On Males, Antioxidants and Infertility (MOXI): Certitudes, Uncertainties and Trends

Abstract

Male infertility (MI) involves various endogenous and exogenous facts. These include oxidative stress (OS), which is known to alter several physiological pathways and it is estimated to be present at high levels in up to 80% of infertile men. That is why since the late 20th century, the relationship between OS and MI has been widely studied. New terms have emerged, such as Male Oxidative Stress Infertility (MOSI), which is proposed as a new category to define infertile men with high OS levels. Another important term is MOXI: Male, Antioxidants, and Infertility. This term refers to the hypothesis that antioxidants could improve male fertility without the use of assisted reproductive technology. However, there are no evidence-based antioxidant treatments that directly improve seminal parameters or birth ratio. In this regard, there is controversy about their use. While certain scientists argue against their use due to the lack of results, others support this use because of their safety profile and low price. Some uncertainties related to the use of antioxidants for treating MI are their questionable efficacy or the difficulties in knowing their correct dosage. In addition, the lack of quality methods for OS detection can lead to excessive antioxidant supplementation, resulting in "reductive stress". Another important problem is that, although the inflammatory process is interdependent and closely linked to OS, it is usually ignored. To solve these uncertainties, new trends have recently emerged. These include the use of molecules with anti-inflammatory and antioxidant potential, which are also able to specifically target the reproductive tissue; as well as the use of new methods that allow for reliable quantification of OS and a quality diagnosis. This review aims to elucidate the main uncertainties about MOXI and to outline the latest trends in research to develop effective therapies with clinically relevant outcomes.

Keywords: antioxidants; biomarkers; idiopathic; inflammation; male infertility; oxidative stress; reductive stress.

Figure 1

Worldwide incidence of MOSI in infertile men. ^a National Institutes of Health (NIH). Reproduced with permission from Figure 3, Agarwal, A., et al., World J Mens Health 2019 [5].

Figure 2

Mechanisms to explain ‘antioxidant paradox’ pertaining to male infertility, both by the induction of reductive stress and the failure to address the interconnected link of oxidative stress (OS). Reproduced with permission from Figure 1 of Dutta, S., Antioxidants 2022.

Figure 3

A schematic outline of all the protocols here reviewed in both bottom-up and top-down untargeted MS approaches for the proteomic analysis of human SP. Reproduced with permission from Preianò, M. et al., Int. J. Mol. Sci., 2023.