Antioxidant agents Know about
Heavy Metals ie. Zn in the enzyme Co-
enzymes and improving sperm parameters :-sperm function as mentioned is governed
partly by quantum of Co- Q10 enzymes. Nutritional supplement are not regulated
by the Food and drug administration and are distributed from a wide variety of
different manufacturers. Because sperm are known to be highly susceptible to
oxidation' it is possible that antioxidant materials could protect sperm ,limit
sperm DNA damage, or enhance sperm function, including motility
Unfortunately, limited studies have evaluated the role of nutritional supplement in male fertility. Because such limited studies have been published, it is possible, and quite likely, that a publication bias exists towards positive studies .a recent Cochran meta-analysis reported the benefit of nutritional supplements for male fertility based on only 20 live birthday. in addition, most studies on male supplements involve combination agents, making the benefit of any individual agent difficult to determine. In this analysis, we will discuss some of the in vitro effects of nutritional agents on sperm, As well as clinical trials for male infertility patients who are attempting to conceive naturally, and emphasize clinical trials of treatment prior to assisted reproduction. The antioxidant agents that have been described for potential use will be reviewed as will.
1) Vitamin E
Vitamin E is known to be lipid-soluble antioxidant that is present in cell membranes. The presence of vitamin E protects the integrity of the phospholipid bilayer of the cell membrane as well as the mitochondrial sheath . In part, it acts as an antioxidant by interrupting the chain reaction of lipid peroxidation. Vitamin E can increase production of scavengers antioxidant enzymes, and it enhances the antioxidant activity of other agents. In vitro, it is known to protect sperm during cryopreservation.
2)
Zinc is a necessary mineral for optimal function-in of antioxidant enzymes, including superoxide dismutase. It inhibits membrane oxidative enzymes, such as NADP oxidase. It may also have a role in supporting the immunological system. It is well documented that lower Zink levels are present in the semen of infertile males and zinc deficiency has been associated with abnormal flagellation and microtubules defect in sperm. It is not clear, since zinc levels are so high in semen to begin with, whether the relative zinc deficiency seen in infertile males is this mineral . Systemic therapy is associated with reduced seminal fluid oxidative activity, apoptotic markers, and DNA fragmentation with a trend towards semen parameters.
3) Vitamin C
Vitamin C is high potency water-soluble reactive oxygen species scavenger. It has been shown to neutralize superoxide, hydroxyl, and hydrogen per-oxide radicals. It is naturally concentrated in semen at levels that are tenfold higher than hat seen in serum . Systemic therapy with vitamin C decreases sperm DNA fragmentation, admeasured by the presence the expression of genes involved in intra-cellular redox pathways. Of note, Vitamin C can act as a pro-oxidant at high doses.
4 Selenium
Selenium is mineral that is required for normal testicular development, spermatogenesis, sperm motility, and function. It reduces ant oxidative stress by an unknown mechanism. Enzymes require selenium for normal fuction,including those that are involved in ant oxidative pathways, such as phospholipid, hydroperoxide, glutathione peroxyl-case. Selenium administration increases glutathione peroxdation-1 expression, which destroys hydro-ventricular peroxide, a potent oxidative agent.
5 folate
Folate reduces homocysteine concentrations by its free radical scavenging properties it May work synergistically with zinc to improve quality. It is known that defects in folate synthesis, such as defects in MTHF enzymes, are associated with male infertility. There is limited evidence for a role folate deficiency in idiopathic male infertility.
6 carnitine
Carnitine is a water-soluble antioxidant that is also our primary fuel for sperm motility. Carnitine involved in the transport of long chain fatty acids into the mitochondrial matrix, possibly explaining its role in supporting sperm motility. Carnitine increases expression of antioxidant enzymes, including home oxygenasys-1 and endothelial nitric oxide synthase (eNOS). carnitine enhances cellular energetic in mitochondria by facilitating the free fatty acid entry into that organelle. Carnitine are thought to protect sperm DNA and cell membranes from reactive oxygen species induced DNA damage and apoptosis.
7 carotenoids
Carotenoids work synergistically with selenium and vitamin E as antioxidants .The most commonly studied carotenoids is lycopene that is naturally derived from fruits and vegetables and found in especially high concentration in tomatoes. carotenoids have a high reactive oxygen species quenching rate and are found in higher plasma levels than beta-carotene. High lycopene concentration are found in the testes and seminal plasma. Another additional carotenoid has been described recently, Astaxanthin, carotenoids extracted from algae. This agent has a high number of conjugated double bonds, making it a potent antioxidant then vitamin E or carnitine. Its role in Male fertility has only recently been explored.
8 coenzyme Q10
Coenzyme Q10 function in electron transport and is an antioxidant. It is thought to be important in mitochondrial function. It is found at high levels in metabolically active tissues. The semen concentrations and motility, suggesting an intrinsic role in the production of sperm and sperm motility treatment of patients with coenzyme Q10 was associated with improved sperm concentration 6-9 months of treatment. It is also associated with improved sperm motility. In a small trial, couples where the mail pregnancies versus no pregnancies in the control group coenzyme Q10 is suggested to have a benefit on sperm production.
9 antioxidant agents
The following agents have been described as being nutritional supplement and represent vitamin, minerals, and other substances that may have a role in protecting sperm , enhancing sperm function or potentially improving fertility both naturally and/or after assisted reproduction. Each of these agents will be reviewed in terms of its mode of action and studies involving these agents presented.
Where is the evidence that antioxidants will help?? Quality of Antioxidant Trials
Most antioxidant Trials have not been performed in a rigorous, randomized, controlled fashion . The scientific quality of antioxidant trials to-date has been relatively poor, as summarized by Ross et al. In most studies, the randomization method was not clear and allocation concealment was not clear as well. Double
Blinding was done for most of the studies, and no intention to treat analysis was done in the majority of the studies. Follow -up was typically strong with most studies reporting 90-100% follow-up rate. Interpretation of these studies was often difficult because multiple agents were used and in some cases no placebo was applied. For example, in one study by Emu et al. Vitamin C, Vitamin E, zinc, and other combination of agents were used together. Similarly ,Scott et al. Used vitamin A, Vitamin C, Vitamin E, and selenium, many of which have not been demonstrated to have antioxidant activities. Although most studies have suggested an odds ratio for effect of agents that was >1, the exact benefit, if any , of antioxidant therapies is not clear , in large part because of likely potential publications bias. In other words, studies were most likely to have been published if they demonstrated a benefit of intervention.
Abnormal DN A fragmentation get corrected or inhibited by antioxidants .
One of the most interesting interventional studies was a randomized controlled trail of antioxidant prior to IVF in a series of patients where the man had abnormal sperm DNA fragmentation. A total of 60 couple were enrolled. The men were treated with lycopene 6 mg , Vitamin E , Vitamin C, zinc , selenium ,folate ,and garlic in palm oil vehicle. The placebo arm received palm oil vehicle alone. There was a randomization of drug versus placebo and treatment was provided for 3 months before IVF-ICSI. Couples had to have had a prior failed IVF attempt and abnormal semen parameters. Suggesting oxidative stress with abnormal sperm DNA fragmentation. The mean pre-treatment DFI was 39% and female age was less than 39% . The primary outcome was reported to be embryo quality.
Unfortunately no difference was seen in embryo quality and the pregnancy rate was not statistically different. However the viable pregnancy test differed between treatment and placebo groups, defined as ongoing pregnancy per embryo transferred. Interestingly the raw implantation rate in the treatment and control groups not different and the row biochemical pregnancy rate was not different. Although the treatment was presumed to affect sperm DNA fragmentation there was actually no repeat evaluation of sperm DNA fragmentation during treatment raising a question as to whether any benefits or treatment were modulated by a direct effect on sperm.
Vitamin E and zinc
The Cochran collaboration reported an evaluation of antioxidants on ART outcome .Any dose or type of antioxidant could be compared to placebo or no treatment. The primary outcomes were analyzed in only three studies for live births. A secondary outcome pregnancy rate was available in 15 studies. The Cochran meta analysis demonstrated benefiting the use of oral antioxidants for a beneficial effect on live birth dates. The pregnancy rate was improved by an factor of antioxidant use. Interestingly each of the studies looking at live birth had a positive result with comparisons involving vitamin E versus placebo oral zinc versus no treatment. Overall ,only 18 out of 116 experimental arm patients achieved a live birth with 2 out of 98 in the control arm. Despite analysis of 34 trials involving 2,876 couples undergoing ART, the primary outcome for this meta-analysis could be determined by only three trials . A total of 20 live births occurred in these three trials. Both zinc and vitamin E were used. Of note, there is significant concern about high dose Of vitamin E use and it's cardiovascular risk. Interestingly, in two of the trials, there were no pregnancies in the control arm. It is quite unusual for an ART intervention trial to have no pregnancies in the control arm. Using pregnancy rate as an outcome, a larger number of studies were involved but the antioxidants used ranged from multiple agents, to vitamin E, to L-acetyl carnitine plus L-carnitine, L-carnitine alone, Vitamin C and vitamin E, magnesium, coenzyme Q10, and zinc. In the meta-analysis for pregnancy rates, a total of 53 pregnancies were analyzed.
When the pregnancy rate was evaluated as an outcome the magnitude of benefit appeared to be greater than the effect that should be expected by improving sperm DNA fragmentation. Antioxidants are thought to function by decreasing sperm DNA fragmentation and the magnitude of benefit was 4.18.One meta- analysis of the effect of DNA fragmentation on pregnancy rates during ART reported a diagnostic. Therefore the magnitude of benefit appeared to greatly outweigh the magnitude of benefit that would be suggested from DNA fragmentation. Of note the pregnancy rate in the control group was 0-11% in most of the trials with 3% as a mean value .This very low pregnancy rate after assisted reproduction suggests some concern with the type of ART performed or the site for these trials.
Taken together only 20 pregnancies were involved in demonstrating the treatment effect that is proposed in the Cochran meta- analysis , from a total of three trials. The risk of publication bias appears to intervention. Multiple agents were considered together to evaluate this effect. Even though the magnitude of bene5for live births suggests benefit it is not clear how to interpret these results
Summary
Antioxidants appear to have some promise as agents that could provide a benefit of improving fertility potential for men with abnormal sperm DNA fragmentation and possibly men with idiopathic infertility. The most promising agents appear to be vitamin, E carnitines, Astaxanthin, Vitamin C , zinc and possibly coenzyme Q.10 . Unfortunately based on published data it is impossible to make evidence based recommendations of a specific agent dose or concoction of supplements for a couple with male factor infertility. What dose should be used what combination of agents and the actual mechanism of action is impossible to determine from published data . All that one can say at this point is that antioxidants might have benefit in the treatment of male infertility especially for men with abnormal sperm DNA fragmentation or idiopathic infertility. Unfortunately the magnitude of benefit and treatment regimen to be recommended is yet to be determined
The effects of paternal age on a couple's fertility are real and may be greater than has previously been thought. After adjustments for other factors, it has been demonstrated that the probability of a fertile couple will take >12 months to conceive nearly doubled from 8% when the man is <25 years to 15% when he is >35 years ; thus, paternal age is a further factor to be taken into account 15% when he is >35 years thus paternal age is a further factor to be taken into account when deciding the prognosis for infertile couple. Also the increased male age is associated with a significant decline in fertility. Which is independent of the woman's age, coital frequency and lifestyle effect as well as effect of other subfertility risk factor . Furthermore fathering at older age may have significant effects on the viability and genetic health of human pregnancies and offspring primarily as a result of structural chromosomal aberrations In sperm. The evidence for sex chromosomal aneuploidy suggests that there may be about a twofold increase in risk at the age of 50 .In fact the risk for a father over 40 years old to have a child with an autosomal dominant mutation equals the risk of Down syndrome for a child whose mother is 35-40 years old. Although individual Lessing cell volume does change with age the total eluding cell volume and the absolute number of Leydig cells decrease significantly with age . Also anatomical studies of Sertoli cell populations in humans show that the young adult male testis is endowed with 500 million Sertoli cells and appears to decline to approximately 300 million cells in the older adult suggesting that there is also an age related decline in Sertoli cell numbers in the human testis. Furthermore estimations of individual.
Unfortunately, limited studies have evaluated the role of nutritional supplement in male fertility. Because such limited studies have been published, it is possible, and quite likely, that a publication bias exists towards positive studies .a recent Cochran meta-analysis reported the benefit of nutritional supplements for male fertility based on only 20 live birthday. in addition, most studies on male supplements involve combination agents, making the benefit of any individual agent difficult to determine. In this analysis, we will discuss some of the in vitro effects of nutritional agents on sperm, As well as clinical trials for male infertility patients who are attempting to conceive naturally, and emphasize clinical trials of treatment prior to assisted reproduction. The antioxidant agents that have been described for potential use will be reviewed as will.
1) Vitamin E
Vitamin E is known to be lipid-soluble antioxidant that is present in cell membranes. The presence of vitamin E protects the integrity of the phospholipid bilayer of the cell membrane as well as the mitochondrial sheath . In part, it acts as an antioxidant by interrupting the chain reaction of lipid peroxidation. Vitamin E can increase production of scavengers antioxidant enzymes, and it enhances the antioxidant activity of other agents. In vitro, it is known to protect sperm during cryopreservation.
2)
Zinc is a necessary mineral for optimal function-in of antioxidant enzymes, including superoxide dismutase. It inhibits membrane oxidative enzymes, such as NADP oxidase. It may also have a role in supporting the immunological system. It is well documented that lower Zink levels are present in the semen of infertile males and zinc deficiency has been associated with abnormal flagellation and microtubules defect in sperm. It is not clear, since zinc levels are so high in semen to begin with, whether the relative zinc deficiency seen in infertile males is this mineral . Systemic therapy is associated with reduced seminal fluid oxidative activity, apoptotic markers, and DNA fragmentation with a trend towards semen parameters.
3) Vitamin C
Vitamin C is high potency water-soluble reactive oxygen species scavenger. It has been shown to neutralize superoxide, hydroxyl, and hydrogen per-oxide radicals. It is naturally concentrated in semen at levels that are tenfold higher than hat seen in serum . Systemic therapy with vitamin C decreases sperm DNA fragmentation, admeasured by the presence the expression of genes involved in intra-cellular redox pathways. Of note, Vitamin C can act as a pro-oxidant at high doses.
4 Selenium
Selenium is mineral that is required for normal testicular development, spermatogenesis, sperm motility, and function. It reduces ant oxidative stress by an unknown mechanism. Enzymes require selenium for normal fuction,including those that are involved in ant oxidative pathways, such as phospholipid, hydroperoxide, glutathione peroxyl-case. Selenium administration increases glutathione peroxdation-1 expression, which destroys hydro-ventricular peroxide, a potent oxidative agent.
5 folate
Folate reduces homocysteine concentrations by its free radical scavenging properties it May work synergistically with zinc to improve quality. It is known that defects in folate synthesis, such as defects in MTHF enzymes, are associated with male infertility. There is limited evidence for a role folate deficiency in idiopathic male infertility.
6 carnitine
Carnitine is a water-soluble antioxidant that is also our primary fuel for sperm motility. Carnitine involved in the transport of long chain fatty acids into the mitochondrial matrix, possibly explaining its role in supporting sperm motility. Carnitine increases expression of antioxidant enzymes, including home oxygenasys-1 and endothelial nitric oxide synthase (eNOS). carnitine enhances cellular energetic in mitochondria by facilitating the free fatty acid entry into that organelle. Carnitine are thought to protect sperm DNA and cell membranes from reactive oxygen species induced DNA damage and apoptosis.
7 carotenoids
Carotenoids work synergistically with selenium and vitamin E as antioxidants .The most commonly studied carotenoids is lycopene that is naturally derived from fruits and vegetables and found in especially high concentration in tomatoes. carotenoids have a high reactive oxygen species quenching rate and are found in higher plasma levels than beta-carotene. High lycopene concentration are found in the testes and seminal plasma. Another additional carotenoid has been described recently, Astaxanthin, carotenoids extracted from algae. This agent has a high number of conjugated double bonds, making it a potent antioxidant then vitamin E or carnitine. Its role in Male fertility has only recently been explored.
8 coenzyme Q10
Coenzyme Q10 function in electron transport and is an antioxidant. It is thought to be important in mitochondrial function. It is found at high levels in metabolically active tissues. The semen concentrations and motility, suggesting an intrinsic role in the production of sperm and sperm motility treatment of patients with coenzyme Q10 was associated with improved sperm concentration 6-9 months of treatment. It is also associated with improved sperm motility. In a small trial, couples where the mail pregnancies versus no pregnancies in the control group coenzyme Q10 is suggested to have a benefit on sperm production.
9 antioxidant agents
The following agents have been described as being nutritional supplement and represent vitamin, minerals, and other substances that may have a role in protecting sperm , enhancing sperm function or potentially improving fertility both naturally and/or after assisted reproduction. Each of these agents will be reviewed in terms of its mode of action and studies involving these agents presented.
Where is the evidence that antioxidants will help?? Quality of Antioxidant Trials
Most antioxidant Trials have not been performed in a rigorous, randomized, controlled fashion . The scientific quality of antioxidant trials to-date has been relatively poor, as summarized by Ross et al. In most studies, the randomization method was not clear and allocation concealment was not clear as well. Double
Blinding was done for most of the studies, and no intention to treat analysis was done in the majority of the studies. Follow -up was typically strong with most studies reporting 90-100% follow-up rate. Interpretation of these studies was often difficult because multiple agents were used and in some cases no placebo was applied. For example, in one study by Emu et al. Vitamin C, Vitamin E, zinc, and other combination of agents were used together. Similarly ,Scott et al. Used vitamin A, Vitamin C, Vitamin E, and selenium, many of which have not been demonstrated to have antioxidant activities. Although most studies have suggested an odds ratio for effect of agents that was >1, the exact benefit, if any , of antioxidant therapies is not clear , in large part because of likely potential publications bias. In other words, studies were most likely to have been published if they demonstrated a benefit of intervention.
Abnormal DN A fragmentation get corrected or inhibited by antioxidants .
One of the most interesting interventional studies was a randomized controlled trail of antioxidant prior to IVF in a series of patients where the man had abnormal sperm DNA fragmentation. A total of 60 couple were enrolled. The men were treated with lycopene 6 mg , Vitamin E , Vitamin C, zinc , selenium ,folate ,and garlic in palm oil vehicle. The placebo arm received palm oil vehicle alone. There was a randomization of drug versus placebo and treatment was provided for 3 months before IVF-ICSI. Couples had to have had a prior failed IVF attempt and abnormal semen parameters. Suggesting oxidative stress with abnormal sperm DNA fragmentation. The mean pre-treatment DFI was 39% and female age was less than 39% . The primary outcome was reported to be embryo quality.
Unfortunately no difference was seen in embryo quality and the pregnancy rate was not statistically different. However the viable pregnancy test differed between treatment and placebo groups, defined as ongoing pregnancy per embryo transferred. Interestingly the raw implantation rate in the treatment and control groups not different and the row biochemical pregnancy rate was not different. Although the treatment was presumed to affect sperm DNA fragmentation there was actually no repeat evaluation of sperm DNA fragmentation during treatment raising a question as to whether any benefits or treatment were modulated by a direct effect on sperm.
Vitamin E and zinc
The Cochran collaboration reported an evaluation of antioxidants on ART outcome .Any dose or type of antioxidant could be compared to placebo or no treatment. The primary outcomes were analyzed in only three studies for live births. A secondary outcome pregnancy rate was available in 15 studies. The Cochran meta analysis demonstrated benefiting the use of oral antioxidants for a beneficial effect on live birth dates. The pregnancy rate was improved by an factor of antioxidant use. Interestingly each of the studies looking at live birth had a positive result with comparisons involving vitamin E versus placebo oral zinc versus no treatment. Overall ,only 18 out of 116 experimental arm patients achieved a live birth with 2 out of 98 in the control arm. Despite analysis of 34 trials involving 2,876 couples undergoing ART, the primary outcome for this meta-analysis could be determined by only three trials . A total of 20 live births occurred in these three trials. Both zinc and vitamin E were used. Of note, there is significant concern about high dose Of vitamin E use and it's cardiovascular risk. Interestingly, in two of the trials, there were no pregnancies in the control arm. It is quite unusual for an ART intervention trial to have no pregnancies in the control arm. Using pregnancy rate as an outcome, a larger number of studies were involved but the antioxidants used ranged from multiple agents, to vitamin E, to L-acetyl carnitine plus L-carnitine, L-carnitine alone, Vitamin C and vitamin E, magnesium, coenzyme Q10, and zinc. In the meta-analysis for pregnancy rates, a total of 53 pregnancies were analyzed.
When the pregnancy rate was evaluated as an outcome the magnitude of benefit appeared to be greater than the effect that should be expected by improving sperm DNA fragmentation. Antioxidants are thought to function by decreasing sperm DNA fragmentation and the magnitude of benefit was 4.18.One meta- analysis of the effect of DNA fragmentation on pregnancy rates during ART reported a diagnostic. Therefore the magnitude of benefit appeared to greatly outweigh the magnitude of benefit that would be suggested from DNA fragmentation. Of note the pregnancy rate in the control group was 0-11% in most of the trials with 3% as a mean value .This very low pregnancy rate after assisted reproduction suggests some concern with the type of ART performed or the site for these trials.
Taken together only 20 pregnancies were involved in demonstrating the treatment effect that is proposed in the Cochran meta- analysis , from a total of three trials. The risk of publication bias appears to intervention. Multiple agents were considered together to evaluate this effect. Even though the magnitude of bene5for live births suggests benefit it is not clear how to interpret these results
Summary
Antioxidants appear to have some promise as agents that could provide a benefit of improving fertility potential for men with abnormal sperm DNA fragmentation and possibly men with idiopathic infertility. The most promising agents appear to be vitamin, E carnitines, Astaxanthin, Vitamin C , zinc and possibly coenzyme Q.10 . Unfortunately based on published data it is impossible to make evidence based recommendations of a specific agent dose or concoction of supplements for a couple with male factor infertility. What dose should be used what combination of agents and the actual mechanism of action is impossible to determine from published data . All that one can say at this point is that antioxidants might have benefit in the treatment of male infertility especially for men with abnormal sperm DNA fragmentation or idiopathic infertility. Unfortunately the magnitude of benefit and treatment regimen to be recommended is yet to be determined
The effects of paternal age on a couple's fertility are real and may be greater than has previously been thought. After adjustments for other factors, it has been demonstrated that the probability of a fertile couple will take >12 months to conceive nearly doubled from 8% when the man is <25 years to 15% when he is >35 years ; thus, paternal age is a further factor to be taken into account 15% when he is >35 years thus paternal age is a further factor to be taken into account when deciding the prognosis for infertile couple. Also the increased male age is associated with a significant decline in fertility. Which is independent of the woman's age, coital frequency and lifestyle effect as well as effect of other subfertility risk factor . Furthermore fathering at older age may have significant effects on the viability and genetic health of human pregnancies and offspring primarily as a result of structural chromosomal aberrations In sperm. The evidence for sex chromosomal aneuploidy suggests that there may be about a twofold increase in risk at the age of 50 .In fact the risk for a father over 40 years old to have a child with an autosomal dominant mutation equals the risk of Down syndrome for a child whose mother is 35-40 years old. Although individual Lessing cell volume does change with age the total eluding cell volume and the absolute number of Leydig cells decrease significantly with age . Also anatomical studies of Sertoli cell populations in humans show that the young adult male testis is endowed with 500 million Sertoli cells and appears to decline to approximately 300 million cells in the older adult suggesting that there is also an age related decline in Sertoli cell numbers in the human testis. Furthermore estimations of individual.
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