madman
Super Moderator
ABSTRACT
Testosterone boosters (TB) are multi-ingredient dietary supplements that have gained popularity among athletes and the general population. However, certain ingredients in TB are associated with adverse events. The aim of the present study was to analyze dietary TB supplements available for sale online on shop.bodybuilding.com and amazon.com in ten distribution area markets. We evaluated the top five best-selling TB and the most frequently used ingredients of 50 selected TB and the evidence for their efficacy and safety, as well as legislation, statements in the European Union (EU) and sports organizations such as the International Olympic Committee (IOC), International Society of Sports Nutrition (ISSN), Australian Institute of Sport(AIS) and World Anti- Doping Agency (WADA). Among 50 TB, 361 components and 98 ingredients were identified. The following ingredients were included in the final review: fenugreek, D- aspartic acid (DAA), 3,3′-diindolylmethane (DIM) or indole-3-carbinol (I3C), Eurycoma longifolia, Cordycepsspp., and ecdysteroids. In the EU authorized health claims refer to a few ingredients in TB, mainly minerals, and vitamins. Some ingredients were recognized by international sports organizations such as the ISSN, AIS, and WADA, and some were identified as unauthorized ingredients/novel food in the EU. Selected ingredients can possibly increase the risk of endocrine system dysregulation.
Introduction
Testosterone boosters (TB) are dietary supplements claimed to enhance testosterone levels. Frequently, producers report that ingredients contained in TB contribute to increased libido, sexual performance, muscle strength, or support physical capacity.[1]
These dietary supplements are gaining popularity among both athletes and the general population. The athletic society may be especially interested in TB, considering the well-established relationship between testosterone levels and strength, power, and speed[2,4] as well as increased awareness of low testosterone-associated relative energy deficiency in sports and its prevalence among both amateur and professional athletes.[5,6] However, reported many unfortunate cases of detection of adulterations or contaminations with anabolic-androgenic steroids (AAS) in dietary supplements. The use of AAS remains prohibited by the World Anti-Doping Agency (WADA).[8,9,11–13]
The increasing popularity of TB dietary supplements emphasizes the need inclusion of some ingredients in selected regulations by the authorities. Some studies with ingredients contained in TB were performed on individuals with late-onset hypogonadism or infertility.[14]
Clemesha et al. showed that on average, one TB contained 8.3 components. Only 24.8% of TB had data that supported claims regarding the impact of their components on testosterone concentration. A total of 10.1% contained components that negatively affected testosterone levels. Many individuals use supra-therapeutic doses of vitamins and minerals, occasionally over the upper tolerable limit, which have associated risks. The authors found that no studies were conducted on the effects of 67 out of 109 individual ingredients, and all performed studies confirmed an increase in the concentration of testosterone only in relation to 12 ingredients.[15]
Our search, which included the ingredient, as well as the term “testosterone,” yielded 191 studies across the 10 most common ingredients in TB, of which only 19% involved human subjects, 53% animal models, 15% in vitro studies, and 12% other types of studies, such as case reports or review articles.[1]
A review by Lazarev et al. showed that out of 15 ingredients frequently used in TB, only 3 showed the strongest evidence: Eurycoma longifolia (Tongkat Ali), ashwagandha, and fenugreek.[14]
Smith et al. indicated that fenugreek and ashwagandha have positive effects on testosterone concentrations in men. Overall, four out of six studies on fenugreek demonstrated significant increases in testosterone concentrations in humans. Supplementation with ashwagandha showed positive findings in three out of four studies in terms of increases in testosterone levels.[16]
The safety of their consumption is another concern. The use of TB is associated with liver injury and nephrotoxic effects.[17,18] Certain TB components may be linked to coagulation and pancreatic disorders.[14]
Regulation-wise, a few organizations have evaluated the efficacy and safety of various ingredients present in TB supplements. Among them is the International Society of Sports Nutrition (ISSN), International Olympic Committee (IOC), and Australian Institute of Sport (AIS), as well as the European Commission (EC) and European Food Safety Authority (EFSA), which provided recommendations in their regulatory documents. The inclusion of these regulations guides athletes, as well as their personnel and the general population, regarding making decisions on dietary supplements/sports nutrition.[19,20,22,23]
In our review, we aimed to evaluate the steroidogenic or ergogenic effects of selected TB components and review safety assessment and its inclusion in the current international or government regulations.
D-aspartic acid
On the basis of the abovementioned studies, DAA was classified as category III as a substance with little to no evidence to support the efficacy and/or safety of the ISSN recommendations.[22] DAA is not included in the IOC consensus statement or recommendations of the AIS.[19,23]
Despite being recognized as safe by regulators, residual information on DAA is present in theItalian document Ministero della Salute “Altri nutrienti e le altre sostanze ad effetto nutritivo ofisiologico.” This document states that in addition to the L-form of aspartic acid, the D form is allowed in dietary supplements [20].
More information on L-aspartic acid is available in the report from the Norwegian ScientificCommittee for Food Safety (VKM) or the Report of the Scientific Committee of the Spanish Agency for Consumer Affairs, Food Safety and Nutrition (AECOSAN) on the conditions of use of certain substances in food supplements.[34,35] A comparison of the enantiomers of D-aspartic acid and L-aspartic acid is shown in Fig. 3
The DAA has not authorized health claims by the EFSA and EC.[36] VKM performed the safety assessment only for L-aspartic acid; according to them, in adults (≥18 years) and adolescents (14 to less than 18 years), doses of 3000, 3500, 4000, 4500, 5000, and 5700 mg/day of L-aspartic acid in dietary supplements may represent a risk of adverse effects.[34] AECOSAN estimated that 490 mg of L-aspartic acid is the maximum daily acceptable quantity for human use as a dietary supplement.[35]
Ecdysteroids
According to the ISSN 2018 recommendations, ecdysterone is included among category III ingredients, which have “Little to No Evidence to Support Efficacy and/or Safety”.[22] Ecdysterone was not included in IOC or AIS statements.[19,23]
R. carthamoides (a source of ecdysterone) is included in the EFSA novel food catalog. According to the status, this product was on the market as a food or food ingredient and was consumed before 1997. Thus, its access to the market is not subject to Novel Food Regulation (EU) 2015/2283, and it is an authorized and approved ingredient. Nonetheless, other specific legislation may restrict placing R.carthamoides on the market as a food or food ingredient in some Member States.[20] The root of R.carthamoides is authorized in food supplements in Belgium and Italy. In the Czech Republic, the entire plant is authorized. In France, the root is authorized, but the substances to be monitored are ecdysterones.[20,80]
A monograph for R. carthamoides is absent in the Ayurvedic Pharmacopoeia of India, the European Medicines Agency (EMA), the WHO monographs, the British Pharmacopoeia, The Korean Pharmacopoeia, the Japanese Pharmacopoeia, and the monograph of European ScientificCooperative on Phytotherapy (ESCOP).[80]
Eurycoma longifolia (quassinoids)
E. longifolia is not included in ISSN, IOC, or AIS recommendations.[19,22,23] In the EU, E. longifoliais an unauthorized novel food.[20] The EFSA Panel concluded that E. longifolia has the potential to induce DNA damage, and its safety has not been established under any condition of use.[43]
Cruciferous vegetables (indole-3-carbinol or 3,3′-diindolylmethane)
Studies have demonstrated that DIM exerts anti-androgenic activity, as well as activates estrogen receptor alpha (ERα). This effect may lead to a pro-estrogenic response, rendering the use of this substance irrational in terms of increasing testosterone levels. Therefore, some authors warn about the administration of DIM and its precursors until further studies show their effectiveness and safety.[94,101–103]
I3C and DIM were included in the CFSAN Adverse Event Reporting System (CAERS). CAERS is a database related to the collection and archiving of information on potential/suspected adverse events associated with products other than medicines, such as foods or dietary supplements.[104 ] In a randomized crossover trial in healthy men and women, consumption of cruciferous vegetables was proven to contribute to decreased levels of IL-6; nonetheless, it had no impact on other inflammatory markers, such as C-reactive protein (CRP) or tumor necrosis factor α (TNF-α).[105]
I3C and DIM were not included in the ISSN, IOC, or AIS recommendations.[19,22,23] In the EU, health claims associated with I3C or DIM have not been authorized by the EFSA and EC. In the past, health claims have been reported for I3C (150–450 mg daily), such as “support to balance the level of sex hormones in the human body needed for the correct function of reproductive organs” or “induction of apoptosis of transformed and damaged cells”; however, they have not been approved in EU.[36]Isolated I3C, and synthetic form of DIM, is considered a novel food ingredient in the EU.[20]
Trigonella foenum-graecum (sapogenins)
According to the ISSN recommendations from 2018, fenugreek was placed in category III of dietary supplements, which have insufficient scientific evidence confirming the effectiveness or safety of use.[22] The IOC and AIS did not include T. foenum-graecum in any group of dietary supplements or ingredients that can support or enhance sports performance.[19,23]
T. foenum-graecum is an authorized ingredient in food and dietary supplements in the EU. Only the seeds of fenugreek were used as the source or raw material for food or dietary supplements within the EU before 1997.[20] The health claims for fenugreek have not been approved by the EFSA and EC, because the cause-and-effect relationship between consumption and corresponding health benefits has not yet been established.[36]
Cordyceps spp. (cordycepin)
Although ISSN mentioned C. sinensis in a previous study, they never included this mushroom in their recommendations through the years 2004, 2010, and 2018.[22,150] C. sinensis has also been mentioned in reports published in The American Journal of Clinical Nutrition.[151]
IOC, similar to AIS, did not recognize Cordyceps spp. in their statements.[19,23] According to EU regulations, only C. sinensis is an authorized ingredient in foods and food supplements. C. militaris is not an authorized ingredient in dietary supplements or foods.[20,80,152]
The EFSA and EC did not approve the following health claims for C. sinensis: antioxidant properties (400–800 mg/day), stimulation of the immune system, and increasing performance during exercise (3 g of dried powder or equivalent extracts).[36]
Conclusions
The most prevalent individual TB components are zinc, Maca, vitamin B6, fenugreek, T. terrestris, DIM (or I3C), black pepper, vitamin D3, magnesium, vitamin B12, DAA, and E. longifolia. Currently, insufficient evidence is available regarding the inclusion of TB in the diets of professional athletes. Selected ingredients are unauthorized novel food in EU such as I3C and DIM, E. longifolia, E.grandiflorum (icariin), and C. yohimbe (yohimbine). Ingredients such as T. terrestris, L. meyenii(Maca), ecdysteroids, and DAA are not recommended based on the current statements of ISSN or AIS. A few ingredients not found in any of reviewed databases – Cissus quadrangularis (ketosterone),hecogenin, and dicyclopentanone. Further studies are needed to evaluate the efficacy and safety of cordyceps spp. (or cordycepin). Fenugreek and E. longifolia have the most promising results based onprevious studies, but the purity and safety of TB are still of concern. TB can pose significant risks of adulteration with prohibited substances.
Some TB, according to the label, contains ingredients that may have a lowering effect on testosterone levels, contrary to consumer expectations. Nevertheless, they are combined with other ingredients that have been proven to stimulate the production of testosterone. Certain TB contain a mixture of several plant materials standardized for saponins, often providing high single (or daily) doses of saponins. Hypothetically, all cases pose a possible risk of endocrine system dysregulation or imbalance. Some ingredients are backed by low scientific evidence and primary animal studies. Many ingredients in TB have been used in ethnomedicine in several countries as traditional aphrodisiac agents that support erections, sex drive, and potency in men. Most ingredients in TB do not have authorized health claims.
In an analysis of TB, only one ingredient – DHEA included in the WADA Prohibited List. Ecdysterone is covered by the Monitoring Program. Nonetheless ecdysterone not included in the EFSA Novel Food Catalog. Three ingredients, colostrum, pregnenolone, and 5α-hydroxylaxogenin are not recommended by WADA or USADA for elite athletes.
Testosterone boosters (TB) are multi-ingredient dietary supplements that have gained popularity among athletes and the general population. However, certain ingredients in TB are associated with adverse events. The aim of the present study was to analyze dietary TB supplements available for sale online on shop.bodybuilding.com and amazon.com in ten distribution area markets. We evaluated the top five best-selling TB and the most frequently used ingredients of 50 selected TB and the evidence for their efficacy and safety, as well as legislation, statements in the European Union (EU) and sports organizations such as the International Olympic Committee (IOC), International Society of Sports Nutrition (ISSN), Australian Institute of Sport(AIS) and World Anti- Doping Agency (WADA). Among 50 TB, 361 components and 98 ingredients were identified. The following ingredients were included in the final review: fenugreek, D- aspartic acid (DAA), 3,3′-diindolylmethane (DIM) or indole-3-carbinol (I3C), Eurycoma longifolia, Cordycepsspp., and ecdysteroids. In the EU authorized health claims refer to a few ingredients in TB, mainly minerals, and vitamins. Some ingredients were recognized by international sports organizations such as the ISSN, AIS, and WADA, and some were identified as unauthorized ingredients/novel food in the EU. Selected ingredients can possibly increase the risk of endocrine system dysregulation.
Introduction
Testosterone boosters (TB) are dietary supplements claimed to enhance testosterone levels. Frequently, producers report that ingredients contained in TB contribute to increased libido, sexual performance, muscle strength, or support physical capacity.[1]
These dietary supplements are gaining popularity among both athletes and the general population. The athletic society may be especially interested in TB, considering the well-established relationship between testosterone levels and strength, power, and speed[2,4] as well as increased awareness of low testosterone-associated relative energy deficiency in sports and its prevalence among both amateur and professional athletes.[5,6] However, reported many unfortunate cases of detection of adulterations or contaminations with anabolic-androgenic steroids (AAS) in dietary supplements. The use of AAS remains prohibited by the World Anti-Doping Agency (WADA).[8,9,11–13]
The increasing popularity of TB dietary supplements emphasizes the need inclusion of some ingredients in selected regulations by the authorities. Some studies with ingredients contained in TB were performed on individuals with late-onset hypogonadism or infertility.[14]
Clemesha et al. showed that on average, one TB contained 8.3 components. Only 24.8% of TB had data that supported claims regarding the impact of their components on testosterone concentration. A total of 10.1% contained components that negatively affected testosterone levels. Many individuals use supra-therapeutic doses of vitamins and minerals, occasionally over the upper tolerable limit, which have associated risks. The authors found that no studies were conducted on the effects of 67 out of 109 individual ingredients, and all performed studies confirmed an increase in the concentration of testosterone only in relation to 12 ingredients.[15]
Our search, which included the ingredient, as well as the term “testosterone,” yielded 191 studies across the 10 most common ingredients in TB, of which only 19% involved human subjects, 53% animal models, 15% in vitro studies, and 12% other types of studies, such as case reports or review articles.[1]
A review by Lazarev et al. showed that out of 15 ingredients frequently used in TB, only 3 showed the strongest evidence: Eurycoma longifolia (Tongkat Ali), ashwagandha, and fenugreek.[14]
Smith et al. indicated that fenugreek and ashwagandha have positive effects on testosterone concentrations in men. Overall, four out of six studies on fenugreek demonstrated significant increases in testosterone concentrations in humans. Supplementation with ashwagandha showed positive findings in three out of four studies in terms of increases in testosterone levels.[16]
The safety of their consumption is another concern. The use of TB is associated with liver injury and nephrotoxic effects.[17,18] Certain TB components may be linked to coagulation and pancreatic disorders.[14]
Regulation-wise, a few organizations have evaluated the efficacy and safety of various ingredients present in TB supplements. Among them is the International Society of Sports Nutrition (ISSN), International Olympic Committee (IOC), and Australian Institute of Sport (AIS), as well as the European Commission (EC) and European Food Safety Authority (EFSA), which provided recommendations in their regulatory documents. The inclusion of these regulations guides athletes, as well as their personnel and the general population, regarding making decisions on dietary supplements/sports nutrition.[19,20,22,23]
In our review, we aimed to evaluate the steroidogenic or ergogenic effects of selected TB components and review safety assessment and its inclusion in the current international or government regulations.
D-aspartic acid
On the basis of the abovementioned studies, DAA was classified as category III as a substance with little to no evidence to support the efficacy and/or safety of the ISSN recommendations.[22] DAA is not included in the IOC consensus statement or recommendations of the AIS.[19,23]
Despite being recognized as safe by regulators, residual information on DAA is present in theItalian document Ministero della Salute “Altri nutrienti e le altre sostanze ad effetto nutritivo ofisiologico.” This document states that in addition to the L-form of aspartic acid, the D form is allowed in dietary supplements [20].
More information on L-aspartic acid is available in the report from the Norwegian ScientificCommittee for Food Safety (VKM) or the Report of the Scientific Committee of the Spanish Agency for Consumer Affairs, Food Safety and Nutrition (AECOSAN) on the conditions of use of certain substances in food supplements.[34,35] A comparison of the enantiomers of D-aspartic acid and L-aspartic acid is shown in Fig. 3
The DAA has not authorized health claims by the EFSA and EC.[36] VKM performed the safety assessment only for L-aspartic acid; according to them, in adults (≥18 years) and adolescents (14 to less than 18 years), doses of 3000, 3500, 4000, 4500, 5000, and 5700 mg/day of L-aspartic acid in dietary supplements may represent a risk of adverse effects.[34] AECOSAN estimated that 490 mg of L-aspartic acid is the maximum daily acceptable quantity for human use as a dietary supplement.[35]
Ecdysteroids
According to the ISSN 2018 recommendations, ecdysterone is included among category III ingredients, which have “Little to No Evidence to Support Efficacy and/or Safety”.[22] Ecdysterone was not included in IOC or AIS statements.[19,23]
R. carthamoides (a source of ecdysterone) is included in the EFSA novel food catalog. According to the status, this product was on the market as a food or food ingredient and was consumed before 1997. Thus, its access to the market is not subject to Novel Food Regulation (EU) 2015/2283, and it is an authorized and approved ingredient. Nonetheless, other specific legislation may restrict placing R.carthamoides on the market as a food or food ingredient in some Member States.[20] The root of R.carthamoides is authorized in food supplements in Belgium and Italy. In the Czech Republic, the entire plant is authorized. In France, the root is authorized, but the substances to be monitored are ecdysterones.[20,80]
A monograph for R. carthamoides is absent in the Ayurvedic Pharmacopoeia of India, the European Medicines Agency (EMA), the WHO monographs, the British Pharmacopoeia, The Korean Pharmacopoeia, the Japanese Pharmacopoeia, and the monograph of European ScientificCooperative on Phytotherapy (ESCOP).[80]
Eurycoma longifolia (quassinoids)
E. longifolia is not included in ISSN, IOC, or AIS recommendations.[19,22,23] In the EU, E. longifoliais an unauthorized novel food.[20] The EFSA Panel concluded that E. longifolia has the potential to induce DNA damage, and its safety has not been established under any condition of use.[43]
Cruciferous vegetables (indole-3-carbinol or 3,3′-diindolylmethane)
Studies have demonstrated that DIM exerts anti-androgenic activity, as well as activates estrogen receptor alpha (ERα). This effect may lead to a pro-estrogenic response, rendering the use of this substance irrational in terms of increasing testosterone levels. Therefore, some authors warn about the administration of DIM and its precursors until further studies show their effectiveness and safety.[94,101–103]
I3C and DIM were included in the CFSAN Adverse Event Reporting System (CAERS). CAERS is a database related to the collection and archiving of information on potential/suspected adverse events associated with products other than medicines, such as foods or dietary supplements.[104 ] In a randomized crossover trial in healthy men and women, consumption of cruciferous vegetables was proven to contribute to decreased levels of IL-6; nonetheless, it had no impact on other inflammatory markers, such as C-reactive protein (CRP) or tumor necrosis factor α (TNF-α).[105]
I3C and DIM were not included in the ISSN, IOC, or AIS recommendations.[19,22,23] In the EU, health claims associated with I3C or DIM have not been authorized by the EFSA and EC. In the past, health claims have been reported for I3C (150–450 mg daily), such as “support to balance the level of sex hormones in the human body needed for the correct function of reproductive organs” or “induction of apoptosis of transformed and damaged cells”; however, they have not been approved in EU.[36]Isolated I3C, and synthetic form of DIM, is considered a novel food ingredient in the EU.[20]
Trigonella foenum-graecum (sapogenins)
According to the ISSN recommendations from 2018, fenugreek was placed in category III of dietary supplements, which have insufficient scientific evidence confirming the effectiveness or safety of use.[22] The IOC and AIS did not include T. foenum-graecum in any group of dietary supplements or ingredients that can support or enhance sports performance.[19,23]
T. foenum-graecum is an authorized ingredient in food and dietary supplements in the EU. Only the seeds of fenugreek were used as the source or raw material for food or dietary supplements within the EU before 1997.[20] The health claims for fenugreek have not been approved by the EFSA and EC, because the cause-and-effect relationship between consumption and corresponding health benefits has not yet been established.[36]
Cordyceps spp. (cordycepin)
Although ISSN mentioned C. sinensis in a previous study, they never included this mushroom in their recommendations through the years 2004, 2010, and 2018.[22,150] C. sinensis has also been mentioned in reports published in The American Journal of Clinical Nutrition.[151]
IOC, similar to AIS, did not recognize Cordyceps spp. in their statements.[19,23] According to EU regulations, only C. sinensis is an authorized ingredient in foods and food supplements. C. militaris is not an authorized ingredient in dietary supplements or foods.[20,80,152]
The EFSA and EC did not approve the following health claims for C. sinensis: antioxidant properties (400–800 mg/day), stimulation of the immune system, and increasing performance during exercise (3 g of dried powder or equivalent extracts).[36]
Conclusions
The most prevalent individual TB components are zinc, Maca, vitamin B6, fenugreek, T. terrestris, DIM (or I3C), black pepper, vitamin D3, magnesium, vitamin B12, DAA, and E. longifolia. Currently, insufficient evidence is available regarding the inclusion of TB in the diets of professional athletes. Selected ingredients are unauthorized novel food in EU such as I3C and DIM, E. longifolia, E.grandiflorum (icariin), and C. yohimbe (yohimbine). Ingredients such as T. terrestris, L. meyenii(Maca), ecdysteroids, and DAA are not recommended based on the current statements of ISSN or AIS. A few ingredients not found in any of reviewed databases – Cissus quadrangularis (ketosterone),hecogenin, and dicyclopentanone. Further studies are needed to evaluate the efficacy and safety of cordyceps spp. (or cordycepin). Fenugreek and E. longifolia have the most promising results based onprevious studies, but the purity and safety of TB are still of concern. TB can pose significant risks of adulteration with prohibited substances.
Some TB, according to the label, contains ingredients that may have a lowering effect on testosterone levels, contrary to consumer expectations. Nevertheless, they are combined with other ingredients that have been proven to stimulate the production of testosterone. Certain TB contain a mixture of several plant materials standardized for saponins, often providing high single (or daily) doses of saponins. Hypothetically, all cases pose a possible risk of endocrine system dysregulation or imbalance. Some ingredients are backed by low scientific evidence and primary animal studies. Many ingredients in TB have been used in ethnomedicine in several countries as traditional aphrodisiac agents that support erections, sex drive, and potency in men. Most ingredients in TB do not have authorized health claims.
In an analysis of TB, only one ingredient – DHEA included in the WADA Prohibited List. Ecdysterone is covered by the Monitoring Program. Nonetheless ecdysterone not included in the EFSA Novel Food Catalog. Three ingredients, colostrum, pregnenolone, and 5α-hydroxylaxogenin are not recommended by WADA or USADA for elite athletes.
