(1)
Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA
Abstract
Oxidative stress is associated with up to 80 % of the male subfertility cases. A notable Cochrane Database of Systematic Reviews provided one of the most extensive analyses of 34 randomized trials of supplements for male subfertility during ART (assisted reproductive technologies). It found a highly statistically significant increased chance of pregnancy and live birth for men that used one or several dietary supplements, with side effects that were identical to placebo. Critics might argue that the pregnancy rate (96 pregnancies, 15 clinical trials, 964 couples) and especially the live birth rate (20 events, 3 clinical trials, 214 couples) were not large enough to endorse some supplementation for male subfertility. I strongly disagree because when considering the cost of ART, the added cost of supplementation is just pennies per day for most science-based products, and I believe the benefit greatly outweighs the risk.
Dietary supplementation for male subfertility without the use of ART is also plausible. There is accumulating evidence that the use of one or several low-cost dietary supplement options for men with idiopathic asthenozoospermia or oligoasthenoteratozoospermia (OAT) can improve various aspects of infertility (motility, concentration, morphology) and perhaps even pregnancy and live birth rates. Yet the specific supplements recommended should be curtailed by experts because, overall, some of the supplements that may be successful in improving male subfertility have other acute and chronic health issues according to the medical literature. This has been the limitation of most of the extensive reviews of supplements for male subfertility—the lack of recommending specific compounds based on efficacy and safety. In other words, only the supplements that follow a “first do no harm” approach within fertility and for overall health should be currently considered. Thus, it makes it easier to recommend supplements such as coenzyme Q10, carnitine, N-acetylcysteine (NAC), omega-3 fatty acids, and/or vitamin C, or perhaps combinations of multiple low-dose formulas/multivitamins (along with encouraging research of novel supplements such as L-citrulline), but to discourage the use of arginine, astaxanthin, DHEA, folic acid, glutathione, lycopene, magnesium, plant estrogens, selenium, Tongkat ali, vitamin D, vitamin E, and zinc.
Using a dietary supplement for male subfertility to improve pregnancy probability has diverse encouraging data, but using any supplement currently to maintain fertility or prevent future issues as a preventive agent does not have adequate clinical research or justification and could theoretically do harm.
Introduction
Authoritative medical reviews have suggested for some time that antioxidant supplement treatment could be considered a primary treatment with conventional therapy, or at least an option for some male fertility issues [1], but more clinical evidence was needed [2, 3]. Yet, it is difficult to at least argue with the consistent suggestion that up to 80 % of male factor subfertility cases are believed to be the result of “oxidative stress” [4]. Perhaps some of the evidence to espouse the use of dietary supplements for male infertility has now been fulfilled.
A Cochrane systematic review was arguably one of the most extensive ever published in male fertility and dietary supplements, as it reviewed 34 randomized clinical trials with 2,876 couples in total [5]. Studies used in this analysis were for couples undergoing ART, for example, in vitro fertilization (IVF), intrauterine insemination (IUI), or intracyclic sperm injection (ICSI). The inclusion criteria were randomized controlled trials that included only men who were part of a couple with unexplained subfertility or subfertility and who were using ART with their own gametes. Excluded trials were nonrandomized and included men taking any other fertility-enhancing medications or men who had used chemotherapy treatment. The primary outcome was the live birth rate per couple, randomized, as well as these multiple secondary outcomes:
Pregnancy rate per couple
Miscarriage rate per couple or spontaneous abortion
Stillbirth rate per couple
Level of sperm DNA damage after treatment
Sperm concentration and sperm motility
Side effects associated with dietary supplements and withdrawals
The overall findings continue to surprise a number of healthcare professionals and patients, in my opinion, by concluding that antioxidant supplementation in males appears to have a positive role in improving the outcomes of live birth and pregnancy rates in couples participating in ART [5]. In fact, for live births the p-value was 0.0008 and for pregnancy rates it was p < 0.00001. Critics of this analysis on “live births” will also arguably point toward the small number of such events: 20 live births that occurred from a total of 214 couples in only three studies were used in this part of the analysis, or the “pregnancy rates,” which actually were derived from 96 pregnancies in 15 trials that included 964 couples. However, it is still remarkable that this is a viable minimal or moderate option for some men, given the low cost of most “antioxidants” utilized in these studies. Additionally, acute side effects were similar to a placebo with no serious adverse events reported in any trial.
Some of the antioxidants/complementary and alternative medicine (CAM) that may have demonstrated some impact (positive or negative) from this large analysis and from my experience include:
Acupuncture and other CAM
Astaxanthin
Combined unique formula antioxidants
Coenzyme Q10
DHEA (and other prohormone supplements)
Folic acid
Glutathionine
L-arginine
L-carnitine
Lycopene
Magnesium
Multivitamin
N-acetylcysteine (NAC)
Omega-3 fatty acids
Plant estrogens
Selenium
Tongkat ali (Eurycoma longifolia)
Vitamin C
Vitamin D
Vitamin E
Zinc
The common question that will result from this or any other positive analysis for male fertility and antioxidants is, which specific dietary supplements and at what dosage and frequency? Interestingly, this extensive Cochrane review could not identify one superior individual antioxidant or combination product from these trials [5], so readers and patients are left with multiple questions. Thus, an overview of antioxidant supplements used in past, well-designed placebo-controlled trials is needed with an overall cost, safety, and health perspective to determine which products should be recommended and perhaps avoided by patients. This was the primary weakness of the Cochrane review and other reviews in male fertility [5]; the overall lack of specific recommendations based on overall safety and efficacy of these agents long-term for overall health and fertility maintenance.
This chapter will attempt to provide clarity on this issue of which supplements to recommend, and which ones should be avoided, based on heart healthy and overall health sensitivity recommendations. The endpoints of past, current, and future studies also matter, so clinicians need to constantly ask themselves in which of the following areas does this supplement impact:
Oxidative stress reduction/markers
Total sperm number
Sperm concentration
Sperm morphology
Sperm motility (% motility and/or forward progression)
Pregnancy rate
Live births
Short- and long-term safety
Miscellaneous (ejaculate volume, pH, viscosity, sperm agglutination, other parameters)
Obviously, the impact on pregnancy and live birth rates along with overall safety are the more important variables and are in desperate need of more results in these areas for all of the dietary supplements mentioned in this chapter. And it is also of interest that if some supplements may improve male infertility when dealing with ART, then can it also be said that for those with motility issues (asthenospermia) or idiopathic oligoasthenoteratozoospermia (OAT), there may also be some benefit because of the overlap in those who use ART and men with this condition.
Dietary Supplements
Coenzyme Q10
CoQ10 (also known as “ubiquinone”) appears to be a safe dietary supplement that requires a low dose for male fertility preservation. CoQ10 supplements have an excellent overall safety profile and actually have some clinical data to suggest that they may reduce blood pressure, but primarily in those with some form of hypertension. These supplements might also have some role in reducing myalgia from statin therapy [6, 7], but these results have been inconsistent, yet still proven to be safe at a variety of dosages [8]. The role of CoQ10 in the respiratory pathway as a method to improve energy production and reduce oxidative stress is well known in basic human physiology. It is for this reason that there should be some interest in utilizing this dietary supplement for the reduction of oxidative stress.
Seminal fluid also contains a measurable quantity of CoQ10 that appears to be associated with sperm count and motility. Patients with idiopathic asthenozoospermia may benefit in terms of spermatozoa motility when consuming 200 mg/day of CoQ10 for 6 months [9]. Another study of 212 infertile men taking 300 mg/day over 26 weeks found significant improvements in multiple parameters including sperm density, motility, and acrosome reaction [10]. Serum levels of FSH (follicle-stimulating hormone) and LH (luteinizing hormone) were significantly reduced by the supplement by the end of the study. But in a randomized trial of men with oligoasthenoteratozoospermia at a dosage of 200 mg/day compared to placebo, it appeared to reduce markers of oxidative stress, but did not demonstrate significant impacts on sperm concentration, motility, and morphology [11].
CoQ10 can be a costly supplement, so patients should be encouraged to compare prices from multiple commercial resources to determine the most cost-effective product. I have not observed in the medical literature profound differences in clinical effects with low-cost CoQ10 products compared to high-cost products. CoQ10 appears to be a heart-healthy or safe supplement [6], except it does have the rare potential to reduce the impact of warfarin because it has vitamin K-like properties [12], but ironically its slight antiplatelet effects may increase bleeding when combined with aspirin or clopidogrel. Regardless, it is a supplement that could be encouraged for fertility improvement in most men at a dosage of 200–300 mg/day.
My biggest reservation about CoQ10 is not side effects, or finding a low-cost product, but in its true efficacy over time. The reason I make this statement is due to the initial promise and then slight to moderate disappointment in this product in other areas of medicine. For example, the impact on statin-induced myalgia reduction was interesting initially [7], but is not a clear solution [8], and this is also true for the product in terms of its antihypertensive [13] effects and its role in Parkinson’s disease research [14]. Still, the benefit outweighs the risk, so it should be part of the potential dietary supplement regimen approach for men with subfertility.
Folic Acid
Folic acid (vitamin B9) is not an ideal antioxidant for male fertility in my opinion and should not be used at this time in certain patients, for example, those with a personal history or strong family history of cancer, especially prostate cancer. Folate is a water-soluble B vitamin, which is also known as vitamin B9, and it occurs naturally in many healthy foods and multiple diverse beverages and foods [15]. Folic acid is the synthetic, human-produced, or manufactured form of folate that is found in dietary supplements and added to a variety of grain products, which are also known as “fortified foods.”
Folate from foods and folic acid both assist in the production of DNA, RNA, and other items that are critical for the production and maintenance of cells, especially ones involved in rapid cell division and growth, such as in pregnancy and infancy [16]. Humans of all ages need folate to produce normal red blood cells and to prevent macrocytic anemia. Folate is also critical for metabolizing an amino acid known as “homocysteine,” which may cause cellular damage in abnormally high amounts and is important for the synthesis of methionine. Folate has diverse roles in the development of a human being, which is why this compound is probably best known for preventing neural tube defects (NTDs) [15].
Green leafy vegetables, fruits, and legumes (beans, peas, lentils) are just some of the natural sources of folate. Still, due to the importance of folate in the prevention of NTDs, the Food and Drug Administration (FDA) required the addition of folic acid to grain products like breads, cereals, corn, flours, meals, pastas, and rice. In 1998, the USA and Canada officially began fortifying grain products with folic acid [15]. The recommended daily allowance (RDA) is only 400 micrograms (μg) a day [17]. A partial listing of food and other sources of folate and folic acid appears in Table 4.1 [17]. It is important to keep in mind that folic acid is generally added to foods that are labeled “enriched” and/or “fortified” in the USA and other countries. For this reason, it is easy to find recommended daily allowances of folate on products like breakfast cereals.
Table 4.1
A partial list of beverage/food and other sources of folate and folic acid
Food/beverage or other | Micrograms (μg) |
|---|---|
100 % fortified breakfast cereals | 400 |
Multivitamin (on average 1 pill) | 400 |
B-complex vitamin (on average 1 pill) | 400–800 |
Brewer’s yeast (1 tablespoon) | 250 |
Beef liver (cooked, 3 oz) | 185 |
Spinach (cooked, 1/2 cup) | 100 |
Asparagus (4 spears) | 85 |
Rice (white, enriched, 1/2 cup) | 65 |
Beans (baked, 1 cup) | 60 |
Green peas (boiled, 1/2 cup) | 50 |
Avocado (1/2 cup) | 45 |
Broccoli (2 spears) | 45 |
Lettuce (1/2 cup) | 40 |
Peanuts (dry roasted, 1 oz) | 40 |
Orange or orange juice (6 oz) | 30–35 |
Tomato Juice (6 oz) | 35 |
Bread (white, whole wheat, enriched, 1 slice) | 25 |
Egg (whole) | 25 |
Banana (medium) | 20 |
Wheat germ (1 tablespoon) | 20 |
Rice (brown, 1/2 cup) | 5–10 |
Synthetic folic acid was believed to be more bioavailable compared to folate from food, which may have been one of the many reasons to fortify foods around the world, along with the fact that a deficiency of folate in women of reproductive age can have devastating consequences. Research has now suggested that folate from foods may be only slightly less absorbable (about 20 %) compared to what was previously believed [18].
Other more critical issues with the overall safety and impact of folic acid on male health now exist. A large-scale meta-analysis has reviewed all of the randomized trial data on folic acid and other B-vitamin supplementation to reduce the risk of cardiovascular disease and cancer, or impact all-cause mortality [19]. It concluded that there was minimal to no impact of these supplements in reducing the risk of these conditions. In other words, currently it does not seem to impact the risk of most chronic diseases, despite the fact that it can reduce blood homocysteine levels by at least 25 %. Still, folic acid supplements may increase or encourage the growth of a variety of common tumors and precancerous lesions or polyps in high-risk individuals [20]. The cancer that receives the most attention in terms of a potential increased risk is prostate cancer [21, 22]. Serum levels of folic acid also appear to be increasing in the elderly such that unmetabolized folic acid (UMFA) has become a concern in men [23].
Still, the controversy over the clinical significance of a potential increased risk of prostate cancer will and should continue without any resolution in the near future. A meta-analysis of randomized trials found a significant increased risk of prostate cancer [24]. Arguably, another larger meta-analysis of randomized trials in cancer suggested that there was no risk and that past meta-analyses were influenced by a higher rate of cancer from one clinical trial [21], where prostate cancer incidence in the folic acid arm was probably increased due to chance [25]. Although these researchers make a compelling argument for this case, the problem with this theory is that most of the major trials looking at prostate cancer incidence still found at least nonsignificant increases in risk that cannot be disregarded due to chance, and this is confirmed by other recent meta-analysis [26], including population studies [27]. In other words, the sum of the data is not showing a neutral or reduced effect, only an increased risk overall, and the argument is whether or not it is statistically or clinically significant.
This argument tends to miss the forest for the trees in men’s health, and until the risk is justified there is no sound benefit for most men in taking higher doses of supplemental folic acid for overall health and wellness. Thus, clinicians should not encourage supplemental folic acid use, especially in men with a history of cancer who are concerned about fertility, despite some minimal positive or just non-impressive data in the area of fertility itself [28, 29], because other supplements are safer, just as effective, and do not appear to require megadosage (like folic acid) for a clinical impact. Some of the early and only clinical trials that involved folic acid were using dosages such as 5 mg/day (along with zinc), which is 12.5 times the recommended daily intake [28]. Only sperm concentration, but not motility or morphology, was improved.
There is a dearth of studies, a question of safety in some men, and the potential need to utilize very high dosages of supplemental folic acid. Granted, the time periods that men need to be on these supplements are variable, but it is still not unusual in my experience to observe men taking these pills for several years. Food sources of folate can be recommended, because these have not been concerning overall, but the concentrated nutraceuticals do not follow the mantra right now of benefit exceeding risk.
L-Carnitine
L-Carnitine is a potential amino acid supplement for male fertility, but large dosages may be needed, and it is not a low-cost product in comparison to many other supplements mentioned in this chapter. L-Carnitine is an amino acid that transports fatty acids from the cytosol to the mitochondria for energy production in each cell of the body [30]. Humans can produce carnitine de novo in the liver from lysine and methionine (25 %), but dietary intake is the primary source of carnitine (75 %). Foods high in carnitine include dairy and meat; a plant-based diet is, in general, a poor source of carnitine. Excretion of carnitine occurs from the kidneys, but reabsorption is also efficient so that vegans are still able to maintain close to normal blood levels of this amino acid despite consuming 10 % less carnitine than omnivores.
Some preliminary research suggests that carnitine may slightly reduce fatigue in some cancer patients in higher dosages, but a phase III trial demonstrated 2,000 mg/day worked no better than a placebo for this specific situation over a 4-week testing period [31]. Even subset analysis revealed that those individuals who had lower blood levels of carnitine at baseline did not benefit. The future of L-carnitine in terms of energy production for patients with fatigue is now questionable, but there is still adequate data in other areas of medicine, for example, the ability of this product to increase the body weight or nutritional status of high-risk cachectic patients [32] and improve peripheral artery disease [33], and the impact of this supplement on male fertility—primarily motility [30].
It is of interest that vitamin C (ascorbic acid) is needed to synthesize carnitine in the human body [30]. The highest concentration of carnitine apart from supplements occurs in red meat and dairy products, so vegetarians who are trying to maintain fertility would potentially be better candidates for this supplement.
There are several minimally different forms of L-carnitine available for purchase that have been used in clinical trials, including L-carnitine, acetyl-l-carnitine (ALC), and propionyl-l-carnitine (PLC). These other types of L-carnitine have been tested because L-carnitine itself tends to be unstable. Yet these other forms of L-carnitine do not necessarily have better fertility data, especially when compared to each other at 3,000 mg/day [34], and they are more costly for the patient. Some clinical trials have suggested that the combination of these supplements may improve motility [35], but again this is not what I am deriving from these same studies with similar authors [35, 36]. Thus, multiple clinical trials have demonstrated the ability of L-carnitine, or other forms of carnitine, to improve primarily sperm motility and, potentially, pregnancy rates [34–42]. Yet there has been inconsistent or minimal evidence that it can impact sperm concentration and morphology.
A small US randomized, double-blind placebo-controlled study in men with idiopathic asthenospermia has challenged the potentially positive results with carnitine [43]. Male patients with sperm motility of 10–50 % were utilized, and over 24 weeks 2,000 mg/day of L-carnitine and 1,000 mg/day of acetyl-L-carnitine were ingested compared to placebo (n = 12 vs. n = 9). No significant differences in motility or total motile sperm counts occurred at 12 weeks or 24 weeks. These researchers called into question the clinical significance of the effect of L-carnitine for infertile men. They also reviewed past studies and suggested several methodology issues, such as exclusion of some patients from final analysis, as an issue [36], and also found carnitine to cause statistical significance in the past, but the clinical significance of the results are questionable. Another concern is lack of improvement in seminal plasma or sperm carnitine levels following supplementation [36, 43], which could be the result of adequate baseline levels or simply no ability to improve these concentrations with these supplements [43].
After this critical publication, a systematic review of nine clinical trials was published by independent researchers on the impact of L-CARNITINE for male infertility [44]. A significant improvement was shown in pregnancy rates (p < 0.0001), total and forward sperm motility (p = 0.04), and atypical sperms cell (p < 0.00001), but no impact was found for sperm concentration or semen volume. Therefore, again clinicians are left to decide on this controversial supplement. L-carnitine causes an unpredictable change or minimal to moderate increase in sperm motility without a consistent change in sperm morphology and concentration, nor increase in seminal plasma carnitine levels, but there is a potential increase in pregnancy without any current safety issues. Is this enough to endorse the utilization of high doses of carnitine for male infertility? It should not be endorsed for preventive measures to preserve fertility, but its other features (especially safety) make it a controversial option at least.
Adverse events using L-carnitine or serious drug interactions have not been identified. Doses of 2–4 g (2,000–4,000 mg/day, divided doses two to three times a day) on average have been used in clinical trials. L-carnitine or acetyl-L-carnitine or the combination was used in these past studies. There was no commentary as to whether L-CARNITINE was ingested with or without a meal, so it seems there is flexibility with regard to this issue.
Omega-3 Fatty Acids
Recommending dietary sources of omega-3 should be encouraged in most individuals. There are numerous marine or fish sources that contain high levels of omega-3 fatty acids, vitamin D, protein, and selenium, including salmon, tuna, and sardines. A variety of other baked, broiled, raw, but not fried, fish are potentially beneficial [45]. Variety should be encouraged to increase compliance and exposure.
The benefit of fish consumption to reduce the risk or progression of cancer is preliminary, but its positive role in reducing a cardiovascular event or impacting all-cause mortality is a more definitive conclusion based on older clinical trials encouraging fish consumption [46] and other later selective clinical trials utilizing fish oil consumption [47, 48] in patients with a history of heart disease. Still, the overall and most up-to-date clinical trial data with fish oil supplementation on primary endpoints has been minimal to controversial and discouraging [49] and in perfectly healthy individuals does not currently espouse the use of these supplements [50]. Thus, fish oil supplements should probably be reserved for patients who want to reduce triglycerides [45], where they are FDA approved for this purpose.
The data on fish oil for male subfertility are minimal and controversial because there have not been enough studies. For example, in a randomized trial of DHA (docosahexaenoic acid) at 400 or 800 mg/day compared to placebo over 3 months for 28 asthenozoospermic (50 % or less motility) men, the omega-3 supplement did appear to increase serum and potentially seminal plasma DHA levels. However, it did not impact DHA into the spermatozoa phospholipid, which may have explained why it did not impact sperm motility compared to placebo [51]. A later trial of men with idiopathic oligoasthenoteratospermia (OAT) randomized to 1,840 mg of total omega-3 (EPA [eicosapentaenoic acid] and DHA) product compared to placebo over 32 weeks found a significant increase in sperm count, concentration, morphology, and motility, which may have been associated with the reductions in markers of oxidative stress [52]. Several cases of reflux, itching, and diarrhea occurred in the omega-3 group, which are known rare side effects of these supplements [45]. Again, until more research is conducted taking one to two omega-3 supplements that equate to 1,000–1,840 mg/day of EPA and DHA could be of benefit, but this is speculative.
Still, dietary sources of healthy fish can be encouraged. Mercury concentrations in specific fish have been reported by the FDA and in the overall medical literature, but the preliminary data are controversial and it is not known at this time what kind of clinical impact these mercury levels may have on the individual [45]. Four types of larger predatory fish have been most concerning because these fish (king mackerel, shark, swordfish, and tilefish) have the ability to retain greater amounts of methylmercury. Moderate consumption (two to three times/week) of most fish should have minimal impact on overall human mercury serum levels, but more ongoing research in this area should soon provide better clarity.
The positive impact of consuming fish seems to outweigh the negative impact in the majority of individuals, with the exception of women considering pregnancy or who are pregnant. A variety of fish have consistently demonstrated low levels of mercury, as summarized here [45]:
Anchovies
Catfish
Cod
Crab
Flounder/sole
Haddock
Herring
Lobster
Mahi-mahi
Ocean perch
Oysters
Rainbow trout
Salmon (farmed and wild)
Sardines
Scallops
Shrimp
Spiny lobster
Tilapia
Trout (farmed)
White fish (Great Lakes)
It should be kept in mind that approximately two servings per week of fatty, oily low-mercury fish is the equivalent to ingesting approximately one 250- to 500-mg fish oil pill per day. Clinicians who still desire to recommend high dosages of fish oil supplements must keep in mind that these supplements could increase the risk of internal bleeding at higher dosages and in combination with other blood thinners [12]. Although the risk of bleeding events is extremely rare, it has been observed in some clinical trials of healthy individuals and in combination with statins at a dosage of only 1,800 mg/day [48].
Some fish are low in mercury levels, but also low in omega-3 fatty acid concentration. Tilapia, which is high in protein, is a classic example. On the other hand, it is interesting that low-cost, small, and short-lived fish—such as anchovies and sardines—are low in mercury and have some of the highest concentrations of omega-3 oils and are used more than any other fish in the manufacturing of fish oil pills utilized by the public and in many clinical trials [45]. Patients who cannot eat fish or do not want to utilize fish oil because of an allergy or a personal belief could be recommended the newer algae-based omega-3 oils or encouraged to regularly consume the largest plant-based source of omega-3 fatty acids, which are found in plant oils (canola and soy), flaxseed, and chia seed.
Plant Estrogens or Phytoestrogens
It is easy to presume that weak plant estrogens found in foods, such as flaxseed, red clover, and soy, and in supplements could increase the risk of male infertility. This will be discussed in greater detail in the dietary section. There is simply no tangible evidence that these foods alter testosterone, or other parameters that would cause impairments in fertility [53–55]. The arguably largest two reviews of soy isoflavone supplements or foods and nine clinical trials and a review examining 15 placebo-controlled treatment groups all found no evidence to indicate any feminizing effects in men, including reduction in testosterone or changes in sperm or semen parameter [56, 57]. Although most clinical trials were less than 3 months in length, I do believe there is the potential for some plant estrogen supplements (not foods), such as red clover or any other plant estrogen supplements in excess, to cause some harm, and even have the potential to reduce DHT, so it should not be promoted in infertile men until proved otherwise.
A 1-year trial of 20 older men (mean age of 65 years) found significant increases in liver transaminases at a dosage of only 60 mg/day of red clover, and there was a suggestion of a 5-alpha reductase inhibition [58]. Other isoflavone studies using 60 mg/day of a concentrated supplement also appeared to significantly reduce DHT in a study of 28 healthy men [59], or free testosterone when tested for a 1-year period in a separate group of 20 men [60]. If there is even the slightest probability that consuming plant estrogen dietary supplements may reduce DHT levels, then there could be a potential and profound impact on libido and fertility. This is due to the ongoing concerns with more potent prescription drug DHT reducers, such as finasteride and dutasteride, that do not benefit sexual health or fertility, especially in cases of subfertility [61–66].
There is simply no reason to utilize these concentrated dietary plant estrogen supplements to improve male fertility or overall health. Instead, dietary sources are safe and can be recommended for general health. Soy and flaxseed have minimal calories, ample fiber, and omega-3 fatty acids and are low caloric foods that can improve lipid profiles and be utilized in most weight-loss interventions, in my opinion. These heart-healthy changes could theoretically improve fertility by also improving androgen levels and normalization of these hormones, especially if it helps those men in need of weight loss [67–70].
Selenium and Vitamin E
Selenium or vitamin E supplements should not be recommended to improve fertility in subfertile men strictly based on their overall safety issues and not on efficacy. For example, the initiation and even the final results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT), trial of selenium and/or vitamin E, to prevent prostate cancer were concerning for a multitude of reasons [71, 72]. Both agents failed to prevent prostate cancer, and there were multiple past and current safety issues with these nutritional supplement agents. Selenium had a history of potentially increasing the risk of skin cancer recurrence [73], and there were concerns over an increased risk of type 2 diabetes [74]. Interestingly, SELECT observed a nonsignificant increased risk of type 2 diabetes when the trial was stopped [71]. And, there was a nonsignificant increase in the risk of aggressive (Gleason score 7–10) prostate cancer with vitamin E and/or selenium [72].
Vitamin E supplements were also replete with some similar but even more concerning issues compared to selenium during the SELECT. Past meta-analyses of other clinical trials found a potential increased risk of all-cause mortality with higher doses of vitamin E supplements [75]. Other large clinical trials found a significant increased risk of heart failure in those with vascular disease or diabetes [76]. A significant increased risk of hemorrhagic stroke was found for vitamin E supplements in another major chemoprevention trial of healthy physicians (Physicians’ Health Study II) that was concurrently being conducted during the time of SELECT [77]. And, again SELECT found a nonsignificant (p = 0.06) increased risk of prostate cancer in the vitamin E arm when the study was terminated and a significantly higher risk with more follow-up after termination [71, 72]. Thus, both of these supplements have no impressive overall or heart-health research unless there is a profound deficiency in these compounds [78–82], and multiple past and ongoing concerns abound [83, 84], as outlined earlier.
There needs to be more clinician and patient awareness over the multiple serious safety issues with vitamin E and selenium, and these supplements should not be encouraged for any healthy individual attempting to improve fertility, despite past trials in infertility demonstrating some benefit [85–87]. It is also interesting that all of the past trials of vitamin E and/or selenium that have suggested benefit in male subfertility have also been at dosages equivalent or actually larger than past clinical trials in other areas of health that found large concerns [71, 72, 75–77]. And, since these supplements have not been found to have profound benefits beyond what has been observed with other supplements discussed in this chapter [5], then it would be prudent again to not recommend this particular compound, which has such a negative and nebulous history.
Tongkat Ali
This is a dietary supplement extract derived from a common shrub (Eurycoma longifolia, also known as “Malaysian ginseng” but is not in the ginseng family) found along the slopes of hilly areas in the Malaysian rainforest. It has preliminary human data that shows it might improve various aspects of male health—including sex drive—normalize testosterone in men with age-related androgen deficiency, and improve sperm quality and quantity at 200–300 mg/day [88–90].
Multiple laboratory studies have shown an ability of this herbal product to potentially improve male fertility status [91–94]. I also learned from multiple visits with healthcare professionals in this region that there is a history of using this product in Malaysia and other nearby locations to enhance fertility and male sexual health.
The one open-label study involved 75 men with idiopathic infertility who utilized the supplement for at least the first 3 months, and also followed pregnancy rates and improved semen measurements [90]. Significant improvement in all semen parameters occurred and 11 (14.7 %) spontaneous pregnancies occurred, although multiple methodologic issues still need to be resolved in a placebo-controlled trial. For example, the authors claim that 350 men started the trial and only 75 completed one full cycle of supplementation (3 months) and fulfilled the inclusion criteria, and only 17 men completed all 9 months of supplementation. This is a concerning exclusion and/or noncompliance rate that needs further investigation. The authors also point toward the possibility of a “bioactive peptide” that can increase testosterone levels in animals and humans and may reduce oxidative stress.
The product that has the most research and the only one with real clinical data is the standardized water-soluble extract (Physta) of E. longifolia root from the company Biotropics Malaysia Berhad, Kuala Lumpur, Malaysia. The company has also financially supported most of these studies. Their proprietary standardized water-soluble extract from the root of the plant and other Tongkat ali studies shows that this root has multiple diverse ingredients, such as [88–95]:
Amino acid isoleucine
Calcium, magnesium, and potassium
Glycoproteins mucopolysacchrides
High-molecular-weight polysaccharides
Quassinoid alkaloids
Tannins
It is theorized that this product may produce benefits in the area of male health because it may have a prohormone effect or DHEA mimic (yet, DHEA supplementation has not been adequately researched for its impact on male fertility), or perhaps because it is acting more like a diverse multivitamin for men. It could be that this product is no better than a really low-cost source or another supplement of Tongkat ali, but the problem is that other brands or just generic Tongkat ali do not have adequate clinical trials or quality control testing (for lead, arsenic, etc.).
Therefore, Tongkat ali does not have enough clinical evidence to recommend its use in men with idiopathic infertility, but few herbal supplements have even received adequate laboratory and clinical testing in this area with quality control and standardization measures. Thus, it could be utilized for a trial period if other less costly products appear not to be efficacious.
Vitamin C
There is enough indirect information and long-term safety of vitamin C that this supplement may have a small role in improving male subfertility [5]. Some positive preliminary data exists for improving fertility in men consuming 200–1,000 mg/day of vitamin C supplements in combination with other antioxidants [5]. Whether or not vitamin C alone can perform as well as the combination supplement treatments is not adequately known.
Vitamin C utilization for potentially improving male fertility has a long history, but there is a lack of good placebo-controlled trials [96, 97]. One small placebo-controlled trial of vitamin C (1,000 mg) in combination with high-dose vitamin E (800 mg) for 31 patients with asthenospermia showed no difference compared to placebo for 56 days and no pregnancies [98]. Interestingly, prolonged abstinence increased sperm count, concentration, total number of motile spermatozoa, and ejaculate volume. This highlights the difficulty in truly identifying what is working to improve fertility in some of these antioxidant studies. Yet, it is known that supplementation improves seminal plasma vitamin C in nonsmokers and smokers and could be correlated with improved morphology [99–101].
Seminal plasma has concentrations of vitamin C that are several orders of magnitude higher than that found in the bloodstream. Smoking has the ability to profoundly reduce vitamin C concentration [102]. A placebo-controlled trial of smokers found improvements in sperm quality at 200 and 1,000 mg/day [103]. Therefore, for smokers, ex-smokers, or those who have recently quit or are on smoking cessation regimens and trying to improve subfertility, including vitamin C, supplementation up to 1,000 mg/day seems logical. Whether or not it is needed outside of this population is questionable. Perhaps this is why there was also such interest in vitamin C years ago as opposed to recently, because such a large percentage of the population were smokers. It is also possible that the low cost of this supplement does not lead to much industry support for this product and fertility. Regardless of the reason, it still seems appropriate for all patients to be encouraged to eat a healthy diet high in vitamin C.
Some of the best dietary sources of vitamin C are listed in Table 4.2 [45, 104], but keep in mind that although these foods are healthy, one should be careful about getting an excessive amount of calories from them. It is also possible that with the stasis in fruit and vegetable consumption and the growing popularity of the low-carbohydrate dietary programs for weight loss, a consequence of this behavioral change may be a lower intake of citrus fruits, which could lead to lower vitamin C blood levels. Regardless, being able to achieve vitamin C concentrations from diet that are similar to the dosage utilized in clinical trials of supplementation is simply unrealistic. Still, a combination of regular vitamin C intake from food and daily dietary supplementation may be one of the best methods of maintaining adequate ascorbic acid and antioxidant blood levels that could improve fertility.
Table 4.2
Food/beverage sources of vitamin C
Portion size | Vitamin C amount (mg) | |
|---|---|---|
Fruit | ||
Guava | 1 medium | 100 |
Strawberry | 1 cup < div class='tao-gold-member'>
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