Clin Sports Med 27 (2008) 131151

CLINICS IN SPORTS MEDICINE

Supplements and the Endocrine System in Athletes
Luigi Di Luigi, MD
Unit of Endocrinology, Department of Health Sciences, University Institute of Movement Sciences, Piazza Lauro de Bosis, 15, 00194 Rome, Italy

A
  

thletes are a section of the population who have particular functional needs and who perform particular activities; the main nutritional goals in this very special population are

To provide athletes with adequate nutrients and energy intake for the maintenance of homeostasis, and to avoid exercise-stress related risks to health as much as possible To achieve and maintain an appropriate body composition (fat-free mass, glycogen stores, fat stores, and so on) and body mass for sport To minimize any risk to health or risk of performance deterioration caused by daily-life or training-related reductions in the physiological quantity of essential substances in the body

In the world of athletes nutrition, there are many ethical concerns, because there is the suspicion that, in practice, large doses of supplements in athletes are not taken for nutritional purposes. It is beyond the scope of this article, however, to highlight the possible roles of supplements or methods of supplementation in the improvement of athletic performance in elite athletes. Very often, the effects of many supplements are hormone-related, or supplements inuence hormone secretion. Examples of possible links between supplements or ergogenic compounds and the endocrine/metabolic system are addressed. To date, the scientic world almost universally accepts that a well-balanced isocaloric diet of commonly available foods is sufcient to guarantee basic nutritional requirements for the majority of athletes, both in terms of macronutrients (carbohydrates, proteins, and lipids) and micronutrients (vitamins, minerals, and trace elements) [13]. In fact, the hypothesis that there might be an exercise-induced disproportional need for a special group of essential micronutrients is nowadays considered obsolete. Based on the above considerations, the most adequate denition of a dietary supplement is something that supplies one or more essential nutrients missing from an athletes diet. Sometimes, in conditions of intense exercise
E-mail address: luigi.diluigi@iusm.it 0278-5919/08/$ see front matter doi:10.1016/j.csm.2007.09.003 2008 Elsevier Inc. All rights reserved. sportsmed.theclinics.com

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and training, there may be an increased consumption of carbohydrate-rich foods or sport drinks containing insufcient doses of different nutrients. Furthermore, in certain particular circumstances (ie, the need for very high energy intake, difculty in guaranteeing complete intake of nutrients, or the need to avoid gastrointestinal distress, and so forth) or in selected physiological or clinical situations (eg, master athletes, hot temperatures, and the like) [4], supplements or specially adapted nutritional foods or uids may become necessary. For example, in some conditions, amino acid supplements offer athletes the possibility of reaching their desired protein intake without an unacceptable increase in fat intake and without major changes to their eating habits [2]. When necessary, nutritional supplementation in elite athletes should be practiced only with particular purposes in mind: (1) to maintain an adequate nutritional balance in terms of quality and correct quantities of specic nutrients (eg, not less than minimal but not beyond the maximum safe daily macro- and micronutrient requirements), (2) to minimize any deterioration in physical or mental performance caused by possible daily-life or exercise-related reduction in the physiological quantity of essential nutrients in the body, (3) to improve muscle 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 scientic agreement on the question of whether a sufcient quantity of antioxidants can be supplied to athletes by well-balanced daily food intake alone. Correct nutritional supplementation in athletes is related to the administration of a specic quantity of the supplement, to reach physiological doses of the nutrient when combined with the quantity of nutrients contained in the athletes diet. This must be undertaken with regard to recommended dietary allowance 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 supplements that they consume can make the difference between success and failure. Also, owing to social and economical factors, the concept of supplementation has changed, and many athletes take mega-doses of essential nutrients as dietary-supplements (amino acids, vitamins, minerals, and so on), very often above tolerable upper-intake levels. Furthermore, in most cases, athletes take many chemical 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 of the classical nutrition-related metabolic pathways because of the doses used or to the substances per se. Many of these compounds/supplements are also called ergogenic aids, independently of their real capacity to improve strength or performance.

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Ergogenic supplements are used worldwide without any consideration of their real effectiveness or usefulness, or of their real mechanisms of action when effective. Neither is much thought given to possible risks to health. Furthermore, it is unethical to perform longitudinal studies on the real efcacy or on the risks/benets of many ergogenic substances in healthy volunteers using the doses commonly taken by athletes and body builders. Hence, there is an almost total lack of realistic scientic data on the phenomenon. As mentioned above, athletes represent a special population, and for educational and health reasons it is essential to identify the maximal daily total safe dose of all the substances taken along with the normal diet (as natural foods or as nutritional supplements). It is also fundamental to clarify whether nutrients commonly found in the normal human diet (water, carbohydrates, fats, proteins, amino acids, electrolytes, vitamins, and so forth) might became deleterious to health if taken beyond previously established recommended dietary allowances, especially in the case of athletes and in certain clinical circumstances. 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 the substance per se becomes potentially dangerous to health. In the case of abnormal methods of supplementation, and particularly if improvement in performance is demonstrated (or is potentially possible), the concept of a doping method could be taken into consideration. Furthermore, some authors have posed the interesting question of whether some nutritional supplements, in particular in preadolescent individuals, could serve as a gateway to prohibited substances [79]. Anecdotal evidence suggests that athletes want to use permitted substances (eg, supplements, ergogenic aids, and so forth) to promote adaptation to training, to improve training-responses, to optimize recovery, and to improve performance in competition [2]. As reported in the literature, supplements are currently used in an attempt to increase sport performance in various way, such as providing an increased energy supply, increased energy-releasing muscular metabolic processes, enhanced oxygen delivery to active muscles, increased oxygen use, decreased accumulation of fatigue-related substances, and improved neural control of muscle contraction [6]. Furthermore, many ergogenic substances are effective or are believed to be effective in improving sport performance through their often-promoted functional link with some anabolic hormone pathways (eg, growth hormone, testosterone, and the like). Consequently, the use of supplements beyond nutritional needs in 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 found 100% 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 attention to the possible effects on performance [2,3,6,1316]. Owing to the paucity of literature on the real mechanisms of action of the different supplements or supplementation methods, the following sections briey review some of the substances taken by athletes, with particular attention to their mechanisms of action and the pathways involved. This is obvious when some prohibited prohormones or hormones are considered and used as supplements (eg, DHEA, androstenedione, and so forth), but it is difcult for the general public to understand when natural products are used. For example, herbal products and phytochemicals have different effects on testosterone and estrogen pathways, on luteinizing hormone (LH) secretion, on insulin or glucagon effects, and on many cellular enzymes (eg, ecdysteroids, phytoestrogens, plants sterols, and so on). The relationships between substances used as supplements, their mechanisms of action, and the desired effects in athletes raise many medical, ethical, and social considerations. In fact, it seems rather strange that the possible relationships between supplements and hormones are commonly used by manufacturers to promote supplement abuse, or that supplements are widely used without any ethical or clinical considerations of their real effects in the body. Examples are found in (Table 1) [1726]. Furthermore, it is important to state that, theoretically, the interactions between supplements and hormones are not necessarily associated with performance improvements. In fact, further evaluations are needed to establish when and how these interactions might become deleterious to the physiological adaptations to exercise-related stress, to performance, and to health. As reported in literature, the use of many supplements and nutraceuticals in the management of endocrine diseases also has to be associated with an adequate evaluation of the risk/benet prole; otherwise, the use of unproven treatments can be dangerous to health [27]. AMINO ACIDS Because there is a clear increase in muscle amino acid use during physical activity, it may be natural to think that amino acid supplementation might be useful in sport. In fact, the use of such supplementation is greatly increasing all over the world in competitive, but also noncompetitive sports. Unfortunately, amino acids are usually supplied and administered without medical supervision. Users frequently decide their own dosages and combinations without any consideration of efcacy, 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 pharmacological purposes or for the enhancement of physiological functions rather than for nutritional purposes. There may be possible side effects and risks to health in all subjects using amino acids, and unfortunately, more than gastrointestinal distress or altered renal functions might be involved (Table 2) [28,29]. The real problems in terms of the safety of amino acid supplements are the

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nonphysiological doses used and associations with normal nutritional substances (particularly if these are also taken together with prohibited substances). This might induce a new hormonal and metabolic milieu in a particular functional situation (the athletic status) characterized by specic endocrine-metabolic pathways and high risk of stress-related harm to health. Furthermore, most of the published studies on the nutritional effects of added amino acids are investigations of amino acids added to food to improve protein quality. Little scientic literature exists on most amino acids ingested, in single or multiple doses, as dietary supplements, in capsule, tablet, or liquid forms. The effects of amino acid supplementation in athletes have been evaluated in different experimental protocols, mainly with respect to possible inuences on muscle strength and athletic performance [30]. It has been postulated that the benecial effects of amino acid supplementation on strength and endurance performance, when observed, might be caused by increased protein synthesis, by the use of amino acids for energy production, by their role in preserving muscle integrity, and by possible positive effects on hematopoiesis [3135]; however, different studies have shown amino acids administration to have no effect on physical performance, endurance, muscle strength, or aerobic power [36,37]. Possible effects on muscle strength or on athletic performance related to amino acid supplementation might be linked to nonclassical nutritional-metabolic pathways. Independently of their effects on athletic activities, it is necessary to emphasize that amino acids inuence different endocrine-metabolic pathways 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 dopamine from tyrosine; 5-hydroxytryptamine from tryptophan; GABA from glutamate) neurotransmitters and neuromodulators (glutamate-glutamine, aspartate, glycine, 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-hormone releasing agents [38]. The administration of BCAAs (ie, leucine, isoleucine, and valine), or other amino acids, including arginine, lysine, ornithine, histydine, phenylalanine, and methionine, at specic dosages and in combination stimulates growth hormone (GH) secretion [39,40]. On the basis of existing evidence, both intravenous and oral arginine administration per se stimulate GH

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Table 1 Some general examples of interaction between supplements administration in athletes and endocrine system, as reported in abstracts from scientic literature Supplements Caffeine Described endocrine effects . . . there were signicant increases in plasma norepinephrine in response to caffeine ingestion . . . . Cortitrol was effective in modulating the physiological stress responses of exercise . . . by reducing cortisol . . . . . . . however, serum cortisol during recovery tended to be higher in creatine group than in placebo . . . . . . . resting testosterone concentrations were elevated in the creatine group . . . this study demonstrates the efcacy of creatine on strength performance. . . . . . . norepinephrine and dopamine concentrations were signicantly higher at 24 h . . . following 24-h sleep deprivation, creatine supplementation had a positive effect on mood state and tasks that place a heavy stress on the prefrontal cortex. . . . . . . the serum testosterone concentration increased by 20.7% and the serum cortisol concentration by 8% in all subjects during the rst weeks . . . . . . . oral ingestion of melatonin (6 mg) during daytime with heavy resistance exercise may slightly decrease GH concentrations . . . . . . . there was a signicant trial x time interaction effect for plasma cortisol concentration (P .039) which tended to be lower in the vitamin C trial . . . . References Van Soeren et al [17]

Cortitrol (Magnolia ofcinalis, l-theatine, epimedium extract, phosphatidyl serine, b-sitosterol) Creatine

Kraemer et al 2005 [18]

Op t Eijnde et al [19]

Hoffman et al [20]

McMorris et al [21]

Leucine

Mero et al [22]

Melatonin

Mero et al [23]

Vitamin C

Davison et al [24]

(continued on next page)

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Table 1 (continued) Supplements Described endocrine effects . . . supplementation with vitamin C . . . may be associated . . . with an attenuation of the exercise induced increase in serum cortisol. . . . . . . the role that vitamin B6 may play in attenuating the rise in plasma growth hormone observed during exercise is also reviewed . . . . References Peters et al [25]

Vitamin B6

Manore et al [26]

secretion [41] and amplify the GH response to growth-hormonereleasing hormone (GHRH) at all ages, probably inhibiting somatostatin secretion at the hypothalamic level [42,43]. During exercise, arginine may facilitate the effect of exercise in limiting somatostatin secretion, thus facilitating GH secretion [44]; however, even though GH release might be increased by oral ingestion of amino acids, it might require doses of amino acids high enough to cause gastrointestinal discomfort. BCAA supplementation stimulates basal insulin synthesis and secretion and increases insulin-sensitivity, without modifying the insulin response to acute physical exercise [4547]. It has also been found that a single administration of BCAAs increases testosterone and cortisol response to acute physical exercise [45], whereas glutamic acid can stimulate adrenocorticotropic hormone (ACTH)-mediated cortisol secretion [48], and ornhitine was able to increase plasma 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 signicant increases in basal cortisol and testosterone plasma concentrations and in 24-hour urinary cortisol when compared with placebo-treated athletes [50]. In a simulated overreaching state, amino acid supplementation abolished training-related reduction of the sex hormone-binding globulin and maintained higher levels of plasma testosterone when compared to placebo [51]. Furthermore, the acute administration of an amino acid mixture (L-arginine hydrocloride 100 mg/kg L-ornithine hydrocloride 80 mg/kg L-BCAAs 140 mg/kg: 50%L-leucine, 25%L-isoleucine, 25% L-valine) enhanced the ACTH, LH, and follicle-stimulating hormone (FSH) response to corticotropin-releasing hormone (CRH) gonadotropin-releasing hormone (GnRH) administration in healthy male athletes [52]. Amino acids might inuence the pituitary secretion in various ways; they might act directly at the hypothalamic-pituitary level, or indirectly through a modication of the concentration of neuroendocrine amino acid components. Such modications would inuence the neuroendocrine pathways that regulate pituitary secretion. Furthermore, some amino acids (eg, excitatory amino acids) exert a specic excitatory activity at brain level [53].

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Table 2 Examples of amino acids-linked biological side effects/risks for health, as reported in literature Amino acids Branched-chain amino acids In humans Changes in brain chemistry Competition with other amino acids  Increased risk for bladder cancer  Inuence on insulin sensitivity
 

In animals
 

Developmental changes Promoter of carcinogenesis

Histidine

Changes in biochemical parameters  Changes in food intake  Neurological symptoms: headache, nausea, weakness  Competition with other amino acids
  

 

Changes in food intake or body intake Changes in organ morphology

Lysine

Increased protein excretion Nausea Hepatic encephalopathy in impaired liver function Hyper-homocysteinemia Psychosis in schizophrenic patients Risk factor for cardiovascular diseases

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

Methionine

   

Altered sleep-wake cycle Aortic lesions Depression of food intake and growth Enlargement of the spleen and kidney Pancreatic abnormality Pregnancy disorders Altered sleep-wake cycle Aortic lesions Brain damage Increased insulin and glucagons Pancreatic abnormality Pregnancy disorders Decreased tumor growth Growth depression Inuence immune function Secretagogue for many hormones (GH, insulin, and so forth)

L-Phenylalanine

  

Brain damage Dermatologic abnormalities Growth retardation

     

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

   

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 inuence the secretion of many pituitary hormones. The rate of synthesis of these neurotransmitters depends on various factors, including the availability and rate of uptake of their precursors (tyrosine, phenylalanine, and tryptophan) from the circulation [54,55]. The uptake of these precursors across the blood-brain barrier has been reported to occur via a membrane-bound transport system, known as the large neutral amino acids transporter (LNAA). The uptake of these precursors is affected by the plasma levels of other amino acids (isoleucine, leucine, methionine, valine) competing for uptake into the brain via LNAA-mediated transport. Thus, for example, acute administration of BCAAs might decrease the 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 hormone secretion. It has been demonstrated that BCAA administration in rats decreases the brain concentration of several amino acids (tyrosine, gammaaminobutyric acid [GABA], metionine, phenylalanine, glycine, histidine, threonine, and so forth) and increases glutamic acid, a metabolite in BCAA catabolism [56]. These results indicate preferential transport of BCAAs across the blood-brain barrier by LNAA. Furthermore, a BCAA-dependent reduction of a free tryptophan in the brain, with the consequent reduction in serotonin production in the central nervous system, may be responsible for the reduced fatigue 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 dehydrogenase, BCAA catabolism may provide glutamine [57], which is a precursor for the neurotransmitters glutamate, and GABA, which is essential for detoxication of brain ammonia. The specic actions of arginine and ornithine on pituitary function might be dependent on: (1) the inuence of arginine on brain concentration and metabolism 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 specic modulator of cerebral mitochondrial glutamate transport [58]; (4) the stimulating action of arginine on hormone secretion (ie, prolactin, catecholamines, and so forth), which may inuence the secretion of other pituitary hormones; and (5) the fact that arginine is the main source of nitric oxide (NO) production in the brain (although it has yet to 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 NO synthase (NOS), and has multiple regulatory effects in a variety of tissues and systems. For example, the pulsatile release of luteinising-hormonereleasing hormone (LHRH) induced by norepinephrine is brought about by an increase in hypothalamic NO, resulting in LHRH secretion into the portal vessels [59]. Endogenous NO also modulates the hypothalamic-pituitary-adrenal axis activity via CRH/ACTH secretion and their response to arginine-vasopressin, prostaglandins, the adrenergic system, and so forth [60]. Finally, rat steroidogenesis

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is also inuenced, at testicular and adrenal levels, by NO [61], and thus indirectly by arginine. In particular, arginine alpha-glutarate is used by athletes because of its capacity to increase NO production in the body; however, although NO might theoretically improve work capacity, increase muscle growth, and decrease recovery time, no studies have demonstrated any effects on an athletes performance. It is of interest that systemic infusion of arginine in healthy subjects induces vasodilatation and inhibits platelet aggregation and blood viscosity [62]. Based on the reported inuence of amino acids on the endocrine system, it is possible to speculate that particular combinations or the prevalence of some amino acids in the diet might inuence the characteristics of the basal endocrine status or of the general-stress or exercise-stressrelated hormonal pathways. From an ethics standpoint: (1) the use of amino acid supplementation in competitive 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 of amino acids supplementation in competitive athletes should occur only in certain circumstances (ie, when necessary for nutritional reasons) and if possible, under medical supervision; (3) the use of protein or amino acid supplements in healthy noncompetitive individuals engaged in recreational sports is not warranted, and, nally (4) because in the athletic world amino acids are taken to improve performance and might be associated with risks to health, their use in some circumstances should be reconsidered in terms of doping methods.

CHROMIUM PICOLINATE Chromium occurs in both trivalent (Cr-III) and hexavalent (Cr-VI) forms. CrVI is chiey known as an industrial, man-made product. Cr-III is found naturally in foods and is associated with nutritional supplements in various complex forms. The most popular complex form is chromium picolinate, although chromium 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 trace mineral and cofactor to insulin, enhances insulin activity and has been the subject of studies assessing its effects in carbohydrate, protein, and lipid metabolism [6567]. In fact, it is speculated that chromium picolinate works by stimulating the activity of insulin, thus signicantly improving the bodys glucose and fat metabolism, managing the breakdown of glucose and fat. The exact mechanisms by which chromium improves this insulin activity are currently unclear; it has been suggested that chromium works to increase the sensitivity of insulin receptors. Some claim that the improved insulin activity causes an increase in the production of serotonin, which subsequently reduces appetite. In fact, chromium picolinate has been used to suppress appetite and food cravings; however, because research has yet to produce any denite

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answers as to the exact function of chromium picolinate, competing theories exist about its precise effects. A placebo-controlled trial of 27 postmenopausal women given 200 mcg/day of chromium as picolinate for 60 days found a decrease in insulin levels (38%), plasma glucose (26%), and urinary calcium (19%), whereas DHEA levels increased by 24% [68]. Chromium picolinate is often promoted as a supplement that helps build muscle and burn fat. One hypothesis states that chromium picolinate increases protein synthesis, which in turn stimulates muscle growth. Reported effects include an increase in lean body mass, a decrease in percentage body fat, and an increase in the basal metabolic rate. Because of its possible action on weight reduction and body composition, it is commonly used when these effects are necessary for athletic performance; however, it seems that the observed effect with chromium picolinate is, though statistically signicant, not clinically meaningful [69]. Chromium toxicity has been almost exclusively linked to the hexavalent form. Ingestion of hexavalent chromium is 10 to 100 times more toxic than trivalent compounds. In the few existing trials, no adverse events have been observed after very short-term use in patients receiving chromium picolinate. Unfortunately, there is a paucity of research concerning side effects after high doses or prolonged treatments. Several case studies reporting subtle behavioral changes as a result of chromium picolinate are scattered throughout the literature. For example, one patient took chromium picolinate on three separate occasions and had three distinct episodes of progressively worse cognitive, perceptual, and motor changes. These episodes included sensations of feeling funny to reports of mental short circuiting and even a complete disruption of motor abilities. Other sources report vague symptoms including irregular heartbeat, leading the UAS Food and Drug Administration (FDA) to cite safety concerns. Further studies are necessary to evaluate possible chromium-linked DNA damage in humans [64].

b-HYDROXY-b-METHYLBUTYRATE b-hydroxy-b-methylbutyrate is a metabolite of leucine that has shown to posses anticatabolic actions by inhibiting protein breakdown [70]. b-hydroxyb-methylbutyrate is available as a dietary supplement and has been studied in athletes, bodybuilders [70,71], unhealthy individuals [72,73] and older adults [74,75] as a method to modify body composition by lean body mass increase. The b-hydroxy-b-methylbutyrate may play an important role in reducing protein degradation or in increasing recovery of damaged muscle cells [76]. The b-hydroxy-b-methylbutyrate prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. Experimental results suggest that b-hydroxy-b-methylbutyrate attenuates the tumor factor proteolysis-inducing factor (PIF)induced

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activation, and increases gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation [77]. Studies of b-hydroxy-b-methylbutyrate supplementation have shown minimal gains in strength and lean body mass in specic populations, mainly untrained athletes and patients who have wasting syndromes [78]. In fact, recent experimental clinical data suggest that supplementation with b-hydroxyb-methylbutyrate alone may improve nitrogen balance in critically injured adult patients, and that this effect is not a result of lowered muscle protein turnover [73]. Furthermore, b-hydroxy-b-methylbutyrate supplementation may also have anti-inammatory and anticatabolic effects, and may improve pulmonary function in chronic obstructive pulmonary disease (COPD) patients in an intensive care unit setting [72]. A daily supplementation of b-hydroxy-b-methylbutyrate, arginine, and lysine for 12 weeks in elderly women positively alters measurements of functionality, strength, fat-free mass, and protein synthesis, suggesting that the strategy of targeted nutrition has the ability to affect muscle health in this population [74]. If conrmed, and adequately authorized in terms of safety and risk/benets ratio, these effects might be of some interest to older competitive athletes. In athletes, b-hydroxy-b-methylbutyrate in association with creatine has been 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-ketoisocaproic acid supplementation reduced signs and symptoms of exercise-induced muscle damage in nonresistance-trained males following a single bout of resistance exercise [81]; however, on the basis of the existing literature, b-hydroxyb-methylbutyrate use in athletes involved in regular high-intensity exercise has not been proven to be benecial when multiple variables are evaluated [2,78,82]. Unlike other ergogenics, no adverse events have been reported with b-hydroxy-b-methylbutyrate in association with short-term use. Furthermore, in the few existing studies, no alterations of serum biochemical parameters, testosterone and cortisol concentrations, or urinary testosterone/epitestosterone ratio have been observed after b-hydroxy-b-methylbutyrate administration [83,84]. Beyond ethical considerations, b-hydroxy-b-methylbutyrate cannot be recommended as a safe supplement, even when theoretically necessary, until further studies in larger groups have been performed [78].

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

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Most clinical research on DHEA has focused on its putative effects as androgen replacement therapy in hypoadrenalism with hypoandrogenisms and in aging, because of the possible presence of a functional form of age-related adrenal androgens deciency in both sexes. DHEA is mildly androgenic and can be converted to estrogen at the target tissue level. At replacement doses of 25 to 50 mg per day, DHEA increased testosterone concentration in women, and induced supra-physiological blood testosterone concentrations with high doses (eg, 100 mg per day) [8587]. In healthy men, even massive daily DHEA dose administration (eg, 1600 mg/d) had no effect on blood testosterone concentrations, although in elderly men blood estradiol was markedly increased after DHEA administration [85,88]. Androstenedione is a preandrogen that was advertised as promoting muscle growth, improving muscular strength, reducing fat, and slowing aging before being taken off the market by the FDA in 2004. In hypogonadal men, androstenedione administration (eg, 1500 mg daily, which replicates a model of hormone abuse) produced a 10 fold increase in blood androstenedione concentration as well as a 2 fold increase in testosterone concentrations [89]. Despite the relatively inefcient 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 increase of testosterone concentration may become evident. On the basis of current literature, androstenedione has both proper androgenic effects, through a possible interaction with androgen receptors [89], and indirect androgenic effects, acting as prosteroid and becoming biologically active after conversion to more potent natural androgens in vivo. The curious paucity of studies on DHEA and on androstenedione for enhancing sport performance or body building may reect a dichotomy between its exploitation in the anti-aging substances market and a more pragmatic world of professional elite athletes expecting to base investment decisions on sound evidence and risk-benet calculations. DHEA and androstenedione are without proven benets for athletic performance, and their use in the world of sports or body building seems to be mainly linked to anecdotal evidence. Currently, DHEA and androstenedione are considered prohibited substances by the WADA, consequently their use in athletes is banned. DHEA and androstenedione share many endocrine-metabolic pathways with different anabolic steroids and androgens (eg, testosterone), and they also share the same adverse effects and risks to health. Consequently, owing to different ethical and endocrinological concerns, their nontherapeutic use in healthy individuals (athletes and non-athletes) is not advised, especially in young people [90,91].

CONTAMINATED NUTRITIONAL SUPPLEMENTS The relationships between taking supplements and hormones may also be related to possible accidental (or voluntary) contamination with prohibited

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compounds (hormones or prohormones) not declared on the labels of different nonhormonal supplements (products containing vitamins, amino acids, creatine, and so forth). To date, there are numerous reports in the literature with respect to contamination of dietary supplements with toxic or prohibited substances that are not identied on the label [9298]. In a recent large-scale study, androgenic anabolic steroids were detected in 14.8% of 634 different steroid-free nutritional supplements purchased in 13 countries from 215 different suppliers: the positive supplements showed androgenic steroid concentrations of from 0.01 lg/g up to 190 lg/g [95]. In fact, after the rst scientic demonstration that some steroid-free supplements also contained undeclared androgenic anabolic steroids [94], strategies for the detection of hormone contamination in athletes supplements have improved [99]. For example, Baume and colleagues [100] recently analyzed the composition of 103 dietary supplements (creatine, prohormones, mental enhancers, and branched chain amino acids) bought on the Internet. All the supplements were screened for the presence of stimulants and main anabolic steroids parent compounds (precursors and metabolites of testosterone and nandrolone). The study identied three products containing an anabolic steroid, metandienone, at a very high level. The results have also shown that one creatine product and three mental enhancers contained traces of hormones or prohormones not declared on the labels, and that 14 prohormone products contained substances other than those indicated by the manufacturer. The oral intake of the creatine product revealed the presence of the two main nandrolone metabolites (19-norandrosterone and 19-noretiocholanolone) in urine [100]. The presence of undeclared substances (testosterone, 19-nortestosterone and respective precursors, DHEA, and so forth) can cause health risks to consumers, and might lead to positive results in sports doping controls, especially for the nandrolone metabolite norandrosterone [94,101]. Furthermore, many Authors have highlighted the potential for legal damages and the risks to athletes health linked to this involuntary taking of prohibited substances. [94,101,102]. Interestingly, the German Federal Supreme Court stated that nutritional supplements should indisputably be considered drugs if they contain substances banned by antidoping organizations [102].

SUMMARY It should be emphasized that the term food supplements ought to be used only for specially adapted products containing nutrients normally found in the usual human diet; these would be suitable only to substitute or complete an athletes diet in particular conditions. Consequently, it is necessary to avoid any reference to taking supplements as a way to improve athletic performance or optimize energy production, metabolism, or muscle growth in athletes. In fact, this denition of supplements is much too similar to the denition commonly

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used for many doping substances, and could encourage food supplement misuse. From a clinical and ethical point of view, this is particularly evident for the so-called ergogenic substances or ergogenic aids supplements (sometimes also normal nutrients). In fact the term ergogenic is related to a hypothetical capacity of some substance to increase energy, physical work capacity, or physical performance. Furthermore, ergogenic substances very often act in the body through well-known metabolic or endocrine pathways, in ways similar to different active molecules included by the WADA in the list of prohibited substances. Because many athletes acquire their nutritional supplements outside the health care system, and also considering that many supplements may be contaminated with prohibited substances (eg, anabolic steroids), athletes and their physicians need to be aware of the many problems (eg, health, the law, and so forth) that can follow supplement abuse. The need for appropriate worldwide regulation and homogenization of dietary supplement and ergogenic substance use by athletes is further emphasized [98], both to protect athletes long-term health and, because of the parallelism in desired effects and mechanisms of action, to have coherent denitions of the many methods of supplementation, ergogenic substances, and different prohibited substances. For example, with respect to an allowed supplement (eg, arginine), which stimulates GH secretion, and the prohibited GHRH, which also stimulates GH secretion, the question must be why the two are treated differently. Both substances are believed to have positive effects on athletic performance and are taken for this purpose, both act through similar functional pathways (eg, GH secretion) and are associated with potential risks to health, yet only one is a prohibited substance. Arginine and GHRH could be used by athletes (for nutritional purposes or for 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 mechanisms of action and safety are concerned [28,29]. It is necessary


To use supplements according to well-identied daily recommended doses of nutrients for athletes, to be used only for nutritional goals (and not to improve performance or muscle growth) To identify if there are real (or potential) extra-dose or association-related further effects of nutritional supplements on performance (dose-related or association-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 quantitatively beyond individual, absolute or relative (ie, in some clinical situations) maximal safe daily dose, and to the use of particular, nonphysiological associations of supplements and ergogenic aids

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Box 1: Ergogenic aids used as supplements by athletes can be categorized as follows Essential nutrients (at non-nutritional doses): Amino acids (arginine, ornithine, tryptophan, branched-chain amino acids (BCAAs), and the like) Vitamins (B1,B6, B12, niacin) Mineral and trace elements (potassium, magnesium, calcium, boron, chromium, sodium bicarbonate, and phosphates) Engineered metabolic by-products of essential nutrients: b-hydroxy-bmethylbutyrate (HMB) Dihydroxyacetone plus pyruvate (DHAP) Fructose diphosphate (FDP) Nonessential nutrients (carnitine, choline, creatine, and so on) Herbal productsphytochemicals (ginseng, yohimbine, tribulus terrestris, and so on) Drug nutrients (caffeine, and so on) Prohormones and hormones (dehydroepiandrosterone [DHEA]a, androstenedionea, melatonin, and so on)
Now prohibited by the World Anti-Doping Agency (WADA). Data from Williams MH, Leutholtz BC. Nutritional ergogenic aids. In: Maughan R, editor. Nutrition in sport. Oxford (United Kingdom): Blackwell Science; 2000. p. 35666.
a

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