Abstract
Content:
Dietary supplements (DS) for male infertility marketed in Italy were evaluated for composition, concentration of ingredients, and recommended daily dose. A systematic review of literature identified ingredients potentially effective on sperm parameters and their minimal effective daily dose (mED).
Objective:
This study was conducted in order to critically evaluate the composition and efficacy of DS marketed in Italy.
Design, Setting, and Participants:
This was a systematic review of randomized controlled trials.
Evidence Acquisition:
A formula allowed us to classify the expected efficacy of each DS, based on composition. Each DS was scored and included into three classes of expected efficacy: high, low, and none.
Evidence Synthesis:
Among 24 supplements, 3 (12.5%) fall in high, 9 (37.5%) in lower, and 12 (50.0%) in no expected efficacy class. DS composition showed 36 substances, 18 with no literature on male fertility and 18 showing positive effect on sperm parameters, thus considered potentially active ingredients (PAI). All DS were mixtures of ingredients, containing from 2 to 17 different substances. Fifteen supplements (65.2%) contained at least 1 ingredient without evidence of efficacy and 21 formulations had PAI dosed below mED. Some PAI were associated to the improvement of specific sperm parameters.
Conclusions:
DS were usually blends of many substances that are frequently employed at negligible dose or without any evidence of efficacy on male reproduction. Some ingredients have been demonstrated to be effective on specific sperm parameters by RCTs. We report a list of ingredients with potential efficacy on specific sperm parameters, aimed to allow a tailored use of DS.
Patient Summary:
The market of DS for male infertility offers products with potential efficacy in the improvement of sperm parameters but also many with uncertain effects. Based on current scientific literature, our study can help in the choice of DS that are more likely to be effective on specific sperm alterations, so providing the best supplementation for each patient.
Introduction
Male factor infertility accounts the most varied and multifactorial causes (, ). Besides idiopathic infertility (up to 25% of cases), organic causes range from genital tract infections/inflammation, hormonal alterations, varicocele, and genetic problems (–). Many recent studies emphasized the role of other risk factors such as incorrect lifestyles, malnutrition, and abuse substances (, ). The hypothesis is that these conditions, inducing an elevation of radical oxygen and nitrogen species, might impair spermatogenesis, both directly, through an alteration of a redox status, and indirectly, interfering with the hypothalamic–pituitary–testicular axis (–). A recent survey performed by American urologists on clinical practice in the treatment of idiopathic male infertility showed that 64.9% of caregivers use dietary supplements (DS), empirically in the face of a lack of recommendations on the guidelines for the use of these products (). The European Food Safety Authority (EFSA) stated that “supplements aren’t intended to treat or prevent diseases in humans or to modify physiological functions, but only to support specific physiological functions” (). Anyway, all meta-analyses and guidelines citing the use of DS for male infertility advise to carefully evaluate the causes of infertility, as well as to accurately assess nutritional status (, ).
The term “nutraceutical” is not defined by law and products that fall into this category are mainly contained in the DS (, ). In recent years, a growing use of nutraceutical products has been recorded among men seeking fertility or complaining other andrological problems (, ). DS are widely available on the market, even if a proven efficacy has not yet been demonstrated for most of them. Despite many authors showing the positive effects of some substances on semen parameters and fertility outcomes (–), many others reported the lack of efficacy and even potential side effects (, ). We recently summarized the state-of-the-art of single ingredients currently present in the DS marketed to improve sperm parameters (). The main conclusion was that some DS were mixtures of ingredients with uncertain or unreported benefits and contained substances with very low dosage.
Despite these attempts to clarify the specific role of each ingredient, several confounding factors make difficult and still empirical the choice of the proper formulation for each patient at the right time, in a perspective of personalized medicine. This is due to several issues: i) prescribers rarely know the nutritional state of the patient before administering a nutraceutical product; ii) it is still unclear which infertile patient may have beneficial effects from nutraceutical substances; iii) many supplements are available as mixtures of different substances, confounding the effects of individual components; iv) in different products, the same substance is often present at different doses; and vi) patients who are likely to have a condition of oxidative stress could find benefit from the use of substances with an antioxidant effect.
However, it still incompletely known which molecule reaches the testis, at which dose, and sometimes the molecular mechanism of action ().
The aim of this study was to evaluate the potential efficacy of each DS using an adapted version of the scoring system by the American Heart Association. In particular, the effect of any ingredients was evaluated according to semen alterations.
Evidence Acquisition
Systematic Review of Literature
We performed the present review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement ().
On the website of the Italian Ministry of Health, we found 23 supplements marketed for male infertility (). Two investigators (GP and GG) performed a systematic electronic search on Google Scholar, Embase, MEDLINE, and Cochrane Register of Controlled Trials since 2000 until September 30, 2021. The following search strategy was used: (“name of each active ingredient” AND (“supplements” OR “nutraceuticals”) AND (“fertility” OR “male reproduction” OR “semen parameters”). The references of retrieved articles together with the proceedings of relevant conferences were hand-searched in order to identify other potentially eligible studies for inclusion in the analysis missed by the initial search or any unpublished data. The literature search, assessment of inclusion and exclusion criteria, quality of studies, and extraction of data were independently undertaken and verified by two investigators (AG and FF-P). The results were then compared, and in case of discrepancies, a consensus was reached with the involvement of a third senior investigator (AV). There was no language restriction applied.
We considered as eligible only randomized clinical trials (RCTs) evaluating substances included in DS marketed for male infertility. Figure 1 displays the flow diagram of the selection of eligible papers.
Figure 1
To ascertain the certainty of evidence, the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used ().
Definition of Potential Active Ingredients and Minimal Effective Daily Dose
Selected articles allowed us to identify potential active ingredients (PAI) that were substances with a reported efficacy on at least one sperm parameter (sperm count, motility, morphology, DNA damage, etc.). The minimal effective daily dose (mED) was considered as the lowest effective dose reported in RCTs for each PAI, able to improve at least one sperm parameter.
Formula to Score DS
In our previous paper (), we suggested a formula derived from the study by Kuchakulla et al. () to evaluate the possible efficacy of DS based on their composition. We included both papers evaluating effective and ineffective ingredients in the improvement of sperm parameters aimed to better weigh the possible efficacy of each single molecule. The used formula was conceived as follows: ingredients contained in each supplement were classified into four categories (A, B, C, or D) based on the reported efficacy and suggested daily dose. An ingredient was assigned to category A if multiple randomized control trials showed a net positive impact, level B if just one positive RCT was found, level C if multiple RCTs showed opposing results in an indeterminate outcome, and level D if RCT showed no or even negative effect. Once a category was designated to each ingredient, a score was assigned: A = 5, B = 3, C = 1, D = −1. Subsequently, the scores were designated to each of the supplements depending on their respective composition: briefly, the score of each ingredient constituting the supplement (i.e., A = 5, B = 3, C = 1, D = −1) was summed.
Then this score was weighted for the total number of ingredients in the supplement (N). Finally, in order to reward those supplements with only class A and B ingredients, the relative score was multiplied by the number of class A ingredients plus half the number of class B ingredients, finally resulting in the final score of the supplement.
Given the distribution of the scores resulted in three main clusters, we classified DS into three categories, resembling the potential efficacy of the ingredients: high expected efficacy (corrected score ≥ 3), low expected efficacy (1 > corrected score < 3), and no expected efficacy (corrected score ≤ 1). To obtain the whole list of DS, actually marketed in Italy for male infertility, we referred to the register available on the website of the Italian Ministry of Health, updated to 01/03/2020 [23].
Evidence Synthesis
Among the 1,731 studies for initial examination, we identified 164 eligible papers in our systematic literature search following the exclusion of duplicate publication, after screening of the title and the abstract sections of the paper. Among those, we found that only 45 RCTs reporting their efficacy on sperm parameters were retrieved as full text, in order to be included in the systematic review (Figure 1).
DS Evaluation Based on Literature and Results
The analysis of literature allowed us to evaluate the potential efficacy of ingredients. We found 18 ingredients active on at least one sperm parameter and other 18 substances without any evidence. The list of PAI, references, effect on evaluated sperm parameters, and employed daily doses are summarized in Table 1. In the last column, the mED with demonstrated efficacy of each substance is reported. In some studies, marked with an asterisk, the employed daily dose of ingredients (zinc and α-tocopherol) exceeded the UL.
Table 1
| Active Ingredients | References | Evaluated Sperm Parameters | Employed Daily Dose | Number Included Patients | Minimal Effective Dose (mED) |
|---|---|---|---|---|---|
| Zinc—C/D | ()* | ↑ Motility | 66 mg | 211 | 66 mg |
| ()* | ↑ Concentration | 66 mg | 87 | ||
| ()* | ↑ Morphology | 66 mg | 160 | ||
| ()* | ↑ Motility/DNA integrity | 400 mg | 47 | ||
| () | ↓ DNA integrity | 30 mg | 2,370 | ||
| () | ↔ No effect | 220 mg | 83 | ||
| Selenium—B/C | () | ↑ Motility | 100 µg | 69 | 100 µg |
| () | ↑ Concentration/motility | 200 µg | 468 | ||
| () | ↔ No effect | 300 µg | 42 | ||
| Vitamin B12—A/B | () | ↑ Count | 25 µg | 23 | 25 µg |
| () | ↑ Count | 1,500 µg | 375 | ||
| () | ↑ Count | 6,000 µg | 39 | ||
| Folic acid—C/D | () | ↑ Count/motility | 400 µg | 194 | 400 µg |
| () | ↑ Volume/motility | 500 µg | 211 | ||
| () | ↑ Count | 500 µg | 87 | ||
| () | ↓ DNA integrity | 500 µg | 2,370 | ||
| () | ↔ No effect | 500 µg | 83 | ||
| L-arginine—A/B | () | ↑ Progressive motility | 1.4 g | 50 | 1.4 g |
| () | ↑ Concentration/motility | 1.4 g | 50 | ||
| L-citrulline—B/C | () | ↑ Volume/concentration ↑ Motility/vitality | 1.2 g | 50 | 1.2 g |
| α-Lipoic acid—B/C | () | ↑ Count/motility | 600 mg | 44 | 600 mg |
| L-carnitine—B/C (LC/LAC) | () | ↑ Motility | 1 g LC | 212 | 1 g LC |
| () | ↑ Count/motility | 2 g LC | 30 | ||
| () | ↑ Concentration/motility | 2 g LC | 100 | ||
| () | ↑ Motility | 3 g LC | 60 | ||
| () | ↔ No effect | 2 g LC + 1 g LAC | 21 | ||
| N-acetyl cysteine—A/B (NAC) | () | ↑ Motility/DNA integrity | 600 mg | 120 | 600 mg |
| () | ↑ Motility/morphology | 600 mg | 468 | ||
| Coenzyme Q10—C/D | () | ↑ Motility | 200 mg | 47 | 200 mg |
| () | ↑ Count/motility | 200 mg | 228 | ||
| () | ↑ Concentration/morphology | 300 mg | 212 | ||
| () | ↔ No effect | 200 mg | 47 | ||
| Astaxanthin—B/C | () | ↑ Motility | 16 mg | 30 | 16 mg |
| D-aspartic acid—B/C (DAA) | () | ↑ Count/motility | 2.6 g | 60 | 2.6 g |
| Tribulus terrestris DE—B/C | () | ↑ Count/motility | 750 mg | 66 | 750 mg |
| () | ↑ Morphology/motility | 1,500 mg | 30 | ||
| () | ↑ Count/motility | 6,000 mg | 63 | ||
| () | ↔ No effect | 750 mg | 30 | ||
| Inositol—A/B | () | ↑ Count/motility | 4 g | 194 | 4 g |
| () | ↑ Count | 4 g | 62 | ||
| α-Tocopherol—C/D | () | ↑ Motility/morphology | 20 mg | 47 | 20 mg |
| () | ↑ Motility/lipid stability | 300 mg | 87 | ||
| () | ↑ DNA integrity | 1,000 mg | 64 | ||
| () | ↔ No effect | 300 mg | 50 | ||
| () | ↔ No effect | 600 mg | 30 | ||
| () | ↔ No effect | 800 mg | 31 | ||
| Vitamin C—B/C | (63) | ↑ Concentration/motility | 0.5 g | 115 | 0.5 g |
| () | ↑ DNA integrity | 1 g | 64 | ||
| () | ↔ No effect | 1 g | 31 | ||
| EPA + DHA—B/C | (64) | ↑ Concentration/motility | 0.72 g + 0.48 g | 238 | DHA 0.48 g |
| (65) | ↑ DNA integrity | 0.12 g + 1 g | 46 | ||
| (66) | ↑ DNA integrity | 1.5 g DHA | 74 | ||
| (67) | ↔ No effect | 400/800 mg DHA | 28 | ||
| Lycopene—B/C | (68) | ↑ Count/motility | 25 mg | 44 | 25 mg |
Active ingredients with evidence of potential efficacy, class of expected efficacy, references, efficacy on sperm parameters, employed daily dose, and minimal effective dose (mED).
The letters (A/B/C/D) after each active ingredient refer to the categories of the reported efficacy. In the various supplements, they can get the highest or lowest category, respectively, based on whether they are present reaching the mED or not.
LC, L-carnitine; LAC, acetyl L-carnitine; EPA, eicosapentaenoic acid; DE, dry extract; DHA, docosahexaenoic acid; ↑, improved; ↔, no effect; ↓, employed. Ingredients in bold have only studies showing positive effect.
*Employed daily dose of ingredients exceeded the UL.
Excluding astaxanthin, D-aspartic acid, and lycopene, each having just one reference, the evidence of efficacy of the other ingredients was supported by at least two RCTs. Half of the PAI had at least one study showing no or even negative effects on sperm parameters. Regarding zinc, folic acid, CQ10, and α-tocopherol, we found more than one study showing no or even negative effects.
In particular, for α-tocopherol, we found six studies: three showed a positive effect and three showed no effect. Nine ingredients (evidenced in bold in Table 1) were evaluated only in studies showing a positive effect. However, five substances of this group had just one paper supporting their efficacy.
The characteristics of the 23 DS are summarized in Table 2. In this table, compositions, recommended daily dose for each ingredient, grade of evidence, and score of efficacy are reported for each DS. A total of 36 ingredients were used by manufacturers in the DS. All the evaluated supplements were mixtures ranging from 2 up to 17 substances. Fifteen out of 23 supplements (65.2%), marked with an asterisk, contained at least 1 ingredient without evidence of efficacy on sperm parameters (evidence by cursive in Table 2). In 21 formulations, there were ingredients dosed below mED. In particular, one supplement (DS 12) counted 17 ingredients, of which 7 were without proven efficacy and 13 dosed below mED. Two DS (2 and 21) contained only ingredients with demonstrated efficacy and satisfying mED. DS 9 had the zinc dosed at the UL (40 mg/day). Among the DS, the most used ingredient was zinc, followed by selenium, arginine, coenzyme Q, folic acid, and carnitine. These six molecules were used in more than 60% of formulations.
Table 2
| Active Ingredients | DS 1 | DS 2 | DS 3* | DS 4* | DS 5* | DS 6* | DS 7 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| S = 0.8 | S = 1.5 | S = 1.9 | S = 0.2 | S = 2.8 | S = 0.8 | S = 2.7 | ||||||||
| Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | |
| Zinc | 7.5 mg | D | 10 mg | D | 12.5 mg | D | 1.5 mg | D | 13 mg | D | ||||
| Selenium | 60 µg | C | 83 µg | C | 30 µg | C | 55 µg | C | ||||||
| Vitamin B12 | 33 mg | A | ||||||||||||
| Folic acid | 200 µg | D | 400 µg | C | 400 µg | C | 200 µg | D | ||||||
| L-arginine | 100 mg | B | 1,000 mg | B | 2,500 mg | A | 125 mg | B | 30 mg | B | ||||
| L-citrulline | ||||||||||||||
| α-Lipoic acid | 50 mg | C | ||||||||||||
| L-carnitine | 1,000 mg | B | 200 mg | C | 30 mg | C | ||||||||
| N-acetyl cysteine (NAC) | ||||||||||||||
| Coenzyme Q10 | 10 mg | D | 200 mg | C | 10 mg | D | 200 mg | C | 7.5 mg | D | ||||
| Astaxanthin | 15 mg | C | ||||||||||||
| D-aspartic acid (DAA) | 2,660 mg | B | ||||||||||||
| Tribulus terrestris DE | 800 mg | B | ||||||||||||
| Inositol | 1,000 mg | B | ||||||||||||
| α-Tocopherol | 30 mg | C | 12 mg | D | 30 mg | C | 36 mg | C | 30 mg | C | ||||
| Vitamin C | 60 mg | C | 180 mg | C | ||||||||||
| DHA | ||||||||||||||
| Lycopene | 15 mg | C | ||||||||||||
| Astragalus DE | 300 mg | D | ||||||||||||
| Damiana DE | ||||||||||||||
| Nettle DE | ||||||||||||||
| Catuba DE | ||||||||||||||
| Ecklonia bicyclis DE | ||||||||||||||
| L-taurine | 500 mg | D | ||||||||||||
| Glutathione | 30 mg | D | 40 mg | D | ||||||||||
| Glucosamine | ||||||||||||||
| SOD | 154 UI | D | ||||||||||||
| Vitamin D3 | ||||||||||||||
| Vitamin B1 | ||||||||||||||
| Vitamin B2 | 25 mg | D | ||||||||||||
| Vitamin B3 | 36 mg | D | ||||||||||||
| Vitamin B5 | ||||||||||||||
| Vitamin B6 | 9.5 mg | D | ||||||||||||
| Biotin | ||||||||||||||
| Manganese | ||||||||||||||
| Resveratrol | ||||||||||||||
| Active Ingredients | DS 8* | DS 9* | DS 10 | DS 11* | DS 12* | DS 13 | DS 14* | |||||||
| S = 0.90 | S = 0.80 | S = 1.50 | S = 0.75 | S = 0.70 | S = 5.60 | S = 2.50 | ||||||||
| Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | |
| Zinc | 40 mg | D | 12.5 mg | D | 10 mg | D | 15 mg | D | ||||||
| Selenium | 60 µg | C | 55 µg | C | 55 µg | C | 83 µg | C | ||||||
| Vitamin B12 | 2.5 µg | B | 5 µg | B | ||||||||||
| Folic acid | 800 µg | C | 400 µg | C | 200 µg | D | ||||||||
| L-arginine | 200 mg | B | 250 mg | B | 100 mg | B | 30 mg | B | ||||||
| L-citrulline | 800 mg | C | ||||||||||||
| α-Lipoic acid | 300 mg | C | 800 mg | B | ||||||||||
| L-carnitine | 200 mg | C | 400 mg | C | 500 mg | C | 30 mg | C | ||||||
| N-acetyl cysteine (NAC) | 300 mg | B | 600 mg | A | ||||||||||
| Coenzyme Q10 | 15 mg | D | 15 mg | D | 100 mg | D | 20 mg | D | 200 mg | C | ||||
| Astaxanthin | ||||||||||||||
| D-aspartic acid (DAA) | 80 mg | C | ||||||||||||
| Tribulus terrestris DE | 300 mg | C | ||||||||||||
| Inositol | 1,000 mg | B | 100 mg | B | 1,000 mg | B | 1,000 mg | B | ||||||
| α-Tocopherol | 30 mg | C | 120 mg | C | 30 mg | C | 30 mg | C | ||||||
| Vitamin C | ||||||||||||||
| DHA | ||||||||||||||
| Lycopene | 4 mg | C | ||||||||||||
| Astragalus DE | ||||||||||||||
| Damiana DE | ||||||||||||||
| Nettle DE | ||||||||||||||
| Catuba DE | 50 mg | D | ||||||||||||
| Ecklonia bicyclis DE | 200 mg | D | ||||||||||||
| L-taurine | ||||||||||||||
| Glutathione | 80 mg | D | ||||||||||||
| Glucosamine | 150 mg | D | ||||||||||||
| SOD | ||||||||||||||
| Vitamin D3 | ||||||||||||||
| Vitamin B1 | 1.1 mg | D | ||||||||||||
| Vitamin B2 | 1.4 mg | D | 2.8 mg | D | ||||||||||
| Vitamin B3 | 16 mg | D | ||||||||||||
| Vitamin B5 | 6 mg | D | ||||||||||||
| Vitamin B6 | 1.4 mg | D | 2.8 mg | D | ||||||||||
| Biotin | 100 µg | D | ||||||||||||
| Manganese | 2 mg | D | ||||||||||||
| Resveratrol | ||||||||||||||
| Active ingredients | DS 15* | DS 16 | DS 17* | DS 18* | DS 19 | DS 20* | DS 21 | |||||||
| S = 2.10 | S = 2.00 | S = 3.70 | S = 0.70 | S = 0.00 | S = 2.00 | S = 6.00 | ||||||||
| Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | |
| Zinc | 15 mg | D | 22.5 mg | D | 10 mg | D | 10 mg | D | 6.5 mg | D | 10 mg | D | ||
| Selenium | 50 µg | C | 80 µg | C | 50 µg | C | 55 µg | C | ||||||
| Vitamin B12 | 2.5 µg | B | 1.5 µg | B | ||||||||||
| Folic acid | 400 µg | C | 300 µg | D | 200 µg | D | 200 µg | D | 400 µg | C | ||||
| L-arginine | 2,500 mg | A | 200 mg | B | 30 mg | B | ||||||||
| L-citrulline | 3,000 mg | B | 200 mg | C | ||||||||||
| α-Lipoic acid | ||||||||||||||
| L-carnitine | 1,000 mg | B | 200 mg | C | 400 mg | C | 44.7 mg | C | ||||||
| N-acetyl cysteine (NAC) | 600 mg | A | ||||||||||||
| Coenzyme Q10 | 200 mg | C | 100 mg | D | 90 mg | D | ||||||||
| Astaxanthin | 16 mg | B | 10 mg | C | ||||||||||
| D-aspartic acid (DAA) | 1,000 mg | C | ||||||||||||
| Tribulus terrestris DE | ||||||||||||||
| Inositol | 50 mg | B | 500 mg | B | 4,000 mg | A | ||||||||
| α-Tocopherol | 40 mg | C | 30 mg | C | 12 mg | D | ||||||||
| Vitamin C | 80 mg | C | 100 mg | C | 180 mg | C | ||||||||
| DHA | 100 mg | C | ||||||||||||
| Lycopene | 10 mg | C | ||||||||||||
| Astragalus DE | ||||||||||||||
| Damiana DE | 400 mg | D | ||||||||||||
| Nettle DE | 300 mg | D | ||||||||||||
| Catuba DE | ||||||||||||||
| Ecklonia bicyclis DE | ||||||||||||||
| L-taurine | 300 mg | D | ||||||||||||
| Glutathione | 40 mg | D | 40 mg | D | ||||||||||
| Glucosamine | ||||||||||||||
| SOD | 150 mg | D | ||||||||||||
| Vitamin D3 | 3.75 µg | D | ||||||||||||
| Vitamin B1 | ||||||||||||||
| Vitamin B2 | ||||||||||||||
| Vitamin B3 | ||||||||||||||
| Vitamin B5 | ||||||||||||||
| Vitamin B6 | ||||||||||||||
| Biotin | ||||||||||||||
| Manganese | ||||||||||||||
| Resveratrol | ||||||||||||||
| Active Ingredients | DS 22* | DS 23* | DS 24 | |||||||||||
| S = 0.90 | S = 0.30 | S = 0.70 | ||||||||||||
| Daily Dose | EV | Daily Dose | EV | Daily Dose | EV | |||||||||
| Zinc | 15 mg | D | 15 mg | D | ||||||||||
| Selenium | 100 µg | C | 55 µg | C | ||||||||||
| Vitamin B12 | 5 µg | B | 2.5 µg | B | 7.5 µg | B | ||||||||
| Folic acid | 400 µg | C | 400 µg | C | 600 µg | C | ||||||||
| L-arginine | 415 mg | B | ||||||||||||
| L-citrulline | ||||||||||||||
| α-Lipoic acid | ||||||||||||||
| L-carnitine | 340 mg | C | ||||||||||||
| N-acetyl cysteine (NAC) | ||||||||||||||
| Coenzyme Q10 | 100 mg | D | 30 mg | D | ||||||||||
| Astaxanthin | 4 mg | C | ||||||||||||
| D-aspartic acid (DAA) | ||||||||||||||
| Tribulus terrestris DE | ||||||||||||||
| Inositol | ||||||||||||||
| α-Tocopherol | 60 mg | C | 12 mg | D | ||||||||||
| Vitamin C | 80 mg | C | 240 mg | C | ||||||||||
| DHA | 235 mg | C | ||||||||||||
| Lycopene | ||||||||||||||
| Astragalus DE | ||||||||||||||
| Damiana DE | ||||||||||||||
| Nettle DE | ||||||||||||||
| Catuba DE | ||||||||||||||
| Ecklonia bicyclis DE | ||||||||||||||
| L-taurine | ||||||||||||||
| Glutathione | 30 mg | D | ||||||||||||
| Glucosamine | ||||||||||||||
| SOD | ||||||||||||||
| Vitamin D3 | 25 µg | D | 5 µg | D | ||||||||||
| Vitamin B1 | ||||||||||||||
| Vitamin B2 | 1.4 mg | D | ||||||||||||
| Vitamin B3 | ||||||||||||||
| Vitamin B5 | ||||||||||||||
| Vitamin B6 | 1.4 mg | D | 4.2 mg | D | ||||||||||
| Biotin | ||||||||||||||
| Manganese | ||||||||||||||
| Resveratrol | 150 mg | D | ||||||||||||
List of dietary supplements (DS), their composition, and score of expected efficacy.
Ingredients without proven efficacy are in cursive.
S, score of the expected efficacy of the supplement; EV, efficacy value of active ingredients in relation to literature and achievement of mED; SOD, superoxide dismutase.
*DS containing at list one ingredient without evidence of efficacy.
In Figure 2, the distribution of supplements divided into three classes of expected efficacy based on their corrected scores is reported. Three out of 23 supplements (12.5%) resulted in the higher efficacy group and 9 (37.5%) in the lower efficacy group. The remaining 12 DS (50.0%) were expected to have no efficacy. In Table 3, active ingredients and DS were grouped based on the supposed efficacy on specific seminal targets (count, total motility, morphology, or DNA integrity). The most part of the ingredients showed a positive effect on sperm count and total motility. Interestingly, zinc showed evidence of efficacy on all the sperm parameters here considered. In the lower part of the table, DS were grouped in relation to their expected efficacy on specific sperm parameters, matching the corrected score and contained ingredients.
Figure 2
Table 3
| Effect on Sperm Parameters | ||||
|---|---|---|---|---|
| Count | Total Motility | Morphology | DNA Damage | |
| Active ingredients | Zinc Selenium Folic acid Vitamin B12 Folic acid L-citrulline L-arginine α-Lipoic acid L-carnitine C-Q10 DAA TT Inositol Vitamin C DHA Lycopene | Zinc Selenium Folic acid L-arginine L-citrulline α-Lipoic acid L-carnitine NAC C-Q10 Astaxanthin DAA TT Inositol α-Tocopherol Vitamin C Lycopene DHA | Zinc NAC Coenzyme Q10 TT α-Tocopherol | Zinc NAC α-Tocopherol Vitamin C DHA |
| Number of DS with evidence of efficacy on the parameters | 21; 14; 15 | 17; 14; 5 | 13; 17; 5 | 13; 17; 15 |
Effect of active ingredients on specific sperm parameters (in the lower part of the table, DS with higher expected efficacy on each sperm parameter are listed).
Discussion
The use of supplements in the enhancement of male fertility is as interesting and promising topic as it is still much debated. However, most trials used unsatisfactory methodology due to lack of a control group, lack of randomized and placebo-controlled well-designed study, use of many different doses of ingredients, evaluation of different outcomes, small number of included patients, etc. In fact, in the trials concerning male infertility, there is too much focus on the seminological characteristics without taking into consideration the female outcomes and also the pregnancy rate, which should always be our target (69, 70). Moreover, many clinical studies were sponsored and analyzed mixtures of many ingredients without evidence of clinical efficacy. However, these supplements are frequently prescribed in clinical practice to infertile patients, and sometimes, subjects seeking fertility spontaneously purchase these products since medical prescription is unnecessary (70). In 2019, the Italian market of supplements generated 3.7 billion euros, with an increase of +4.3% compared to 2018 (71).
In this study, we developed a new approach to evaluate DS marketed for male infertility. By a literature review, aimed to understand the clinical efficacy of each ingredient in the improvement of sperm parameters, we developed a new formula able to weigh the potential efficacy of DS. In a previous study (70), we used a similar approach to evaluate the DS for female infertility. Using the same formula, here, we included only RCTs both showing positive, none, and even negative effects of each ingredient. Moreover, we related the potential efficacy of substances on each sperm parameter. Using this method, we observed that the composition of DS marketed in Italy for male infertility is little supported by scientific evidence. In fact, most products evaluated in this study contained a huge number of ingredients, up to 17 different substances in the same supplement, frequently below the mED. A relevant issue consists in the presence of many ingredients at low dosages and/or without any evidence of efficacy. Some substances without evidence of efficacy in the literature, such as vitamin D3, taurine, B group vitamins, glucosamine, glutathione, various enzymes, and non-standardized dry herbal extracts, were widely present in DS for male infertility (69, 70). This evidence reflects the lack of knowledge in this field of reproductive medicine by manufacturers.
Several studies demonstrated that some substances such as omega 3 fatty acid, lycopene, and Tribulus have a positive effect on sperm parameters (sperm motility, number, morphology, DNA integrity, and mitochondrial function) (72–74). However, the mechanism of actions was documented for selenium (75), zinc (76, 77), and carnitine (78), but just supposed for other ingredients or still unknown in most cases. The synergistic effect of more ingredients can also be supposed. Therefore, the benefit that is obtained following the use of DS, which are always combinations of substances, is likely to be given by an overall synergistic effect. For example, the combinations of vitamin B12 and folic acid could have a positive effect on DNA integrity, able to improve homocysteine metabolism (79, 80).
Some ingredients, in particular amino acids, or their derivatives such as arginine and carnitine, were present in most DS aimed to improve sperm parameters and ameliorate spermatogenic process. However, these substances need to be administered at doses close to grams to be effective (81, 82). In contrast, our data demonstrate that ingredients are used even in doses 10 times below mED. In the case of arginine, the dosage should take into account the incomplete intestinal absorption and the liver metabolism which strongly reduce its bioavailability in the reproductive system (83, 84).
Using the new formula, proposed here, we scored, for the first time, the possible efficacy of each DS based on the number of ingredients, their reported or no reported efficacy, their effective or no effective dose, and their level of action at the seminal level. Only a few DS (3 products) resulted in the highest scoring level, while most products (21 DS) fell in the intermediate or lower level. This observation should be taken into account by manufacturers in order to align more and more the DS market according to scientific evidence to conceive more effective DS formulations. Despite actual literature could help to conceive better DS, it is largely insufficient to better drive clinicians on the tailored choice of the DS regarding the specific alteration of an infertile patient. This gap derives from the lack of accuracy in the diagnosis of infertility cause, observed in most clinical studies. In fact, their design often does not consider the cause that underlies sperm abnormalities. It is well known that the same sperm alteration can be induced by different causes (85). For example, a reduction of sperm motility is related both to testicular impairment, semen infections, or inflammation of accessory glands or varicocele (86). The same example can be performed for sperm count, morphology, DNA integrity, and other sperm parameters (87). For this reason, RCTs should be performed in populations of infertile patients stratified according to the etiology of infertility and not only based on seminal parameters. Moreover, to reach an effective dietary supplementation, aimed to improve sperm parameters, the mechanism of action and the effective dose of each ingredient should be clearly elucidated (88–90). With this aim, many and well-designed in-vitro and in-vivo studies are needed.
The choice to include in this review only evidence from RCTs was made in order to minimize bias in the critical evaluation of DS, in order to have for each active ingredient analyzed studies that have reported a positive effect but also studies that have shown a negative or no effect.
The main limitation of this study in the restricted focus of research on DS based on the Italian market, and the most analyzed RCTs are based on combinations of more than one substance, so it cannot be excluded that what is obtained is the result of an interaction (both positive and negative) between the different substances used together.
Conclusions
In the light of our findings, we raise three final considerations: i) the Italian market of DS for male infertility offers products with potential efficacy in the improvement of sperm parameters but also many with uncertain effects; ii) the actual literature is poor of well-designed studies on PAI investigating their mechanisms of action and effective dose in different pathological conditions; and iii) based on current literature, our study can help in the choice of DS and PAI that are more likely to be effective on specific sperm alterations.
Our critical analysis suggests a rational strategy for a tailored use of DS in male infertility.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author contributions
AG, GP, and FF-P contributed to the concept/design of the research and acquisition/analysis of the literature data. AG, GP, and FF-P equally contributed to and drafted the manuscript. AN contributed to the concept and performed the data analyses. LT, AV, GG, and CF critically revised the paper for important intellectual content. All authors revised and approved the final manuscript and agreed to be fully accountable for ensuring the integrity and accuracy of the work. All authors had full access to all the data in the study and took responsibility for the integrity of the study and the accuracy of the analysis.
Acknowledgments
The authors thank Dr. Marco Ghezzi for his helpful discussion.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
WintersBRWalshT. The Epidemiology of Male Infertility. Urol Clin North Am (2014) 41:195–204. doi: 10.1016/j.ucl.2013.08.006
2
DawsonEBHarrisWAPowellLC. Relationship Between Ascorbic Acid and Male Fertility. World Rev Nutr Diet (1990) 62:1–26. doi: 10.1159/000417532
3
ISS. Istituto Superiore Di Sanità. Available at: http://old.iss.it/rpma/ (Accessed January 3, 2021).
4
Salas-HuetosABullóMSalas-SalvadóJ. Dietary Patterns, Foods and Nutrients in Male Fertility Parameters and Fecundability: A Systematic Review of Observational Studies. Hum Reprod Update (2017) 23:371–89. doi: 10.1093/humupd/dmx006
5
SimonLMurphyKShamsiMBLiuLEmeryBAstonKIet al. Paternal Influence of Sperm DNA Integrity on Early Embryonic Development. Hum Reprod (2014) 29:2402–12. doi: 10.1093/humrep/deu228
6
LottiFMaggiM. Ultrasound of the Male Genital Tract in Relation to Male Reproductive Health. Hum Reprod Update (2015) 21:56–83. doi: 10.1093/humupd/dmu042
7
BanihaniSA. Vitamin B12 and Semen Quality. Biomolecules (2017) 9:7. doi: 10.3390/biom7020042
8
FerlinAForestaC. New Genetic Markers for Male Infertility. Curr Opin Obstet Gynecol (2015) 26:193–8. doi: 10.1097/GCO.0000000000000061
9
AlahmarAT. Role of Oxidative Stress in Male Infertility: An Updated Review. J Hum Reprod Sci (2019) 12:4. doi: 10.4103/jhrs.JHRS_150_18
10
WalczakJRWolskiJKSlowikowskaHJ. The Role of Oxidative Stress and Antioxidants in Male Fertility. Cent European J Urol (2013) 66:60–7. doi: 10.5173/ceju.2013.01.art19
11
CuiTKovellRCBrooksDCTerleckiRP. A Urologist’s Guide to Ingredients Found in Top-Selling Nutraceuticals for Men’s Sexual Health. J Sex Med (2015) 12:2105–17. doi: 10.1111/jsm.13013
12
EFSA. European Food Safety Authority (2021). Available at: http://data.europa.eu/eli/reg/2006/1924/2012-11-29/ (Accessed February 1, 2021).
13
CalogeroAEAversaALa VigneraSCoronaGFerlinA. The Use of Nutraceuticals in Male Sexual and Reproductive Disturbances: Position Statement From the Italian Society of Andrology and Sexual Medicine (SIAMS). J Endocrinol Invest (2017) 40:1389–97. doi: 10.1007/s40618-017-0699-6
14
EUR-Lex.Internet. Available at: https://eurlex.europa.eu/legalcontent/EN/ALL/?uri=celex%3A32002L0046 (Accessed August 2, 2021).
15
U.S Food & Drug Administration. Dietary Supplements Guidance Documents & Regulatory Information. Available at: https://www.fda.gov/food/guidance-documents-regulatory-information-topic-food-and-dietary-supplements/dietary-supplements-guidance-documents-regulatory-information (Accessed December 3, 2021).
16
HenkelRSandhuISAgarwalA. The Excessive Use of Antioxidant Therapy: A Possible Cause of Male Infertility? Andrologia (2019) 51:0303–4569. doi: 10.1111/and.13162
17
GarollaAPetreGCFrancini-PesentiFDe ToniLVitaglianoADi NisioAet al. Dietary Supplements for Male Infertility: A Critical Evaluation of Their Composition. Nutrients (2020) 12:1472. doi: 10.3390/nu12051472
18
SalasHARosiqueENBecerraTNVizmanosBBullóMSalasSJ. The Effect of Nutrients and Dietary Supplements on Sperm Quality Parameters: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Adv Nutr (2018) 9:833–48. doi: 10.1093/advances/nmy057
19
SanagooSOskoueiBSAbdollahiNGSalehiPHHazhirNFarshbafKA. Effect of Tribulus Terrestris L. @ on Sperm Parameters in Men With Idiopathic Infertility: A Systematic Review. Complement Ther Med (2019) 42:95–103. doi: 10.1016/j.ctim.2018.09.015
20
KuchakullaMSoniYPatelPParekhNRamasamyR. A Systematic Review and Evidence-Based Analysis of Ingredients in Popular Male Fertility Supplements. Urology (2019) 136:133–41. doi: 10.1016/j.urology.2019.11.007
21
MajzoubAAgarwalA. Antioxidant Therapy in Idiopathic Oligoasthenoteratozoospermia. Indian J Urol (2017) 33:207–14. doi: 10.4103/iju.IJU_15_17
22
PageMJMcKenzieJEBossuytPMBoutronIHoffmannTCMulrowCDet al. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. BMJ (2021) 372:71. doi: 10.1136/bmj.n71
23
Italian Ministry of Health. Available at: http://www.salute.gov.it/portale/temi/p26.jsp?id=3668&area=Alimenti%20particolari%20e%20integrat ri&menu=registri (Accessed October 3, 2021).
24
GuyattGOxmanADAklEAKunzRVistGBrozekJet al. GRADE Guidelines: 1. Introduction-GRADE Evidence Profiles and Summary of Findings Tables. Clin Epidemiol (2011) 64:383–94. doi: 10.1016/j.jclinepi.2010.04.026
25
WongWWYMerkusHHMWThomasCMMenkveldRZielhuisGASteegersTRP. Effects of Folic Acid and Zinc Sulfate on Male Factor Subfertility: A Double-Blind, Randomized, Placebo-Controlled Trial. Fertil Steril (2002) 77:491–8. doi: 10.1016/S0015-0282(01)03229-0
26
EbischIMPierikFHDe JongFHThomasCMSteegers-TheunissenRP. Does Folic Acid and Zinc Sulphate Intervention Affect Endocrine Parameters and Sperm Characteristics in Men? Int J Androl (2003) 29:339–45. doi: 10.1111/j.1365-2605.2005.00598.x
27
AzizollahiGAzizollahiSBabaeiHKianinejadMBaneshiMRNematollahi-mahaniSN. Effects of Supplement Therapy on Sperm Parameters, Protamine Content and Acrosomal Integrity of Varicocelectomized Subjects. J Assist Reprod Genet (2013) 30:593–9. doi: 10.1007/s10815-013-9961-9
28
OmuAAl-AzemiMKKehindeEOAnimJTOriowoMAMathewTC. Indications of the Mechanisms Involved in Improved Sperm Parameters by Zinc Therapy. Med Princ Pract (2008) 17:108–16. doi: 10.1159/000112963
29
SchistermanEFSjaardaLAClemonsTCarrellDTPerkinsNJJohnstoneEet al. Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. JAMA (2020) 323:35–48. doi: 10.1001/jama.2019.18714
30
RaiganiMYaghmaeiBAmirjanntiNLakpourNAkhondiMMZeraatiH. The Micronutrient Supplements, Zinc Sulphate and Folic Acid, Did Not Ameliorate Sperm Functional Parameters in Oligoasthenoteratozoospermic Men. Andrologia (2014) 469:956–62. doi: 10.1111/and.12180
31
ScottRMacPhersonAYatesRWHussainBDixonJ. The Effect of Oral Selenium Supplementation on Human Sperm Motility. Br J Urol (1998) 82:76–80. doi: 10.1046/j.1464-410x.1998.00683.x
32
SafarinejadMRSafarinejadS. Efficacy of Selenium and/or N-Acetyl-Cysteine for Improving Semen Parameters in Infertile Men: A Double-Blind, Placebo Controlled, Randomized Study. J Urol (2009) 181:741–51. doi: 10.1016/j.juro.2008.10.015
33
HawkesWCAlkanZWongK. Selenium Supplementation Does Not Affect Testicular Selenium Status or Semen Quality in North American Men. J Androl (2009) 30:525–33. doi: 10.2164/jandrol.108.006940
34
GoodhopeCD. The Treatment of Oligospermia With Stilbestrol and Vitamin B. Fertil Steril (1961) 12:469–73. doi: 10.1016/S0015-0282(16)34271-6
35
KumamotoYMarutaHIshigamiJKamidonoSOrikasaSKimuraMet al. Clinical Efficacy of Mecobalamin in the Treatment of Oligozoospermia—Results of Double-Blind Comparative Clinical Study. Hinyokika Kiyo (1988) 34:1109–32.
36
MoriyamaHNakamuraKSandaNFujiwaraESekoSYamazakiAet al. Studies on the Usefulness of a Long-Term, High-Dose Treatment of Methylcobalamin in Patients With Oligozoospermia. Hinyokika Kiyo (1987) 33:151–6.
37
CalogeroAEGulloGLa VigneraSCondorelliRAVaiarelliA. Myoinositol Improves Sperm Parameters and Serum Reproductive Hormones in Patients With Idiopathic Infertility: A Prospective Double-Blind Randomized Placebo-Controlled Study. Andrology (2015) 3:491–5. doi: 10.1111/andr.12025
38
StanislavovRNikolovaVRohdewaldP. Improvement of Seminal Parameters With Prelox: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Phytother Res (2009) 23:297–302. doi: 10.1002/ptr.2592
39
NikolovaVStanislavovRVatevINalbanskiBPŭnevskaM. Sperm Parameters in Male Idiopathic Infertility After Treatment With Prelox. Akush Ginekol (Sofiia) (2007) 46:7–12.
40
StanislavovRRohdewaldP. Sperm Quality in Men Is Improved by Supplementation With a Combination of L-Arginine, L-Citrullin, Roburins and Pycnogenol®. Minerva Urol Nefrol (2014) 66:217–23.
41
HaghighianHKHaidariFMohammadi-AslJDadfarM. Randomized, Triple-Blind, Placebo-Controlled Clinical Trial Examining the Effects of Alpha-Lipoic Acid Supplement on the Spermatogram and Seminal Oxidative Stress in Infertile Men. Fertil Steril (2015) 104:318–24. doi: 10.1016/j.fertnstert.2015.05.014
42
MehniMNKetabchiAAHosseiniE. Combination Effect of Pentoxifylline and L-Carnitine on Idiopathic Oligoasthenoteratozoospermia. Iran J Reprod Med (2014) 12:817–24.
43
PeivandiSAbasaliKNargesM. Effects of L-Carnitine on Infertile Men’s Spermogram; a Randomised Clinical Trial. J Reprod Infertil (2010) 10:331.
44
LenziALombardoFSgròPSalaconePCaponecchiaLDonderoFet al. Use of Carnitine Therapy in Selected Cases of Male Factor Infertility: A Double-Blind Crossover Trial. Fertil Steril (2003) 79:292–300. doi: 10.1016/S0015-0282(02)04679-4
45
BalerciaGRegoliFArmeniTKoverechAManteroFBoscaroM. Placebo-Controlled Double-Blind Randomized Trial on the Use of L-Carnitine, L-Acetylcarnitine, or Combined L-Carnitine and L-Acetylcarnitine in Men With Idiopathic Asthenozoospermia. Fertil Steril (2005) 84:662–71. doi: 10.1016/j.fertnstert.2005.03.064
46
SigmanMGlassSCampagnoneJPryorJL. Carnitine for the Treatment of Idiopathic Asthenospermia: A Randomized, Double-Blind, Placebo-Controlled Trial. Fertil Steril (2006) 85:1409–14. doi: 10.1016/j.fertnstert.2005.10.055
47
CiftciHVeritASavasMYeniEErelO. Effects of N-Acetylcysteine on Semen Parameters and Oxidative/Antioxidant Status. Urology (2009) 74:73–6. doi: 10.1016/j.urology.2009.02.034
48
NadjarzadehASadeghiMRAmirjannatiNVafaMRMotevalianSAGohariMRet al. Coenzyme Q10 Improves Seminal Oxidative Defense But Does Not Effect on Semen Parameters in Idiopathic Oligoasthenoteratozoospermia: A Randomized Double-Blind, Placebo-Controlled Trial. J Endocrinol Invest (2011) 34:224–8. doi: 10.3275/7572
49
SafarinejadMRSafarinejadSSShafieiNSafarinejadSS. Effects of the Reduced Form of Coenzyme Q10 (Ubiquinol) on Semen Parameters in Men With Idiopathic Infertility: A Double-Blind, Placebo Controlled, Randomized Study. J Urol (2012) 188:526–31. doi: 10.1016/j.juro.2012.03.131
50
SafarinejadMR. Efficacy of Coenzyme Q10 on Semen Parameters, Sperm Function and Reproductive Hormones in Infertile Men. J Urol (2009) 182:237–48. doi: 10.1016/j.juro.2009.02.121
51
ComhaireFHEl GaremYMahmoudAEertmansFSchoonjansF. Combined Conventional/Antioxidant “Astaxanthin” Treatment for Male Infertility: A Double Blind, Randomized Trial. Asian J Androl (2005) 7:257–62. doi: 10.1111/j.1745-7262.2005.00047.x
52
D’AnielloGRonsini STNotariTGriecoNInfanteVD’AngeloNet al. D-Aspartate, a Key Element for the Improvement of Sperm Quality. Adv Sex Med (2012) 2:47–53.
53
IsmailSBBakarMBNik HussainNHNorhayatiMNSulaimanSAJaafarHet al. Comparison on the Effects and Safety of Tualang Honey and Tribestaan in Sperm Parameters, Erectile Function and Hormonal Profile Among Oligospermia Males. Evid Based Complement Altern Med (2014) 2014:126138. doi: 10.1155/2014/126138
54
SetiawanL. Tribulus Terrestris L. Extract Improves Spermatozoa Motility and Increases the Efficiency of Acrosome Reaction in Subjects Diagnosed With Oligoastheno-Teratozoospermia. Adv Male Reprod Physiol (1996) 2:105–14.
55
SellandiTMThakarABBaghelMS. Clinical Study of Tribulus Terrestris Linn. In Oligozoospermia: A Double Blind Study. Ayu (2012) 33:356–64. doi: 10.4103/0974-8520.108822
56
RoaiahMFElkhayatYIAbd El SalamMADinSFG. Prospective Analysis on the Effect of Botanical Medicine (Tribulus Terrestris) on Serum Testosterone Level and Semen Parameters in Males With Unexplained Infertility. J Diet Suppl (2017) 14:25–31. doi: 10.1080/19390211.2016.1188193
57
GulinoFALeonardiEMarilliIMusmeciGVitalesGLeanzaVet al. Effect of Treatment With Myo-Inositol on Semen Parameters of Patients Undergoing an IVF Cycle: In Vivo Study. Gynecol Endocrinol (2016) 32:65–6. doi: 10.3109/09513590.2015.1080680
58
SuleimanSEamin AliMZakiZEl-MalikENasrM. Lipid Peroxidation and Human Sperm Motility: Protective Role of Vitamin E. J Androl (1996) 17:530–7.
59
GrecoEIacobelliMRienziLUbaldiFFerreroSTesarikJ. Reduction of the Incidence of Sperm DNA Fragmentation by Oral Antioxidant Treatment. J Androl (2005) 26:349–53. doi: 10.2164/jandrol.04146
60
MoilanenJHovattaOLindrothL. Vitamin E Levels in Seminal Plasma can be Elevated by Oral Administration of Vitamin E in Infertile Men. Int J Androl (1993) 16:165–6. doi: 10.1111/j.1365-2605.1993.tb01171.x
61
KessopoulouEPowersHJSharmaKKPearsonMJRussellJM. A Double-Blind Randomized Placebo Cross-Over Controlled Trial Using the Antioxidant Vitamin E to Treat Reactive Oxygen Species Associated Male Infertility. Fertil Steril (1995) 64:825–31. doi: 10.1016/S0015-0282(16)57861-3
62
RolfCCooperTGYeungCHNieschlagE. Antioxidant Treatment of Patients With Asthenozoospermia or Moderate Oligoasthenozoospermia With High-Dose Vitamin C and Vitamin E: A Randomized, Placebo-Controlled, Double-Blind Study. Hum Reprod (1999) 14:1028–33. doi: 10.1093/humrep/14.4.1028
63
CyrusAKabirAGoodarziDMoghimiM. The Effect of Adjuvant Vitamin C After Varicocele Surgery on Sperm Quality and Quantity in Infertile Men: A Double Blind Placebo Controlled Clinical Trial. Int Braz J Urol (2015) 41:230–8. doi: 10.1590/S1677-5538.IBJU.2015.02.07
64
SafarinejadMR. Effect of Omega-3 Polyunsaturated Fatty Acid Supplementation on Semen Profile and Enzymatic Anti-Oxidant Capacity of Seminal Plasma in Infertile Men With Idiopathic Oligoasthenoteratospermia: A Double-Blind, Placebo-Controlled, Randomized Study. Andrologia (2011) 43:38–47. doi: 10.1111/j.1439-0272.2009.01013.x
65
Martinez-SotoJCDomingoJCCardobillaLPPellicerALanderasJEL. Effect of Dietary DHA Supplementation on Sperm DNA Integrity. Fertil Steril (2010) 94:235–6. doi: 10.1016/j.fertnstert.2010.07.914
66
Martínez-SotoJCDomingoJCCordobillaBNicolásMFernándezLAlberoPet al. Dietary Supplementation With Docosahexaenoic Acid (DHA) Improves Seminal Antioxidant Status and Decreases Sperm DNA Fragmentation. Syst Biol Reprod Med (2016) 62:387–95. doi: 10.1080/19396368.2016.1246623
67
ConquerJAMartinJBTummonIWatsonLTekpeteyF. Elect of DHA Supplementation on DHA Status and Sperm Motility in Asthenozoospermic Males. Lipids (2000) 35:149–54. doi: 10.1007/BF02664764
68
NouriMAmaniRNasr-EsfahaniMTarrahiMJ. The Effects of Lycopene Supplement on the Spermatogram and Seminal Oxidative Stress in Infertile Men: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Phytother Res (2019) 33:3203–11. doi: 10.1002/ptr.6493
69
AgarwalAFinelliRSelvamMKPLeisegangKMajzoubATadrosNet al. A Global Survey of Reproductive Specialists to Determine the Clinical Utility of Oxidative Stress Testing and Antioxidant Use in Male Infertility. World J Mens Health (2021) 39:470–88. doi: 10.5534/wjmh.210025
70
VitaglianoAPetreGCFrancini-PesentiFDe ToniLDi NisioAGrandeGet al. Dietary Supplements for Female Infertility: A Critical Review of Their Composition. Nutrients (2021) 13:3552. doi: 10.3390/nu13103552
71
Federsalus. Associazione Nazionale Produttori E Distributori Prodotti Salutistici. Available at: https://www.federsalus.it/il-mercato-degli-integratori-dinamiche-aggiornate-a-marzo-2019/ (Accessed January 4, 2021).
72
FalsigALGleerupCSKnudsenUB. The Influence of Omega-3 Fatty Acids on Semen Quality Markers: A Systematic PRISMA Review. Andrology (2019) 22:2047–919. doi: 10.1111/andr.12649
73
GuptaNPKumarR. Lycopene Therapy in Idiopathic Male Infertility–a Preliminary Report. Int Urol Nephrol (2002) 34:369–72. doi: 10.1023/A:1024483520560
74
SantosHOHowellSTeixeiraFJ. Beyond Tribulus (Tribulus Terrestris L.): The Effects of Phytotherapics on Testosterone, Sperm and Prostate Parameters. J Ethnopharmacol (2019) 235:392–405. doi: 10.1016/j.jep.2019.02.033
75
ForestaCFlohéLGarollaARoveriAUrsiniFMaiorinoM. Male Fertility is Linked to the Selenoprotein Phospholipid Hydroperoxide Glutathione Peroxidase. Biol Reprod (2002) 67:967–71. doi: 10.1095/biolreprod.102.003822
76
ForestaCGarollaACosciIMenegazzoMFerigoMGandinVet al. Role of Zinc Trafficking in Male Fertility: From Germ to Sperm. Hum Reprod (2014) 29:1134–45. doi: 10.1093/humrep/deu075
77
PrasadASMantzorosCSBeckFWHessJWBrewerGJ. Zinc Status and Serum Testosterone Levels of Healthy Adults. Nutrition (1995) 12:344–8. doi: 10.1016/S0899-9007(96)80058-X
78
GarollaAMaiorinoMRoveratoARoveriAUrsiniFForestaC. Oral Carnitine Supplementation Increases Sperm Motility in Asthenozoospermic Men With Normal Sperm Phospholipid Hydroperoxide Glutathione Peroxidase Levels. Fertil Steril (2005) 83:355–61. doi: 10.1016/j.fertnstert.2004.10.010
79
SinghKJaiswalD. One-Carbon Metabolism, Spermatogenesis, and Male Infertility. Reprod Sci (2013) 20:622–30. doi: 10.1177/1933719112459232
80
InglesDPCruz RodriguezJBGarciaH. Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment. Curr Cardiol Rep (2020) 22:22. doi: 10.1007/s11886-020-1270-1
81
VanderhoutSMRastegar PanahMGarcia-BailoBGrace-FarfagliaPSamselKDockrayJet al. Nutrition, Genetic Variation and Male Fertility. Transl Androl Urol (2021) 10:1410–31. doi: 10.21037/tau-20-592
82
BalerciaGMorettiSVigniniAMagagniniMManteroFBoscaroMet al. Role of Nitric Oxide Concentrations on Human Sperm Motility. J Androl (2004) 25:245–9. doi: 10.1002/j.1939-4640.2004.tb02784.x
83
PalenciaJYPSaraivaAAbreuMLTZangeronimoMGSchinckelAPPospissil GarbossaCA. Effectiveness of Citrulline and N-Carbamoyl Glutamate as Arginine Precursors on Reproductive Performance in Mammals: A Systematic Review. PloS One (2018) 13:e0209569. doi: 10.1371/journal.pone.0209569
84
MorrisSMJr.Recent Advances in Arginine Metabolism. Curr Opin Clin Nutr Metab Care (2004) 7:45–51. doi: 10.1097/00075197-200401000-00009
85
VazquezLMHVerónGL. Myo-Inositol in Health and Disease: Its Impact on Semen Parameters and Male Fertility. Andrology (2020) 8:277–98. doi: 10.1111/andr.12718
86
KizilayFAltayB. Evaluation of the Effects of Antioxidant Treatment on Sperm Parameters and Pregnancy Rates in Infertile Patients After Varicocelectomy: A Randomized Controlled Trial. Int J Impot Res (2019) 31:424–31. doi: 10.1038/s41443-018-0109-4
87
KumarSMurarkaSMishraVVGautamAK. Environmental & Lifestyle Factors in Deterioration of Male Reproductive Health. Indian J Med Res (2014) 140:29–35.
88
KamenovZFilevaSKalinovKJanniniEA. Evaluation of the Efficacy and Safety of Tribulus Terrestris in Male Sexual Dysfunction? A Prospective, Randomized, Double-Blind, Placebocontrolled Clinical Trial. Maturitas (2017) 99:20–6. doi: 10.1016/j.maturitas.2017.01.011
89
ShowellMGBrownJYazdaniAStankiewiczMTHartRJ. Antioxidants for Male Subfertility. Cochrane Database Syst Rev (2011) 19:CD007411. doi: 10.1002/14651858.CD007411.pub2
90
SmitsRMMackenzie-ProctorRYazdaniAStankiewiczMTJordanVShowellMG. Antioxidants for Male Subfertility. Cochrane Database Syst Rev (2019) 3:CD007411. doi: 10.1002/14651858.CD007411.pub4
Summary
Keywords
fertility, male reproduction, nutraceuticals, semen parameters, supplements
Citation
Garolla A, Petre GC, Francini-Pesenti F, De Toni L, Vitagliano A, Di Nisio A, Grande G and Foresta C (2022) Systematic Review and Critical Analysis on Dietary Supplements for Male Infertility: From a Blend of Ingredients to a Rationale Strategy. Front. Endocrinol. 12:824078. doi: 10.3389/fendo.2021.824078
Received
28 November 2021
Accepted
30 December 2021
Published
04 February 2022
Volume
12 - 2021
Edited by
Rosita Angela Condorelli, University of Catania, Italy
Reviewed by
Arcangelo Barbonetti, University of L’Aquila, Italy; Francesco Lombardo, Sapienza University of Rome, Italy
Updates
Copyright
© 2022 Garolla, Petre, Francini-Pesenti, De Toni, Vitagliano, Di Nisio, Grande and Foresta.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Andrea Garolla, andrea.garolla@unipd.it
†These authors share first authorship
This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology
Disclaimer
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