Certitudes in Male Infertility: History
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Manuel Alfaro Gómez
,
María del Rocío Fernández-Santos
,
Alejandro Jurado-Campos
,
Pedro Javier Soria-Meneses
,
Vidal Montoro Angulo
,
Ana Josefa Soler
,
José Julián Garde
,
Virginia Rodríguez-Robledo

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. Infertility refers to the problem of couples who achieve a pregnancy but do not carry it to term. Male infertility (MI) is defined as the inability of a male to make a fertile female pregnant, also for a minimum of a one year of unprotected intercourse. As for the male factor, males are found to be solely responsible for 20–30% of infertility cases and contribute to 50% of cases overall.

  • male infertility
  • idiopathic
  • oxidative stress
  • reductive stress

1. Oxidative Stress and Idiopathic Male Infertility: MOSI

One of the main certainties of male-factor infertility is that it has become one of the major global health problems, currently accounting for 20–30% of infertility cases worldwide. As previously mentioned, idiopathic male infertility accounts for a large majority of cases where the underlying cause(s) remains elusive [1][2]. In this respect, most of the articles published over the last 10 years show a strong correlation between elevated reactive oxygen species (ROS) levels in semen and worse reproductive outcomes. Therefore, another certainty is that oxidative stress (OS) is currently the most widely accepted mechanism as a key factor in explaining idiopathic MI cases, [3] through phenomena such as mitochondrial dysfunction, lipid peroxidation, DNA damage and fragmentation, and finally, sperm apoptosis [4][5]. Thus, all factors which have been traditionally associated with male infertility and poor sperm quality, such as alcohol, smoking [6], obesity, varicocele, infections, and psychological stress may indeed exploit their effect through oxidative stress [7]. With regard to the latter and having in mind the strong relationship between OS and MI, some authors are currently starting to refer to the category, MOSI (Male Oxidative Stress Infertility) [8], as a medical term to describe infertile men with abnormal sperm parameters and oxidative stress (OS), including those previously classified as having idiopathic infertility [9].
One of the first authors to propose the term MOSI was Agarwal et al. at 2019, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility [10] (see Figure 1). Miccogullari et al. have published a study on the role of thiol/disulfide homeostasis with a novel and automated assay in MOSI [11], for the determination of oxidant/antioxidant status in serum samples by using a novel test of patients with IMI and comparing their results to those of healthy controls.
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 [10].
Therefore, since OS occurs when seminal reactive oxygen species (ROS) generation exceeds endogenous antioxidant capacity, oral antioxidant supplementation has been proposed, from many years ago [12] until now [13], as a key strategy in the treatment of IMI. Another certainty is, consequently, the popularization in the scientific field of the use of antioxidants during the last decades, despite the lack of conclusive results regarding their use. This may be due to two main reasons. The first is that these compounds are widely available and inexpensive when compared to other fertility treatments and also because of the proved safety of oral supplementation with antioxidants [12], being an attractive area for the study of MI [14].

2. Antioxidants, as an Alternative in the Treatment of Idiopathic MI: MOXI

The enzymatic antioxidant system in semen is composed of endogenous molecules, the three most relevant ones being superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) [15]. However, non-enzymatic antioxidants can be both endogenous or exogenous, and the most important ones in spermatozoa are glutathione, selenium, carotenoids, such as lycopene, ascorbic acid, and -tocopherol, which exert their antioxidant effects through direct neutralization, promoting expression of antioxidant enzymes, or acting as cofactors for antioxidant enzymes. There are many papers and review articles on studies of antioxidants’ effects on MI, particularly the review published in 2010 by Agarwal et al. [16], based on many reputable studies, which described the effects of various antioxidants such as carnitines, vitamin C, and vitamin E as a first-line treatment, and others such as as glutathione, selenium, and coenzyme Q10 as the second line.
However, it was not until the year 2020 that the term, MOXI (Male, Antioxidants and Fertility) trial, was described by Steiner et al. [17]. This study was designed to test the hypothesis that antioxidants would improve male fertility without the use of assisted reproductive technology (ART) (Table 1). They examined the efficacy of a commercially available antioxidant combination pill, containing 500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1000 mg of L-carnitine, 20 mg of zinc, 1000 mg of folic acid, 10 mg of lycopene daily for three to six months, as a treatment for infertile men with abnormal semen parameters. The conclusion of this study suggested that the commercial antioxidant mixture did not improve semen parameters or DNA integrity among men with male factor infertility, nor did it improve in vivo pregnancy or live birth rates. This work has been included as a reference in other similar studies. For example, Knudtson et al. [18] studied the role of plasma antioxidant levels in male fertility in the USA (α-tocopherol, zinc, and selenium) through analysis of the MOXI randomized clinical trial. In this study, the primary endpoints in this secondary analysis were semen parameters, DNA fragmentation, and clinical outcomes including pregnancy and live birth. There was no association between selenium, zinc, or vitamin E levels and semen parameters or DNA fragmentation, and no association was observed between antioxidant administration and semen parameters or clinical outcomes in male infertility in men with sufficient or higher plasma antioxidant levels. So, it does not appear to confer benefits on semen parameters or male fertility.
Table 1. Characteristics at screening for all enrolled men in the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Reproduced with permission from Table 1 of Steiner, Antioxidants 2020.
Data Are Presented as the Number (%) or Median (Interquartile Range).
  Antioxidants (n = 85) Placebo (n = 86)
Age (years) 34.0 34.0
  (30.0, 37.0) (30.0, 38.0)
Body mass index (kg/m2) 27.8 27.6
  (24.2, 31.7) (24.4, 31.0)
  n = 82  
Ethnicity    
Hispanic or Latino 7 (8.2) 5 (5.8)
Non-Hispanic 72 (84.7) 78 (90.7)
Unknown 6 (7.1) 3 (3.5)
Race    
White 63 (74.1) 69 (80.2)
Black 6 (7.1) 7 (8.1)
Asian 7 (8.2) 2 (2.3)
American Indian or Alaska Native 1 (12) 1 (12)
Unknown 8 (9.4) 5 (5.8)
Mixed Race 0 (0) 2 (2.3)
Abnormal semen parameters    
Single abnormal parameter    
Sperm concentration ≤ 15 million/mL 4 (4.7) 5 (5.8)
Total motility ≤ 40% 9 (10.6) 10 (11.6)
Normal morphology # ≤ 4% 33 (38.8) 29 (33.7)
>1 abnormal parameters 39 (45.9) 42 (48.8)
Fathered a prior pregnancy ^    
Yes 25 (29.4) 38 (44.2)
No 60 (70.6) 48 (55.8)
Prior infertility treatment and/or surgery    
Yes 25 (29.4) 24 (27.9)
No 60 (70.6) 62 (72.1)
Duration of infertility (months) 24.0 24.0
  (18.0, 48.0) (15.0, 36.0)
  n = 81 n = 83
History of smoking    
Never 54 (63.5) 47 (54.7)
Current 8 (9.4) 11 (12.8)
Former 23 (27.1) 28 (32.6)
History of alcohol use    
Never 6 (7.1) 4 (4.7)
Current (in the past year) 72 (84.7) 81 (94.2)
Former (not in the past year) 7 (8.2) 1 (12)
# WHO 5th criteria. ^ p < 0.05, Wilcoxon’s rank-sum test was used for the continuous variables, and Chi-square or Fisher’s exact test was used for categorical variables. Wilcoxon’s rank-sum test was used to test the distributional difference, instead of mean or median of the two groups.
Finally, a review paper has recently been published by Chen et al. [14], including several studies that are less susceptible to bias because of being placebo-controlled and more highly powered. Among them, the MOXI trial is of particular interest, being a large, multicenter RCT, which demonstrated no improvement in semen parameters or live-birth rates with antioxidant use [17][18].
In this way, a systematic review and meta-analysis of randomized controlled trials (RCT) published in early 2023 by Agarwal et al. [19] assesses the impact of antioxidant therapy on natural pregnancy outcomes and semen parameters in MI. Among more than 1.300 papers, 45 RCT, and 4332 infertile patients, a significantly higher pregnancy rate was found in patients treated with AOX compared to placebo-treated or untreated controls. However, no effects on live-birth or miscarriage rates were observed in four studies, because, according to the author of the review, very few RCTs specifically assess the impact of AOX. Therefore, further RCTs assessing the impact of AOX on live-birth rates, miscarriage rate, and SDF will be helpful.
Barati et al. [20] explain the roles of oral antioxidants and herbs in coping with oxidative stress in male infertility, among other studies, in a review published in 2020. Low-molecular-weight compounds later described and nutrients such as selenium, zinc, and copper can protect the body against OS. For years, many urologists have prescribed oral antioxidants for infertility and nowadays, the use of herbal therapy has also been considered to prevent infertility because these antioxidants can reduce the destructive effects of oxidative stress [21].

3. Other Antioxidants and Their Role as Biomarkers

Therefore, it seems timely and relevant to dedicate a section to explore evidence on other types of antioxidants, traditionally used or having emerged in recent years, taking into account recently published review papers.
Lucignani et al. recently published a review based on the evidence of the efficacy of coenzyme Q10 (CoQ10) and melatonin on male infertility [22]. On the one hand, CoQ10, is one of the antioxidants historically studied for years [23][24] and is a fat-soluble ubiquinone with intracellular antioxidant activity, the lack of which has been observed in various sub-fertile conditions, (e.g., varicocele, oligozoospermia) [25], while melatonin is a hormone secreted by the pineal gland of the brain, and its metabolites act as free radical scavengers, hence protecting cells from oxidative stress, which could have a significant impact on infertility [26]. In both cases, the conclusion is that larger studies are needed to assess their clinical efficacy and potential in male infertility.
N-Acetyl-l-cysteine (NAC) is a reduced glutathione precursor with strong anti-inflammatory and antioxidant effects. It is widely used in the respiratory system, treatment of diseases of the digestive and cardiovascular systems [27]. In addition, some articles have been currently published on the role of NAC orally in IMI [28]. Daily N-acetyl-cysteine administration resulted in a statistically significant improvement in semen parameters, particularly sperm motility and normal morphology, but had no effect on the patient’s hormone profile [29][30]. Its potential therapeutic benefits lie in its direct antioxidant capacity, thanks to its ability to chelate heavy metals and the reducing effect of the thiol group (-SH) present in its molecular structure, and indirectly, as a precursor of glutathione, as mentioned above. It also has anti-inflammatory and immunomodulatory effects, which makes it an interesting alternative for the treatment of IMI [31].
Antioxidant compounds may also have a dual role, not only as bioactive molecules that can be used for the treatment of IMI, but also as biomarkers. The identification and then determination of certain biomarkers has great potential for the diagnosis, confirmation and prevention of imbalances affecting, in this case, fertility. In addition, they can be used to determine the physiological state of an organism or to measure the response to a particular drug. By evaluating these molecules, it is possible to get closer to the possible background of the disorder causing a fertility problem.
Several studies have been carried out in this regard, among which the determination of levels of coenzyme-Q10 and α-tocopherol (Vitamin E) in blood plasma [32] and seminal fluid, are proposed as important metabolic biomarkers for diagnosis, treatment, and even monitoring of male infertility by measuring of concentration levels of bioactive compounds [33]. After administration during 3 and 6 months of treatment, concentration levels of antioxidants are significantly increased and the OS decreased. On the other hand, Vitamin D has been also studied as a potential biomarker of MI [34] and a review article with this issue has been published. Such article even explores the possible relationship between obesity and vitamin D deficiency, and its role in male infertility has been also published [35]. Other biomarkers have been described in the literature as good candidates for the diagnosis of MI, such as 17-hydroxyprogesterone (17-OHP) and insulin-like factor 3 (INSL3) as accurate secondary biomarkers of intratesticular testosterone in the context of male infertility [36].
Finally, it should be noted that currently, -omics platforms (genomics, epigenomics, transcriptomics, proteomics and metabolomics, among others) are very powerful tools to identify the most robust molecular biomarkers for the diagnosis of diseases, in this case, in sperm and seminal plasma. For this reason, these techniques may be interesting for the diagnosis of male infertility, and to evaluate the clinical uses of some biomarkers [37]. Proteomics untargeted approaches, depending on the study design, might provide a plethora of biomarkers not only for a male infertility diagnosis but also to address a new MS-biomarkers classification of infertility subtypes [38]. On the other hand, seminal fluid contains the highest concentration of molecules from the male reproductive glands; therefore, these molecules could be potential seminal biomarkers in certain male infertility scenarios, including natural fertility, differentiating azoospermia etiologies, and predicting assisted reproductive technique success [39]. Seminal protein-based assays of TEX101, ECM1, and ACRV1 are already available or under final development for clinical use.

This entry is adapted from the peer-reviewed paper 10.3390/antiox12081626

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