Stesura Seveso 121Archivio Italiano di Urologia e Andrologia 2020; 92, 2 ORIGINAL PAPER The impact of nutrition and lifestyle on male fertility Mahmoud Benatta 1, 2, Redha Kettache 1, 3, Noor Buchholz 1, Alberto Trinchieri 1 1 U-merge Ltd. (Urology for Emerging Countries), London, UK. 2 Department of Urology, Djilali Lyabes University Hospital, Sidi Bel Abbes, Algeria; 3 Department of Urology, EPH Bachir Bennacer, Biskra, Algeria. Background and aims: Male unexplained infertility has long been suspected to result from environmental, lifestyle and nutritional factors. However, the literature on the subject is still scarce, and clinical studies providing robust evidence are even scarcer. In addition, some similar studies come to different conclusions. Dietary pattern can influence spermatogenesis by its content of fatty acids and antioxidants. Yet, in an age of industrialized mass food produc- tion, human bodies become more exposed to the ingestion of xenobiotics, as well as chemicals used for production, preserva- tion, transportation and taste enhancement of foods. We attempted in this paper to collect the available evidence to date on the effect of nutritional components on male fertility. Material and methods: A systematic search of the relevant liter- ature published in PubMed, ScienceDirect and Cochrane Central Register of Controlled Trials Database was conducted. Literature was evaluated according to the Newcastle-Ottawa- Scale. Results: Epidemiological observations are concordant in demon- strating an association of low-quality sperm parameters with higher intake of red meat, processed and organ meat and full- fat dairy. On the contrary, better semen parameters were observed in subjects consuming a healthy diet, rich in fruit, veg- etables, whole grains and fish. Evidences of the negative impact on male fertility of by-products of water disinfection, accumula- tion in food chain of persistent organochlorine pollutants, pesti- cides, phthalates from food and water containers and hormones used in breeding cattle have been reported. Clinical trials of the effects of micronutrients on semen parameters and outcomes of assisted fertilization are encouraging, although optimal modali- ty of treatment should be established. Conclusions: Although quality of evidence should be ameliorat- ed, it emerges that environmental factors can influence male fertility. Some nutrients may enhance fertility whereas others will worsen it. With diagnostic analysis on a molecular or even sub-molecular level, new interactions with micronutrients or molecular components of our daily ingested foods and leisure drugs may lead to a better understanding of so far suspected but as yet unexplained effects on male spermatogenesis and fertility. KEY WORDS: Male fertility; Nutrients; Micronutrients; Dietary supplements; Lifestyle; Xenobiotics. Submitted 13 April 2020; Accepted 20 April 2020 Summary No conflict of interest declared. DOI: 10.4081/aiua.2020.2.121 INTRODUCTION Male infertility is attracting increasing interest due to its worldwide prevalence and the evidence of decline in semen quality of young health men (1). Prevalence of reported male infertility ranges from 2.5% to 12% with highest rates in Africa and Central/Eastern Europe (2). Rates of male infertility in North America, Australia, and Central and Eastern Europe varied from 4.5-6%, 9%, and 8-12%, respectively. Male infertility is defined as the fail- ure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse as reported by couples or female partners of a couple. Seminal quality is a prognostic factor of fertility which can be considered a proxy of male infertility although fecun- dity also depends from other couple-based covariates (3). Along the last 50 years a progressive decrease of the qual- ity of the seminal parameters has been observed. A recent systematic review of 185 studies involving more than 40.000 men who provided semen analysis in the period 1973-2011 demonstrated a significant decline between 1973 and 2011 (4). This trend may arise from genetic, developmental and lifestyle factors. Particularly, involve- ment of nutritional factors has been highlighted by many studies. Cross-sectional population studies or case-control stud- ies using food questionnaires evaluated the association of dietary patterns or quality of foods with seminal parameters (count, concentration, motility, morphology, DNA fragmentation) or with testis volume or sex hor- mone levels. In addition, some studies from fertility clin- ics considered more robust outcomes such as implanta- tion rate, rate of clinical pregnancy and of live birth. Most of studies focused on the content of saturated fats that could have a negative impact on fertility or on the content of antioxidants and folates that could improve fertility. Molecular pathways of the effects of these nutri- ents in male fertility have been studied but they are not yet fully explained (Figure 1) (5-7). Saturated fats are prevalent in animal-derived foods as red meat, processed meat and full-fat dairy product while fats from vegetable foods and fishes are polyunsaturated. Sperm cell are characterized by a high content of polyun- saturated fatty acids, as docosahexaenoic acid (DHA). Concentrations of DHA with respect to saturated or trans fatty acids influence the melting point of plasmatic mem- brane, regulate the expression of peroxisome proliferator- activated receptor gamma (PPARG), anti-apoptosis and hormone activity. Particularly, omega-3 PUFAs in fish are precursors of eicosanoids, which contribute to sperm Archivio Italiano di Urologia e Andrologia 2020; 92, 2 M. Benatta, R. Kettache, N. Buchholz, A.Trinchieri 122 structure) and have a positive impact on testicular func- tion. On the contrary, trans saturated fats interfere with the incorporation of long-chain polyunsaturated fatty acids into sperm membranes during epididymal matura- tion, and have a negative impact on testicular function, with reduction in total and free testosterone. Antioxidants molecules, that are abundant in fruits and vegetables, have a positive effect on male fertility and in general on health conditions, by contrasting the activity of reactive oxygen species (ROS). ROS (reactive oxygen species) show a biphasic effect on sperm cell function, because at physiological concentra- tions ROS from mitochondria have an important role in capacitation by activation of different intracellular mech- anisms (high levels of cAMP, activating the PKA path- way, and leading to tyrosine phosphorylation). On the contrary, oxidative stress from excess ROS production causes peroxidation of lipids in the plasmatic membrane together with a damage of spermatic DNA. ROS have a negative effect on sperm motility by damaging plasmatic membrane and mitochondrial function. Folates are involved in DNA synthesis and in methyla- tion processes connected with protein synthesis. Folate deficiency causes instability and fragility of DNA by reducing availability of methylic groups that are a pro- tection factor of DNA. Other micronutrients are involved in the development of male infertility, as divalent cations such selenium, zinc or manganese that have a role in oxidative stress being incorporated in enzymes such as glutathione peroxidase or superoxide dismutase (8). Optimal levels are request- ed for spermiogenesis, whereas both deficiency and excess intake are associated with alterations of seminal parameters and serum testosterone levels. In addition to the effects of nutrients, food intake can be associated to exposure to food-contaminating toxic sub- stances or hormones that can have a relevant impact on male fertility. In an age of progressive industrialization, and moreover industrial mass food production using her- bicides, pesticides, antibiotics, hormones, and chemicals to preserve and enhance the taste of heavily processed foods, these components can be absorbed into the human body. Evaluation of the effects of toxic contamination of foods is difficult by using dietary question- naires whereas more reliable results can be obtained by using biological markers to evalu- ate exposure to toxic substances. The effects of the intake of some foods on seminal parameters can be biased by the con- comitant effect of contamination. By exam- ple, it is difficult to differentiate the impact of consumption of vegetables from that of pesti- cides that are used in agriculture or the effect of red meat from that of residual hormones that could have been used in breeding or that of fish consumption by the risk of contami- nation from sea water pollution. Finally, other information can be derived from the evaluation of the effect of the admin- istration of dietary supplements to ameliorate seminal parameters of subfertile men attend- ing fertility centres. In this paper, we tried to review and summarize the available evidence on the topic. Our results are subdi- vided in two chapters describing review of epidemiolog- ical observations and clinical studies respectively. METHODS A systematic search of the relevant literature published in PubMed, ScienceDirect and Cochrane Central Register of Controlled Trials Database was conducted. We reviewed separately epidemiological observations as reported in the literature and clinical trials with various nutritional com- ponents and their influence on male fertility. For this reason, two separate searches (up to December 2018) were done using a combination of terms as both, Medical Subject Headings (MeSH) and keywords. In the first search, male fertility-related keywords (“male fertility” OR “male infertility” OR “semen quality” OR “oligoas- thenozoospermia” OR “sperm DNA fragmentation” OR “sperm DNA damage” OR “sperm aneuploidy” OR “Y chromosome”) were used in combination with key words relating to food or nutrient (“food” OR “diet” OR “nutrition” OR “meat” OR “fish” OR “sugar” OR “vegetables” OR “fruits” OR “dairy” OR “genetically modified food” OR “alcohol” OR “pesticides” Figure 1. Molecular pathways of the effects of fatty acids and antioxidants in sperm cell (negative effect in red, positive in green). Figure 2. Systematic literature search 1. Figure 3. Systematic literature search 2. OR “hormone food contaminated” OR “tobacco” OR “cannabis”) and combined with ‘questionnaire’ (Limit: Human, English). Reviews, clinical trials and case reports were excluded (Figure 2). In the second search the same male fertility-related key- words were used in combination with key words relating to vitamin or micronutrient or herbal treatments (“seleni- um” OR “vitamin E” OR “coenzyme Q10” OR “zinc” OR “L- Carnitine” OR “folic acid” OR “L Arginine” OR “herbal”). (Limit: Human, English). Only clinical trials were included (Figure 3). The first search screened 103 studies, that were reduced to 38 after evaluation by title and abstract; 29 studies were retrieved by references of the selected studies; a total of 67 studies was assessed and 50 were included in the review. In the second search, the number of study screened, selected by title/abstract, retrieved by refer- ences, assessed and included were 79, 43, 14, 57 and 19 respectively. Information extracted from each study was charted including: first author's last name; year of publication; number of subjects; food or nutrients or dietary pattern studied. Literature was evaluated using the Newcastle- Ottawa-Scale and evaluation forms. A narrative review of the data from the included studies was done. RESULTS Epidemiological observations Nutrition and lifestyle are considered by several authors as main factors in reproduction and fertility (9-11). Recent studies indicate that male obesity (12), as well as lifestyle factors as smoking and alcohol intake affect neg- atively the sperm quality (13). Diet plays a key role in the improvement of sperm parameters, particularly the Mediterranean diet which is rich in omega 3 fatty acids, antioxidants and vitamins (vitamin E, vitamin C, beta-carotene, lycopene, cryptox- anthin, lutein) that all are associated with better semen 123Archivio Italiano di Urologia e Andrologia 2020; 92, 2 Male fertility and nutrition Table 1. Vitamin, mineral and antioxidant intake and sperm quality. Archivio Italiano di Urologia e Andrologia 2020; 92, 2 M. Benatta, R. Kettache, N. Buchholz, A.Trinchieri 124 quality parameters (Table 1) (14-18). A better compli- ance with Mediterranean diet was found to be associated with better semen quality parameters (sperm concentra- tion, count, and motility) (19). Similarly, in non-Mediterranean Countries, the so called “Prudent” or “Health Conscious” diets, involving high intakes of fruits, vegetables, legumes, fish and whole grains, were related to better sperm quality than “Western” diet that is rich in red and processed meat, refined grains, high-ener- gy drinks and sweets (Table 2) (20-24). Higher intakes of seafood, poultry, whole grains, fruits and vegetables have been consistently associated with better semen parameters in a wide range of studies in North America, Europe, the Middle East and East Asia. (Table 3) (10, 19-27). A recent review concluded that diets rich in red and processed meats, potatoes, sweets and sweetened beverages were associated with decreased quality of semen parameters whereas higher intakes of fruits and vegetables, whole grains, seafood and poultry had the opposite effect (34). Soy foods have been inversely associated with the quality of semen in some studies (35) although soy food intake in men was not related to outcomes of in vitro fertilization in couples undergoing infertility treatment (36). The intake of trans and saturated fats has been related to poor semen quality. Trans-saturated fat intake has also been related to other markers of poor testicular function, such as lower testosterone and lower testicular volume (37-40) (Table 4). On the contrary, omega-3 polyunsat- urated fats were associated with better seminal parame- ters and testicular volume (37, 40). Table 2. Dietary patterns and sperm quality. 125Archivio Italiano di Urologia e Andrologia 2020; 92, 2 Male fertility and nutrition Critical appraisal of this evidence highlights some possi- ble limitations. In most cross-sectional studies popula- tions were numerically limited and not always represen- tative of the general population. Many studies were per- formed on volunteers recruited among university stu- dents aged 18 to 23 years, whereas other studies consid- ered men from couples who attended fertility clinics. Translation of these results to the general population might be questionable. Only a few studies have been car- ried out in numerically consistent populations represent- ing the general population (23, 38). Similarly, case-con- trol studies were performed by comparing the dietary intakes of men from couples attending fertility clinics with and without alterations of seminal parameters. Alcohol and caffeine Alcohol induces testicular atrophy and alterations of Leydig and Sertoli cells and decrease luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels (41). Daily consumption of alcohol affects sperm quality and decreases ejaculate volume, sperm counts, and sperm motility. Comparing the sperms of 66 "alcoholic" men to Table 3. Foods and sperm quality. Archivio Italiano di Urologia e Andrologia 2020; 92, 2 M. Benatta, R. Kettache, N. Buchholz, A.Trinchieri 126 those of 30 "non-alcoholic" men, there was a significant decrease in sperm count, progressive mobility, and vitali- ty (42). Chronic high consumption of alcohol (more than 60 g per day or 6 glasses of wine) can lead to azoospermia (43). There is a significant inverse relationship between alcohol consumption and sperm concentration, sperm count and percentage of typical spermatozoids. Stopping consumption would restore normal spermatogenesis and azoospermia secondary to alcohol (44). A meta-analysis confirmed that alcohol has a detrimental effect on semen parameters although spermatogenesis seemed to be not affected by a moderate consumption (45). Another meta-analysis of the effects of alcohol on in vitro fertilization (IVF) showed that live birth rates are sig- nificantly reduced when humans consume alcohol even in lower doses in the month or even the week before attempted fertilization. Excessive consumption of alcohol must be avoided in humans during the attempted medical assisted fertilization, but a moderate consumption (one or two glasses of wine per day) might also have an opposite effect on the spermatic characteristics and the results of the medical assisted procreation attempt (46). A systemat- ic review of the effects of coffee and caffeine intake on semen parameters found inconsistent evidences and con- flicting results, although some studies showed a possible association with sperm DNA damage (47). Food and water contamination Most of the literature on the effect of water and food con- taminants on male infertility is derived from experimental Table 4. Dietary fats and semen quality. Table 5. Water and food contaminants and male infertility. 127Archivio Italiano di Urologia e Andrologia 2020; 92, 2 Male fertility and nutrition animal studies or studies of acute occupational exposure. Evidence of the effects in the general population of chron- ic low-dose exposures is limited because of the complexi- ty of the design of the studies. Levels of biological mark- ers of exposure have been correlated with seminal and hormone parameters in general population. Available data has been reviewed by Gabrielsen and Tanrikut (8). In Table 5 we summarized evidences about water and food con- taminants that could affect male fertility. Food contaminants often induce endocrine disorders, as in the case of commonly used glyphosate-based herbicides that act as a disruptor of mammalian cytochrome P450 aromatase activity from concentrations 100 times lower than the recommended use in agriculture and can also affect aromatase gene expression (48). Endocrine disor- ders can also be induced by the presence of residual hor- mones in red meat and processed meat. In some countries anabolic sex steroids are administered to cattle for growth promotion resulting hormone residues in beef. Although the possible biological significance of very low levels of estradiol is neglected, residual hormones are one possible explanation of lower semen quality parameters observed in consumers of processed or red meat (49). On the other hand, maternal beef consumption, and possibly xenobi- otics in beef may alter testicular development in utero and adversely affect offspring reproductive capacity (50). Despite a lack of human studies, a link between infertility and genetically modified foods (GMF) has been postulated although GMF-related infertility seems to affect women more than men (51). Tobacco Smokers have an unusually high concentration of heavy metals in the seminal fluid, such lead and cadmium that are negatively correlated with sperm concentration, mobility and morphology (52). On the other hand, high levels of trans-3’-hydroxycotinine (3HC), a metabolite of nicotine, in seminal fluid are correlated with a decreased sperm mobility (53). The seminal plasma analysis of smokers shows a significantly higher proportion of inflam- matory proteins. In fact, smoking seems associated with an inflammatory state of the accessory glands, which would eventually cause an alteration of the functional quality of spermatozoids, a decrease of acrosome integrity and mitochondrial activity, and an increased DNA frag- mentation (54). Sperm concentration, total motility, and the number of typical spermatozoids is reduced in smok- ers (55). Tobacco also affects the intrinsic quality of spermatozoids. The analysis of the degree of fragmentation of sperm DNA showed a significantly higher fragmentation of DNA in smokers than in non-smokers (32% against 25.9%) (56). In an in-vitro fertilization trial, smoking among men was significantly and positively correlated with an increased risk of early spontaneous abortion (OR = 2.2) (57). Paternal smoking can also influence the health of new- borns by transmission of DNA damaged by oxidative stress. Alterations of the methylation of sperm DNA in male smokers are compatible with alterations observed in their offspring (58). In addition, de-novo mutations in paternal spermatozoids induced by smoking can be transmitted (59). Cannabis After consumption of cannabis, its metabolites are found in the seminal fluid, and spermatozoa are thus exposed during their passage through the epididymis (60). Cannabis interferes with spermatogenesis by central and peripheral mechanisms. The stimulation of receptors coupled to G protein inhibits adenylate cyclase levels decreasing cAMP levels in testicular tissue, spermatozoa, and hypothalamus. Cannabis blocks the hypothalamic release of GnRH and the anterior pituitary production of LH. Furthermore, it reduces the release of testosterone from Leydig cells via specific receptors (61). In a large sample of the general male population of Denmark, there was a significant negative correlation between cannabis consumption and sperm concentra- tion, count, and mobility. In case of regular exposure to cannabis (9 to 18 cannabis joints a week) a decrease in sperm concentration was observed with a significant negative correlation between the amount of cannabis consumed and the sperm count. Chronic and intensive use of cannabis (more than 10 cannabis joints per week) was also associated with an alteration of Leydig cell func- tion resulting in a significant dose-dependent decrease in testosterone serum levels (62). In conclusion, cannabis use should be considered as a potential cause of alter- ation of spermatogenesis or a co-factor aggravating pre- existing spermatogenesis disorders. Obesity Obesity is related to excessive intake of food and reduced physical activity. Oligospermia is more frequent in obese men and in obesity an increase in DNA fragmentation was also described (63). Multiple interdependent mechanisms contribute to the negative effect of obesity on male fertility (64). Obesity is associated to alterations of the hypothala- mic-pituitary axis because of various endocrine mecha- nisms such as production of estrogens by aromatization of testicular and adrenal androgens in excess adipose tissue, leptin resistance at kisspeptin neurons, and excessive pro- duction of endogenous opioids, leading to hypogo- nadotropic hyper-estrogenic hypogonadism. A significant decrease in free and total testosterone levels and a signifi- cant increase in estrogen levels are resulting, both con- tributing to alteration of spermatogenesis. The decrease in serum testosterone concentration is significantly associated with insulin resistance and a lower volume of ejaculate (65). Furthermore, obesity may directly alter spermatoge- nesis by its action on Sertoli cells, as suggested by the more severe decrease in inhibin B levels compared with the decrease in FSH. Finally, an increase in scrotal temperature caused by excessive testicular warming in the seated posi- tion may negatively affect spermatogenesis. Clinical trials Several interventional studies evaluated the effect of dietary supplementation on semen parameters of subfer- tile men or outcomes of assisted fertilization. Oral sup- plements include coenzyme Q10, L-Carnitine, vitamins, zinc and other antioxidants. Coenzyme Q10 A significant improvement of spermatogenesis was evi- Archivio Italiano di Urologia e Andrologia 2020; 92, 2 M. Benatta, R. Kettache, N. Buchholz, A.Trinchieri 128 dent with coenzyme Q10 therapy. Mean sperm concen- tration, sperm progressive motility, and rate of sperm with normal morphology improved significantly after 12 month of coenzyme Q10 therapy (66). A positive corre- lation was found between duration of Q10 treatment duration and sperm count, motility and morphology (67). Even the reduced form of coenzyme Q10 (ubiquinol) was significantly effective in men with unex- plained oligoasthenoteratozoospermia (68). L-Carnitine L-Carnitine (LC) together with acetyl-L-Carnitine (LAC) are commonly used because of their ability to improve sperm quality and pregnancy rate in males suffering from asthenoteratozoospermia (69). LC and LAC improve the total oxyradical scavenging capacity of the seminal fluid (70) and prevent DNA oxidation of human spermatozoa (71). Treatment with LC increased the success rate of intracytoplasmic sperm injection (ICSI) (72). In a double- blind randomized controlled trial, a combination of LC and coenzyme Q10 increased sperm motility and rate of progressively motile sperm more than LC or coenzyme Q10 alone or than In the control group. The percentage of sperm DNA fragments was markedly low and the rate of clinical pregnancy was remarkably higher in the com- bination group than in controls (73). Vitamin E Levels of vitamin E in seminal plasma are related to sperm motility (74). Accordingly, lower levels of vitamin E were observed in the semen of infertile men (75). A prospective, multi-centered, randomized controlled study reported that vitamin E can improve sperm con- centration, percentage of progressively motile sperm, and rate of natural pregnancies (76). Zinc and folic acid The zinc concentration of seminal plasma is significantly higher in fertile men in comparison to subfertile men (77). In a study, supplementation with zinc sulphate and folic acid did not ameliorate sperm functional parame- ters in oligoasthenoteratozoospermic men (78), whilst in another double-blind, placebo-controlled interventional study the total normal sperm count increased after a combined zinc sulfate and folic acid treatment in both subfertile and fertile men (79). Combination treatment A double-blind placebo-controlled study (80) using sup- plementation of L-carnitine, fumarate, acetyl-L-carnitine, Fructose, CoQ10, vitamin C, zinc, folic acid and vitamin B12 reported an increase of sperm concentration, total motil- ity and pregnancy rate in couples whose males had varic- ocele or not. No difference of semen volume and not sig- nificant improvement of progressive motility were observed. Another double-blind, multi-center, random- ized controlled trial showed that a combination of antiox- idants and vitamins (vitamin C, vitamin D3, vitamin E, folic acid, zinc, selenium, L-carnitine) did not improve semen parameters or DNA fragmentation in infertile men (81). An evidence-based review of randomized trials conclud- ed that antioxidant supplements are beneficial in improving semen quality and clinical pregnancy rates for men from couples undergoing infertility treatment (82). More recent meta-analyses confirmed the positive results of the administration of antioxidants in subfertile men, although the poor quality of the studies considered in their analyses was highlighted. A Cochrane meta-analysis considered 61 randomized clinical trials (RCTs) with a total population of 6000 sub- fertile men of couples attending a reproductive clinic to evaluate the effect of the oral administration of a wide range of 18 antioxidants on assisted reproductive tech- niques outcomes pregnancy or live birth rate (83). Only few small studies reported on pregnancy or live birth rate. Use of antioxidants increased, the chance of clinical pregnancy from an estimated baseline of 7% following placebo or no treatment to a 12% to 26% rate after antiox- idants (OR = 2.97). Live birth rate after antioxidants ranged between 14 and 26% whereas a 12% rate was observed after placebo or no treatment (OR = 1.79). Most studies were rated as 'low' to 'very low' quality with high heterogeneity and serious risk of bias (poor report- ing of methods of randomisation, unclear or high attri- tion, low event rates and small sample sizes). In another meta-analysis of 7 studies (84) a significant improvement of semen parameters (count, motility, morphology) was shown after administration of selenium (200 µg/day and 100 µg/day), combination of ), L-carni- tine (2 g/day) and acetyl-L-carnitine (LAC; 1 g/day) and co-enzyme Q10 (200 and 300 mg/day). Information of the effect on pregnancy rate was not obtained because it was evaluated in a limited number of trials. The system- atic review of other trials identified promising results for supplementation with zinc combined with folic acid, eicosapentaenoic acid and docosahexaenoic acid. Phytotherapeutica A poly-herbal formulation (a combination of the roots of Chlorophytum borivilianum, seeds of Mimosa pudica, sap of Acacia Senegal, root of Astragalus membranaceus, seed coat of Plantago ovate, sap of Bombax ceiba, root of Eurycoma longifolia and rocky candy) was tested for its effect on the spermatogenic potential in oligospermic patients. After 90 days, there was a 256% increase in sperm concentration, a 154% increase in semen volume and a 215% increase in sperm motility, respectively (85). REFERENCES 1. Winters BR, Walsh TJ. The epidemiology of male infertility. Urol Clin North Am. 2014; 41:195-204. 2. Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015; 13:37. 3. Levine H, Jergensen N, Martino-Andrade A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. 2017; 23:646-659. 4. Buck Louis GM, et al. 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Smits RM, Mackenzie-Proctor R, Yazdani A, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019; 3:CD007411. 84. Buhling K, Schumacher A, Eulenburg CZ, Laakmann E. Influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review. Reprod Biomed Online. 2019; 39:269-279. 85. Hussain SA, Hameed A, Nasir F, et al. Evaluation of the sper- matogenic activity of polyherbal formulation in oligospermic males. BioMed Research International 2018; 2018:2070895. . . Correspondence Mahmoud Benatta benatta.mahmoud@gmail.com Dept. of Urology, Djilali Lyabes University Hospital, Sidi Bel Abbes/Algeria Redha Kettache kettacher@gmail.com Dept. of Urology, EPH Bachir Bennacer, Biskra/Algeria Noor Buchholz (Corresponding Author) scientific-office@u-merge.com noor.buchholz@gmail.com U-merge Scientific Office 21 Athens/Greece Alberto Trinchieri alberto.trinchieri@gmail.com U-merge Scientific Office