drtbear1967
Musclechemistry Board Certified Member
[h=1]D-Aspartic Acid[/h]
The Holy Grail for male enhancement/performance, life, or sexual enhancement, is boosting testosterone, particularly if it can be done safely and legally. A number of means and methods can boost testosterone, albeit most are temporary and have only a modest effect on enhancements of various sorts. Some methods are consequential to current or anticipated changes in the environment; handling a gun increases testosterone, an obvious advantage in anticipation of meeting a threat or challenge.1
Injecting hCG, or ingesting aromatase inhibitors increase testosterone, but these drugs require a prescription to be obtained and used legally.2,3 Both classes of drug can cause mild side effects in the short-term, and long-term use in males remains unstudied at this time. In fact, over-zealously suppressing estrogen through aromatase inhibition can be detrimental to both health and performance.4,5
The most effective means of increasing testosterone is through the use of exogenous analogs (injectable and oral forms of androgens). Drugs in this class are considered Schedule III controlled substances, carrying substantial legal penalty for use or possession. Further, though millions have used anabolic steroids, the covert potential for harm is nearly completely dwarfed by the tangible and recognized benefits. Anabolic steroids can and have been used [in moderation] for enhancement safely, but the practice of self-administrating black market products introduces so much inconsistency and uncertainty that the concern of legislative agencies is justified. Unfortunately, suppression of research and blockade of access to qualified health care providers has served only to force the practice “underground” and drive a wedge between users and those who would provide care for them. Of course, that is a topic for a later discussion.
A number of dietary supplements have been suggested to boost testosterone for weightlifters. Opinions vary regarding these products, ranging from useless to dubiously promising. Some may remember the promotion of the mineral boron as a testosterone booster over 20 years ago. Initial sales demonstrated the demand in the market for testosterone enhancement among athletes, but ultimately the products failed to deliver. Close scrutiny revealed the initial claims were based upon a study performed on post-menopausal women, hardly the appropriate subjects for verifying testosterone enhancement for healthy young men.6
A follow-up study found no effect of boron on testosterone concentration in men and women over the age of 45.7 Subsequent research has confirmed a role for boron in steroidogenesis, but any benefit seems inconsequential in people eating a complete diet.8 In fact, at least one study suggests boron supplementation may increase circulating estrogen in males.9
Several botanical derivatives (herbs) have been marketed for increasing testosterone. The basis for much of the support relies upon the use of these botanicals in traditional folk medicine (i.e., traditional Chinese medicine, Ayurvedic, etc.).10 The most widely-recognized botanical in this category is Tribulus terrestris. “Trib” was a foundation ingredient in numerous supplements. A number of studies performed in Bulgaria during the 1980s supported the use of Tribestan® for increasing testosterone and androgen-related effects (i.e., libido, erectile function); a later Bulgarian study, and others, found no effect of the Tribulus terrestris extract on testosterone or exercise performance.11-14
Some published studies did demonstrate increases in testosterone, as well as estrogenic hormones, but these involved combination products including androstenedione or other steroidal precursors.15-17 The company which supplies the Tribestan® brand of Tribulus terrestris still makes claims of testosterone increase and improved sexual function/libido, arguing that Tribestan® is a higher quality, naturally-balanced herbal, whereas competing material is lower-grade herb, fortified with the chemical protodioscin, which is believed to be the main active component.18
In the end, demand fell, as little real-world benefit was noted. Published research produced divergent results; increases in testosterone and sexual function were reported in rabbits, rats, and primates; recent human studies demonstrated no effect on testosterone concentration or exercise performance.12,12,19,20
Androgen precursors, or prohormones, entered the market offering a scientifically rational means of increasing testosterone. Testosterone, and other steroidal hormones, are generated in the testes (or ovaries for women) and adrenal glands primarily; synthesized in a step-by-step fashion from “crude” steroids. Testosterone is created from androstenedione, which in turn is generated from DHEA (the process can be traced back several more steps to cholesterol or even more basic precursors, such as squalene).21
By providing an excess of androstenedione, or DHEA, it was postulated that testosterone concentrations would increase correspondingly. Many consumers experienced noticeable gains in mass and strength; the science behind the concept was sound and easily understood. In time, modified forms of precursors appeared, suggesting greater efficiency or conversion to other popular anabolic steroids such as nandrolone (Deca).22 Unfortunately, when the body is flushed with androgen precursors, the end result is not limited to changes in testosterone (or other androgen) concentration. In fact, some products were ineffective at elevating testosterone or improving athletic performance; instead, estrogenic hormones were created from the products resulting in water retention, fat gain, and gynecomastia in some users.23
Many of the products were discovered to be adulterated with actual anabolic steroids, increasing their popularity among many consumers.24 Whether the adulterations were accidental or purposeful, the distribution of banned and/or controlled substances gave cause to the FDA to ban the entire category of products, with the exception of DHEA. As the FDA has classified most prohormones as controlled substances, in the same class as anabolic steroids, the use of such agents is no longer an option for testosterone-boosting.25
In 2002, a major scandal erupted in the sports world. Evidence was seized that cast suspicion on several professional and Olympic athletes that designer drugs, synthesized and distributed in such a manner as to evade doping tests, were used in violation of the ethics and rules of the respective organizations.26
A central character in this network, Victor Conte, operated a nutritional consulting clinic/lab that serviced elite athletes. Conte was also known to low-level, drug-free athletes as the creator of the nutritional supplement ZMA. ZMA (30 mg zinc monomethionine aspartate, 450 mg magnesium aspartate, and 10.5 mg vitamin B-6) was purported to increase circulating testosterone concentration in (American) football players, as determined by a study published in 2000.27
Two subsequent studies refuted the findings, showing that the use of ZMA did not improve exercise performance, body composition, or increase testosterone.28,29 Zinc and magnesium deficiency has been reported in athletes, and there is some science supporting supplementation during periods of intense training. The divergence in results among the studies, as well as the fall in market demand, suggests that zinc and magnesium supplementation, including ZMA, may not provide appreciable results in the real world among men consuming sufficient dietary zinc and magnesium.
Minerals, such as boron, zinc, and magnesium, are not biologically-active in and of themselves. Many minerals are essential co-factors of numerous organic molecules, particularly enzymes. Minerals, as co-enzymes, increase the rate at which certain enzymes are able to drive specific biological reactions. Many of these reactions involve energy (ATP) production and steroidogenesis, offering scientific rationale for their role in sports supplements, at least among those suffering a relative deficiency in one of more of the above.
One component of ZMA that may be no more than consequential in the formulation of that product, but of interest in light of recent research, is the amino acid aspartic acid. The form of zinc and magnesium provided in the product ZMA were chelates. A chelate is a chemical structure wherein a metal is embraced by two organic molecules, such as amino acids. This is necessary to keep the minerals available for absorption and prevent precipitation (basically so the mineral can be dissolved in blood or digestive fluid, rather than forming a crystal). The amino acids used in ZMA are the same as those contained in protein powders. Chemically, these amino acids exist in the L-form; such as L-arginine, L-leucine, and L-tyrosine, some of the familiar amino acids used by bodybuilders and anti-aging advocates.
The human body consumes and utilizes L-amino acids and D-sugars. Many may remember the introduction of D-ribose; others may be surprised to learn that the ubiquitous sugar dextrose is an abbreviation of dextro(rotatory)-glucose. The prefixes L- and D- refer to the optical rotation of the molecule, or “handedness.” The exact same molecule can be “left-handed” or “right-handed.” This may seem to be a trivial difference if the molecule is otherwise exactly the same, but in the world of chemical reactions, it is a huge difference. The biochemical interactions in the body are often described as an orchestra. Imagine how well that orchestra would sound if the musicians were forced to wear gloves on the wrong hands. Suddenly, right and left would be a big deal.
As the diet is composed almost exclusively of L-amino acids, the existence of D-amino acids has been appreciated by relatively few scientists or physicians.30 Research relating to D-amino acids has been nearly non-existent, particularly in humans. Early studies looked at the effect of certain D-amino acids replacing their L-amino acid twins in the diet on growth in chicks and rodents; for the most part, the animals were unable to use the D-amino acids efficiently and growth was stunted.31-33 Once it was determined that D-amino acids had no nutritive value, they were placed into an academic oubliette (a dungeon where prisoners were thrown into a lightless hole, to be forgotten though they lived).
Faint mentions of D-amino acids appeared in life science journals, like a prisoner’s pleas rising through the oubliette grate. Harkening back to the mention of the use of L-aspartic acid in the product ZMA, a string of interesting research has been published on the non-nutritive role of the mirrored twin D-aspartic acid (DAA) on the growth and physiology of living organisms. This research dates back to the 1940s, at the very least.34
Prior to looking at the effect of DAA on physiology, one may wonder: where does DAA arise from, if it is not part of “food?” In fact, for the most part, DAA is created within the body itself. L-aspartic acid is converted to DAA in a time-dependent fashion, and it is also generated through the actions of a racemase enzyme in certain tissues.35 DAA can be degraded by another enzyme, amino acid oxidase.36 These reactions occur in humans, animals, even bacteria. Thus, DAA is both an endogenous substance and part of the natural food supply; exactly the type of bio-molecule that organisms evolve/adapt to use as a means of monitoring and responding to the environment.
To anticipate where DAA may have a physiologic action, one can attempt to identify where the amino acid is present in any significant concentration. DAA is present in many tissues with low protein turnover, such as intervertebral disc, tooth enamel, and the lens of the eye.30 By measuring the ratio of DAA to L-aspartic acid, forensic specialists and archeologists believe they can estimate age. The DAA in such low turnover proteins is likely a non-enzymatic consequence of time that does not have an active role in physiology.
Other tissues where DAA accumulates are metabolically-active sites, where both racemase and oxidase reside. The controlled production and degradation of a simple molecule is further suggestion of possible function as a signaling hormone or para-hormone. Where exactly are these sites? Three areas of distinct interest, particularly to bodybuilders and male athletes, are the hypothalamus, pituitary, and testes.37 The hypothalamus monitors the concentration of certain hormones and other factors (e.g., osmolality).
In response to threshold events, regulatory hormones are raised or lowered accordingly. These hormones travel directly to the pituitary, a gland in the brain that releases stimulatory hormones into the bloodstream that affect metabolism and physiology. The testes are the “balls” and the source of testosterone. The testosterone concentration of normal, drug-free men is regulated as such: testosterone concentration is tracked by hypothalamus which monitors metabolites of testosterone (DHT and estradiol); when the hypothalamus detects that circulating testosterone is low, it releases LHRH; LHRH stimulates cells in the pituitary called luteotrophs, releasing LH; LH enters the bloodstream, traveling to the testes, stimulating the production of testosterone which enters the bloodstream. As circulating testosterone elevates, LHRH release slows down, reducing LH release and thus testosterone production.38 Testosterone rises up and down within a fairly well-defined range, based upon this regulatory mechanism.
Testosterone and other anabolic steroids decrease testes function (and size) as they maintain an artificially high concentration of testosterone metabolites, which the hypothalamus interprets as testosterone overload. [The hypothalamus apparently never went to medical school.] Bodybuilders restart testes function after their cycle ends by injecting hCG which has the same function (in men) as LH; aromatase inhibitors or SERMs are used to alleviate estrogen-related suppression of LHRH. A drug used for certain hormone-sensitive tumors called Lupron® also stimulates the LHRH receptors on the pituitary, but does it so potently that it effectively burns the pituitary out.39 Hopefully, no bodybuilders have used this drug indiscriminately.
As stated before, drug-free men with normal testes function can increase circulating testosterone concentration by using hCG. The increase in testosterone is usually accompanied by an increase in estrogen, as estradiol is formed from testosterone.40 Yet, hCG requires a prescription to be obtained and used legally; it is also an injectable drug, making it less convenient and an unattractive option to those averse to needles.
It is suggested that prolonged [physiologic] excess of LH (the pituitary hormone) and hCG could also downregulate testicular function, just as the drug Lupron® does by design.41 This background should provide an understanding, allowing people to appreciate the potential value of DAA as a testosterone booster, based upon published studies. Some of the data, including the most recent, is based on human data; the remainder come from animal models or test tube data.
The coming explosion of media coverage and undoubtedly dietary supplements is inspired by a study published in the journal Reproductive Biology and Endocrinology.42 In this study, performed by scientists and physicians in Italy, the role and mechanisms of DAA relating to testosterone and LH in humans and rats was evaluated and reported. To sum the study’s finding in the briefest and most relevant manner: DAA was found to accumulate in the pituitary and testes (in rats); in humans, DAA increased circulating (blood) LH by 33 percent (p<0.0001) and testosterone concentration by 42 percent (p<0.0082) on average, in men aged 27-37 years, after taking slightly more than 3 grams a day, orally.
Consider that closely; taking a flat teaspoon full of an amino acid (DAA) daily increased testosterone about 40 percent on average in healthy men who were at their peak of natural testosterone production. This was not castrated rats, elderly men, post-menopausal women, or men suffering from low testosterone. This was not a vaguely-defined herbal extract, steroidal prohormone, or dietary ingredient that only works if there is a deficiency.
DAA did not elevate testosterone at the cost of pituitary suppression; in fact, it increased pituitary stimulation of the testes, while directly stimulating the testes, offering a two-pathway effect. The effect was seen in the human subjects, as well as the rats, and has been reported in reptiles and birds, suggesting it is a highly-preserved pathway along the eons old time-trail of evolution/adaptation.43-45
It is also critical to note that no adverse effects were noted in the human or animal trials. These results followed just 12 days of DAA use; however, testosterone concentration began to return to baseline value just three days after DAA treatment stopped.42 [The human study used a blended product combining DAA with specific B-vitamins, but the rat data was based upon DAA consumption only and was equally impressive.]
This entire article could have began and ended with just the preceding paragraph, and still captured the attention of every single reader. Yet, there are some who wish to understand what explains these findings. Honestly, every reader who pursues this topic (DAA) by reading more or purchasing the inevitable product offerings should make the effort to evaluate the mechanisms involved so as to better educate himself, so that any decision to use or pass on this ingredient is made as an informed consumer.
As noted earlier, the existence of D- forms of amino acids has been known for many, many decades. As living organisms use only the L- form of amino acids to meet structural (e.g., muscle tissue) or functional (e.g., enzymes) needs, and the inclusion of D- forms of amino acids in the diet was learned to be detrimental to growth, D- form amino acids were little considered.31-33 However, as analytic methods became more fine, it was discovered that D-amino acids were present in certain locations and tissue types. Some areas accumulated D-amino acids as a result of aging changes; others seem to generate free D-amino acids, suggesting certain D-amino acids may have a functional role— similar to neurotransmitters, hormones, or secondary messengers.
It is suggested that prolonged [physiologic] excess of LH (the pituitary hormone) and hCG could also downregulate testicular function, just as the drug Lupron® does by design.41 This background should provide an understanding, allowing people to appreciate the potential value of DAA as a testosterone booster, based upon published studies. Some of the data, including the most recent, is based on human data; the remainder come from animal models or test tube data.
The coming explosion of media coverage and undoubtedly dietary supplements is inspired by a study published in the journal Reproductive Biology and Endocrinology.42 In this study, performed by scientists and physicians in Italy, the role and mechanisms of DAA relating to testosterone and LH in humans and rats was evaluated and reported. To sum the study’s finding in the briefest and most relevant manner: DAA was found to accumulate in the pituitary and testes (in rats); in humans, DAA increased circulating (blood) LH by 33 percent (p<0.0001) and testosterone concentration by 42 percent (p<0.0082) on average, in men aged 27-37 years, after taking slightly more than 3 grams a day, orally.
Consider that closely; taking a flat teaspoon full of an amino acid (DAA) daily increased testosterone about 40 percent on average in healthy men who were at their peak of natural testosterone production. This was not castrated rats, elderly men, post-menopausal women, or men suffering from low testosterone. This was not a vaguely-defined herbal extract, steroidal prohormone, or dietary ingredient that only works if there is a deficiency.
DAA did not elevate testosterone at the cost of pituitary suppression; in fact, it increased pituitary stimulation of the testes, while directly stimulating the testes, offering a two-pathway effect. The effect was seen in the human subjects, as well as the rats, and has been reported in reptiles and birds, suggesting it is a highly-preserved pathway along the eons old time-trail of evolution/adaptation.43-45
It is also critical to note that no adverse effects were noted in the human or animal trials. These results followed just 12 days of DAA use; however, testosterone concentration began to return to baseline value just three days after DAA treatment stopped.42 [The human study used a blended product combining DAA with specific B-vitamins, but the rat data was based upon DAA consumption only and was equally impressive.]
This entire article could have began and ended with just the preceding paragraph, and still captured the attention of every single reader. Yet, there are some who wish to understand what explains these findings. Honestly, every reader who pursues this topic (DAA) by reading more or purchasing the inevitable product offerings should make the effort to evaluate the mechanisms involved so as to better educate himself, so that any decision to use or pass on this ingredient is made as an informed consumer.
As noted earlier, the existence of D- forms of amino acids has been known for many, many decades. As living organisms use only the L- form of amino acids to meet structural (e.g., muscle tissue) or functional (e.g., enzymes) needs, and the inclusion of D- forms of amino acids in the diet was learned to be detrimental to growth, D- form amino acids were little considered.31-33 However, as analytic methods became more fine, it was discovered that D-amino acids were present in certain locations and tissue types. Some areas accumulated D-amino acids as a result of aging changes; others seem to generate free D-amino acids, suggesting certain D-amino acids may have a functional role— similar to neurotransmitters, hormones, or secondary messengers.
The potential for D-amino acids to act as neurotransmitters is not difficult to accept. Many neurotransmitters are derivatives of amino acids, such as dopamine and serotonin which arise from tyrosine and tryptophan respectively.46 Another amino acid which is a neurotransmitter is glutamic acid; the flavor-enhancer MSG is glutamate (the salt form of glutamic acid), and sensitive individuals can suffer debilitating headaches if they consume MSG.
The practice of using MSG or glutamic acid-rich seaweed extract in Asian cooking caused MSG-induced headaches to be known as Chinese Restaurant Syndrome many years ago.47 Interestingly, a synthetic (lab-created) amino acid called N-methyl-D-aspartate (NMDA), was found to activate only a specific subset of glutamate receptors in the brain. NMDA is so potent at stimulating the NMDA-sensitive nerves that it over-excites them and the nerve dies. A very valuable trait in the lab, but toxic in high concentration to living organisms— which is why NMDA is classified as an excitotoxin.
Of course, NMDA-sensitive nerves exist for a purpose, and certain mental health conditions appear to be associated with an understimulation of these (NMDA-sensitive) nerves, such as the condition schizophrenia.48 Even more interesting for those so inclined to gain a broad awareness, D-serine (another D-form amino acid) acts to enhance activity of the NMDA-subtype of the glutamate receptor.49 This rambles a bit, but it shows that not only are amino acids either directly or indirectly used as neurotransmitters, but D-forms of certain amino acids have an endogenous role in central nervous system (brain) function.
DAA has been found to be present in, and accumulate in following peripheral injection or ingestion, both white and grey matter of the brain. White matter refers to cells that insulate and protect the nerve cells that actually produce thought or respond to the environment. Grey cells are nerve cells. The same group that published the DAA testosterone paper also has another peer-reviewed paper accepted, showing that DAA supplementation improved learning and memory in rats; it also showed untreated rats who were better learners had higher concentrations of DAA in the hippocampus (a region of the brain).50
More relevant to those interested in the testosterone-associated pathways, research published in 2007 showed DAA is present in nerve endings and is released when the nerve is stimulated, confirming its function as a neurotransmitter.44 DAA stimulation increases cyclic AMP (cAMP) in the “receiving” nerves. In the neuroendocrine axis (the hypothalamus and pituitary), DAA enhances the release of GnRH (the hormone that tells the pituitary that testosterone concentration is falling), as well as the production of two other hormones, oxytocin and vasopressin.
37,44
At the pituitary, DAA stimulates the secretion of three hormones: LH (testosterone-related), prolactin (promotes milk production in nursing mothers, sexual gratification, and in excess can impair libido and erectile function), and GH (growth hormone).37,44 Unfortunately, the Italian study did not measure changes in prolactin or GH/IGF-1 concentrations in the human subjects. Bodybuilders, athletes and anti-aging advocates, particularly those prone to gynecomastia or suffering from erectile dysfunction, may wish to delay using a DAA-based product until data relating to potential increases in prolactin are available.
The function of DAA is not solely as a neurotransmitter, though its effectiveness and oral bioavailability alone makes this intriguing. It also appears to have function at the testes directly, acting as a paracrine-hormone (a chemical that communicates with nearby cells). In rat testes, DAA has been shown to increase testosterone release (more than doubling testosterone synthesis), by increasing the concentration of cAMP, a secondary messenger that stimulates cell response to hormones.
42 DAA holds the potential to be an effective testosterone booster, available as a dietary supplement. It appears to satisfy the criteria to be considered a DSHEA-eligible candidate, being an endogenous bio-molecule, and present in common food products.33
DAA accumulates in tissues involved in sex steroid production (hypothalamus, pituitary, and testes); sites where enzymes involved in DAA production and clearance are present. Its activity has been demonstrated in numerous biological models, including human subjects, to increase circulating testosterone and LH concentration. It has been shown in tissue cultures to increase secondary messengers involved in testosterone synthesis or regulation. Its testosterone-boosting properties are not suppressive to the hypothalamic-pituitary axis, supporting rather than suppressing normal reproductive function. It may even aid in sperm maturation.
If no adverse effects are noted with DAA use, who could benefit? Seemingly, most adult men may benefit from DAA supplementation. In addition to the positive effects of increasing testosterone production, possibly enhancing physical and sexual performance, DAA supplementation may aid in learning and memory. Even anabolic steroid-using athletes could possibly benefit from DAA supplementation, as it may reduce the suppressive effect of anabolic steroids on natural testosterone production, and/or maintain testes sensitivity to LH/hCG, and/or maintain testes size/function on-cycle. DAA could also be a potent adjunct to hCG as part of post-cycle recovery, though all these concepts would need to be studied before any claim could be made.
DAA. It sounds like a do-it-all wonder product, which is usually the first warning sign of market fraud. However, given the research supporting this amino acid as a neurotransmitter and neuroendocrine agent in man, rats, and reptiles, it holds more promise than most unproven products. When DAA products arrive on the market, and they inevitably will, consumers should look for a company that: 1) tests the raw material received from their supplier, as it would be simple to substitute L-aspartic acid; 2) performs clinical testing to show that the marketed product increases testosterone and LH (possibly GH/IGF-1 as well); 3) justifies the inevitable “kitchen sink” of added ingredients; 4) tests to assure that prolactin and estradiol concentrations are not elevated above physiologic normal range. Times are hard for everyone right now, but it is critical that consumers support only such companies, as the low road companies will be able to undercut more ethical companies by cutting corners to cut cost.
A number of questions remain to be considered. There is no documented evidence that DAA would increase testosterone in women. In fact, in the lizard study, testosterone decreased in female lizards, though estrogen was elevated.51 There appear to be benefits to mental function, and possibly protective effects against certain psychological states, but it is unknown what effect DAA will have long-term. The long-term safety of supplementing DAA has not been studied; neither has the therapeutic range. It should be noted that higher doses did not generate significantly higher testosterone response.42 Thus, it is critical (yes, I am using that word again) that consumers monitor changes in mood, concentration, and physical symptoms. At the first sign of gynecomastia or mood changes, DAA use should be discontinued. The effect of DAA on developing brains and sexually immature subjects has not been studied in humans. Therefore, DAA should not be given to children or adolescents. It would be a shame to see a potentially beneficial product removed from the market, due to irresponsible use.
References:
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39. Ravivarapu HB, Moyer KL, et al. Sustained suppression of pituitary-gonadal axis with an injectable, in situ forming implant of leuprolide acetate. J Pharm Sci, 2000 Jun;89(6):732-41.
40. Cailleux-Bounacer A, Reznik Y, et al. Evaluation of endocrine testing of Leydig cell function using extractive and recombinant human chorionic gonadotropin and different doses of recombinant human LH in normal men. Eur J Endocrinol, 2008 Aug;159(2):171-8.
41. Dufau ML, Tsai-Morris C, et al. Regulation of steroidogenic enzymes and a novel testicular RNA helicase. J Steroid Biochem Mol Biol, 2001 Jan-Mar;76(1-5):187-97.
42. Topo E, Soricelli A, et al. The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. Reprod Biol Endocrinol, 2009 Oct 27;7:120.
43. D’Aniello A, Di Cosmo A, et al. Involvement of D-aspartic acid in the synthesis of testosterone in rat testes. Life Sci, 1996;59(2):97-104.
44. D’Aniello A. D-Aspartic acid: an endogenous amino acid with an important neuroendocrine role. Brain Res Rev, 2007 Feb;53(2):215-34.
45. Raucci F, D’Aniello S, et al. Endocrine roles of D-aspartic acid in the testis of lizard Podarcis s. sicula. J Endocrinol, 2005 Dec;187(3):347-59.
46. Fernstrom JD, Fernstrom MH. Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J Nutr, 2007 Jun;137(6 Suppl 1):1539S-1547S.
47. Geha RS, Beiser A, et al. Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study. J Nutr, 2000 Apr;130(4S Suppl):1058S-62S.
48. Bennett M. Positive and negative symptoms in schizophrenia: the NMDA receptor hypofunction hypothesis, neuregulin/ErbB4 and synapse regression. Aust N Z J Psychiatry, 2009 Aug;43(8):711-21.
49. Tsai G, Yang P, et al. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry, 1998 Dec 1;44(11):1081-9.
50. Topo E, Soricelli A, et al. Evidence for the involvement of D: -aspartic acid in learning and memory of rat. Amino Acids, 2009 Nov 5. [Epub ahead of print]
51. Assisi L, Botte V, et al. Enhancement of aromatase activity by D-aspartic acid in the ovary of the lizard Podarcis s. sicula. Reproduction, 2001 May;121(5):803
The Holy Grail for male enhancement/performance, life, or sexual enhancement, is boosting testosterone, particularly if it can be done safely and legally. A number of means and methods can boost testosterone, albeit most are temporary and have only a modest effect on enhancements of various sorts. Some methods are consequential to current or anticipated changes in the environment; handling a gun increases testosterone, an obvious advantage in anticipation of meeting a threat or challenge.1
Injecting hCG, or ingesting aromatase inhibitors increase testosterone, but these drugs require a prescription to be obtained and used legally.2,3 Both classes of drug can cause mild side effects in the short-term, and long-term use in males remains unstudied at this time. In fact, over-zealously suppressing estrogen through aromatase inhibition can be detrimental to both health and performance.4,5
The most effective means of increasing testosterone is through the use of exogenous analogs (injectable and oral forms of androgens). Drugs in this class are considered Schedule III controlled substances, carrying substantial legal penalty for use or possession. Further, though millions have used anabolic steroids, the covert potential for harm is nearly completely dwarfed by the tangible and recognized benefits. Anabolic steroids can and have been used [in moderation] for enhancement safely, but the practice of self-administrating black market products introduces so much inconsistency and uncertainty that the concern of legislative agencies is justified. Unfortunately, suppression of research and blockade of access to qualified health care providers has served only to force the practice “underground” and drive a wedge between users and those who would provide care for them. Of course, that is a topic for a later discussion.
A number of dietary supplements have been suggested to boost testosterone for weightlifters. Opinions vary regarding these products, ranging from useless to dubiously promising. Some may remember the promotion of the mineral boron as a testosterone booster over 20 years ago. Initial sales demonstrated the demand in the market for testosterone enhancement among athletes, but ultimately the products failed to deliver. Close scrutiny revealed the initial claims were based upon a study performed on post-menopausal women, hardly the appropriate subjects for verifying testosterone enhancement for healthy young men.6
A follow-up study found no effect of boron on testosterone concentration in men and women over the age of 45.7 Subsequent research has confirmed a role for boron in steroidogenesis, but any benefit seems inconsequential in people eating a complete diet.8 In fact, at least one study suggests boron supplementation may increase circulating estrogen in males.9
Several botanical derivatives (herbs) have been marketed for increasing testosterone. The basis for much of the support relies upon the use of these botanicals in traditional folk medicine (i.e., traditional Chinese medicine, Ayurvedic, etc.).10 The most widely-recognized botanical in this category is Tribulus terrestris. “Trib” was a foundation ingredient in numerous supplements. A number of studies performed in Bulgaria during the 1980s supported the use of Tribestan® for increasing testosterone and androgen-related effects (i.e., libido, erectile function); a later Bulgarian study, and others, found no effect of the Tribulus terrestris extract on testosterone or exercise performance.11-14
Some published studies did demonstrate increases in testosterone, as well as estrogenic hormones, but these involved combination products including androstenedione or other steroidal precursors.15-17 The company which supplies the Tribestan® brand of Tribulus terrestris still makes claims of testosterone increase and improved sexual function/libido, arguing that Tribestan® is a higher quality, naturally-balanced herbal, whereas competing material is lower-grade herb, fortified with the chemical protodioscin, which is believed to be the main active component.18
In the end, demand fell, as little real-world benefit was noted. Published research produced divergent results; increases in testosterone and sexual function were reported in rabbits, rats, and primates; recent human studies demonstrated no effect on testosterone concentration or exercise performance.12,12,19,20
Androgen precursors, or prohormones, entered the market offering a scientifically rational means of increasing testosterone. Testosterone, and other steroidal hormones, are generated in the testes (or ovaries for women) and adrenal glands primarily; synthesized in a step-by-step fashion from “crude” steroids. Testosterone is created from androstenedione, which in turn is generated from DHEA (the process can be traced back several more steps to cholesterol or even more basic precursors, such as squalene).21
By providing an excess of androstenedione, or DHEA, it was postulated that testosterone concentrations would increase correspondingly. Many consumers experienced noticeable gains in mass and strength; the science behind the concept was sound and easily understood. In time, modified forms of precursors appeared, suggesting greater efficiency or conversion to other popular anabolic steroids such as nandrolone (Deca).22 Unfortunately, when the body is flushed with androgen precursors, the end result is not limited to changes in testosterone (or other androgen) concentration. In fact, some products were ineffective at elevating testosterone or improving athletic performance; instead, estrogenic hormones were created from the products resulting in water retention, fat gain, and gynecomastia in some users.23
Many of the products were discovered to be adulterated with actual anabolic steroids, increasing their popularity among many consumers.24 Whether the adulterations were accidental or purposeful, the distribution of banned and/or controlled substances gave cause to the FDA to ban the entire category of products, with the exception of DHEA. As the FDA has classified most prohormones as controlled substances, in the same class as anabolic steroids, the use of such agents is no longer an option for testosterone-boosting.25
In 2002, a major scandal erupted in the sports world. Evidence was seized that cast suspicion on several professional and Olympic athletes that designer drugs, synthesized and distributed in such a manner as to evade doping tests, were used in violation of the ethics and rules of the respective organizations.26
A central character in this network, Victor Conte, operated a nutritional consulting clinic/lab that serviced elite athletes. Conte was also known to low-level, drug-free athletes as the creator of the nutritional supplement ZMA. ZMA (30 mg zinc monomethionine aspartate, 450 mg magnesium aspartate, and 10.5 mg vitamin B-6) was purported to increase circulating testosterone concentration in (American) football players, as determined by a study published in 2000.27
Two subsequent studies refuted the findings, showing that the use of ZMA did not improve exercise performance, body composition, or increase testosterone.28,29 Zinc and magnesium deficiency has been reported in athletes, and there is some science supporting supplementation during periods of intense training. The divergence in results among the studies, as well as the fall in market demand, suggests that zinc and magnesium supplementation, including ZMA, may not provide appreciable results in the real world among men consuming sufficient dietary zinc and magnesium.
Minerals, such as boron, zinc, and magnesium, are not biologically-active in and of themselves. Many minerals are essential co-factors of numerous organic molecules, particularly enzymes. Minerals, as co-enzymes, increase the rate at which certain enzymes are able to drive specific biological reactions. Many of these reactions involve energy (ATP) production and steroidogenesis, offering scientific rationale for their role in sports supplements, at least among those suffering a relative deficiency in one of more of the above.
One component of ZMA that may be no more than consequential in the formulation of that product, but of interest in light of recent research, is the amino acid aspartic acid. The form of zinc and magnesium provided in the product ZMA were chelates. A chelate is a chemical structure wherein a metal is embraced by two organic molecules, such as amino acids. This is necessary to keep the minerals available for absorption and prevent precipitation (basically so the mineral can be dissolved in blood or digestive fluid, rather than forming a crystal). The amino acids used in ZMA are the same as those contained in protein powders. Chemically, these amino acids exist in the L-form; such as L-arginine, L-leucine, and L-tyrosine, some of the familiar amino acids used by bodybuilders and anti-aging advocates.
The human body consumes and utilizes L-amino acids and D-sugars. Many may remember the introduction of D-ribose; others may be surprised to learn that the ubiquitous sugar dextrose is an abbreviation of dextro(rotatory)-glucose. The prefixes L- and D- refer to the optical rotation of the molecule, or “handedness.” The exact same molecule can be “left-handed” or “right-handed.” This may seem to be a trivial difference if the molecule is otherwise exactly the same, but in the world of chemical reactions, it is a huge difference. The biochemical interactions in the body are often described as an orchestra. Imagine how well that orchestra would sound if the musicians were forced to wear gloves on the wrong hands. Suddenly, right and left would be a big deal.
As the diet is composed almost exclusively of L-amino acids, the existence of D-amino acids has been appreciated by relatively few scientists or physicians.30 Research relating to D-amino acids has been nearly non-existent, particularly in humans. Early studies looked at the effect of certain D-amino acids replacing their L-amino acid twins in the diet on growth in chicks and rodents; for the most part, the animals were unable to use the D-amino acids efficiently and growth was stunted.31-33 Once it was determined that D-amino acids had no nutritive value, they were placed into an academic oubliette (a dungeon where prisoners were thrown into a lightless hole, to be forgotten though they lived).
Faint mentions of D-amino acids appeared in life science journals, like a prisoner’s pleas rising through the oubliette grate. Harkening back to the mention of the use of L-aspartic acid in the product ZMA, a string of interesting research has been published on the non-nutritive role of the mirrored twin D-aspartic acid (DAA) on the growth and physiology of living organisms. This research dates back to the 1940s, at the very least.34
Prior to looking at the effect of DAA on physiology, one may wonder: where does DAA arise from, if it is not part of “food?” In fact, for the most part, DAA is created within the body itself. L-aspartic acid is converted to DAA in a time-dependent fashion, and it is also generated through the actions of a racemase enzyme in certain tissues.35 DAA can be degraded by another enzyme, amino acid oxidase.36 These reactions occur in humans, animals, even bacteria. Thus, DAA is both an endogenous substance and part of the natural food supply; exactly the type of bio-molecule that organisms evolve/adapt to use as a means of monitoring and responding to the environment.
To anticipate where DAA may have a physiologic action, one can attempt to identify where the amino acid is present in any significant concentration. DAA is present in many tissues with low protein turnover, such as intervertebral disc, tooth enamel, and the lens of the eye.30 By measuring the ratio of DAA to L-aspartic acid, forensic specialists and archeologists believe they can estimate age. The DAA in such low turnover proteins is likely a non-enzymatic consequence of time that does not have an active role in physiology.
Other tissues where DAA accumulates are metabolically-active sites, where both racemase and oxidase reside. The controlled production and degradation of a simple molecule is further suggestion of possible function as a signaling hormone or para-hormone. Where exactly are these sites? Three areas of distinct interest, particularly to bodybuilders and male athletes, are the hypothalamus, pituitary, and testes.37 The hypothalamus monitors the concentration of certain hormones and other factors (e.g., osmolality).
In response to threshold events, regulatory hormones are raised or lowered accordingly. These hormones travel directly to the pituitary, a gland in the brain that releases stimulatory hormones into the bloodstream that affect metabolism and physiology. The testes are the “balls” and the source of testosterone. The testosterone concentration of normal, drug-free men is regulated as such: testosterone concentration is tracked by hypothalamus which monitors metabolites of testosterone (DHT and estradiol); when the hypothalamus detects that circulating testosterone is low, it releases LHRH; LHRH stimulates cells in the pituitary called luteotrophs, releasing LH; LH enters the bloodstream, traveling to the testes, stimulating the production of testosterone which enters the bloodstream. As circulating testosterone elevates, LHRH release slows down, reducing LH release and thus testosterone production.38 Testosterone rises up and down within a fairly well-defined range, based upon this regulatory mechanism.
Testosterone and other anabolic steroids decrease testes function (and size) as they maintain an artificially high concentration of testosterone metabolites, which the hypothalamus interprets as testosterone overload. [The hypothalamus apparently never went to medical school.] Bodybuilders restart testes function after their cycle ends by injecting hCG which has the same function (in men) as LH; aromatase inhibitors or SERMs are used to alleviate estrogen-related suppression of LHRH. A drug used for certain hormone-sensitive tumors called Lupron® also stimulates the LHRH receptors on the pituitary, but does it so potently that it effectively burns the pituitary out.39 Hopefully, no bodybuilders have used this drug indiscriminately.
As stated before, drug-free men with normal testes function can increase circulating testosterone concentration by using hCG. The increase in testosterone is usually accompanied by an increase in estrogen, as estradiol is formed from testosterone.40 Yet, hCG requires a prescription to be obtained and used legally; it is also an injectable drug, making it less convenient and an unattractive option to those averse to needles.
It is suggested that prolonged [physiologic] excess of LH (the pituitary hormone) and hCG could also downregulate testicular function, just as the drug Lupron® does by design.41 This background should provide an understanding, allowing people to appreciate the potential value of DAA as a testosterone booster, based upon published studies. Some of the data, including the most recent, is based on human data; the remainder come from animal models or test tube data.
The coming explosion of media coverage and undoubtedly dietary supplements is inspired by a study published in the journal Reproductive Biology and Endocrinology.42 In this study, performed by scientists and physicians in Italy, the role and mechanisms of DAA relating to testosterone and LH in humans and rats was evaluated and reported. To sum the study’s finding in the briefest and most relevant manner: DAA was found to accumulate in the pituitary and testes (in rats); in humans, DAA increased circulating (blood) LH by 33 percent (p<0.0001) and testosterone concentration by 42 percent (p<0.0082) on average, in men aged 27-37 years, after taking slightly more than 3 grams a day, orally.
Consider that closely; taking a flat teaspoon full of an amino acid (DAA) daily increased testosterone about 40 percent on average in healthy men who were at their peak of natural testosterone production. This was not castrated rats, elderly men, post-menopausal women, or men suffering from low testosterone. This was not a vaguely-defined herbal extract, steroidal prohormone, or dietary ingredient that only works if there is a deficiency.
DAA did not elevate testosterone at the cost of pituitary suppression; in fact, it increased pituitary stimulation of the testes, while directly stimulating the testes, offering a two-pathway effect. The effect was seen in the human subjects, as well as the rats, and has been reported in reptiles and birds, suggesting it is a highly-preserved pathway along the eons old time-trail of evolution/adaptation.43-45
It is also critical to note that no adverse effects were noted in the human or animal trials. These results followed just 12 days of DAA use; however, testosterone concentration began to return to baseline value just three days after DAA treatment stopped.42 [The human study used a blended product combining DAA with specific B-vitamins, but the rat data was based upon DAA consumption only and was equally impressive.]
This entire article could have began and ended with just the preceding paragraph, and still captured the attention of every single reader. Yet, there are some who wish to understand what explains these findings. Honestly, every reader who pursues this topic (DAA) by reading more or purchasing the inevitable product offerings should make the effort to evaluate the mechanisms involved so as to better educate himself, so that any decision to use or pass on this ingredient is made as an informed consumer.
As noted earlier, the existence of D- forms of amino acids has been known for many, many decades. As living organisms use only the L- form of amino acids to meet structural (e.g., muscle tissue) or functional (e.g., enzymes) needs, and the inclusion of D- forms of amino acids in the diet was learned to be detrimental to growth, D- form amino acids were little considered.31-33 However, as analytic methods became more fine, it was discovered that D-amino acids were present in certain locations and tissue types. Some areas accumulated D-amino acids as a result of aging changes; others seem to generate free D-amino acids, suggesting certain D-amino acids may have a functional role— similar to neurotransmitters, hormones, or secondary messengers.
It is suggested that prolonged [physiologic] excess of LH (the pituitary hormone) and hCG could also downregulate testicular function, just as the drug Lupron® does by design.41 This background should provide an understanding, allowing people to appreciate the potential value of DAA as a testosterone booster, based upon published studies. Some of the data, including the most recent, is based on human data; the remainder come from animal models or test tube data.
The coming explosion of media coverage and undoubtedly dietary supplements is inspired by a study published in the journal Reproductive Biology and Endocrinology.42 In this study, performed by scientists and physicians in Italy, the role and mechanisms of DAA relating to testosterone and LH in humans and rats was evaluated and reported. To sum the study’s finding in the briefest and most relevant manner: DAA was found to accumulate in the pituitary and testes (in rats); in humans, DAA increased circulating (blood) LH by 33 percent (p<0.0001) and testosterone concentration by 42 percent (p<0.0082) on average, in men aged 27-37 years, after taking slightly more than 3 grams a day, orally.
Consider that closely; taking a flat teaspoon full of an amino acid (DAA) daily increased testosterone about 40 percent on average in healthy men who were at their peak of natural testosterone production. This was not castrated rats, elderly men, post-menopausal women, or men suffering from low testosterone. This was not a vaguely-defined herbal extract, steroidal prohormone, or dietary ingredient that only works if there is a deficiency.
DAA did not elevate testosterone at the cost of pituitary suppression; in fact, it increased pituitary stimulation of the testes, while directly stimulating the testes, offering a two-pathway effect. The effect was seen in the human subjects, as well as the rats, and has been reported in reptiles and birds, suggesting it is a highly-preserved pathway along the eons old time-trail of evolution/adaptation.43-45
It is also critical to note that no adverse effects were noted in the human or animal trials. These results followed just 12 days of DAA use; however, testosterone concentration began to return to baseline value just three days after DAA treatment stopped.42 [The human study used a blended product combining DAA with specific B-vitamins, but the rat data was based upon DAA consumption only and was equally impressive.]
This entire article could have began and ended with just the preceding paragraph, and still captured the attention of every single reader. Yet, there are some who wish to understand what explains these findings. Honestly, every reader who pursues this topic (DAA) by reading more or purchasing the inevitable product offerings should make the effort to evaluate the mechanisms involved so as to better educate himself, so that any decision to use or pass on this ingredient is made as an informed consumer.
As noted earlier, the existence of D- forms of amino acids has been known for many, many decades. As living organisms use only the L- form of amino acids to meet structural (e.g., muscle tissue) or functional (e.g., enzymes) needs, and the inclusion of D- forms of amino acids in the diet was learned to be detrimental to growth, D- form amino acids were little considered.31-33 However, as analytic methods became more fine, it was discovered that D-amino acids were present in certain locations and tissue types. Some areas accumulated D-amino acids as a result of aging changes; others seem to generate free D-amino acids, suggesting certain D-amino acids may have a functional role— similar to neurotransmitters, hormones, or secondary messengers.
The potential for D-amino acids to act as neurotransmitters is not difficult to accept. Many neurotransmitters are derivatives of amino acids, such as dopamine and serotonin which arise from tyrosine and tryptophan respectively.46 Another amino acid which is a neurotransmitter is glutamic acid; the flavor-enhancer MSG is glutamate (the salt form of glutamic acid), and sensitive individuals can suffer debilitating headaches if they consume MSG.
The practice of using MSG or glutamic acid-rich seaweed extract in Asian cooking caused MSG-induced headaches to be known as Chinese Restaurant Syndrome many years ago.47 Interestingly, a synthetic (lab-created) amino acid called N-methyl-D-aspartate (NMDA), was found to activate only a specific subset of glutamate receptors in the brain. NMDA is so potent at stimulating the NMDA-sensitive nerves that it over-excites them and the nerve dies. A very valuable trait in the lab, but toxic in high concentration to living organisms— which is why NMDA is classified as an excitotoxin.
Of course, NMDA-sensitive nerves exist for a purpose, and certain mental health conditions appear to be associated with an understimulation of these (NMDA-sensitive) nerves, such as the condition schizophrenia.48 Even more interesting for those so inclined to gain a broad awareness, D-serine (another D-form amino acid) acts to enhance activity of the NMDA-subtype of the glutamate receptor.49 This rambles a bit, but it shows that not only are amino acids either directly or indirectly used as neurotransmitters, but D-forms of certain amino acids have an endogenous role in central nervous system (brain) function.
DAA has been found to be present in, and accumulate in following peripheral injection or ingestion, both white and grey matter of the brain. White matter refers to cells that insulate and protect the nerve cells that actually produce thought or respond to the environment. Grey cells are nerve cells. The same group that published the DAA testosterone paper also has another peer-reviewed paper accepted, showing that DAA supplementation improved learning and memory in rats; it also showed untreated rats who were better learners had higher concentrations of DAA in the hippocampus (a region of the brain).50
More relevant to those interested in the testosterone-associated pathways, research published in 2007 showed DAA is present in nerve endings and is released when the nerve is stimulated, confirming its function as a neurotransmitter.44 DAA stimulation increases cyclic AMP (cAMP) in the “receiving” nerves. In the neuroendocrine axis (the hypothalamus and pituitary), DAA enhances the release of GnRH (the hormone that tells the pituitary that testosterone concentration is falling), as well as the production of two other hormones, oxytocin and vasopressin.
37,44
At the pituitary, DAA stimulates the secretion of three hormones: LH (testosterone-related), prolactin (promotes milk production in nursing mothers, sexual gratification, and in excess can impair libido and erectile function), and GH (growth hormone).37,44 Unfortunately, the Italian study did not measure changes in prolactin or GH/IGF-1 concentrations in the human subjects. Bodybuilders, athletes and anti-aging advocates, particularly those prone to gynecomastia or suffering from erectile dysfunction, may wish to delay using a DAA-based product until data relating to potential increases in prolactin are available.
The function of DAA is not solely as a neurotransmitter, though its effectiveness and oral bioavailability alone makes this intriguing. It also appears to have function at the testes directly, acting as a paracrine-hormone (a chemical that communicates with nearby cells). In rat testes, DAA has been shown to increase testosterone release (more than doubling testosterone synthesis), by increasing the concentration of cAMP, a secondary messenger that stimulates cell response to hormones.
42 DAA holds the potential to be an effective testosterone booster, available as a dietary supplement. It appears to satisfy the criteria to be considered a DSHEA-eligible candidate, being an endogenous bio-molecule, and present in common food products.33
DAA accumulates in tissues involved in sex steroid production (hypothalamus, pituitary, and testes); sites where enzymes involved in DAA production and clearance are present. Its activity has been demonstrated in numerous biological models, including human subjects, to increase circulating testosterone and LH concentration. It has been shown in tissue cultures to increase secondary messengers involved in testosterone synthesis or regulation. Its testosterone-boosting properties are not suppressive to the hypothalamic-pituitary axis, supporting rather than suppressing normal reproductive function. It may even aid in sperm maturation.
If no adverse effects are noted with DAA use, who could benefit? Seemingly, most adult men may benefit from DAA supplementation. In addition to the positive effects of increasing testosterone production, possibly enhancing physical and sexual performance, DAA supplementation may aid in learning and memory. Even anabolic steroid-using athletes could possibly benefit from DAA supplementation, as it may reduce the suppressive effect of anabolic steroids on natural testosterone production, and/or maintain testes sensitivity to LH/hCG, and/or maintain testes size/function on-cycle. DAA could also be a potent adjunct to hCG as part of post-cycle recovery, though all these concepts would need to be studied before any claim could be made.
DAA. It sounds like a do-it-all wonder product, which is usually the first warning sign of market fraud. However, given the research supporting this amino acid as a neurotransmitter and neuroendocrine agent in man, rats, and reptiles, it holds more promise than most unproven products. When DAA products arrive on the market, and they inevitably will, consumers should look for a company that: 1) tests the raw material received from their supplier, as it would be simple to substitute L-aspartic acid; 2) performs clinical testing to show that the marketed product increases testosterone and LH (possibly GH/IGF-1 as well); 3) justifies the inevitable “kitchen sink” of added ingredients; 4) tests to assure that prolactin and estradiol concentrations are not elevated above physiologic normal range. Times are hard for everyone right now, but it is critical that consumers support only such companies, as the low road companies will be able to undercut more ethical companies by cutting corners to cut cost.
A number of questions remain to be considered. There is no documented evidence that DAA would increase testosterone in women. In fact, in the lizard study, testosterone decreased in female lizards, though estrogen was elevated.51 There appear to be benefits to mental function, and possibly protective effects against certain psychological states, but it is unknown what effect DAA will have long-term. The long-term safety of supplementing DAA has not been studied; neither has the therapeutic range. It should be noted that higher doses did not generate significantly higher testosterone response.42 Thus, it is critical (yes, I am using that word again) that consumers monitor changes in mood, concentration, and physical symptoms. At the first sign of gynecomastia or mood changes, DAA use should be discontinued. The effect of DAA on developing brains and sexually immature subjects has not been studied in humans. Therefore, DAA should not be given to children or adolescents. It would be a shame to see a potentially beneficial product removed from the market, due to irresponsible use.
References:
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2. Stenman UH, Hotakainen K, et al. Gonadotropins in doping: pharmacological basis and detection of illicit use. Br J Pharmacol, 2008 Jun;154(3):569-83.
3. Handelsman DJ. Indirect androgen doping by oestrogen blockade in sports. Br J Pharmacol, 2008 Jun;154(3):598-605.
4. Khosla S. Testosterone: more is not always better. J Clin Endocrinol Metab, 2009 Dec;94(12):4665-7.
5. Burnett-Bowie SA, McKay EA, et al. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab, 2009 Dec;94(12):4785-92.
6. Nielsen FH, Hunt CD, et al. Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J, 1987 Nov;1(5):394-7.
7. Beattie JH, Peace HS. The influence of a low-boron diet and boron supplementation on bone, major mineral and sex steroid metabolism in postmenopausal women. Br J Nutr, 1993 May;69(3):871-84.
8. Ferrando AA, Green NR. The effect of boron supplementation on lean body mass, plasma testosterone levels, and strength in male bodybuilders. Int J Sport Nutr, 1993 Jun;3(2):140-9.
9. Naghii MR, Samman S. The effect of boron supplementation on its urinary excretion and selected cardiovascular risk factors in healthy male subjects. Biol Trace Elem Res, 1997 Mar;56(3):273-86.
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13. Rogerson S, Riches CJ, et al. The effect of five weeks of Tribulus terrestris supplementation on muscle strength and body composition during preseason training in elite rugby league players. J Strength Cond Res, 2007 May;21(2):348-53.
14. Antonio J, Uelmen J, et al. The effects of Tribulus terrestris on body composition and exercise performance in resistance-trained males. Int J Sport Nutr Exerc Metab, 2000 Jun;10(2):208-15.
15. Brown GA, Vukovich MD, et al. Effects of anabolic precursors on serum testosterone concentrations and adaptations to resistance training in young men. Int J Sport Nutr Exerc Metab, 2000 Sep;10(3):340-59.
16. Brown GA, Vukovich MD, et al. Endocrine and lipid responses to chronic androstenediol-herbal supplementation in 30 to 58 year old men. J Am Coll Nutr, 2001 Oct;20(5):520-8.
17. Brown GA, Vukovich MD, et al. Effects of androstenedione-herbal supplementation on serum sex hormone concentrations in 30- to 59-year-old men. Int J Vitam Nutr Res, 2001 Sep;71(5):293-301.
18. Sopharma AD. Tribestan®. Available at: http://www.tribestan.com/, accessed December 10, 2009.
19. Gauthaman K, Ganesan AP. The hormonal effects of Tribulus terrestris and its role in the management of male erectile dysfunction–an evaluation using primates, rabbit and rat. Phytomedicine, 2008 Jan;15(1-2):44-54.
20. Gauthaman K, Ganesan AP, et al. Sexual effects of puncturevine (Tribulus terrestris) extract (protodioscin): an evaluation using a rat model. J Altern Complement Med, 2003 Apr;9(2):257-65.
21. Miller WL. Steroidogenic enzymes. Endocr Dev, 2008;13:1-18.
22. Diel P, Friedel A, et al. The prohormone 19-norandrostenedione displays selective androgen receptor modulator (SARM) like properties after subcutaneous administration. Toxicol Lett, 2008 Apr 1;177(3):198-204.
23. Ziegenfuss TN, Berardi JM, et al. Effects of prohormone supplementation in humans: a review. Can J Appl Physiol, 2002 Dec;27(6):628-46.
24. Geyer H, Parr MK, et al. Nutritional supplements cross-contaminated and faked with doping substances. J Mass Spectrom, 2008 Jul;43(7):892-902.
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