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Summary We investigated the effects of folic acid and zinc sulphate supplementation on the improvement of sperm function in subfertile oligoasthenoteratozoospermic (OAT) men. Eighty‐three OAT men participated in a 16‐week intervention randomised, double‐blind clinical trial with daily treatment of folic acid (5 mg day−1) and zinc sulphate (220 mg day−1), or placebo. Before and after treatment, semen and blood samples were obtained for determining sperm concentration, motility, and morphology, sperm viability, sperm mitochondrial function, sperm chromatin status using toluidine blue, aniline blue, acridine orange and chromomycin A3 staining; and semen and blood folate, zinc, B12, total antioxidant capacity (TAC) and malondialdehyde (MDA) concentrations. Sperm concentration (×106 ml−1) increased in subfertile men receiving the combined treatment of folic acid and zinc sulphate and also in the group receiving only folic acid treatment; however, it was not statistically significant (P = 0.056 and P = 0.05, respectively). Sperm chromatin integrity (%) increased significantly in subfertile men receiving only zinc sulphate treatment (P = 0.048). However, this improvement in sperm quality was not significant after adjusting placebo effect. This study showed that zinc sulphate and folic acid supplementation did not ameliorate sperm quality in infertile men with severely compromised sperm parameters, OAT. Male infertility is a multifactorial disorder, and also nutritional factors play an important role in results of administration of supplementation on sperm parameters. However, these results should be confirmed by multiple studies in larger populations of OAT men.

Background Male infertility is a significant contributor to the need for fertility treatment. Treatment currently involves correcting any identifiable adverse lifestyle factors in men with suboptimal sperm parameters, and if these measures are unsuccessful, assisted conception is offered, which can be quite expensive. Raised scrotal temperature is one of the least studied but easily corrected risk factors for male infertility. In a recent review of the literature, sperm count, motility and morphology improved with scrotal cooling devices. The devices used to achieve testicular cooling were, however, not practical for day-to-day use. A potentially more practical device for scrotal cooling has recently been developed. The Babystart® FertilMate™ Scrotum Cooling Patch is a hydrogel pad which allows for comfortable application. The aims of this study were to investigate whether exposing the scrotum to lower temperatures by means of these new patches could improve semen parameters, thereby improving fertility, and to assess the feasibility of a clinical trial. Methods/design This is a randomised controlled trial set in a university teaching hospital in the United Kingdom. The proposed sample size was 40 men with mild, moderate or severe oligoasthenospermia, of whom 20 would be randomised to wearing the scrotum cooling patch for 90 days and 20 men would be acting as controls and not wearing the patches. The primary outcome measure was the change in sperm concentration. Secondary outcome measures included the change in sperm volume, motility and morphology; endocrine parameters; metabolomic biomarkers; testicular volume and blood flow. Reasons for dropping out and non-compliance were also going to be noted and reported. Discussion The study started recruiting in October 2011 and as of November 2011 four men had been consented and were participating in the study. No operational challenges had been encountered at the time of the submission of this manuscript. Although the study also aimed to evaluate the feasibility of a definitive study, the change in sperm count after 90 days of wearing the scrotal cooling patches was made the primary outcome measure because a statistically significant improvement in sperm parameters with the scrotal patches would in itself be a definitive finding. Trial registration Current Controlled Trials ISRCTN94041896

Azoospermia, characterized by the absence of spermatozoa in the ejaculate, is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings, we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease‐induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit toward the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes. Synopsis SPINK2, a serine protease inhibitor, is believed to target the acrosin, the main sperm acrosomal protease. This study confirms SPINK2 in that role and finds it essential for spermiogenesis as SPINK2 deficiency induces a post meiotic block at the round spermatid stage leading to azoospermia in mice and men. In round spermatids, SPINK2 is necessary to inactivate the acrosin during its transit through the endoplasmic reticulum and the Golgi apparatus. In the absence of SPINK2, acrosin can auto‐activate, disorganize the Golgi apparatus, prevent the production of the acrosome and induce a block at the round spermatid stage. A reduced amount of SPINK2 in heterozygotes is also deleterious, inducing a milder phenotype of oligozoospermia and/or teratozoospermia without a systematic infertility. Graphical Abstract SPINK2, a serine protease inhibitor, is believed to target the acrosin, the main sperm acrosomal protease. This study confirms SPINK2 in that role and finds it essential for spermiogenesis as SPINK2 deficiency induces a post meiotic block at the round spermatid stage leading to azoospermia in mice and men.

Male infertility is a common and complex problem affecting 1 in 20 men. Despite voluminous research in this field, in many cases, the underlying causes are unknown. Epigenetic factors play an important role in male infertility and these have been studied extensively. Epigenetic modifications control a number of processes within the body, but this review will concentrate on male fertility and the consequences of aberrant epigenetic regulation/modification. Many recent studies have identified altered epigenetic profiles in sperm from men with oligozoospermia and oligoasthenoteratozoospermia. During gametogenesis and germ cell maturation, germ cells undergo extensive epigenetic reprogramming that involves the establishment of sex-specific patterns in the sperm and oocytes. Increasing evidence suggests that genetic and environmental factors can have negative effects on epigenetic processes controlling implantation, placentation and fetal growth. This review provides an overview of the epigenetic processes (histone-to-protamine exchange and epigenetic reprogramming post-fertilization), aberrant epigenetic reprogramming and its association with fertility, possible risks for ART techniques, testicular cancer and the effect of environmental factors on the epigenetic processes.

With increased population and urban development, there are growing concerns regarding health impacts of environmental noise. We assessed the relationship between nighttime environmental noise and semen quality of men who visited for fertility evaluation. This is a retrospective cohort study of 1,972 male patient who had undertaken semen analysis between 2016-2018 at a single fertility center of Seoul, South Korea. We used environmental noise data of National Noise Information System (NNIS), Korea. Using semiannual nighttime noise measurement closest to the time of semen sampling, individual noise exposures at each patient's geocoded address were estimated with empirical Bayesian kriging method. We explored the association between environmental noise and semen quality indicators (volume, concentration, % of progressive motility, vitality, normal morphology, total motile sperm count, oligozoospermia, asthenozoospermia, and severe teratozoospermia) using multivariable regression and generalized additive models. Estimated exposure to nighttime environmental noise level in the study population was 58.3±2.2 Leq. Prevalence of oligozoospermia, asthenozoospermia, and severe teratozoospermia were 3.3%, 14.0%, and 10.1%. Highest quartile nighttime noise was associated with 3.5 times higher odds of oligozoospermia (95% CI: 1.18, 10.17) compared to lowest quartile. In men whose noise exposure is in 3rd quartile, odds ratio (OR) of severe teratozoospermia was 0.57 (95% CI: 0.33, 0.98). The OR for 4th quartile noise were toward null. In generalized additive model, the risk of oligozoospermia increases when the nighttime noise is 55 Leq dB or higher. Our study adds an evidence of potential impact of environmental noise on semen quality in men living in Seoul. Additional studies with more refined noise measurement will confirm the finding.

Background This study investigates the effect of letrozole on hormone profiles, semen parameters, body mass index (BMI), degree of oxidative stress and sperm chromatin integrity in men with idiopathic oligo/astheno/teratozoospermia (iOAT) and T:E 2 ratio ≤ 10. Materials and methods This study is a longitudinal, prospective, interventional and open-labelled clinical trial. Semen samples were collected from 20 iOAT men with low serum testosterone (T) to estradiol (E 2 ) ratio (T:E 2  ratio ≤ 10). The participants were treated with 2.5 mg letrozole orally per day for 3 months. Then, sperm parameters, hormone profiles, BMI, chromatin integrity and intracellular reactive oxygen species (ROS) level were assessed pre- and post- treatment. The chromatin integrity was evaluated by assessment of DNA fragmentation (with TUNEL assay) and protamine deficiency (with Chromomycin A3, CMA3). Also, the intracellular ROS levels were investigated by 2′, 7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Finally, the differences between the parameters evaluated before and after letrozole treatment were analyzed with the t -test and the Wilcoxon signed-rank test. Results Sperm concentration, percentage of sperm motility and its normal morphology increased significantly after letrozole treatment. Moreover, serum testosterone level increased but estradiol level decreased significantly following treatment. The mean of T:E2 ratio improved 1600%. Also, letrozole treatment significantly reduced the percentage of sperm TUNEL positivity and sperm CMA3 positivity. While no significant difference was observed between intracellular ROS levels and BMI before and after treatment. Finally, as a notable result, four spontaneous pregnancies (20%) were achieved after treatment. Conclusions Letrozole treatment can effectively increase spontaneous pregnancies by improving sperm parameters and sperm chromatin integrity in men with iOAT and T:E2 ratio ≤ 10. Trial registration Trial registration: IRCT, IRCT20191030045283N1. Registered 16 November 2019 - Retrospectively registered, https://fa.irct.ir/user/trial/43484/view

PurposeMale infertility is a complex multifactorial pathological condition, and asthenozoospermia (AZS) is one of the most common causes. Current evidence suggests the underlying role of the circadian clock on male fertility. This study aims to evaluate the expression levels of five principal clock genes in the sperm and their correlations with the sperm parameters in male infertility.MethodsWe determined the expression profiles of BMAL1, CLOCK, CRY1, PER1, and PER2 in the sperm of infertile men with AZS (n=38) and healthy fertile men (n=40) using quantitative real-time PCR. Then we performed comprehensive association analyses on the clock gene levels and the sperm parameters, including progressive and total motility, concentration, and normal morphology of the sperm.ResultsOur results showed that the expression levels of five clock genes (BMAL1, CLOCK, CRY1, PER1, and PER2) are significantly decreased in the sperm of the infertile men with AZS as compared with that of healthy fertile men (P< 0.01). All five clock gene levels are associated with the percentage of progressive/total sperm motility (r= 0.546/0.589~0.677/0.695, P< 0.01). We also discovered that a combination of BMAL1, CLOCK, CRY1, PER1, and PER2 could reach a high diagnostic performance (areas under the curves, 92%) for infertility with AZS.ConclusionsThis study first reports that sperm BMAL1, CLOCK, CRY1, PER1, and PER2 levels are altered in AZS and may be molecular markers for male infertility with AZS. These findings indicate the possibility of stabilizing circadian rhythmicity through therapeutic intervention on clock genes to prevent and treat infertility.

Purpose Idiopathic asthenozoospermia is considered as one of the causes of male infertility and characterized by reduced sperm motility. For a better determination of pathogenic mechanism of asthenozoospermia, the exploration of differentially expressed proteins in normal sperm motility and idiopathic asthenozoospermia was conducted in our study. Methods Sperm proteins were extracted and isolated by two-dimensional electrophoresis. All significantly changed protein spots were picked up from 2D gels and identified by tandem mass spectrometry. Sixteen of the thirty-three total differentially expressed protein spots were successfully identified by matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. Results Sixteen proteins identified belonged to 15 unique protein groups. GRP78, lactoferrin, SPANXB, PGK2, flagellin, DJ-1, XPA binding protein 2, CAB2, GPX4, and GAPDH were the first to be identified as differentially expressed proteins in idiopathic asthenospermia patients. Meanwhile, the analysis of quantitative RT-PCR was carried out to compare the protein levels, and the results indicated that the expression levels of the gene and protein were not entirely consistent. Conclusions These experimental results expand the scope of the protein database, generating targets for further investigation of the pathogenic mechanism of idiopathic asthenozoospermia.

Summary This study aimed to assess the influence of smoking duration and intensity on sperm vitality, sperm DNA fragmentation, reactive oxygen species (ROS) and zinc (Zn) levels in oligoasthenoteratozoospermic (OAT) men with varicocele (Vx). A total of 246 men were investigated who were divided into OAT nonsmokers, OAT smokers, OAT nonsmokers and OAT smokers with Vx. They were subjected to history taking, clinical examination and semen analysis. In their semen, sperm hypo‐osmotic swelling (HOS) test, sperm DNA fragmentation test, seminal ROS and seminal Zn were assessed. The results demonstrated significantly decreased HOS test, seminal Zn level and significantly increased sperm DNA fragmentation, seminal ROS levels in OAT smokers with Vx more than OAT smokers compared with OAT nonsmokers. Smoking intensity, smoking duration and Vx grade demonstrated significant negative correlations with sperm motility, HOS test percentage and significant positive correlations with sperm DNA fragmentation, seminal ROS level. It is concluded that smoking has a negative impact on sperm progressive motility, HOS test, seminal Zn and positive impact on sperm DNA fragmentation, semen ROS level that are exaggerated if Vx is associated being correlated with smoking intensity, smoking duration and Vx grade.

This study was conducted to determine the effects of l-carnitine (LC), as an antioxidant, in preventing spermatozoa damage during the freezing–thawing process in both astheno- and normozoospermic human semen samples. Seventy semen samples (37 asthenozoospermic and 33 normozoospermic) were involved in this study. Cryopreservation medium supplemented with 1.0 g/l LC was mixed with semen at a ratio of 1:1 (v/v). Controls were cryopreserved with freezing medium only. Assessment of motility, viability (VIA), mitochondrial membrane potential (MMP) and DNA fragmentation index (DFI) were performed on aliquots of fresh semen, frozen–thawed control and frozen–thawed LC treated samples. Supplementation of the cryopreservation medium with LC induced a significant improvement in post-thaw sperm parameters in both the asthenozoospermic and normozoospermic semen samples, compared with those of the control, regarding sperm fast forward motility, forward motility, total motility and VIA. LC showed better protective effects towards asthenozoospermia for DFI (F = 115.85, P < 0.01) and VIA (F = 67.14, P < 0.01) than did normozoospermic semen samples. We conclude that supplementation with LC prior to the cryopreservation process reduced spermatozoa cryodamage in both asthenozoospermic and normozoospermic semen samples. LC had better protective effects for asthenozoospermic human semen samples. Future research should focus on the molecular mechanism for and the different protective effects of LC between asthenozoospermic and normozoospermic semen samples during cryopreservation.