Background
Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm and 1 man in 20 will be affected by subfertility. Antioxidants are widely available and inexpensive when compared to other fertility treatments and many men are already using these to improve their fertility. It is thought that oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress. Pentoxifylline, a drug that acts like an antioxidant, was also included in this review.  

Objectives
This Cochrane review aimed to evaluate the effectiveness and safety of oral supplementation with antioxidants for subfertile male partners in couples seeking fertility assistance.

Search methods
We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from inception until January 2014); trial registers; sources of unpublished literature and reference lists. An updated search was run in August 2014 when potentially eligible studies were placed in 'Studies awaiting assessment'.

Selection criteria
We included randomised controlled trials (RCTs) comparing any type or dose of antioxidant supplement (single or combined) taken by the subfertile male partner of a couple seeking fertility assistance with a placebo, no treatment or another antioxidant.

Data collection and analysis
Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates, adverse events, sperm DNA fragmentation, sperm motility and concentration. Data were combined, where appropriate, to calculate pooled odds ratios (ORs) or mean differences (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I2 statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods.  

Main results
This updated review included 48 RCTs that compared single and combined antioxidants with placebo, no treatment or another antioxidant in a population of 4179 subfertile men. The duration of the trials ranged from 3 to 26 weeks with follow up ranging from 3 weeks to 2 years. The men were aged from 20 to 52 years. Most of the men enrolled in these trials had low total sperm motility and sperm concentration. One study enrolled men after varicocelectomy, one enrolled men with a varicocoele, and one recruited men with chronic prostatitis. Three trials enrolled men who, as a couple, were undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) and one trial enrolled men who were part of a couple undergoing intrauterine insemination (IUI). Funding sources were stated by 15 trials. Four of these trials stated that funding was from a commercial source and the remaining 11 obtained funding through non-commercial avenues or university grants. Thirty-three trials did not report any funding sources.

A limitation of this review was that in a sense we had included two different groups of trials, those that reported on the use of antioxidants and the effect on live birth and clinical pregnancy, and a second group that reported on sperm parameters as their primary outcome and had no intention of reporting the primary outcomes of this review. We included 25 trials reporting on sperm parameters and only three of these reported on live birth or clinical pregnancy. Other limitations included poor reporting of study methods, imprecision, the small number of trials providing usable data, the small sample size of many of the included studies and the lack of adverse events reporting. The evidence was graded as 'very low' to 'low'. The data were current to 31 January 2014.

Live birth: antioxidants may have increased live birth rates (OR 4.21, 95% CI 2.08 to 8.51, P< 0.0001, 4 RCTs, 277 men, I2 = 0%, low quality evidence). This suggests that if the chance of a live birth following placebo or no treatment is assumed to be 5%, the chance following the use of antioxidants is estimated to be between 10% and 31%. However, this result was based on only 44 live births from a total of 277 couples in four small studies.

Clinical pregnancy rate: antioxidants may have increased clinical pregnancy rates (OR 3.43, 95% CI 1.92 to 6.11, P < 0.0001, 7 RCTs, 522 men, I2 = 0%, low quality evidence). This suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 6%, the chance following the use of antioxidants is estimated at between 11% and 28%. However, there were only seven small studies in this analysis and the quality of the evidence was rated as low.

Miscarriage: only three trials reported on this outcome and the event rate was very low. There was insufficient evidence to show whether there was a difference in miscarriage rates between the antioxidant and placebo or no treatment groups (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I2 = 0%, very low quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, use of an antioxidant would result in the risk of a miscarriage lying between 1% and 13%.

Gastrointestinal upsets: there was insufficient evidence to show whether there was a difference in gastrointestinal upsets when antioxidants were compared to placebo or no treatment as the event rate was very low (OR 1.60, 95% CI 0.47 to 5.50, P = 0.46, 6 RCTs, 429 men, I2 = 0%).

We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as not enough trials compared the same interventions.

Authors' conclusions
There is low quality evidence from only four small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low quality evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage but this is uncertain as the evidence is of very low quality. Data were lacking on other adverse effects. Further large well-designed randomised placebo-controlled trials are needed to clarify these results.

Antioxidants for male subfertility

Obesity is highly prevalent, and its incidence is increasing. The previous study showing a major effect of paternal obesity on metabolic health of offspring is confounded by comorbidity with diabetes. Therefore, we investigated the effect of diet-induced paternal obesity, in the absence of diabetes, on the metabolic health of two resultant generations and the molecular profiles of the testes and sperm. Founder (F0) male C57BL6 mice were fed either a high-fat diet (HFD) or a control diet (CD); n = 10/diet for a period of 10 wk. Testis expression of mRNA/microRNAs was analyzed by microarray and qPCR and sperm microRNA abundance by qPCR. Two subsequent generations were generated by mating F0 and then F1 mice to CD mice, and their metabolic health was investigated. All mice, other than F0 males, were maintained on a CD. HFD feeding induced paternal obesity with a 21% increase in adiposity, but not overt diabetes, and initiated intergenerational transmission of obesity and insulin resistance in two generations of offspring. This distinct phenotypic constellation is either partially or fully transmitted to both female and male F1 offspring and further transmitted through both parental lineages to the F2 generation, with a heightened effect on female F1 offspring (+67% in adiposity) and their F2 sons (+24% in adiposity). Founder male obesity altered the testes expression of 414 mRNAs by microarray and 11 microRNAs by qPCR, concomitant with alterations in sperm microRNA content and a 25% reduction in global methylation of germ cell DNA. Diet-induced paternal obesity modulates sperm microRNA content and germ cell methylation status, which are potential signals that program offspring health and initiate the transmission of obesity and impaired metabolic health to future generations. This study implicates paternal obesity in the transgenerational amplification of obesity and type 2 diabetes in humans.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.12-224048

Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content

BACKGROUND The global obesity epidemic has paralleled a decrease in semen quality. Yet, the association between obesity and sperm parameters remains controversial. The purpose of this report was to update the evidence on the association between BMI and sperm count through a systematic review with meta-analysis. METHODS A systematic review of available literature (with no language restriction) was performed to investigate the impact of BMI on sperm count. Relevant studies published until June 2012 were identified from a Pubmed and EMBASE search. We also included unpublished data (n = 717 men) obtained from the Infertility Center of Bondy, France. Abstracts of relevant articles were examined and studies that could be included in this review were retrieved. Authors of relevant studies for the meta-analysis were contacted by email and asked to provide standardized data. RESULTS A total of 21 studies were included in the meta-analysis, resulting in a sample of 13 077 men from the general population and attending fertility clinics. Data were stratified according to the total sperm count as normozoospermia, oligozoospermia and azoospermia. Standardized weighted mean differences in sperm concentration did not differ significantly across BMI categories. There was a J-shaped relationship between BMI categories and risk of oligozoospermia or azoospermia. Compared with men of normal weight, the odds ratio (95% confidence interval) for oligozoospermia or azoospermia was 1.15 (0.93-1.43) for underweight, 1.11 (1.01-1.21) for overweight, 1.28 (1.06-1.55) for obese and 2.04 (1.59-2.62) for morbidly obese men. CONCLUSIONS Overweight and obesity were associated with an increased prevalence of azoospermia or oligozoospermia. The main limitation of this report is that studied populations varied, with men recruited from both the general population and infertile couples. Whether weight normalization could improve sperm parameters should be evaluated further.

/pdf/bmi-in-relation-to-sperm-count-an-updated-systematic-review-4u4r9d3mtf.pdf

BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis

Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.

http://www.next-up.org/pdf/OfficialJournalAmericanSocietyReproductiveMedecineEffectCcellPhoneSemenAnalysisObservationalStudy012008.pdf

Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study

This study was conducted to determine a possible relationship between regular cell phone use and different human semen attributes. The history-taking of men in our university clinic was supplemente...

https://www.tandfonline.com/doi/pdf/10.1080/014850190924520

Is there a relationship between cell phone use and semen quality

The aim of this study was to examine the relationship of semen parameters, sexual function-related hormones and waist/hip ratio. Eighty-one selected patients presenting with infertility were examined. Weight, height, waist circumference and hip circumference were measured, and reproduction-related hormone levels were determined. Semen was analysed by conventional methods. Semen volume, sperm concentration, motility, total sperm count, total motile sperm cell number, rapid progressive motile sperm count and reproduction-related hormone levels [follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, 17beta-oestradiol and sexual hormone-binding globulin (SHBG)]. Significant correlations were found: (i) weight, waist circumference and hip circumference versus testosterone level, SHBG level, and testosterone/17beta-oestradiol ratio; (ii) hip circumference versus sperm concentration; (iii) waist circumference and hip circumference versus sperm count, total motile sperm cell number and rapid progressive motile sperm count; (iv) weight versus total sperm count and total motile sperm cell number; (v) waist circumference and hip circumference versus prolactin level (positively) and SHBG (negatively); (vi) waist circumference and waist/hip ratio versus semen volume. It can be concluded that the waist/hip ratio is correlated with the reproductive hormone levels. Although both the waist circumference and hip circumference correlated with the semen characteristics, the waist/hip ratio did not.

Is semen quality affected by male body fat distribution

To evaluate the effect of body mass on the hormonal and semen profiles of subfertile men with oligozoospemia, sperm concentration and reproductive hormone levels were compared in two body mass index (BMI) groups: underweight or normal weight patients (BMI = 25 kg/m2) vs. overweight or obese patients (BMI > 25 kg/m2). The mean BMI was 27 +/- 4.6 kg/m2. The testosterone/estradiol ratio was significantly reduced in the high BMI group as compared to the low BMI group (17 +/- 4 vs. 12 +/- 3; p < 0.05). A similar difference was found in the sperm concentration (11.2 +/- 3.16 x 10(6)/ml vs. 8.1 +/- 2.6 x 10(6)/ml). A nonsignificant difference was found in the LH/FSH ratio (1.41 +/- 0.64 vs. 1.63 +/- 0.72). We concluded that obesity and the consequent estrogen excess decrease the sperm concentration by influencing the hypothalamo-pituitary system.

https://www.tandfonline.com/doi/pdf/10.1080/01485010500315479

Effect of body weight on testosterone/estradiol ratio in oligozoospermic patients

A total of 274 men (aged: 26 ± 4.9 years) with normozoospermia were enrolled into this study. Their body mass index (BMI: kg/m2) varied between 17 and 39. According to BMI, the patients were divided into four groups: Group 1: 17–20, Group 2: 20.1–25, Group 3: 25.1–30 and Group 4: 30.1–39. Twenty-nine subjects were found in the first, 96 in the second, 91 in the third and 58 men in the fourth group. Sperm concentration was significantly lower in the obese group (29 × 106/ml, p < 0.05) than in the group of BMI 17–20, 20–25 and 25–30. In advance, in the obese group, sperm count continuously decreased with aging. We conclude that obesity is associated with a lower sperm count in case of normozoospermia.

Effect of body weight on sperm concentration in normozoospermic males

A randomized, placebo-controlled clinical pilot study was performed in order to examine the effect of magnesium-orotate in male idiopathic infertility. Ten males were treated daily for 90 consecutive days with 3000 mg magnesium-orotate (Magnerot) tablets (Group M). As a control, ten other males were treated in the same way with placebo (Group P). Conventional microscopic sperm characteristics (sperm concentration, motility ratio, total number of motile sperm cells, normal morphology ratio), plus total and ionized magnesium levels in seminal plasma and blood serum were evaluated both prior to treatment and on day 90, at the conclusion of the study. No significant changes in sperm characteristics, blood ionized or total Mg, or ejaculate total Mg levels were detected. However, ejaculate ionized Mg levels increased in Group M from 0.18 +/- 0.05 to 0.30 +/- 0.05 (mmol/l; mean +/- SD, p < 0.05). Within the observation period of 3 months, one pregnancy occurred in the partner of a male from Group M. In conclusion, magnesium-orotate treatment at a dose of 3000 mg/day leads neither to a significant improvement of sperm variables nor does it increase the pregnancy rates of female partners of treated males as compared to those of controls. Thus, magnesium-orotate treatment was not shown to be effective therapy for idiopathic male infertility.

Koloszár S

Papers

Is there a relationship between cell phone use and semen quality

Is semen quality affected by male body fat distribution

Effect of body weight on testosterone/estradiol ratio in oligozoospermic patients

Effect of body weight on sperm concentration in normozoospermic males

Magnesium‐orotate supplementation for idiopathic infertile male patients: a randomized, placebo‐controlled clinical pilot study.