Supplements and the Endocrine System in Athletes 1-s2.0-S0278591907000750-Main [TRIBULUS TERRESTRIS]

8/12/2019 Supplements and the Endocrine System in Athletes 1-s2.0-S0278591907000750-Main [TRIBULUS TERRESTRIS]

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Supplements and the EndocrineSystem in Athletes

Luigi Di Luigi, MDUnit of Endocrinology, Department of Health Sciences, University Institute of Movement Sciences,Piazza Lauro de Bosis, 15, 00194 Rome, Italy

Athletes are a section of the population who have particular functional

needs and who perform particular activities; the main nutritional goalsin this very special population are

To provide athletes with adequate nutrients and energy intake for the mainte-nance of homeostasis, and to avoid exercise-stress related risks to health asmuch as possible

To achieve and maintain an appropriate body composition (fat-free mass, gly-cogen stores, fat stores, and so on) and body mass for sport

To minimize any risk to health or risk of performance deterioration caused bydaily-life or training-related reductions in the physiological quantity of essen-

tial substances in the bodyIn the world of athletes nutrition, there are many ethical concerns, because

there is the suspicion that, in practice, large doses of supplements in athletes arenot taken for nutritional purposes. It is beyond the scope of this article, how-ever, to highlight the possible roles of supplements or methods of supplemen-tation in the improvement of athletic performance in elite athletes. Very often,the effects of many supplements are hormone-related, or supplements influencehormone secretion. Examples of possible links between supplements or ergo-genic compounds and the endocrine/metabolic system are addressed.

To date, the scientific world almost universally accepts that a well-balancedisocaloric diet of commonly available foods is sufficient to guarantee basic nu-tritional requirements for the majority of athletes, both in terms of macronutri-ents (carbohydrates, proteins, and lipids) and micronutrients (vitamins,minerals, and trace elements) [13]. In fact, the hypothesis that there mightbe an exercise-induced disproportional need for a special group of essential mi-cronutrients is nowadays considered obsolete.

Based on the above considerations, the most adequate definition of a die-tary supplement is something that supplies one or more essential nutrients

missing from an athletes diet. Sometimes, in conditions of intense exercise

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and training, there may be an increased consumption of carbohydrate-richfoods or sport drinks containing insufficient doses of different nutrients. Fur-thermore, in certain particular circumstances (ie, the need for very high en-ergy intake, difficulty in guaranteeing complete intake of nutrients, or theneed to avoid gastrointestinal distress, and so forth) or in selected physiolog-ical or clinical situations (eg, master athletes, hot temperatures, and the like)[4], supplements or specially adapted nutritional foods or fluids may becomenecessary. For example, in some conditions, amino acid supplements offerathletes the possibility of reaching their desired protein intake without an un-acceptable increase in fat intake and without major changes to their eatinghabits [2].

When necessary, nutritional supplementation in elite athletes should be prac-ticed only with particular purposes in mind: (1) to maintain an adequate nutri-tional balance in terms of quality and correct quantities of specific nutrients (eg,not less than minimal but not beyond the maximum safe daily macro- andmicronutrient requirements), (2) to minimize any deterioration in physical ormental performance caused by possible daily-life or exercise-related reductionin the physiological quantity of essential nutrients in the body, (3) to improvemuscle protein balance when necessary for clinical purposes (eg, aging,sarcopenia) [5] and (4) at least in theory, to reduce possible exercise-related,oxidative stress-linked damage (eg, antioxidants: use of vitamin C, vitamin

E, and b-carotene). In this sense, there is no scientific agreement on the ques-tion of whether a sufficient quantity of antioxidants can be supplied to athletesby well-balanced daily food intake alone.

Correct nutritional supplementation in athletes is related to the administra-tion of a specific quantity of the supplement, to reach physiological doses ofthe nutrient when combined with the quantity of nutrients contained in the ath-letes diet. This must be undertaken with regard to recommended dietaryallowance and according to an athletes physical characteristics (sex, age,height, weight, body composition, and so forth), to the sports characteristics

(type, intensity, duration, and frequency), and to other factors (temperature,humidity, and other environmental conditions).

Unfortunately, in the opinion of the majority of athletes, the foods and supple-ments that they consume can make the difference between success and failure.Also, owing to social and economical factors, the concept of supplementationhas changed, and many athletes take mega-doses of essential nutrients as die-tary-supplements (amino acids, vitamins, minerals, and so on), very often abovetolerable upper-intake levels. Furthermore, in most cases, athletes take manychemical products of different origins as supplements (herbs, drugs, and so forth)

that are believed to be or are presented as nutritional supplements. In practice,these substances are very often chemical compounds that may act outside ofthe classical nutrition-related metabolic pathways because of the doses used orto the substances per se. Many of these compounds/supplements are also calledergogenic aids, independently of their real capacity to improve strength orperformance.

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Ergogenic supplements are used worldwide without any consideration oftheir real effectiveness or usefulness, or of their real mechanisms of actionwhen effective. Neither is much thought given to possible risks to health. Fur-thermore, it is unethical to perform longitudinal studies on the real efficacyor on the risks/benefits of many ergogenic substances in healthy volunteersusing the doses commonly taken by athletes and body builders. Hence, thereis an almost total lack of realistic scientific data on the phenomenon.

As mentioned above, athletes represent a special population, and for educa-tional and health reasons it is essential to identify the maximal daily total safedose of all the substances taken along with the normal diet (as natural foods oras nutritional supplements). It is also fundamental to clarify whether nutrientscommonly found in the normal human diet (water, carbohydrates, fats, pro-teins, amino acids, electrolytes, vitamins, and so forth) might became deleteri-ous to health if taken beyond previously established recommended dietaryallowances, especially in the case of athletes and in certain clinicalcircumstances.

When a normal nutrient is taken outside the frame of real nutritional need,the method of supplementation (eg, excessive doses, and so on) and not thesubstance per se becomes potentially dangerous to health. In the case of abnor-mal methods of supplementation, and particularly if improvement in perfor-mance is demonstrated (or is potentially possible), the concept of a doping

method could be taken into consideration. Furthermore, some authors haveposed the interesting question of whether some nutritional supplements, in par-ticular in preadolescent individuals, could serve as a gateway to prohibitedsubstances[79].

Anecdotal evidence suggests that athletes want to use permitted sub-stances (eg, supplements, ergogenic aids, and so forth) to promote adaptationto training, to improve training-responses, to optimize recovery, and to im-prove performance in competition [2]. As reported in the literature, supple-ments are currently used in an attempt to increase sport performance in

various way, such as providing an increased energy supply, increasedenergy-releasing muscular metabolic processes, enhanced oxygen delivery toactive muscles, increased oxygen use, decreased accumulation of fatigue-relatedsubstances, and improved neural control of muscle contraction [6]. Further-more, many ergogenic substances are effective or are believed to be effectivein improving sport performance through their often-promoted functional linkwith some anabolic hormone pathways (eg, growth hormone, testosterone,and the like). Consequently, the use of supplements beyond nutritional needsin athletes (ie, supplement abuse) is dramatically and rapidly increasing in all

types of sports.Reviews of the published literature suggest that the use of supplements is

more prevalent in athletes (46%) than in the general population (35%40%),with great prevalence of use among elite athletes (59%); some surveys found100% of weightlifters or bodybuilders to use nutritional supplements [1012].Some recent publications have adequately reviewed the world of

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supplementation, mainly in terms of athletes real needs and with particular at-tention to the possible effects on performance[2,3,6,1316].

Owing to the paucity of literature on the real mechanisms of action of thedifferent supplements or supplementation methods, the following sectionsbriefly review some of the substances taken by athletes, with particular atten-tion to their mechanisms of action and the pathways involved. This is obviouswhen some prohibited prohormones or hormones are considered and used assupplements (eg, DHEA, androstenedione, and so forth), but it is difficult forthe general public to understand when natural products are used. For exam-ple, herbal products and phytochemicals have different effects on testosteroneand estrogen pathways, on luteinizing hormone (LH) secretion, on insulin orglucagon effects, and on many cellular enzymes (eg, ecdysteroids, phytoestro-gens, plants sterols, and so on).

The relationships between substances used as supplements, their mecha-nisms of action, and the desired effects in athletes raise many medical, ethical,and social considerations. In fact, it seems rather strange that the possible rela-tionships between supplements and hormones are commonly used by manufac-turers to promote supplement abuse, or that supplements are widely usedwithout any ethical or clinical considerations of their real effects in the body.Examples are found in (Table 1)[1726]. Furthermore, it is important to statethat, theoretically, the interactions between supplements and hormones are not

necessarily associated with performance improvements. In fact, further evalua-tions are needed to establish when and how these interactions might becomedeleterious to the physiological adaptations to exercise-related stress, to perfor-mance, and to health. As reported in literature, the use of many supplementsand nutraceuticals in the management of endocrine diseases also has to be as-sociated with an adequate evaluation of the risk/benefit profile; otherwise, theuse of unproven treatments can be dangerous to health [27].

AMINO ACIDSBecause there is a clear increase in muscle amino acid use during physical ac-tivity, it may be natural to think that amino acid supplementation might be use-ful in sport. In fact, the use of such supplementation is greatly increasing allover the world in competitive, but also noncompetitive sports. Unfortunately,amino acids are usually supplied and administered without medical supervi-sion. Users frequently decide their own dosages and combinations withoutany consideration of efficacy, nutritional requirements or, most importantly,short- and long-term effects on health.

The use of amino acids as dietary supplements creates a dilemma in safety

evaluation, because they are very often used primarily for pharmacologicalpurposes or for the enhancement of physiological functions rather than for nu-tritional purposes. There may be possible side effects and risks to health in allsubjects using amino acids, and unfortunately, more than gastrointestinal dis-tress or altered renal functions might be involved (Table 2) [28,29]. The realproblems in terms of the safety of amino acid supplements are the

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nonphysiological doses used and associations with normal nutritional sub-stances (particularly if these are also taken together with prohibited substances).This might induce a new hormonal and metabolic milieu in a particular func-tional situation (the athletic status) characterized by specific endocrine-meta-bolic pathways and high risk of stress-related harm to health.

Furthermore, most of the published studies on the nutritional effects ofadded amino acids are investigations of amino acids added to food to improveprotein quality. Little scientific literature exists on most amino acids ingested, insingle or multiple doses, as dietary supplements, in capsule, tablet, or liquidforms.

The effects of amino acid supplementation in athletes have been evaluated indifferent experimental protocols, mainly with respect to possible influences onmuscle strength and athletic performance[30]. It has been postulated that thebeneficial effects of amino acid supplementation on strength and enduranceperformance, when observed, might be caused by increased protein synthesis,by the use of amino acids for energy production, by their role in preservingmuscle integrity, and by possible positive effects on hematopoiesis [3135];however, different studies have shown amino acids administration to haveno effect on physical performance, endurance, muscle strength, or aerobicpower[36,37].

Possible effects on muscle strength or on athletic performance related to

amino acid supplementation might be linked to nonclassical nutritional-meta-bolic pathways. Independently of their effects on athletic activities, it is neces-sary to emphasize that amino acids influence different endocrine-metabolicpathways in the human body. In fact, amino acids are involved in

Synthesis of proteins (structural, muscle proteins, enzymes, plasma proteins,membranes)

Gluconeogenesis Immunocompetence (glutamine) Regulation of many neuro-endocrine function as:precursors for neurotransmitter synthesis (noradrenaline, adrenaline and dopa-

mine from tyrosine; 5-hydroxytryptamine from tryptophan; GABA fromglutamate)

neurotransmitters and neuromodulators (glutamate-glutamine, aspartate, gly-cine, and so forth)

neuro-excitatory substances (glutamate, aspartate, and so forth)precursor for nitric oxide (arginine)

Despite the absence of demonstrated effects on lean body mass or on muscle

function, amino acids are commonly taken by athletes as growth-hormonereleasing agents [38]. The administration of BCAAs (ie, leucine, isoleucine,and valine), or other amino acids, including arginine, lysine, ornithine, histy-dine, phenylalanine, and methionine, at specific dosages and in combinationstimulates growth hormone (GH) secretion[39,40]. On the basis of existing ev-idence, both intravenous and oral arginine administration per se stimulate GH



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Table 1Some general examples of interaction between supplements administration in athletesand endocrine system, as reported in abstracts from scientific literature

Supplements Described endocrine effects References

Caffeine . . .there were significantincreases in plasmanorepinephrine in responseto caffeine ingestion . . ..

Van Soeren et al[17]

Cortitrol (Magnolia officinalis,l-theatine, epimediumextract, phosphatidyl serine,b-sitosterol)

Cortitrol was effective inmodulating the physiologicalstress responses of exercise. . .by reducing cortisol. . ..

Kraemer et al 2005[18]

Creatine . . .however, serum cortisolduring recovery tended to behigher in creatine group thanin placebo . . ..

Op t Eijnde et al [19]

. . .resting testosteroneconcentrations were elevatedin the creatine group . . .thisstudy demonstrates theefficacy of creatine onstrength performance. . ..

Hoffman et al[20]

. . .norepinephrine and

dopamine concentrationswere significantly higher at24 h . . .following 24-h sleepdeprivation, creatinesupplementation hada positive effect on moodstate and tasks that placea heavy stress on theprefrontal cortex. . ..

McMorris et al[21]

Leucine . . . the serum testosteroneconcentration increased by

20.7% and the serum cortisolconcentration by 8% in allsubjects during the firstweeks . . ..

Mero et al[22]

Melatonin . . .oral ingestion of melatonin(6 mg) during daytime withheavy resistance exercisemay slightly decrease GHconcentrations. . ..

Mero et al[23]

Vitamin C . . .there was a significanttrial x time interaction effect

for plasma cortisolconcentration (P .039)which tended to be lower inthe vitamin C trial. . ..

Davison et al[24]

(continued on next page)

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secretion[41]and amplify the GH response to growth-hormonereleasing hor-mone (GHRH) at all ages, probably inhibiting somatostatin secretion at the hy-pothalamic level [42,43]. During exercise, arginine may facilitate the effect ofexercise in limiting somatostatin secretion, thus facilitating GH secretion [44];however, even though GH release might be increased by oral ingestion ofamino acids, it might require doses of amino acids high enough to cause gastro-intestinal discomfort.

BCAA supplementation stimulates basal insulin synthesis and secretion andincreases insulin-sensitivity, without modifying the insulin response to acute

physical exercise [4547]. It has also been found that a single administrationof BCAAs increases testosterone and cortisol response to acute physical exer-cise [45], whereas glutamic acid can stimulate adrenocorticotropic hormone(ACTH)-mediated cortisol secretion [48], and ornhitine was able to increaseplasma GH, ACTH, and cortisol concentrations[49].

Long-term administration of an amino acid mixture (BCAAs, lysine,arginine, ornithine) in athletes during a training period induced significantincreases in basal cortisol and testosterone plasma concentrations and in24-hour urinary cortisol when compared with placebo-treated athletes [50].

In a simulated overreaching state, amino acid supplementation abolished train-ing-related reduction of the sex hormone-binding globulin and maintainedhigher levels of plasma testosterone when compared to placebo[51]. Further-more, the acute administration of an amino acid mixture (L-arginine hydroclor-ide 100 mg/kgL-ornithine hydrocloride 80 mg/kgL-BCAAs 140 mg/kg:50%L-leucine, 25%L-isoleucine, 25% L-valine) enhanced the ACTH, LH, andfollicle-stimulating hormone (FSH) response to corticotropin-releasing hor-mone (CRH) gonadotropin-releasing hormone (GnRH) administration inhealthy male athletes[52].

Amino acids might influence the pituitary secretion in various ways; theymight act directly at the hypothalamic-pituitary level, or indirectly througha modification of the concentration of neuroendocrine amino acid components.Such modifications would influence the neuroendocrine pathways that regulatepituitary secretion. Furthermore, some amino acids (eg, excitatory amino acids)exert a specific excitatory activity at brain level [53].

Table 1(continued)

Supplements Described endocrine effects References. . .supplementation with vitamin C . . .may

be associated . . .with an attenuation of theexercise induced increase in serumcortisol. . ..

Peters et al[25]

Vitamin B6 . . .the role that vitamin B6 may play inattenuating the rise in plasma growth hormoneobserved during exercise is also reviewed. . ..

Manore et al[26]



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Table 2Examples of amino acids-linked biological side effects/risks for health, as reported in literature

Amino acids In humans In animalsBranched-chain

amino acids

Changes in brain chemistry Competition with other amino acids Increased risk for bladder cancer Influence on insulin sensitivity

Developmental changes Promoter of carcinogenesis

Histidine Changes in biochemicalparameters

Changes in food intake Neurological symptoms:

headache, nausea, weakness Competition with other amino acids

Changes in food intake or bodyintake

Changes in organ morphology

Lysine Increased protein excretion Nausea

Abnormal renal function Changes in food intake and growth Effect on sleep latency and length

Methionine Hepatic encephalopathy inimpaired liver function

Hyper-homocysteinemia Psychosis in schizophrenic patients Risk factor for cardiovascular

diseases

Altered sleep-wake cycle Aortic lesions Depression of food intake

and growth Enlargement of the spleen

and kidney Pancreatic abnormality Pregnancy disorders

L-Phenylalanine Brain damage Dermatologic abnormalities Growth retardation

Altered sleep-wake cycle Aortic lesions Brain damage Increased insulin and glucagons Pancreatic abnormality Pregnancy disorders

Arginine Digestive troubles Gastrointestinal side effects Hypotensive effect Increase plasma potassium Increased blood ammonia in

patient with liver diseases Increased tumor protein synthesis

(breast) Metabolic acidosis Neurological development

alterations Secretagogue for many hormones

(GH, insulin, and so forth) Sleepiness Weight increase

Decreased tumor growth Growth depression Influence immune function Secretagogue for many hormones

(GH, insulin, and so forth)

Data from Anderson RD, Raiten DJ. Safety of amino acids used as dietary supplements. Bethesda (MD):Center for food safety and applied nutrition, Food and Drug Administration; 1992. p. 296.

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Central catecholaminergic and serotonergic systems influence the secretionof many pituitary hormones. The rate of synthesis of these neurotransmittersdepends on various factors, including the availability and rate of uptake of theirprecursors (tyrosine, phenylalanine, and tryptophan) from the circulation[54,55]. The uptake of these precursors across the blood-brain barrier hasbeen reported to occur via a membrane-bound transport system, known asthe large neutral amino acids transporter (LNAA). The uptake of these precur-sors is affected by the plasma levels of other amino acids (isoleucine, leucine,methionine, valine) competing for uptake into the brain via LNAA-mediatedtransport. Thus, for example, acute administration of BCAAs might decreasethe rate of uptake of tyrosine, phenylalanine, and tryptophan in the brain,thereby decreasing the pool sizes of the corresponding neurotransmitters,with consequent changes in the neuroendocrine modulation of pituitary hor-mone secretion. It has been demonstrated that BCAA administration in ratsdecreases the brain concentration of several amino acids (tyrosine, gamma-aminobutyric acid [GABA], metionine, phenylalanine, glycine, histidine,threonine, and so forth) and increases glutamic acid, a metabolite in BCAA ca-tabolism[56]. These results indicate preferential transport of BCAAs across theblood-brain barrier by LNAA. Furthermore, a BCAA-dependent reduction ofa free tryptophan in the brain, with the consequent reduction in serotonin pro-duction in the central nervous system, may be responsible for the reduced fa-

tigue in athletes taking BCAA supplementation[32].BCAAs are also precursors of other amino acids and in the central nervous

system, where there is a low concentration of branched-chain keto acid dehy-drogenase, BCAA catabolism may provide glutamine[57], which is a precursorfor the neurotransmitters glutamate, and GABA, which is essential for detoxi-fication of brain ammonia.

The specific actions of arginine and ornithine on pituitary function might bedependent on: (1) the influence of arginine on brain concentration and metab-olism of citrulline and ornithine and vice versa; (2) the competition of arginine

and ornithine with the amino acid lysine and histidine (Ly carrier system); (3)the function of arginine as a specific modulator of cerebral mitochondrial glu-tamate transport[58]; (4) the stimulating action of arginine on hormone secre-tion (ie, prolactin, catecholamines, and so forth), which may influence thesecretion of other pituitary hormones; and (5) the fact that arginine is themain source of nitric oxide (NO) production in the brain (although it has yetto be determined whether oral intake of L-arginine can affect NO synthesis).

NO is formed by the conversion of arginine to citrulline by the enzyme NOsynthase (NOS), and has multiple regulatory effects in a variety of tissues and

systems. For example, the pulsatile release of luteinising-hormonereleasinghormone (LHRH) induced by norepinephrine is brought about by an increasein hypothalamic NO, resulting in LHRH secretion into the portal vessels [59].Endogenous NO also modulates the hypothalamic-pituitary-adrenal axis activ-ity via CRH/ACTH secretion and their response to arginine-vasopressin, pros-taglandins, the adrenergic system, and so forth[60]. Finally, rat steroidogenesis



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is also influenced, at testicular and adrenal levels, by NO[61], and thus indi-rectly by arginine.

In particular, arginine alpha-glutarate is used by athletes because of its capac-ity to increase NO production in the body; however, although NO might the-oretically improve work capacity, increase muscle growth, and decreaserecovery time, no studies have demonstrated any effects on an athletes perfor-mance. It is of interest that systemic infusion of arginine in healthy subjects in-duces vasodilatation and inhibits platelet aggregation and blood viscosity [62].

Based on the reported influence of amino acids on the endocrine system, it ispossible to speculate that particular combinations or the prevalence of someamino acids in the diet might influence the characteristics of the basal endocrinestatus or of the general-stress or exercise-stressrelated hormonal pathways.

From an ethics standpoint: (1) the use of amino acid supplementation incompetitive athletes has to be re-examined in terms of real need[36,63], safety,and possible effects on the endocrine and metabolic systems; (2) the use ofamino acids supplementation in competitive athletes should occur only in cer-tain circumstances (ie, when necessary for nutritional reasons) and if possible,under medical supervision; (3) the use of protein or amino acid supplementsin healthy noncompetitive individuals engaged in recreational sports is notwarranted, and, finally (4) because in the athletic world amino acids are takento improve performance and might be associated with risks to health, their

use in some circumstances should be reconsidered in terms of dopingmethods.

CHROMIUM PICOLINATEChromium occurs in both trivalent (Cr-III) and hexavalent (Cr-VI) forms. Cr-VI is chiefly known as an industrial, man-made product. Cr-III is found natu-rally in foods and is associated with nutritional supplements in various complexforms. The most popular complex form is chromium picolinate, although chro-

mium nicotinate and chromium citrate are also used as nutritional supplements[64].

Chromium picolinate is an organic compound of Cr-III and picolinic acid,a naturally occurring derivative of tryptophan. Chromium, an essential tracemineral and cofactor to insulin, enhances insulin activity and has been the sub-ject of studies assessing its effects in carbohydrate, protein, and lipid metabo-lism [6567]. In fact, it is speculated that chromium picolinate works bystimulating the activity of insulin, thus significantly improving the bodys glu-cose and fat metabolism, managing the breakdown of glucose and fat. The ex-

act mechanisms by which chromium improves this insulin activity arecurrently unclear; it has been suggested that chromium works to increase thesensitivity of insulin receptors. Some claim that the improved insulin activitycauses an increase in the production of serotonin, which subsequently reducesappetite. In fact, chromium picolinate has been used to suppress appetite andfood cravings; however, because research has yet to produce any definite

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answers as to the exact function of chromium picolinate, competing theories ex-ist about its precise effects.

A placebo-controlled trial of 27 postmenopausal women given 200 mcg/dayof chromium as picolinate for 60 days found a decrease in insulin levels (38%),plasma glucose (26%), and urinary calcium (19%), whereas DHEA levels in-creased by 24%[68].

Chromium picolinate is often promoted as a supplement that helps buildmuscle and burn fat. One hypothesis states that chromium picolinate increasesprotein synthesis, which in turn stimulates muscle growth. Reported effects in-clude an increase in lean body mass, a decrease in percentage body fat, and anincrease in the basal metabolic rate. Because of its possible action on weight re-duction and body composition, it is commonly used when these effects are nec-essary for athletic performance; however, it seems that the observed effect withchromium picolinate is, though statistically significant, not clinically meaningful[69].

Chromium toxicity has been almost exclusively linked to the hexavalentform. Ingestion of hexavalent chromium is 10 to 100 times more toxic than tri-valent compounds. In the few existing trials, no adverse events have beenobserved after very short-term use in patients receiving chromium picolinate.Unfortunately, there is a paucity of research concerning side effects afterhigh doses or prolonged treatments. Several case studies reporting subtle be-

havioral changes as a result of chromium picolinate are scattered throughoutthe literature. For example, one patient took chromium picolinate on three sep-arate occasions and had three distinct episodes of progressively worse cogni-tive, perceptual, and motor changes. These episodes included sensations offeeling funny to reports of mental short circuiting and even a complete dis-ruption of motor abilities. Other sources report vague symptoms includingirregular heartbeat, leading the UAS Food and Drug Administration(FDA) to cite safety concerns. Further studies are necessary to evaluate pos-sible chromium-linked DNA damage in humans[64].

b-HYDROXY-b-METHYLBUTYRATEb-hydroxy-b-methylbutyrate is a metabolite of leucine that has shown toposses anticatabolic actions by inhibiting protein breakdown [70]. b-hydroxy-b-methylbutyrate is available as a dietary supplement and has been studiedin athletes, bodybuilders [70,71], unhealthy individuals [72,73] and olderadults [74,75] as a method to modify body composition by lean body massincrease. The b-hydroxy-b-methylbutyrate may play an important role in re-

ducing protein degradation or in increasing recovery of damaged muscle cells[76].

The b-hydroxy-b-methylbutyrate prevents muscle protein degradation incancer-induced weight loss through attenuation of the ubiquitin-proteasomeproteolytic pathway. Experimental results suggest that b-hydroxy-b-methylbu-tyrate attenuates the tumor factor proteolysis-inducing factor (PIF)induced



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activation, and increases gene expression of the ubiquitin-proteasome proteo-lytic pathway, reducing protein degradation[77].

Studies ofb-hydroxy-b-methylbutyrate supplementation have shown mini-mal gains in strength and lean body mass in specific populations, mainlyuntrained athletes and patients who have wasting syndromes [78]. In fact, re-cent experimental clinical data suggest that supplementation with b-hydroxy-b-methylbutyrate alone may improve nitrogen balance in critically injuredadult patients, and that this effect is not a result of lowered muscle protein turn-over [73]. Furthermore, b-hydroxy-b-methylbutyrate supplementation mayalso have anti-inflammatory and anticatabolic effects, and may improve pulmo-nary function in chronic obstructive pulmonary disease (COPD) patients in anintensive care unit setting[72].

A daily supplementation of b-hydroxy-b-methylbutyrate, arginine, andlysine for 12 weeks in elderly women positively alters measurements of func-tionality, strength, fat-free mass, and protein synthesis, suggesting that the strat-egy of targeted nutrition has the ability to affect muscle health in thispopulation [74]. If confirmed, and adequately authorized in terms of safetyand risk/benefits ratio, these effects might be of some interest to older compet-itive athletes.

In athletes, b-hydroxy-b-methylbutyrate in association with creatine hasbeen shown to increase lean body mass and strength in humans undergoing

progressive resistance exercise training, and the effects were additive [79,80].Furthermore, in a recent study b-hydroxy-b-methylbutyrate and alpha-ketoiso-caproic acid supplementation reduced signs and symptoms of exercise-inducedmuscle damage in nonresistance-trained males following a single bout of resis-tance exercise[81]; however, on the basis of the existing literature, b-hydroxy-b-methylbutyrate use in athletes involved in regular high-intensity exercise hasnot been proven to be beneficial when multiple variables are evaluated[2,78,82].

Unlike other ergogenics, no adverse events have been reported with b-hy-

droxy-b-methylbutyrate in association with short-term use. Furthermore, inthe few existing studies, no alterations of serum biochemical parameters, testos-terone and cortisol concentrations, or urinary testosterone/epitestosterone ratiohave been observed after b-hydroxy-b-methylbutyrate administration[83,84].Beyond ethical considerations, b-hydroxy-b-methylbutyrate cannot be recom-mended as a safe supplement, even when theoretically necessary, until furtherstudies in larger groups have been performed[78].

DEHYDROEPIANDROSTERONE AND ADROSTENEDIONEDHEA and androstenedione are both hormones and precursors of hormones(eg, testosterone). DHEA is a weak androgen that is produced in the adrenalcortex, whereas androstenedione is a more potent androgen produced bothin the adrenal glands and in the gonads. DHEA is converted in the body toandrostenedione, which can be converted to testosterone.

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Most clinical research on DHEA has focused on its putative effects as andro-gen replacement therapy in hypoadrenalism with hypoandrogenisms and inaging, because of the possible presence of a functional form of age-related ad-renal androgens deficiency in both sexes. DHEA is mildly androgenic and canbe converted to estrogen at the target tissue level. At replacement doses of 25 to50 mg per day, DHEA increased testosterone concentration in women, and in-duced supra-physiological blood testosterone concentrations with high doses(eg, 100 mg per day) [8587]. In healthy men, even massive daily DHEAdose administration (eg, 1600 mg/d) had no effect on blood testosterone con-centrations, although in elderly men blood estradiol was markedly increasedafter DHEA administration [85,88]. Androstenedione is a preandrogen thatwas advertised as promoting muscle growth, improving muscular strength, re-ducing fat, and slowing aging before being taken off the market by the FDA in2004. In hypogonadal men, androstenedione administration (eg, 1500 mgdaily, which replicates a model of hormone abuse) produced a 10 fold increasein blood androstenedione concentration as well as a 2 fold increase in testoster-one concentrations[89]. Despite the relatively inefficient conversion (about 6%)of androstenedione into testosterone by 17-ketosteroid reductase in the body,in the case of very high doses of androstenedione supplementation, the increaseof testosterone concentration may become evident. On the basis of current lit-erature, androstenedione has both proper androgenic effects, through a possible

interaction with androgen receptors[89], and indirect androgenic effects, actingas prosteroid and becoming biologically active after conversion to more potentnatural androgens in vivo.

The curious paucity of studies on DHEA and on androstenedione forenhancing sport performance or body building may reflect a dichotomybetween its exploitation in the anti-aging substances market and a more prag-matic world of professional elite athletes expecting to base investmentdecisions on sound evidence and risk-benefit calculations. DHEA and andros-tenedione are without proven benefits for athletic performance, and their

use in the world of sports or body building seems to be mainly linked toanecdotal evidence.

Currently, DHEA and androstenedione are considered prohibited sub-stances by the WADA, consequently their use in athletes is banned. DHEAand androstenedione share many endocrine-metabolic pathways with differentanabolic steroids and androgens (eg, testosterone), and they also share thesame adverse effects and risks to health. Consequently, owing to different eth-ical and endocrinological concerns, their nontherapeutic use in healthy individ-uals (athletes and non-athletes) is not advised, especially in young people

[90,91].

CONTAMINATED NUTRITIONAL SUPPLEMENTSThe relationships between taking supplements and hormones may also berelated to possible accidental (or voluntary) contamination with prohibited



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compounds (hormones or prohormones) not declared on the labels of differentnonhormonal supplements (products containing vitamins, amino acids, crea-tine, and so forth). To date, there are numerous reports in the literature withrespect to contamination of dietary supplements with toxic or prohibited sub-stances that are not identified on the label [9298].

In a recent large-scale study, androgenic anabolic steroids were detected in14.8% of 634 different steroid-free nutritional supplements purchased in13 countries from 215 different suppliers: the positive supplementsshowed androgenic steroid concentrations of from 0.01 lg/g up to 190 lg/g[95].

In fact, after the first scientific demonstration that some steroid-free supple-ments also contained undeclared androgenic anabolic steroids [94], strategiesfor the detection of hormone contamination in athletes supplements haveimproved [99]. For example, Baume and colleagues [100] recently analyzedthe composition of 103 dietary supplements (creatine, prohormones, mentalenhancers, and branched chain amino acids) bought on the Internet. All thesupplements were screened for the presence of stimulants and main anabolicsteroids parent compounds (precursors and metabolites of testosterone andnandrolone). The study identified three products containing an anabolic ste-roid, metandienone, at a very high level. The results have also shown thatone creatine product and three mental enhancers contained traces of hor-

mones or prohormones not declared on the labels, and that 14 prohormoneproducts contained substances other than those indicated by the manufacturer.The oral intake of the creatine product revealed the presence of the two mainnandrolone metabolites (19-norandrosterone and 19-noretiocholanolone) inurine[100].

The presence of undeclared substances (testosterone, 19-nortestosterone andrespective precursors, DHEA, and so forth) can cause health risks to con-sumers, and might lead to positive results in sports doping controls, especiallyfor the nandrolone metabolite norandrosterone [94,101]. Furthermore, many

Authors have highlighted the potential for legal damages and the risks to ath-letes health linked to this involuntary taking of prohibited substances.[94,101,102]. Interestingly, the German Federal Supreme Court stated that nu-tritional supplements should indisputably be considered drugs if they containsubstances banned by antidoping organizations[102].

SUMMARYIt should be emphasized that the term food supplements ought to be used only

for specially adapted products containing nutrients normally found in the usualhuman diet; these would be suitable only to substitute or complete an athletesdiet in particular conditions. Consequently, it is necessary to avoid any refer-ence to taking supplements as a way to improve athletic performance or op-timize energy production, metabolism, or muscle growth in athletes. In fact,this definition of supplements is much too similar to the definition commonly

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used for many doping substances, and could encourage food supplementmisuse.

From a clinical and ethical point of view, this is particularly evident for theso-called ergogenic substances or ergogenic aids supplements (sometimesalso normal nutrients). In fact the term ergogenic is related to a hypotheticalcapacity of some substance to increase energy, physical work capacity, orphysical performance. Furthermore, ergogenic substances very often act inthe body through well-known metabolic or endocrine pathways, in ways sim-ilar to different active molecules included by the WADA in the list of pro-hibited substances.

Because many athletes acquire their nutritional supplements outside thehealth care system, and also considering that many supplements may be con-taminated with prohibited substances (eg, anabolic steroids), athletes and theirphysicians need to be aware of the many problems (eg, health, the law, and soforth) that can follow supplement abuse. The need for appropriate worldwideregulation and homogenization of dietary supplement and ergogenic substanceuse by athletes is further emphasized [98], both to protect athletes long-termhealth and, because of the parallelism in desired effects and mechanisms ofaction, to have coherent definitions of the many methods of supplementation,ergogenic substances, and different prohibited substances. For example, withrespect to an allowed supplement (eg, arginine), which stimulates GH secretion,

and the prohibited GHRH, which also stimulates GH secretion, the questionmust be why the two are treated differently. Both substances are believed tohave positive effects on athletic performance and are taken for this purpose,both act through similar functional pathways (eg, GH secretion) and are asso-ciated with potential risks to health, yet only one is a prohibited substance.Arginine and GHRH could be used by athletes (for nutritional purposes orfor diagnostic/therapeutic purposes), but only if a real need is demonstrated,and if taking that substances does not produce further effects on performance,other than the effects related to the recovery or maintenance of the athletes

health status.In conclusion, further studies and evaluations are needed to clarify the many

open questions on supplementation in athletes, in particular when mechanismsof action and safety are concerned[28,29]. It is necessary

To use supplements according to well-identified daily recommended doses ofnutrients for athletes, to be used only for nutritional goals (and not to improveperformance or muscle growth)

To identify if there are real (or potential) extra-dose or association-related fur-

ther effects of nutritional supplements on performance (dose-related or associ-ation-related doping-like effects) To identify and to communicate to athletes all the possible risks to health linked

to the use of ergogenic aids and to nutritional supplement intakes quantita-tively beyond individual, absolute or relative (ie, in some clinical situations)maximal safe daily dose, and to the use of particular, nonphysiological asso-ciations of supplements and ergogenic aids



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Vitamins (B1,B6, B12, niacin)

Mineral and trace elements (potassium, magnesium, calcium, boron, chromium,sodium bicarbonate, and phosphates)

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Herbal productsphytochemicals (ginseng, yohimbine, tribulus terrestris,and so on)

Drug nutrients (caffeine, and so on)

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a

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