with impaired fertility. In-silico prediction and dual-luciferase assays were used to determine the potential connections between microRNA-23a/b-3p overexpression and reduced expression levels of 16 target genes. Reverse transcription-quantitative PCR (RT-qPCR) was conducted on 41 oligoasthenozoospermic men receiving infertility treatment and 41 age-matched normozoospermic individuals to verify the lower expression level of target genes. By employing dual-luciferase assays, microRNA-23a-3p was found to directly target eight genes, namely NOL4, SOX6, GOLGA6C, PCDHA9, G2E3, ZNF695, CEP41, and RGPD1, while microRNA-23b-3p directly targeted three genes, namely SOX6, GOLGA6C, and ZNF695. The intentional alteration of the microRNA-23a/b binding site within the 3′ untranslated regions (3′UTRs) of the eight genes resulted in the loss of responsiveness to microRNA-23a/b-3p. This confirmed that NOL4, SOX6, GOLGA6C, PCDHA9, and CEP41 are direct targets for microRNA-23a-3p, while NOL4, SOX6, and PCDHA9 are direct targets for microRNA-23b-3p. The sperm samples of oligoasthenozoospermic men had lower expression levels of target genes than age-matched normozoospermic men. Correlation analysis indicated a positive correlation between basic semen parameters and lower expression levels of target genes. The study suggests that microRNA-23a/b-3p plays a significant role in spermatogenesis by controlling the expression of target genes linked to males with impaired fertility and has an impact on basic semen parameters. [ABSTRACT FROM AUTHOR]

BACKGROUND Primary ciliary dyskinesia (PCD) is a genetic condition affecting the structure and function of sperm flagellum and motile cilia including those in the male and female reproductive tracts. Infertility is a commonly reported feature of PCD, but there is uncertainty as to how best to counsel patients on their fertility prognosis. OBJECTIVE AND RATIONALE This review aimed to summarize the prevalence of subfertility, possible underlying mechanisms, and the success of ART in men and women with PCD. The efficacy of ART in this patient group is relatively unknown and, hence, the management of infertility in PCD patients remains a challenge. There are no previous published or registered systematic reviews of fertility outcomes in PCD. SEARCH METHODS Systematic literature searches were performed in Medline, Embase, Cochrane Library, and PubMed electronic databases to identify publications between 1964 and 2022 reporting fertility outcomes in men and women with PCD. Publications were excluded if they reported only animal studies, where gender was not specified or where subjects had a medical co-morbidity also known to impact fertility. Quality of evidence was assessed by critical appraisal and application of an appraisal tool for cross-sectional studies. The primary outcomes were natural conception in men and women with PCD, and conception following ART in men and women with PCD. OUTCOMES A total of 1565 publications were identified, and 108 publications were included after screening by two independent researchers. The quality of available evidence was low. The exact prevalence of subfertility in PCD is unclear but appears to be higher in men (up to 83% affected) compared to women (up to 61% affected). Variation in the prevalence of subfertility was observed between geographic populations which may be explained by differences in underlying genotype and cilia function. Limited evidence suggests subfertility in affected individuals is likely caused by abnormal cilia motion in the fallopian tubes, endometrium and efferent ductules, and dysmotile sperm. Some men and women with PCD benefited from ART, which suggests its use should be considered in the management of subfertility in this patient group. Further epidemiological and controlled studies are needed to determine the predictors of fertility and optimal management in this patient group. WIDER IMPLICATIONS It is important that patients with PCD receive evidence-based counselling about the potential impact of their condition on their fertility prognosis and what management options may be available to them if affected. Understanding the pathophysiology and optimal management of subfertility in PCD will increase our understanding of the role of cilia and the impact of wider secondary ciliopathies on reproduction. [ABSTRACT FROM AUTHOR]

Background: Following thyroidectomy, radioiodine therapy is the standard management of differentiated thyroid cancer. The effects of such treatment on testicular function remained a concern for cases and clinicians. Objective: We aimed to observe changes in fertility indicators in men treated with ablation. Materials and Methods: In this prospective cohort study, 18 men with differentiated thyroid cancer from June to December 2020 underwent thyroidectomy plus radioiodine therapy. Participants were grouped based on iodine dose (8 men with 30 mCi vs. 10 men with = 150 mCi). Baseline values (VB) of the follicular stimulating hormone, luteinizing hormone, testosterone, and sperm analyses were measured 3 wk before iodine ablation and repeated 3 (V3) and 12 (V12) months later. They were analyzed once as a whole and once based on their groups via ANOVA and Friedman's tests where appropriate. Results: The mean age of participants was 35.61 ± 9.74 yr. Follicular stimulating hormone levels showed a significant trend among all participants (VB: 12.51 ± 1.72, V3: 13.54 ± 1.41, and V12: 13.10 ± 1.67 IU/mL; p < 0.001). Luteinizing hormone showed a similar pattern (VB: 4.98 ± 1.27, V3: 5.65 ± 1.29, and V12: 5.21 ± 0.95 IU/mL; p < 0.001). Testosterone levels did not differ significantly from baseline. Sperm count decreased at the first checkpoint and returned to normal after 12 months (VB: 38.22 ± 19.40, V3: 32.05 ± 17.96, and V12: 36.66 ± 18.81 million/mL; p < 0.001). Sperm motility and morphology did not change significantly. Conclusion: Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months. [ABSTRACT FROM AUTHOR]

Male infertility affects approximately 7% of childbearing couples and is a major health issue. Although nearly 50% idiopathic infertile men are assumed to have a genetic basis, the underlying causes remain largely unknown in most infertility cases. Here, we report two rare homozygous variants in two previously uncharacterized genes, C9orf131 and C10orf120 , identified in two unrelated men with asthenozoospermia. Both genes were predominantly expressed in the testes. Furthermore, C9orf131 and C10orf120 knockout mice were successfully generated using the CRISPR-Cas9 technology. However, both C9orf131 −/− and C10orf120 −/− adult male mice were fertile, with testis-to-body weight ratios comparable to those of wild-type mice. No overt differences were found between wild-type, C9orf131 −/−, and C10orf120 −/− mice regarding testicular/epididymal tissue morphology, sperm count, sperm motility, or sperm morphology. Moreover, TUNEL assays indicated that the number of apoptotic germ cells in testes was not significantly different between the three groups. In summary, these findings suggest that C9orf131 and C10orf120 are redundant genes in male infertility. [Display omitted] • C9orf131 and C10orf120 are highly expressed in the testes. • C9orf131 knockout male mice were viable, with normal fertility and spermatogenesis. • C10orf120 knockout male mice were viable, with normal fertility and spermatogenesis. [ABSTRACT FROM AUTHOR]

Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE1 and PGE2), PGF2α, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE1 and PGE2. The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility. [ABSTRACT FROM AUTHOR]

There are conflicting reports on trends of semen parameters from different parts of the globe. However, in recent times there is dearth of information on the trend in Sub-Saharan countries. Therefore, in this study we aimed at determining the trends in semen parameters in Nigeria and South Africa between 2010 and 2019. A retrospective study of semen analyses of 17,292 men attending fertility hospitals in Nigeria and South Africa in 2010, 2015 and 2019. Patients who had undergone vasectomy and those who had a pH less than 5 or greater than 10 were excluded from this study. The following variables were assessed: ejaculate volume, sperm concentration, progressive motility, total progressively motile sperm count (TPMSC), total sperm count, and normal sperm morphology. Between 2010 and 2019, significant trends of decreasing values were observed in normal sperm morphology (− 50%), and the ejaculatory volume (− 7.4%), indicating a progressive deterioration of the values in both countries. In Nigeria, there were significant decreases in progressive motility (− 87%), TPMSC (− 78%), and sperm morphology (− 55%) between 2010 and 2019 (P < 0.001). Spearman's rank correlation revealed significant negative associations between age and morphology (ρ = − 0.24, P < 0.001), progressive motility (ρ = − 0.31. P < 0.001), and TPMSC (ρ = − 0.32, P < 0.001). Patients in South Africa were younger than those from Nigeria, with also a significantly higher sperm morphology, sperm concentration, progressive motility, total sperm count and TPMSC. Our findings provide a quantitative evidence of an alarming decreasing trend in semen parameters in Nigeria and South Africa from 2010 to 2019. It also proves that astheno- and teratozoospermia are the leading causes of male infertility in these regions. In addition to this, it also shows empirically that semen parameters decrease with advancement in age. These findings are the first report of temporal trends in semen parameters in Sub-Saharan countries, necessitating a thorough investigation on the underlying factors promoting this worrisome decline. [ABSTRACT FROM AUTHOR]

Over the past decades there has been a significant decline in the birth rate in many countries raising the question of the role and degree of involvement of biological factors in this process. Up to 30% of couples of reproductive age have fertility problems, and in half of the cases, the cause is due to male factors. However, up to 40% of cases of male infertility are idiopathic, i.e., with unexplained causes. More and more evidence suggests that environmental factors are the causes of growing male infertility and subfertility, among which the individual lifestyle seems to be the most significant. Many researchers believe that lifestyle factors make a significant contribution to the existing negative trend of global decline in the male reproductive potential. The main factors of an individual lifestyle that cause a weakening of male reproductive health are considered to be obesity, unhealthy nutrition, physical inactivity, smoking, excessive alcohol intake, psychological stress, low-level radio-frequency electromagnetic fields (mobile phones and portable computers), aging, and others. Many factors of an individual lifestyle can reduce sperm production, mobility and normal morphology, increase damage to the sperm DNA, and have a negative impact on the endocrine control of reproductive function, which can lead to male subfertility and infertility. In recent years, a significant amount of data has been accumulated that allows us to create an exhaustive and multifaceted picture of the lifestyle effects on the male reproductive function. This review focuses on the negative impact of the most common factors: obesity, diet, sedentary lifestyle, smoking, and alcohol consumption on spermatogenesis and the profile of reproductive hormones in men. [ABSTRACT FROM AUTHOR]

Background: Infertility is one of the three major public health problems in the world, bringing immense physical and psychological damage to men and affecting the quality of men’s fertility life. Thus, the purpose of this study was to analyze the status of social support, fertility stress, mindfulness, and fertility quality of life in infertile men, and to explore the dual mediating effects of social support and fertility stress on mindfulness and fertility quality. Methods: A case–control group study was conducted, with 246 men in the case group and 149 in the control group. The Social Support Scale, Fertility Stress Scale, Mindfulness Scale, and Fertility Quality of Life Scale were used to establish a structural equation model using Mplus 8.3 to explore social support and fertility stress. Pathway relationships were drawn between mindfulness and fertility quality of life in infertile men. Results: There were significant differences between infertile and healthy men in each dimension of the core module of fertility quality of life, in the total score of the treatment module, in the total score of social support, in subjective and objective support, and in the total score of fertility stress, social pressure, sexual pressure, marital relationship, and childless pressure (p < 0.05 in each case). Further, the fertility quality of life in infertile men was positively correlated with mindfulness and social support, and negatively correlated with fertility stress (p < 0.05); mindfulness could directly affect the core and treatment modules of fertility life quality, and indirectly affect the core of fertility life quality through social support (mediation effect accounted for 19.0%), while the treatment module (mediation effect accounted for 13.7%), and the core module indirectly affected fertility life quality through fertility stress (mediation effect accounted for 16.8%). Conclusion: The fertility quality of life of infertile men is not optimistic. Mindfulness-related interventions and programs can improve their fertility quality of life. [ABSTRACT FROM AUTHOR]

Oocyte activation, a fundamental event during mammalian fertilisation, is initiated by concerted intracellular patterns of calcium (Ca2+) release, termed Ca2+ oscillations, predominantly driven by testis-specific phospholipase C zeta (PLCζ). Ca2+ exerts a pivotal role in not just regulating oocyte activation and driving fertilisation, but also in influencing the quality of embryogenesis. In humans, a failure of Ca2+ release, or defects in related mechanisms, have been reported to result in infertility. Furthermore, mutations in the PLCζ gene and abnormalities in sperm PLCζ protein and RNA, have been strongly associated with forms of male infertility where oocyte activation is deficient. Concurrently, specific patterns and profiles of PLCζ in human sperm have been linked to parameters of semen quality, suggesting the potential for PLCζ as a powerful target for both therapeutics and diagnostics of human fertility. However, further to PLCζ and given the strong role played by Ca2+ in fertilisation, targets down- and up-stream of this process may also present a significantly similar level of promise. Herein, we systematically summarise recent advancements and controversies in the field to update expanding clinical associations between Ca2+-release, PLCζ, oocyte activation and human fertility. We discuss how such associations may potentially underlie defective embryogenesis and recurrent implantation failure following fertility treatments, alongside potential diagnostic and therapeutic avenues presented by oocyte activation for the diagnosis and treatment of human infertility. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is a global epidemic characterized by high morbidity and mortality. Diabetes mellitus can lead to acute and chronic systemic complications. Among them, a negative effect of diabetes mellitus on sperm quality and male/couple fertility has been suggested. However, available studies in diabetes mellitus men evaluated relatively small cohorts with discordant results. Objectives: To evaluate the clinical evidences of the effects of diabetes mellitus on sperm quality and fertility outcomes. Methods: An extensive Medline search was performed identifying studies in the English language. Results: The prevalence of diabetes mellitus in infertile men ranges from 0.7% to 1.4%, while the prevalence of infertility in diabetes mellitus men, evaluated in a few studies, ranges from 35% to 51%. Male diabetes mellitus seems to play a negative effect on couple fecundity, while being childless or subfertile men might increase the risk of diabetes mellitus. Available cross-sectional studies investigating semen parameters and male sexual hormones in men with diabetes mellitus are heterogeneous, assessed relatively small cohorts, show often discordant results and frequently are not directly comparable to derive robust conclusions. Two meta-analyses support a negative effect of diabetes mellitus on sperm normal morphology and no effect on sperm total count, with contradictory results regarding other semen parameters. Considering only studies on type 1 diabetes mellitus men, meta-analyses support a negative effect of diabetes mellitus on sperm motility and no effect on sperm total count, with contradictory results regarding other semen parameters. The rate of children observed among type 1 diabetes mellitus men was lower than controls, especially in subjects with a longer diabetes mellitus duration. Couples with a diabetes mellitus male partner undergoing assisted reproduction techniques showed lower pregnancy rates than controls. No study evaluated the impact of diabetes mellitus treatment on semen quality andmale fertility. Conclusions: Overall, available data show that diabetes mellitus might impair male reproductive health and couple fertility. However, further larger and full of details studies are needed. [ABSTRACT FROM AUTHOR]

Male factors are suspected in around half cases of infertility, of which up to 40% are diagnosed as idiopathic. In the context of a continuously increased resort to ART and increased decline of semen parameters, it is of greatest interest to evaluate an additional potential biomarker of sperm quality. According to PRISMA guidelines, this systematic review of the literature selected studies evaluating telomere length in sperm and/or in leukocytes as a potential male fertility biomarker. Twenty-two publications (3168 participants) were included in this review of experimental evidence. For each study, authors determined if there was a correlation between telomere length and semen parameters or fertility outcomes. Of the 13 studies concerning sperm telomere length (STL) and semen parameters, ten found an association between short STL and altered parameters. Concerning the impact of STL on ART results, the data are conflicting. However, eight of the 13 included studies about fertility found significantly longer sperm telomeres in fertile men than in infertile men. In leukocytes, the seven studies reported conflicting findings. Shorter sperm telomeres appear to be associated with altered semen parameters or male infertility. Telomere length may be considered as a new molecular marker of spermatogenesis and sperm quality, and thus is related to male fertility potential. However, additional studies are needed to define the place of the STL in the assessment of individual fertility. [ABSTRACT FROM AUTHOR]

Deciphering the functional relationships of genes resulting from genome-wide screens for polymorphisms that are associated with phenotypic variations can be challenging. However, given the common association with certain phenotypes, a functional link should exist. We have tested this prediction in newly sequenced exomes of altogether 100 men representing different states of fertility. Fertile subjects presented with normal semen parameters and had naturally fathered offspring. In contrast, infertile probands were involuntarily childless and had reduced sperm quantity and quality. Genome-wide association study (GWAS) linked twelve non-synonymous single-nucleotide polymorphisms (SNPs) to fertility variation between both cohorts. The SNPs localized to nine genes for which previous evidence is in line with a role in male fertility maintenance: ANAPC1, CES1, FAM131C, HLA-DRB1, KMT2C, NOMO1, SAA1, SRGAP2, and SUSD2. Most of the SNPs residing in these genes imply amino acid exchanges that should only moderately affect protein functionality. In addition, proteins encoded by genes from present GWAS occupied peripheral positions in a protein–protein interaction network, the backbone of which consisted of genes listed in the Online Mendelian Inheritance in Man (OMIM) database for their implication in male infertility. Suggestive of an indirect impact on male fertility, the genes focused were indeed linked to each other, albeit mediated by other interactants. Thus, the chances of identifying a central player in male infertility by GWAS could be limited in general. Furthermore, the SNPs determined and the genes containing these might prove to have potential as biomarkers in the diagnosis of male fertility. [ABSTRACT FROM AUTHOR]

Background Conception difficulties are a common reason for presentation to general practitioners (GPs), who play an integral part in advising couples regarding optimisation of trying to conceive, timely and relevant investigations, as well as referral to non-GP specialist care. Lifestyle modification to optimise reproductive and offspring health is a crucial, though sometimes overlooked, component of pre-pregnancy counselling. Objective This article provides an update on fertility assistance and reproductive technologies to help GPs care for patients presenting with fertility concerns as well as those who require donor gametes to conceive or are carrying genetic conditions that may affect the chance of having a healthy baby. Discussion Recognition of the impact of a woman’s (and, to a slightly lesser degree, man’s) age remains the highest priority for primary care physicians to allow thorough and timely evaluation/referral. Advising patients about lifestyle modification, such as diet, physical activity and mental health, prior to conception is crucial for overall and reproductive health outcomes. Various treatment options exist to provide personalised and evidence-based care for patients for infertility. Other indications for using assisted reproductive technology include preimplantation genetic testing of embryos to avoid transmission of serious genetic conditions, elective oocyte freezing and fertility preservation. [ABSTRACT FROM AUTHOR]

The negative effect of advanced female age on fertility and offspring health is well understood. In comparison, much less is known about the implications of male age on fertility, with many studies showing conflicting results. Nevertheless, increasing evidence suggests that advanced paternal age has negative effects on sperm parameters, reproductive success, and offspring health. Herein, we summarize the current body of knowledge on this controversial topic, with the belief that this review will serve as a resource for the clinicians providing fertility counseling to couples with older male partners. [ABSTRACT FROM AUTHOR]

Spermatogenesis and male phenotypic development during puberty are mainly done by androgen and their function is controlled by the gene for androgen receptor (AR). This gene has a region of polymorphism in Exon1 which encode androgen receptor and have various length of CAG trinucleotide repeat which causes the production of polyglutamine chain in different length of the N-terminal region of the AR protein, which reduces producing sperm by disrupting spermatogenesis. The aim is to determine the relation of infertility in male with the AR gene which has more CAG repeats than usual, and the correlation between CAG repetition and hormonal changes. The casecontrol study was done in the Immunogene center and IVF center in the Kurdistan region of Iraq's maternity teaching hospital. The illustrative sample included 50 men, 30 infertile and 20 fertile over one year starting from March 2021 to March 2022. The result of the recorded analysis of the CAG repetition on fertility showed men with infertility had CAG repeats in their AR gene, ranging from (17-26) repeats, with a mean (21.3 ±0.16). In infertile men, CAG expansion was longer than the fertile men. The sperm's normal morphology and motility in infertile men have negative relation while sperm count and concentration have a positive relation with CAG expansion. The relation of hormones (Testosterone, LH, and FSH) with CAG repetition was statistically not significant. In conclusion,CAG expansion was longer in infertile (case) men compared with fertile (control) men. Polyglutamine effect on increasing sperm abnormal morphology and immotility which is the reason for infertility is statistically not significant and it will not affect hormonal assay in infertile men. [ABSTRACT FROM AUTHOR]

In case 1, the male patient received multiple cycles of chemotherapy prior to two conditioning regimens, BEAM and flu-mel, containing high-dose melphalan in combination with other drugs. In murine models, anthracyclines can deplete ovarian follicle reserve [[10]], although in humans doxorubicin doses up to 300 mg/m SP 2 sp in ABVD are not associated with impairment of female fertility [[11]]. The observation that the patient was oligospermic but not azoospermic after two conditioning regimens suggests that germ cells within seminiferous tubules may be less sensitive to the sterilizing effects of high-dose chemotherapy than ovarian oocytes. [Extracted from the article]

The gut microbiota (GM) is a complex and dynamic population of microorganisms living in the human gastrointestinal tract that play an important role in human health and diseases. Recent evidence suggests a strong direct or indirect correlation between GM and both male and female fertility: on the one hand, GM is involved in the regulation of sex hormone levels and in the preservation of the blood–testis barrier integrity; on the other hand, a dysbiotic GM is linked to the onset of pro-inflammatory conditions such as endometriosis or PCOS, which are often associated with infertility. Exposure to endocrine-disrupting chemicals (EDCs) is one of the main causes of GM dysbiosis, with important consequences to the host health and potential transgenerational effects. This perspective article aims to show that the negative effects of EDCs on reproduction are in part due to a dysbiotic GM. We will highlight (i) the link between GM and male and female fertility; (ii) the mechanisms of interaction between EDCs and GM; and (iii) the importance of the maternal–fetal GM axis for offspring growth and development. [ABSTRACT FROM AUTHOR]

• Vaccination against SARS-CoV-2 remains an important measure to prevent serious infection. • Misinformation and doubts regarding the vaccines should be properly addressed. • Studies published so far report no association between covid19 vaccines and fertility. • Future studies should focus on longer follow up time, systematic investigation, and representativeness. Despite literature's evidence about COVID-19 vaccines' safety, concerns have arisen regarding adverse events, including the possible impact on fertility, accentuated by misinformation and anti-vaccine campaigns. The present study aims to answer the question: Is there any impact of COVID-19 vaccines on the fertility of men and women of reproductive age? PubMed, Scopus, Web of Science, Cochrane and Embase databases were searched for eligible studies until June 8th, 2022. The search was restricted to articles regarding humans, published in any languages, without additional restrictions. Studies' quality was assessed by the Newcastle-Ottawa and the Before and After Quality Assessment scales for cohort and pre-post studies, respectively. Random-effect meta -analyses were performed for parameters considered in ≥ 2 studies, calculating means, p -values and 95 % Confidence Intervals (CIs). Out of 1406 studies screened, 29 were included in the systematic review. These studies, conducted in Israel (34.5 %), USA (24.1 %), Russia (20.7 %) China (10.3 %), Italy (3.5 %), North America (3.5%) and Turkey (3.5 %) were of poor (34.5 %), moderate (58.6 %) and good (6.9 %) quality. Meta-analyses were performed for pre- and post-vaccination sperm progressive motility (44 %, 95 % CI 42 %-62 % vs 43 %, 95 % CI 31 %-59 % p = 0.07) and concentration (50.6 mln/ml, 95 % CI 35.1–72.8 vs 55.4 mln/ml, 95 % CI 37.4–82.2p = 0.12). Biochemical (0.51, 95 % CI 0.40–0.66 vs 0.60, 95 % CI 0.53–0.68p = 0.45) and clinical (0.45, 95 % CI 0.37–0.54 vs 0.47, 95 % CI 0.40–0.55 p = 0.31) pregnancy rate did not differ among vaccinated and not vaccinated groups. Subgroup meta -analyses based on the type of vaccine showed no significant difference: between vaccinated with mRNA vaccines and non-vaccinated regarding biochemical pregnancy rates; pre- and post-vaccination with Gam-COVID-Vac regarding testosterone, FSH and LH levels; pre- and post-vaccination with BNT162b2 vaccines regarding sperm volumes. Based on the studies published so far, there is no scientific proof of any association between COVID-19 vaccines and fertility impairment in men or women. [ABSTRACT FROM AUTHOR]

Male infertility is a common condition affecting at least 7% of men worldwide and is often genetic in origin. Using whole exome sequencing, we recently discovered three hemizygous, likely damaging variants in DDB1- and CUL4-associated factor 12-like protein 1 (DCAF12L1) in men with azoospermia. DCAF12L1 is located on the X-chromosome and as identified by single cell sequencing studies, its expression is enriched in human testes and specifically in Sertoli cells and spermatogonia. However, very little is known about the role of DCAF12L1 in spermatogenesis, thus we generated a knockout mouse model to further explore the role of DCAF12L1 in male fertility. Knockout mice were generated using CRISPR/Cas9 technology to remove the entire coding region of Dcaf12l1 and were assessed for fertility over a broad range of ages (2–8 months of age). Despite outstanding genetic evidence in men, loss of DCAF12L1 had no discernible impact on male fertility in mice, as highlighted by breeding trials, histological assessment of the testis and epididymis, daily sperm production and evaluation of sperm motility using computer assisted methods. This disparity is likely due to the parallel evolution, and subsequent divergence, of DCAF12 family members in mice and men or the presence of compounding environmental factors in men. • Dcaf12l1 is not required for male fertility in the mouse. • DCAF12L1 has been identified as a gene affected by genetic variation in multiple infertile men. • Loss of Dcaf12l1 in mice does affect male fertility. [ABSTRACT FROM AUTHOR]

Non-obstructive azoospermia (NOA) is a severe factor of male infertility; it affects approximately 1% of the global male population and accounts for 40% of male infertility cases. However, the majority of NOA cases remain idiopathic. This is the first study using whole-exome sequencing (WES) to identify a novel missense mutation in the DND1 gene (c.212A>C, p. E71A) from a Pakistani family, that includes three males with NOA. This mutation is predicted to cause DND1 protein misfolding and weaken the DND1 interaction with NANOS2, a significant regulator in primordial germ cell development. Our study identified a DND1 pathogenic mutation in NOA patients and highlighted its critical role in male fertility in humans. [ABSTRACT FROM AUTHOR]

Thousands of genes are expressed during spermatogenesis and male infertility has a strong genetic component. Within this study, we focus on the role of Zfr2 in male fertility, a gene previously implicated in human male fertility. To date, very little is known about the role of ZFR2 in either humans or mice. To this end, the requirement for ZFR2 in male fertility was assessed using a knockout mouse model. Zfr2 was found to be expressed in the testes of both humans and mice. Deletion of Zfr2 was achieved via removal of exon 2 using CRISPR-Cas9 methods. The absence of Zfr2 did not result in a reduction in any fertility parameters assessed. Knockout males were capable of fostering litter sizes equal to wild type males, and there were no effects of Zfr2 knockout on sperm number or motility. We note Zfr2 knockout females were also fertile. The absence of Zfr2 alone is not sufficient to cause a reduction in male fertility in mice. • ZFR2 has been identified as a gene affected by genetic variation in an infertile man. • Loss of Zfr2 in mice does affect male fertility. • Zfr2 function is not compensated by family member Zfr. [ABSTRACT FROM AUTHOR]

Congenital hypogonadotropic hypogonadism (CHH) is characterized by complete or partial failure of pubertal development because of inadequate secretion of gonadotropic hormones. CHH consists of hypogonadotropic hypogonadism with anosmia or hyposmia, Kallmann syndrome, and the normosmic variation normosmic idiopathic hypogonadotropic hypogonadism. CHH is one of the few treatable diseases of male infertility, although men with primary testicular dysfunction have irreversibly diminished spermatogenic capacity. The approach to CHH treatment is determined by goals such as developing virilization or inducing fertility. This review focuses on the current knowledge of therapeutic modalities for inducing puberty and fertility in men with CHH. [ABSTRACT FROM AUTHOR]

This article discusses the impact of COVID-19 on male fertility and how healthcare providers counsel patients on this topic. It emphasizes that vaccination does not have detrimental effects on fertility, while infection by the virus can negatively affect hormones and sperm production. COVID-19 has been found in semen and testis tissue, and it can cause changes in hormone levels and sperm health. However, these effects are usually temporary and resolve after the infection is cleared. The article also mentions that COVID-19 infection does not significantly impact female fertility or pregnancy outcomes. [Extracted from the article]

This paper explores how organizations within the fertility treatment sector in the UK discursively construct (cis) male infertility and whether, in so doing, they reinforce or reproduce prevailing institutionalized discourses and practices of masculinity. We seek to address the gender disparity in contemporary understandings of reproductive health in Organization Studies (OS) where women's experience of infertility and its impact is well researched, but only occasionally does this extend to issues of male infertility. Specifically, we build on existing literature in the social sciences and OS on male infertility and expand it by investigating the organizations that treat fertility issues. We examine and discuss how they may inadvertently contribute to this neglect, by reflecting and reproducing the masculine norms that surround male infertility. We employ a thematic analysis to examine texts produced by organizations involved in the fertility sector and find that male infertility is discussed and presented through three intersecting lenses: (a) a hegemonic masculinization of infertility; (b) male infertility as an othering experience; and (c) disembodied masculinity. We highlight how these gendered organizational narratives (re)produce prevailing norms and practices of masculinity, and how an organizational shift within the sector needs to take place if substantial changes toward more caring, relational, and collective approaches to gender and reproductive health are to be achieved. [ABSTRACT FROM AUTHOR]

Male infertility is influenced by psychological, biological and environmental factors. Nowadays, the morphological change of genes and biological molecules are the focus of attention. Therefore, this study was conducted with the aim of investigating the relationship between tumor necrosis factor alpha-308 and interleukin-1beta C+3953T polymorphisms with male fertility in Erbil province. This study was conducted between 2020 and 2021 on 270 men who referred to the infertility center in Erbil, Iraq, with infertility problems. The sampling was purposeful and the samples were divided into three groups of 90 people with the characteristics of the first group without fertility problems, the second group with primary infertility and the third group with secondary infertility. Blood samples were taken from each sample and the samples were sent to the laboratory for deoxyribonucleic acid extraction and allele analysis. A polymerase chain reaction machine was used for this purpose. Statistical package for the social sciences version 23 software and descriptive statistical tests, chi-square, odds ratio and conditional regression were used to analyze the obtained data. The results of tumor necrosis factor alpha-308 genotype showed the frequency of alleles in three groups of men, it can be concluded that there is a significant difference between the three groups of men in terms of mutation frequency and fertility (p≤0.001). The results of interleukin-1beta C+3953T genotype have shown that there is a significant difference in mutation frequency and finally fertility in three groups of men (p≤0.001). The tumor necrosis factor alpha-308 genotype GA and GG alleles have a significant relationship with male fertility. In genotype interleukin-1beta C+3953T, CT and CC alleles have a significant relationship with male fertility. The results of this study showed that tumor necrosis factor alpha-308 genotype and interleukin-1beta C+3953T genotype were identified as important risk factors in male infertility. [ABSTRACT FROM AUTHOR]