The antioxidant paradox - Prof Ralf Henkel

The importance of ‘reductive stress’ and the ‘antioxidant paradox’ for reproduction

Most of us have heard about oxidative stress and its detrimental effects on sperm health and general health. Scientifically, oxidative stress is defined as the imbalance in the body between reactive oxygen species (ROS, also sometimes referred to as free radicals) and antioxidants (such as vitamins etc.) where the balance is towards higher levels of ROS and lower levels of antioxidants.

Managing oxidative stress within the body is always about achieving the balance between oxidants and antioxidants and this is why maintaining a healthy diet with a good intake of vegetables and vitamins is essential. It’s also why we should avoid an unhealthy lifestyle as this leads to an increase in the levels of the free radicals causing the oxidative stress. Therefore, many people consider taking antioxidant supplements in the belief that it will only be beneficial. However, things are more complicated, and we should not think of oxidative stress and free radicals as a “black and white” picture.

What is oxidative stress and what is reductive stress?

As mentioned before, oxidative stress is the imbalance in the body between free radicals and antioxidants in favour of the free radicals. There are many reasons why this may be occurring ranging from medical conditions, infections to unhealthy lifestyle choices such as smoking or alcohol abuse. Equally, it could also be a combination of multiple factors along with inadequate levels of antioxidants within your diet.

The fact is that if the amount of free radicals is relatively too high, then your body will be in a state of oxidative stress and damage is likely to occur to the body and to your sperm.

For some this is when they’ll turn to the use of antioxidants, perhaps because their friend suggested it, maybe because someone mentioned it on a forum and sometimes because a physician has recommended them as the belief is that antioxidants are doing good and free radicals are always bad.

It is correct saying that antioxidants are playing a crucial role in neutralising these free radicals and ROS bringing the body back into balance. However, it’s important to understand that a certain, small amount of free radicals is essential important functions for the body’s functions including for fertility. ROS are necessary to trigger some cellular functions within the sperm such as the so-called acrosome reaction which enables sperm to enter and fertilise an oocyte (O’Flaherty et al., 2006; Sies, 2023). Therefore, it is important that the balance between free radicals (oxidants) and antioxidants must be maintained as too much of either oxidants or antioxidants is bad.

Where men sometimes believe that more is better, if they’re taking too many antioxidants, this will push the body’s balance from a state of oxidative stress into a condition known as reductive stress, which is as harmful as oxidative stress (Castagné et al., 1999). Not only will reductive stress impact sperm health and function it has also been shown to induce other cellular dysfunctions and diseases including heart disease (Brewer et al., 2013; Henkel et al., 2019; Ma et al., 2020; Panner Selvam et al., 2020). Hence, one must understand that having too much of a good thing, is a bad thing!

The ’antioxidant paradox’

It’s important to note that some food products are already supplemented with vitamins, antioxidants and minerals such as zinc or selenium. While vitamins and antioxidants at physiological levels are essential for normal bodily functions, excessive supplementation can lead to toxicity and can even increase infertility, mortality and morbidity. If lifestyle changes, antioxidants in general food products, prescribed antioxidants and antioxidants bought over the counter, all come together, it is conceivable that the intake of antioxidants can be much too high and thereby shift the delicate balance from oxidative stress into reductive stress. Particularly if high doses of antioxidants are taken, these antioxidants can have pro-oxidant effects. This contradictory effect of antioxidants is called the ‘antioxidant paradox’ because these substances that are, at physiological levels, beneficial, but can have detrimental effects if the dosage is too high.

What are the risks of over-supplementation?

Among the different antioxidants, vitamins A, C and E are powerful antioxidants which the body needs to remain healthy and to prevent conditions like high blood pressure, stroke, atherosclerosis or colds. Many people will “dose up” on vitamin C, for example, in the hope that it will prevent the flu but there is no benefit to this if the body has already enough vitamin C.

It has also been shown that supplementation of patients with vitamin A, C, E, zinc and selenium resulted in a loosening of the sperm DNA structure and therefore makes sperm DNA more prone to oxidative assault (Menezo et al., 2007). Similarly, the health benefits of vitamin E are massively promoted. However, if excessively administered together with other antioxidants, vitamin E may increase the overall mortality rate as well as increase the risk of prostate cancer and yet it does not prevent cardiovascular diseases (Miller et al., 2005; Dotan et al., 2009).

A recent study revealed that out of 34 antioxidant supplements 27 were advertised to improve male fertility (de Ligny et al., 2023). For 21 of these 34 supplements (62%) no published clinical trials were available and only 2 products were tested in randomised clinical trials with low risk of bias, among them a study using Proxeed (Micic et al., 2019). Another study that investigated the effectiveness of Fertilovit (branded in the UK as testhim M+) showed significantly improved total motile sperm counts (Wirleitner et al., 2012). According to the manufacturers, Fertilovit is the only product worldwide for this application with antioxidants with long-term effects.

So, it’s not always good news when it comes to supplements and not all supplements are created equally!

Conclusion

Although antioxidants are essential for fertility and sperm health, an indiscriminate intake of high doses of antioxidants should be avoided. If you’re experiencing difficulties trying to conceive, then ensure you have a healthy, balanced diet with a good intake of natural antioxidants. If this is being well managed and you still wish to optimise your reproductive health further, we would always recommend talking to a urologist with male fertility expertise who can carry out a so-called redox status or oxidative stress test. If this test shows an imbalance in favour of free radicals (oxidative stress), then antioxidants would be recommended.

If you are taking or plan to take antioxidants, then we strongly recommend that you stick to the recommended formulation and dosage and do not add more in in the belief that more is better. Too much of antioxidants are a double-edged sword.

Once you have been taking antioxidants for 3 months or more, it is recommended that you get retested to assess your redox balance.

References

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2. Brewer A, Banerjee Mustafi S, Murray TV, Namakkal Soorappan R, Benjamin I (2013); Reductive stress linked to small HSPs, G6PD and NRF2 pathways in heart disease. Antioxid Redox Signal 18: 1114-1127
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