The excessive use of antioxidant therapy: A possible cause of male infertility

CAPSULE

Contributors: Akira Tsujimura, MD, PhD (Japan), and Edoardo S. Pescatori, MD (Italy)

Commentary by Prof. Akira Tsujimura:

(article: PMID: 30259539 DOI: 10.1111/and.13162)

In many developed countries, declining fertility has become a national problem, and interest in male infertility has increased over the years. The most common cause of male infertility is spermatogenesis dysfunction, especially for unknown causes (idiopathic). The European Urological Association guidelines for idiopathic male infertility and oligozoospermia state that the effects are not uniform, with some meta-analyses showing that antioxidant therapy improved conception and pregnancy rates, while others reported no improvement in semen findings after treatment. However, it is also true that reactive oxygen species and oxidative stress are closely related to various pathological conditions such as neurodegenerative diseases, aging, and male infertility. Therefore, in actual clinical practice, antioxidants have been used empirically in patients with idiopathic spermatogenesis dysfunction.

Antioxidants are available in a variety of formulations containing various concentrations of selected antioxidants. They are commercially available in the form of dietary supplements and are added to a variety of foods and teas. For male infertility, glutathione, vitamins C and E, carnitine, N-acetylcysteine, coenzyme Q10, selenium, and zinc are antioxidants commonly used as therapeutic agents. However, exact dosages and dosing regimens for these antioxidants are not clearly defined. Some of these substances on the market are in such high concentrations that they do not occur in nature, and there is concern about the side effects of overdose. In fact, the few studies that have evaluated antioxidant overdose and its associated side effects have found that the side effects of high dietary intake of antioxidant supplements vary. Taking selenium as an example, it has been reported that elevated seminal selenium concentrations (>80 ng/ml) are associated with decreased motility, azoospermia, and increased miscarriage rates. In fact, selenium concentrations between 40 and 70 ng/ml are considered optimal for productive reproduction (high pregnancy rates and low miscarriage rates). Furthermore, there is growing evidence that the antioxidant or antioxidant-promoting activity of antioxidants, even if they are of natural origin, is ultimately dependent on their concentration. In addition, because many antioxidant compounds act synergistically, treatment with antioxidants not only fails but may even be toxic.

The study by Henkel et al, addresses the "antioxidant paradox," in which high doses of antioxidant supplements damage cells with free radical substances and reiterates that antioxidant therapy for male infertility has clear benefits and risks.

My Personal Viewpoint on the use of antioxidants for male infertility:

1. When and why do you recommend antioxidant supplements to your patients? What is their diagnosis? (Agarwal)

Prof. Tsujimura: If I make a diagnosis of idiopathic spermatogenesis dysfunction after examination of the patient's semen, blood (hormone) tests, and the presence of varicocele, I suggest that the patient take antioxidants. However, I fully explain that there is no specific treatment for spermatogenesis dysfunction and that antioxidants are the drug of choice by process of elimination.

2. Comment on the kind of antioxidant supplements you recommend and in what dose and for how long? (Agarwal)

Prof. Tsujimura: These drugs are basically not covered by insurance in Japan, so I ask patients to purchase them themselves after explaining them to them. I recommend a combination of L-carnitine (750 mg), zinc (30 mg), astaxanthin (16 mg), coenzyme Q10 (90 mg), and vitamins C, E, and B12. The efficacy of these fixed-dose combinations is reported in Reproductive Medicine and Biology 19: 89-94, 2020. The minimum duration of administration is 3 months, and the maximum is about 1 year.

Commentary by Dr. Edoardo Pescatori:

(article: PMID: 30259539 DOI: 10.1111/and.13162)

Oxidative stress, defined as a disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses, it is acknowledged to be linked, among the others, to disturbances of male fertility. In men oxidative stress may be the result of several factors: wrong lifestyles (overweight/obesity, sedentary lifestyle, smoking, excessive alcohol intake, etc,), varicocele, radiation, exposure to environmental toxic agents. All these may negatively impact the spermio/spermatogenetic process, as witnessed also by altered values at sperm analysis and DNA fragmentation test. Accordingly, several antioxidant supplementations have been proposed, and are widely used, to hypothetically “treat” oxidative stress. The present paper by Henkel, Sandhu and Agarwal elegantly and comprehensively illustrates the potential risks of “too much” antioxidant supplementation, emphasizing the possibility to fall into the “antioxidant paradox”, where an excessive antioxidant load can induce a “reductive stress”, as dangerous as the oxidative stress.

This paper clearly shows how this area is controversial: Authors showed that, although several studies on antioxidant supplementations documented positive effects in clinically infertile men, many others have failed to show positive outcomes on semen parameters, and some have even reported negative outcomes in terms of increased sperm DNA fragmentation or chromatin decondensation.

Authors then explored the possible causes that might explain the present difficulty “to find the truth” about the correct antioxidant treatment: commercially available antioxidants are mostly a mixture of potentially active products, and the role of each specific one is difficult to assess; it would be desirable to know the actual individual redox level in each individual patient, but this is seldom, if ever, done. Authors emphasize the lack of a universally accepted method to test the bodily and seminal redox status. More: the normal seminal redox level is unknown and, consequently, no generally accepted cut‐off values are presently available.

Should the present scientific limits of above be overcome, ideally studies simultaneously evaluating the impact of specific antioxidant supplementations on sperm analysis, sperm DNA fragmentation and decondensation tests, stratified by individual bodily and seminal redox status, could answer many questions on the correct antioxidant treatment in the individual infertile man. Up to then, the role of the Andrologist is crucial in identifying all the potential causes of oxidative stress in each infertile man, to pursue correction of wrong lifestyle habits, with emphasis on a correct diet with natural antioxidants present in food, unlikely at risk of inducing a status of “reductive stress”.

My Personal Viewpoint on the use of antioxidants for male infertility:

1. What is your personal philosophy on the role of antioxidants for the treatment of infertility patients? (Agarwal)

Dr. Pescatori: The priority should be to identify the presence of potential treatable causes of oxidative stress (wrong lifestyle habits, varicocele, environmental causes), and address them. Only after having done so, to consider antioxidant supplementations.

2. When and why do you recommend antioxidant supplements to your patients? What is their diagnosis? (Agarwal)

Dr. Pescatori: I prescribe antioxidants in patients with not correctable risk factors of oxidative stress, and with altered test of sperm DNA fragmentation, besides sperm analysis. I consider antioxidants even more in the presence of recurrent pregnancy loss.

3. When will you prescribe antioxidants and in what dose and for how long? (Agarwal)

Dr. Pescatori: I prescribe antioxidants at the recommended (either scientific or Company) dose, I do not associate more antioxidants. My typical treatment cycle has a 3-month duration, and I request a follow-up visit with the outcomes of: sperm analysis, DNA fragmentation and decondensation tests.

Introducing a NEW item: Expert Opinion

Expert Speaks on the Role of Antioxidants in Male Infertility

Invited Expert: Professor Armand Zini

(article: PMID: 36102104 DOI: 10.5534/wjmh.220067)

Dr. Zini shared his viewpoint on a recent meta-analysis published by GAF researchers on the “Impact of Antioxidant Therapy on Natural Pregnancy Outcomes and Semen Parameters in Infertile Men” Agarwal et al, World J Men’s Health. 2023 Jan;41(1):14-48. Published online Sep 07, 2022. https://doi.org/10.5534/wjmh.220067

The etiology of male infertility is multifactorial and, in many cases the underlying mechanism is the excess production of semen reactive oxygen species (ROS) and oxidative stress. Abnormal semen ROS production is known to cause sperm dysfunction and sperm DNA damage resulting in reduced male fertility potential.

These observations have led clinicians to treat infertile men with antioxidant supplements. Although the mechanism of action of dietary supplements remains to be fully elucidated, in vitro studies have demonstrated that antioxidants can protect sperm function and sperm DNA integrity when spermatozoa are exposed to high levels of ROS. Moreover, most clinical studies have shown that dietary antioxidants can improve sperm function and DNA integrity in infertile men. However, a beneficial effect of these supplements on pregnancy and live birth rates has not been established. Additional work is required to determine the optimal antioxidant supplement and the effect of these agents on sperm parameters and reproductive outcomes.