Twenty-one malformations were categorized as major defects 6 with known genetic cause , 6 were minor, and 2 could not be classified.
The trial recorded a total of 12 serious adverse events 7 in the folic acid and zinc group and 5 in the placebo group and none were judged to be related to the intervention.
Furthermore, this lack of efficacy was accompanied by some increased mild gastrointestinal adverse effects. This report addresses the long-standing need for a rigorous large-scale trial to examine the effects of folic acid and zinc supplementation on semen quality. Although these findings disagree with the conclusion from a recent meta-analysis 14 that a supplement combination with folate and zinc improved semen quality, primarily in sperm concentration, the authors of the meta-analysis had urged caution given the heterogeneity of the included studies.
It is possible prior findings indicated a potential benefit of supplementation due to exclusion of men with azoospermia. A recent smaller trial, 29 which was not included in the meta-analysis, 14 examining a commercial formula of multiple antioxidant nutrients but with lower doses of folic acid and zinc than used herein reported no benefit of supplementation on semen quality, which is consistent with the current trial.
Specific subgroups remain to be examined in this trial population; for example, a methylenetetrahydrofolate reductase gene polymorphism was shown to modify the effect of folic acid and zinc supplementation on sperm count in 1 small trial. In addition to examining the effects of folic acid and zinc supplementation on clinical measures of semen quality, the present trial examined their effects on DNA fragmentation index, a measure of sperm DNA damage from oxidative stress previously associated with infertility 31 - 35 and potentially ameliorated by folic acid and zinc.
However, the present trial results agree with a prior small trial of a general antioxidant supplement in men with a prior elevated DNA fragmentation index 37 in the antioxidant group and 40 in the placebo group when azoospermic or low sperm concentration samples were treated as missing common in other studies , indicating null findings for DNA fragmentation index or clinical semen parameters. The frequency of fetal and maternal complications was similar between groups though the trial was not powered for these outcomes , except an unexpected increase in preterm birth in the folic acid and zinc group.
Despite a statistically significant risk difference of 1. A sensitivity analysis indicated no significant effects using cut points at 36 or 38 weeks for preterm birth. Verification of this result is needed, which could be mediated by paternal influences on placental function, 37 but may be a chance finding. However, there were more frequent adverse events in men randomized to folic acid and zinc supplementation compared with placebo, indicating these doses of folic acid and zinc may be poorly tolerated by some men.
Previous studies of zinc have reported higher rates of gastrointestinal adverse effects. This study has several limitations. First, the present findings are generalizable to a general infertility clinic population and not subfertile men specifically; most patients were white and non-Hispanic, with high socioeconomic status, thus limiting generalizability. Second, because this was a pragmatic trial of couples planning infertility treatment, couples may have conceived via sperm produced prior to initiating the intervention.
However, the median time receiving the intervention prior to the first date of attempted fertilization eg, intrauterine insemination date or equivalent was 85 days, which is even later than the theoretically ideal target of 74 days.
Late-stage exposure of sperm to the intervention would not affect any hypothesized effects of supplementation on protection of sperm quality during maturation and storage. In addition, sensitivity analyses stratifying men by first fertilization attempt before 74 days after randomization vs more than 74 days after randomization produced similar results. Third, due to couples pursuing fewer cycles of infertility treatment than anticipated, the cumulative live birth rate observed for the placebo group was substantially lower than assumed in the sample size calculations.
The reweighted sensitivity analysis suggests that the semen analysis findings were not affected by this limitation. Fifth, because of the potential for type I error due to multiple comparisons for the co—primary and secondary end points, statistically significant findings should be interpreted as exploratory.
Corresponding Author: Enrique F. Correction: This article was corrected on March 24, , to fix 2 transposed rows in Table 1. Author Contributions: Dr Schisterman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Critical revision of the manuscript for important intellectual content: All authors. No other disclosures were reported.
Data Sharing Statement: See Supplement 3. Additional Contributions: We thank the participants for their commitment to the study as well as all of the trial investigators, fellows, and staff. Members of the data and safety monitoring board received compensation for their role in the study. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue. Visual Abstract.
View Large Download. Patient Recruitment, Randomization, and Follow-up. Table 1. Characteristics of Participants. Table 2. Primary Outcome of Live Birth. Table 3. Table 4. Couple-Based Secondary Outcomes. Table 5. Supplement 1. Trial protocol and statistical analysis plan. Supplement 2. Semen quality after six months of trial intervention in the Folic Acid and Zinc Supplementation Trial by intervention group, using non-parametric testing eTable 2.
Supplement 3. Data sharing statement. Grand View Research. Dietary supplements market size analysis report by ingredient botanicals, vitamins , by form, by application immunity, cardiac health , by end user, by distribution channel, and segment forecasts, Accessed November 18, Trends in dietary supplement use among US adults from Most frequently reported prescription medications and supplements in couples planning pregnancy: the LIFE study.
Reprod Sci. Incze M, Katz MH. More than 20 years ago in , research investigated the effects of zinc deficiency on oxidative damage to animal testicular proteins, lipids and DNA. It was conclusively determined that adequate zinc levels are crucial for production of healthy sperm. Taking the long view, a detailed systematic review of multiple research studies was undertaken in to examine the relationship between seminal plasma zinc levels and male infertility, as well as the effects of zinc supplementation on sperm parameters.
The meta-analysis identified 1, unduplicated studies and selected studies involving 2, infertile males and normal controls. The results indicated that zinc concentrations in the semen of infertile males were significantly lower than those in normal controls.
Most importantly, zinc supplementation was found to significantly increase the semen volume, sperm motility, and the percentage of normal sperm morphology. In our clinic, our male patients who include ample zinc in their approach to boosting sperm count, ideally in the picolinate form, regularly experience improved sperm count and improved percentages of healthy motile sperm.
For the entire meta-analysis, the zinc concentrations in seminal plasma from infertile males were significantly lower than those in normal males.
Since zinc plays such a vital role in sperm development, it makes sense that increased zinc levels can positively affect sperm quality. As previously mentioned, zinc can be obtained by eating different foods, but the best way to significantly increase zinc levels is by taking a zinc supplement. Supplementing zinc has been shown to have a direct effect on several different sperm parameters.
Based on the results of the meta-analysis of zinc and male fertility studies referenced above, researchers concluded that zinc supplementation could significantly increase the sperm volume, sperm motility, and percentage of normal sperm morphology.
As you may know, smoking has been shown to decrease male fertility significantly. Research has shown that supplementing zinc may actually help to combat the damage caused by smoking on sperm quality. Smoking increases the amount of harmful reactive oxygen species ROS in the body. ROS can cause oxidative stress, which leads to reduced sperm quality and, in some cases, male infertility.
Zinc plays several vital roles throughout spermatogenesis development of sperm , so it is no surprise that higher zinc levels are associated with better quality sperm. Although zinc may help to reduce the damage caused by smoking, we still recommend stopping smoking if you are trying to conceive.
And if you do smoke, you should certainly consider taking a zinc supplement while you quit! Research has shown that zinc may play a vital role in influencing male testosterone levels. Zinc supplementation has been shown to increase testosterone levels and sperm count for men with low zinc. One common cause of low testosterone is over-exercising.
Men who participate in excessive amounts of high-intensity exercise are more likely to experience low testosterone levels. Research has shown that supplementing zinc can significantly improve the testosterone levels of men who participate in exhaustive exercise. Many men, especially vegetarians, do not obtain adequate amounts of zinc through their diet alone.
In fact, In lieu of a high zinc diet, zinc supplements can help to increase zinc levels and ensure your sperm are getting the support they need to develop properly. Try out PMC Labs and tell us what you think. Learn More. Our investigation showed that Zn contained many unique properties in human, especially males. The antioxidant quality is one of them.
Also, the increased reactive oxygen species levels in the seminal plasma of men who are both infertile and smokers influence the Zn content of seminal plasma in a way that physiology of spermatozoa can be affected as well.
Moreover, Zn acts as a toxic repercussionagainst heavy metals and cigarette inflammatory agents. It plays a role in epithelial integrity, showing that Zn is essential for maintaining the lining of the reproductive organs and may have a regulative role in the progress of capacitation and acrosome reaction. In contrast, Zn deficiency impedes spermatogenesis and is a reason for sperm abnormalities and has a negative effect on serum testosterone concentration.
Based on these findings, Zn microelement is very essential for male fertility. It could be considered as a nutrient marker with many potentials in prevention, diagnosis, and treatment of male infertility. Sexual accessory glands secrete in the seminal plasma containing some elements that protect spermatozoa at the time of ejaculation 1.
Zn is a plentiful microelement in the body and it is found in nuts, legumes 3 , seafood e. Oysters , fortified cereals, cremini mushrooms, low-fat yogurt 4 and animal proteins, such as meat, fish and milk. Some reports showed that consumption of these natural foods can enhance germinal cell proliferation 5 , and poor Zn nutrition may be an important risk factor for the low quality of sperm and idiopathic male infertility 6.
Dietary Zn deficiency less than 5 ppm impairs reproduction in males and females. Zn has many important functions in the spermatozoa physiology, including effects on lipid flexibility and sperm membrane stabilization It also has a regulated role in capacitation and the acrosome reaction of sperm and is essential for conception and embryonic implantation Proteins containing Zn and selenium in mammalian spermatozoa are involved in modulating the amount of reactive oxygen species ROS ; therefore, it is interesting to investigate whether balanced amounts of Zn and other oligoelements that are added to the semen diluent would moderate the deleterious effects of ROS on chromatin structure Contreras et al.
In our previous study, it was demonstrated that an important risk factor for low quality of sperm and idiopathic male infertility is poor Zn nutrition 6. But in this review, the focus was on the various roles of Zn in male health, reproductive system, quality and function of sperm, as well as the effects of epigenetic factors on Zn and finally the molecular and cellular mechanisms of Zn. The nearby organs include prostate, liver, the gastrointestinal tract; kidney, skin, lung, adrenals, brain, heart, eyes and pancreas contain estimable concentrations of Zn.
Blood tests for Zn deficiency are inaccurate because majority of Zn is cumulative inside cells and is not free in the blood. Assisting immune function, patronage of healthy cell growth, having a role in preserving prostate health, sexual health and testosterone hormone levels are typical examples.
It has been demonstrated that Zn plays a significant role in reproductive functions 14 , Hosseinzadeh Colager et al. The level of Zn in fertile men was There are many reports that showed reduction or increase in consumption of Zn which let to overindulge vis-a-vis deficiency damages in many of the human organs Table 1. For example, Zn deficiency is correlated with reduction in testis volume, a decrease in testicular weight, hypogonadism, gonadal dysfunction, inadequate development of secondary sex specifications in human, shrinkage of seminiferous tubules, the failure of spermatogenesis, male gonad growth and hypogonadism 8.
And so, there are many reports for Zn-physiological roles in human Table 2 , including its role in gonads- and some enzyme-functions, treatments of some diseases, and better function of apoptosis and immune systems. Some of these Zn-physiological roles are indicated below. Zn contains many roles in the immune systems Table 3. Zn has a role in almost all aspects of inherent immunity and compatibility, so Zn deficiency may influence weakening of immune system and reproductive system.
Zn is effective in various mechanisms, including DNA replication, RNA transcription, proliferation, and differentiation and activation of immune cells in many organs of the body 9 , 10 , The innate as well as the specific parts of the immune system are influenced by Zn. The effects of Zn are multifaceted. Zn can induce adhesion of myelomonocytic cells to the endothelium, while Zn chelation diminishes cell recruitment.
Thus, Zn is essential, even in the earliest stages of an immune response. At the molecular level, Zn is required for the interaction between the p58 killer cell inhibitory receptor on NK cells and major histocompatibility complex MHC class I molecules, mainly human leukocyte antigen C, on target cells, resulting in the inhibition of the killing activity 8. Interestingly, Zn is needed to maintain the normal function of natural killer cells, and Zn deficiency may result in non-specific killing activity and functional loss.
In addition to effects of upstream signaling molecules, Zn influences gene expression by structural stabilization and functional regulation of various immunological-relevant transcription factors as summarized earlier Zn corrects these adverse effects of cadmium on the immune system and biochemical processes as a component of the antioxidant superoxide dismutase and protects the testicular endothelium and sperm cell membranes Zn exists at high levels in the testis of vertebrates which are comparable to liver and kidney.
Moreover, there are certain reports that manifest Zn can reduce testis injury by stresses such as heavy metals, fluoride, and heat Zn is assembled in the testis during early spermatogenesis and may play a main role in the adjustment of the spermatogonial reproduction and in the meiosis of germ cells Mostly, Zn assembles in germ cells and its concentration in testis increments during spermatogenesis.
Some researchers have witnessed that Zn is needed for the normal functioning of the hypothalamus-pituitary-gonadal axis. Because of the important role of Zn in male reproductive potential, it is paramount to recognize that andrological variations which are most sensitive to Zn depletion. An evaluation of those variables in clinical cases of possible Zn deficiency would accelerate treatment.
Zn influences male fertility in several different ways. Low Zn levels have a negative effect on serum testosterone concentration Thyroid hormones have several important roles in the body including metabolism, development and even body temperature.
Zn helps the body maintain proper thyroid function by producing hormones in the brain called thyroid-releasing hormones. Whenever men are low in Zn, they may fail to produce enough of these hormones. That can also affect testosterone levels 4. Seminal Zn is considered as an indicator of prostatic function; however, the function of Zn in seminal plasma and semen is unknown. Most Zn secreted from the prostate in humans seems to target the proteins secreted from seminal vesicle.
Other research shows that the Zn and albumin secreted from the prostate constitute a complex that covers the sperm and thereby protects the cells Zn is situated primarily in the Leydig cells, the late type B spermatogonia, and the spermatids. And also is vital for the production and secretion of testosterone from the Leydig cells.
Zn in human semen seems to play an important role in the physiology of spermatozoa. On the other hand, there is remarkable evidence that Zn deficiency causes primary testicular failure, lessens function of the luteinizing hormone receptor, lessens steroid synthesis and Leydig cell damage due to oxidative stress The prostate compared to other tissues and body fluids has high concentration of Zn.
Actually, Zn is a marker of prostatic function. Its other roles are regulation of the functions of spermatozoa, acting as a co-factor for most enzymatic reactions, and helping in preservation of sperm motility Zn as a downward molecular weight complex with citrate or bound to glycoproteins of the sperm vesicles is discharged from the prostate demonstrating that biologic Zn therapy has a positive effect on sperm motility and the use of biologic Zn supplementation was an efficient method for the treatment of infertile males with chronic prostatitis Zn oxide nanoparticles have bactericidal effects on both gram-positive and gram-negative bacteria and are also effective against spores which are resistant to high temperature and high pressure 28 , Prostatic Zn may have antibacterial activity because trichomonas vaginalis is easily killed at concentrations of Zn that occur in the prostatic fluid of healthy men Furthermore, Zn has antibacterial activity and antilipid peroxidation properties that maintain sperm membrane stability and protect the testis against the degenerative changes Evidence suggests that seminal Zn has an important role in the physiologic functions of the sperm and that its reduced levels result in low seminal quality and subsequent chances of fertilization 6.
Zn is known to be essential for sexual maturity and onset of estrus. Zn plays a role in epithelial integrity, showing that Zn is essential for maintaining the lining of the reproductive organs 6.
Furthermore, it has an important role in stabilizing the cell membrane and nuclear chromatin of spermatozoa in seminal plasma. It may have a regulative role in the progress of capacitation and acrosome reaction. The Zn concentration in human seminal plasma is higher than in other tissues Zn has been shown to be vital for spermatogenesis.
It plays a significant role in testis development and sperm physiologic functions 6. Zn contains a variety of roles in the spermatogenesis phases Table 4. For example, in the initiation of spermatogenesis, Zn is important in participation of ribonuclease activities that is highly active during mitosis of spermatogonia and meiosis of spermatocytes. During spermatogenesis, spermatids obtain tail and motility with a developed mid-piece which connects the head compartment with the tail.
This physical maturation process occurs in seminiferous tubule. Sperm maturation and storage happens in the epididymis. At the end of spermatogenesis, Zn is highly concentrated in the tail of mature spermatozoa and involved in sperm motility Though the dynamics of Zn during sperm expansion is far to be ambiguous but, the significant role of Zn in normal spermatogenesis and sperm suitability is known. Foresta et al.
Optimal concentrations of Zn in the seminal plasma have also been related to an increase in sperm concentration of the ejaculate 11 , high motility, viability 32 and enhancing antioxidant activity A low concentration of Zn has been indicated to disturb the fatty acid composition of the testis and interfere with normal endocrine regulation of the testis Zn is associated with catabolism of lipid that is done in sperm middle piece and provides energy for motion of spermatozoa.
Testicular Zn is crucial for normal spermatogenesis and for sperm physiology; it maintains genomic integrity in the sperm and fixes attachment of sperm head to tail Zn ions can increase male fertility by regulation of the expression of testis GC-specific genes during the differentiation process and spermatogenesis 35 , Also Zn therapy reduced asthenozoospermia Supra-nutritional doses of Zn, Co, and Se were used to enhance the production of motile sperm with intact membranes The negative correlation between seminal plasma Zn and sperm viability is a good sign of the importance of Zn in spermatogenesis This may be clarified by the necessary role of Zn in protein metabolism and nucleic acid synthesis.
Alteration of seminal plasma Zn changes count, motility, viability, pH and viscosity. Seminal plasma Zn-T Zn per ejaculate is the better marker for assessing the relationship between Zn and semen quality Low seminal Zn levels have been related with decreased fertility potential. However, other authors reported that normozoospermic and oligoasthenozoospermic patients had similar seminal plasma Zn concentrations Akinloye et al.
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