FACTS Men’s Health Series
Antioxidants for Male Subfertility
By Bryson Bellefeuille
Editor’s Note: As we continue to mark National Men’s Health Month, we are featuring another research study examining men’s fertility, infertility and, in this case, subfertility and the role of antioxidants. Bryson Bellefeuille, a medical student and participant in the FACTS elective, summarized a 2014 study called Antioxidants for Male Subfertility, published by Smits et al.
Between 48.5 and 186 million people are affected by infertility worldwide, and literature would suggest that up to 50% of infertility cases involve male infertility [1]. Of male infertility cases, oxidative stress has been found to play a role in 25% to 87% of cases [2]. Oxidative stress occurs in all living tissues that require oxygen to survive. The result of regular metabolic processes can cause the accumulation of toxic end-products, known as reactive oxygen species (ROS), which can lead to cellular damage. Both enzymes and antioxidants act physiologically to reduce the stress of ROS on the body — the latter being the first line of defense for scavenging and neutralizing free radicals, while the former chemically reduces ROS to neutral or excretable forms. ROS are of particular concern in the field of fertility medicine due to their potential to decrease sperm function and semen production.
Two major sources of ROS production in male reproductive organs are semen leukocytes and immature spermatozoa [3]. This is concerning because most ROS-reducing enzymes are found in the cellular cytoplasm, which spermatozoa lack and are therefore particularly susceptible to oxidative stress (OS). This stress disrupts the motility of sperm and further affects fertility through direct alteration of the spermatic DNA[4]. Increased sperm DNA fragmentation has been shown to decrease the potential for natural conception [5]. Previous studies have shown that infertile men, when compared to fertile men, have higher levels of ROS and lower antioxidant levels in their semen[4]. Thus, antioxidants have long been proposed as a potential treatment for infertility in men and have indeed been shown to increase semen quality[6].
“Increased sperm DNA fragmentation has been shown to decrease the potential for natural conception.”
In the literature review, Antioxidants for Male Subfertility, by Smits et al. [7], researchers asked whether antioxidants provide a fertility benefit for males struggling with subfertility. Only studies that included randomized control trials and cross-over trials of subfertile men treated with an oral antioxidant of any dose were included. Researchers specifically examined 18 different oral antioxidants that have been previously shown to protect spermatozoa from oxidative stress. The primary outcome measured in these studies was live birth rate, though in some, clinical pregnancy, any adverse event such as miscarriage, level of DNA fragmentations, sperm motility, and sperm concentration were also measured.
In total, 62 studies were selected for the literature review and data was collected from a total population of over 6,200 subfertile men between the ages of 18 and 65. However, evidence proving that oral supplementation of antioxidants improves the rates of live birth for subfertile men was “low” to “very low.” There was no statistically significant difference between the control group and treatment group in terms of live birth rate, particularly when studies with a high risk of bias were removed. Similarly, clinical pregnancy rates were not shown to be significantly affected once studies with high risk of bias were removed. And adverse events, such as miscarriage rates, were not shown to be any different from control groups, with the exception of gastrointestinal upset for some men who took antioxidants.
Based on the current science available, this research was thorough in its examination of the effects of antioxidants on male subfertility. However, a more apt title for the project might be: Antioxidants for Male Subfertility, a Reminder in Translating Hypothesis to Clinical Outcomes. Male subfertility is a significant issue worldwide for couples wishing to conceive and extremely nuanced in etiology. Oxidative stress is a real problem for sperm quality, and a variety of antioxidants have been shown to improve that quality and production. The idea to use antioxidants is a great one, but the research may suffer from too broad a question, among other limitations.
“Male subfertility is a significant issue worldwide for couples wishing to conceive and extremely nuanced in etiology. Oxidative stress is a problem for sperm quality.”
Subfertility in males often requires ample time for treatment, with consistent semen sampling every three months. Not all of the studies examined in this review required longitudinal follow up, according to the inclusion criteria. Also, included studies were not required to have specific dosage regimens of supplement use, as few protocols exist for most of these antioxidants. Any research that includes undefined dosages of supplements, which are unregulated in concentration and quality, is prone to heterogeneous results. Multiple antioxidants from the list were shown not only to have antioxidant effects, but exhibited pro-oxidative effects — a classic ‘dose makes the poison’ story. Fortunately, adverse events were not found significant in the men of these studies, but the risk was present.
Another limitation of this body of research is the measure of treatment efficacy; only a minority (12 of 62) of the included studies measured the primary outcome of live birth, indicating that the majority of studies were included based on secondary inclusion criteria. Data from the live birth studies were positive, but sample size was too small to provide high-quality data. Once again, the answer is more research.
In short, subfertility is slow to respond to treatment, and antioxidants may be too broad and unregulated to provide their purported benefits. Even if there is a benefit, current research is too sparse to provide convincing results. Yet, if condoning a supplement provides a patient assurance and relieves some of the pressure of subfertility, it might be an acceptable treatment for now. It is possible that many of these antioxidants do provide a fertility benefit without known risk of adverse events.
References
[1] Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment‐seeking: potential need and demand for infertility medical care. Hum Reprod 2007;22(6):1506‐12.
[2] Irvine DS. Epidemiology and aetiology of male infertility. Hum Reprod 1998;13 Suppl 1:33‐44.
[3] Iwasaki A, Gagnon C. Formation of reactive oxygen species in spermatozoa of infertile patients. Fertil Steril 1992;57(2):409‐16.
[4] Aktan G, Dogru‐Abbasoglu S, Kucukgergin C, Kadioglu A, Ozdemirler‐Erata G, Kocak‐Toker N. Mystery of idiopathic male infertility: is oxidative stress an actual risk?. Fertil Steril 2013;99(5):1211‐5.
[5] Evenson D, Wixon R. Meta‐analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online 2006;12(4):466‐72.
[6] Lewis SE, Sterling ES, Young IS, Thompson W. Comparison of individual antioxidants of sperm and seminal plasma in fertile and infertile men. Fertil Steril 1997;67(1):142‐7.
[7] Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev 2019;3(3):CD007411. doi:10.1002/14651858.CD007411.pub4
ABOUT THE AUTHOR
Bryson Bellefeuille
Bryson Bellefeuille recently completed medical school at the University of the Incarnate Word SOM in San Antonio, Texas. He is a prospective family medicine physician planning to practice full spectrum care with particular interest in obstetrics, Native American and rural health. His interest in FABMs stems from a call to provide fertility awareness and comprehensive reproductive planning options to all interested patients while empowering couples to understand their shared fertility. He resides in San Antonio with his wife and three young children.
