Antioxidants and Oxidative Stress
Elevated levels of oxidative stress are a common and important cause of male infertility problems, including sperm quality and elevated levels of sperm DNA fragmentation. The elimination of oxidative stress risk factors as well as the use of supplementation of antioxidants have been shown to have the potential to improve male fertility as well as the outcomes of treatments including IVF.
Antioxidant Supplements and Male Fertility
Over-the-counter antioxidant supplements can help eliminate the deleterious effects of oxidative stress within the genital duct system. Different male fertility experts take varying approaches to antioxidant therapies, including:
1) Recommending antioxidants for all men with fertility issues
2) Reserve antioxidants for men who have certain significant risk factors (such as tobacco use or pyospermia)
3) Only use antioxidants if elevated levels of oxidative stress are found upon testing (as discussed above)
None of these approaches has been proven superior. I personally tend to start all of my men on antioxidants due to their ease of accessibility (you do not need a prescription), affordability, and good safety and side effect profile in most men.
In general, most of these supplements contain some mixture of the following common nutrients:
1) Vitamin A
2) Vitamin C
3) Vitamin E
8) Coenzyme Q10
9) Folic acid
Other ingredients you may see in these supplements include vitamin B6 , vitamin B12, vitamin D, vitamin K, copper, manganese, fructose, arginine, quercetin, L-glutathione, niacin, thiamine, riboflavin, iodine, and chromium.
Coenzyme Q10 (CoQ10)
Also known as ubiquinone or ubiquinol, CoQ10 is a vitamin-like substance that has antioxidant properties and is also involved in cellular energy production. Studies have associated CoQ10 supplementation with improvements in semen parameters, though the literature has not to date documented a definitive improvement in pregnancy rates.
L-carnitine is an amino acid (a building block for proteins) that has antioxidant properties and is also involved in cellular fatty acid metabolism. Supplementation of L-carnitine has been associated with improvement in semen parameters (especially motility).
L-Carnitine and Cardiovascular Risk
Recent research from the Cleveland Clinic has linked L-carnitine intake to increased cardiovascular risk factors, alongside fat and cholesterol. L-carnitine is found in high levels in red meat. When consumed by people who regularly eat red meat, L-carnitine can be broken down by intestinal bacteria into TMAO, a by-product that can lead to increased atherosclerotic vessel damage. Interestingly, vegetarians may not have the necessary bacteria in their intestines to break down L-carnitine into TMAO. More research is certainly needed on this topic. My current take on the subject is this: L-carnitine may modestly increase cardiovascular risk if taken over long periods of time. I therefore only recommend that men take L-carnitine while they are trying to achieve a pregnancy. Once their partner is pregnant, I recommend that they stop all fertility-related supplements. Men who have a strong personal or family history of cardiovascular disease should discuss L-carnitine use with their cardiologist or primary care physician before starting this supplement.
Folic acid (vitamin B9) is a vitamin found in a variety of foods, including green leafy vegetables. Folic acid supplementation is strongly recommended in all women wishing to become pregnant due to its proven ability to reduce the risk of neural tube defects in newborns. In men, there is some evidence that folate deficiency can lead to decreased fertility, as well as an increased risk of birth defects.
Zinc is a mineral that is found in large concentrations within the epididymis. Though having no antioxidant properties itself, zinc assists with the antioxidant actions of some enzymes. Some studies have correlated lower sperm quality with decreased zinc levels, though others were inconclusive. The daily recommended intake of zinc for men is 11mg per day.
Similar to zinc, selenium does not have direct antioxidant effects, but helps to facilitate antioxidant activity. Several small studies have shown improvements in sperm quality with selenium supplementation, though others have shown no improvement.
relative effectiveness of different ANTIOXIDANTS
A wide variety of male fertility supplements are available to men. There does exist evidence that antioxidants can improve semen parameters and IVF outcomes in some men. However, the problem with deciding between antioxidants is that there does not exist any good scientific data on comparing their relative effectiveness to one another.
I currently think that there is decent evidence to suggest that any antioxidant regimen that you use should contain at least the following components:
1) A general antioxidant formula containing the following vitamins and minerals, once a day:
a) Vitamin A: 10,000 IU
b) Vitamin C: 250 mg
c) Vitamin E: 200 IU
d) Selenium: 15 mcg
e) Zinc: 7.5 mcg
2) L-carnitine: 500 mg once a day (or 1,000 mg every other day)
3) Coenzyme Q10 (CoQ10): 200 mg once a day (or 400 mg every other day)
4) Folic acid: 400 mcg once a day (or 800 mcg every other day)
Note on Supplements and Dosages: the above listed dosages are general recommendations of minimum amounts that may benefit fertility potential in men. These are approximations for the general population, and there is not solid scientific data to back up these specific amounts. Also, final decisions on dosages should be made with your medical provider, as some men with certain medical conditions or taking certain medications may need to modify their intake accordingly.
Once a pregnancy has been established, I generally recommend that the supplements should be discontinued.
Commercially Available Supplements
The following is a list of commercially available supplements (in alphabetical order) in a chart which contains their relative quantities of 7 common ingredients. Some supplements do not list the amounts of L-carnitine and/or Co-enzyme Q, but just have them listed as part of a "proprietary blend" making comparisons with other supplements difficult. Of note, most supplements have additional ingredients beyond the 7 on the chart, which may or may not assist with male fertility potential. The pricing is based on an April 2017 survey, primarily from Amazon. Below the chart you will find the individual supplements with a picture of their bottle/box as well as their full ingredient list.
[Note: We try to keep this information as accurate as possible for each supplement, but sometimes errors are made in transcription or formulations are changed. So that we can keep our information as accurate as possible, please contact us with any corrections/updates either in our "Comments" section (link at the bottom of this page) or by email at firstname.lastname@example.org.]
Individual Antioxidant Supplements and Their Ingredient Lists
OXIDATIVE STRESS AND ANTIOXIDANTS
Oxidative stress is an important contributor to male infertility problems. Antioxidants are therefore important for men who are having fertility problems as they try and maximize their fertility potential. This section of the website will review the causes and testing for oxidative stress. The "Antioxidants" section reviews the wide variety of commercially available antioxidants.
WHAT IS OXIDATIVE STRESS?
The body’s normal metabolic processes create by-products called reactive oxygen species (ROS), also called free radicals. These metabolic by-products have the potential to negatively affect individual cells, tissues, and organs, but under normal circumstances the body is well equipped with antioxidants, substances that mop up excess reactive oxygen species before significant problems occur. Small amounts of ROS are normally present within the genital duct system, and in fact they are thought to play an important positive role in normal sperm production and function.
However, when the amount of ROS becomes greater than the body’s normal cleanup mechanisms can easily handle, the result is increased oxidative stress on the body. Unfortunately, sperm are especially sensitive to oxidative stress, which can result in cellular and DNA damage and lead to decreases in both sperm numbers and quality.
CAUSES OF OXIDATIVE STRESS
One reason for increased levels of ROS in the genital duct system is the presence of higher-than-normal levels of white blood cells, which can be a sign of infection or inflammation. Pyospermia is the term for semen that contains elevated levels of WBCs. The presence of immature sperm cells may be another cause of oxidative stress. Increased scrotal temperature and varicoceles can also play a role in oxidative stress.
Certain lifestyle factors increase oxidative stress. These include:
1) Use of cigarettes or other tobacco products, or exposure to secondhand smoke
2) Exposure to chemicals or environmental toxins
3) Excessive alcohol intake
4) Use of marijuana or other drugs
TESTING FOR OXIDATIVE STRESS
There are several different ways to try and measure oxidative stress levels in the male genital duct system. However, measuring oxidative stress is not at this time considered a routine male fertility test in most clinical practices. Since antioxidant regimens are not very expensive and have minimal side effects in most men, many clinicians just choose to start all of their male fertility patients on antioxidants, thus eliminating the cost and time of antioxidant testing. However, some clinicians do routinely check for levels of oxidative stress in the semen of male infertility patients. Others reserve this testing for special circumstances, such as men with persistent pyospermia (elevated white blood cells in the semen) despite adequate antimicrobial and anti-inflammatory therapies. See "Reversible Semen Analysis Factors" for more information on pyospermia.
The white blood cells can contribute to oxidative stress which can decrease fertility potential. If a man taking antioxidants has persistent pyospermia but no increased oxidative stress, then their fertility potential will likely not be adversely affected. However, if the oxidative stress in that man is persistently elevated, then a sperm wash combined with IUI (intrauterine insemination) may increase their chances of success. See "Female Fertility Treatments" for more information on IUI and sperm washes.
Many different methods for testing oxidative stress (ROS) in cells exist, including chemiluminescense and colorimetric assays, thiobarbituric acid, and annexin V. However, from a practical standpoint, sperm oxidative stress testing is generally performed by the oxidative stress adduct (OSA) test, as well as the MiOXSYS sytem.
ROS OF SEMEN
Tests the amount of reactive oxidative species (ROS) within the semen. These generally are measured indirectly, by the ability of the semen to absorb the potentially damaging free oxygen radicals. Generally these tests measure the total antioxidant capacity of the seminal plasma.
OXIDATIVE STRESS ADDUCT TEST
A specialized test, called the oxidative stress adduct (OSA) test, can directly measure the degree of oxidative damage to the sperm. OSA testing is available from Reprosource (www.reprosource.com) and is part of the company’s Advanced Semen Report, which also includes DNA fragmentation index testing.
For the oxidative stress adduct (OSA) test, a normal result is under 3.8, a borderline result is between 3.8 and 4.4, and an abnormal result is over 4.4.
For cost information on the OSA test, please see the "Genetics and Advanced Sperm Testing Costs" section of this website.
This is a test developed at the Cleveland Clinic. The supposed advantage of the MiOXSYS test is that it evaluates both the amount of oxidants in the semen (like the ROS test) as well as the amount of oxidative reductants present (which eliminate oxygen free radicals). There are also other supposed advantages in terms of cost of testing, amount of specimen needed to be tested, and the ability to evaluate both fresh and frozen specimens. Tests results are reported as oxidation reduction potential (ORP) in 2 ways:
1) Static ORP (sORP)
-sORP measures the current balance between total antioxidants and reductants, and is measured in millivolts (mV).
2) Antioxidant capacity reserve (cORP)
-cORP measures the semen’s antioxidant potential, measured in micro-coulombs (µC)
Semen levels of ORP as reported in a recent study [Agarwal A, et al. Fertility and Sterility 2016]
Men with normal motility Men with low motility
sORP 2.55 35.28
cORP 1.71 3.49
The MiOXSYS is available through AYTU BioScience Inc. which sells the testing device to specific fertility labs. Availability and pricing are going to vary regionally.
SUMMARY OF OXIDATIVE STRESS TESTING
There are no specific guidelines on the performing of oxidative stress testing. Four possible clinical uses for oxidative stress testing:
1) For physicians who use these tests to guide which patients should be started on antioxidant supplements.
2) Patients who are having trouble with certain fertility risk factors, such as smoking cessation, to see if there is some objective evidence that this risk factor is causing on-going problems with fertility potential.
3) Evaluation for the presence of male factor problems in men with normal semen parameters, since elevated levels of oxidative stress is often associated with decreased fertility potential. For example, a man who has been unable to conceive for a year who has normal semen parameters but smokes cigarettes. An elevated level of oxidative stress may be an indicator that male factor issues may be contributing to their inability to conceive despite normal semen parameters. This man may benefit from smoking cessation and/or antioxidant supplements.
4) A man with persistent pyospermia that is resistant to treatment, since pyospermia can be associated with increased oxidative stress on sperm. The presence or absence of elevated oxidative stress could potentially provide information about whether the sperm are still experiencing oxidative stress despite antioxidant therapy, in which case sperm wash and IUI may be helpful.
MANAGEMENT OF OXIDATIVE STRESS
Managing oxidative stress in men generally takes two approaches
1) Eliminating oxidative stress factors where possible
2) Supplementation with antioxidants (as described above)
ELIMINATION OF OXIDATIVE STRESS FACTORS
1) Treatment of pyospermia
2) Avoiding sperm toxins (e.g. tobacco, drug use, work-related and environmental toxins)
3) Limiting alcohol intake to no more than 4 drinks per week
4) Varicoceles (dilated veins in the scrotum)
5) Avoiding excessive elevations of scrotal temperature
Please see the "Sperm Boot Camp" and "Medical Optimization Program" sections for a much more detailed discussion of these topics.