Androgenic Anabolic Steroids have been used by athletes for performance enhancement and aesthetic reasons for many years. The first reported case of misuse of AAS by an athlete was in the 1950s, when competition weightlifters used androgens to enhance performance and after winning competitions, the use of AAS became more prevalent. In the 1960s, the International Olympic Committee started producing its first doping controls, and in 1976, AAS was placed on the list of banned substances by the IOC (Yesalis et al 2000). Recently, scandals concerning anabolic steroids have put it in the forefront, with the admission of guilt of Marion Jones to the rumors looming Barry Bonds. However, the abuse of AAS is not limited to elite athletes, but is also commonly used by amateur and recreational athletes. These abuses have led to published reports of many side effects of these substances in athletes (Wilson 1988).

These substances are synthetic derivatives of the male hormone testosterone, which is produced in humans in the Leydig cells in the testes (Kochakian, 1993). The androgenic actions of AAS primarily include the development of male characteristics, that is, increased strength, voice deepening, and the typical male hair growth. The anabolic actions of AAS include affect on protein metabolism by stimulation of protein synthesis and inhibition of protein breakdown (Wilson, 1996).

Androgenic anabolic steroids are not only used for performance enhancement, but also have several therapeutic uses. The therapeutic uses of steroids vary between steroids, but some steroids are used to treat endocrine dysfunction of the testes and of the hypothalamus-pituitary-gonadal axis. Some other therapeutic uses of steroids are also to treat nitrogen balance and muscular development and several other non-endocrine diseases, including several forms of anemia, hereditary angioneurotic oedema, breast carcinoma and osteoporosis. Clinical data supports the use of AAS in the treatment of acute and chronic diseases from the positive effect on nitrogen balance in polytrauma patients to increasing muscle mass in patients with HIV or chronic obstructive pulmonary disease (Wilson, 1996, Ferreira, 1998, Gold, 1996).

Scientific research on the effects of AAS in athletes has been conducted since the 1960's but the first studies focused on athletic performance. However, later, that research evolved into effects of AAS on lean body mass and its adverse effects. There have been several studies published on AAS, but several different conclusions and interpretations have been drawn. Conducting studies on AAS is difficult because it is potentially dangerous to expose healthy humans to these dangerous drugs for the purpose of improving sports performance. The studies that have been conducted are not very scientifically sound, and have also included the side-effects of AAS. Therefore, the studies designs have dictated the conclusion and interpretation of the use of AAS.
Chemistry
Exogenous testosterone (Figure 1) cannot exert significant effects in the human body when administered orally or parenterally because it is metabolized so rapidly. Therefore, several modifications have been made to exogenous testosterone, including three major modifications. The first major modification is the alkylation at the 17-α-position with methyl or ethyl group. Alkylation is important for orally active compounds because this implies that there will be slower degradation of the drug by the liver. Second modification was through esterification of testosterone and nortestosterone at the 17-β-position, which makes it possible for the substance to be parenterally administered and the duration of effectiveness can be prolonged. Finally, alterations of the ring structure of testosterone are applied to both oral and parenteral agents and this increases the activity of these substances (Wilson, 1996).

Mechanism of Action

Although the exact mechanism of AAS is unknown there are several general mechanisms that have been postulated. The mechanism of action of AAS differs for the different compounds because of variations of steroid molecules. These variations in steroids are responsible for the differences in the specificity of binding to receptor proteins or to interactions with various steroid-metabolizing enzymes (Wilson, 1988, Bartsch, 2000). Several pathways can be distinguished regarding intracellular steroid receptor protein (Wilson, 1998). These steroids are recognized as strong androgens for the affinity to androgen receptors. There are also several compounds that are characterized by binding with low affinity to androgens and are therefore weak androgenic substance (Toth and Zakar, 1982). Some AAS do not bind to androgen receptors at all (Toth and Zakar, 1982).

The enzyme 5-α-reductase is accepted as playing an important role in mechanism of action of AAS. It is primarily responsible for converting AAS into a more active compound dihydrotestosterone. After diffusion into the cells of the target tissue, AAS may be subject to two different pathways (Toth and Zakar, 1982).The steroid binds directly or after conversion into dihydrotestosterone, to specific receptors for androgens, which results in the formation of a steroid-receptor complex in the cell nucleus. The steroid-receptor complex stimulates the protein synthesis by interaction with RNA and DNA (Wilson et al, 1996).

The organ systems with the highest amount of the enzyme 5-α-reductase activity are the male accessory sex glands, the skin, the prostate, the lungs, the brain, fat cells, and bone, posing a high affinity to androgenic rather than anabolic compounds. Organs such as the heart and skeletal muscle, which have low 5-α-reductase have a stronger response to anabolic substances (Wilson et al, 1996).

An enzyme that plays a limited role in mechanism of action of AAS is aromatase. Aromatase is located inside the cell and is responsible for converting AAS into female sex hormones such as estrone and estradiol. These sex hormones bind to estrogen receptors to form estrogen receptor complexes, which, in turn, exert their effects in fat tissue, Leydig and Sertoli tissue and in the nuclei in the Central Nervous System (CNS). This mechanism is thought to be activated only when the androgen receptor is saturated by the circulating androgens and anabolic steroids. It is theorized that AAS may have an antagonistic action on estrogens when supraphysiological serum levels of AAS are present, which leads to saturation and down-regulation of androgen receptors. Excess AAS then tries to bind to the estrogen receptors in competition with the estrogen available, making the net outcome of the two conflicting pathways unpredictable (Wilson et al, 1996).

Complimentary to the competitive antagonism with the estrogen receptors, a similar competitive, a similar competitive antagonism has been described with respect to glucocorticoid receptors. Glucocorticoids are substances with catabolic properties that are released in the serum as a result of strong physical or mental stress. To counteract the breakdown of proteins the by glucocorticoids, AAS bind to glucocorocoid receptors (Hickson et al. 1990).

Hematological system is also influenced by AAS via two main pathways. Anabolic steroids stimulate erythropoiesis directly and erythropoietin synthesis in the kidney. The effects of androgens have also been demonstrated to promote erythropoietic stem cell differentiation and to increase the sensitivity of erythroid progenitors (Berns et al, 1991).

Researchers hypothesize that AAS induced increase in muscle mass can be attributed to both muscle hypertrophy and formation of new muscle fibers. It is hypothesized that the process of muscle fiber growth is the incorporation of the satellite cells into pre-existing fibers to maintain a constant nucleus to cytoplasm ratio. Satellite cells are enhanced by AAS administration and androgen receptors. Androgen receptors are expressed in myonuclei of muscle fibers and in capillaries. AAS use increases the androgen receptor containing myonuclei (Kadi et al, 1999)
Effects of Androgenic Anabolic Steroids on Athletes

Scientific studies conducted on the effects of AAS have used small amounts of AAS unlike the doses currently taken by athletes who use AAS for performance enhancement. Therefore, the current scientific knowledge of the effects of AAS provides only a glimpse of the actual effects of these steroids in athletes. Scientific studies have focused on changes in body composition, strength, hematology, and endurance performance, neuromuscular changes and recovery.

Body composition, in most studies focusing on the effects of AAS, is categorized into lean-body mass and fat mass. However, bodyweight and body dimensions also have to be considered when studying the effects of AAS on body composition. Athletes administering AAS tend to report increases of 10-15kg of bodyweight due to AAS administration. However, most duties show that bodyweight may increase by 2-5kg as a result of short-term (
Body dimension is another factor studied in scientific studies. While some studies tend to show no changes in body dimensions, most research studies tend to show alterations in body composition in athletes using AAS. The largest gains in circumference has been found in the neck, thorax, shoulder and upper arm, but is dependant on the drug and the doses administered in the study. (Hartagens, etc al, 2001, Kuipers et al, 1991)

Most studies point to no significant change in fat mass in athletes using AAS (Hartgens et al, 2001, Kuipers et al, 1991). The alterations in fat mass may be attributed mainly to an increase in lean body mass. Studies have shown that there is an increase in lean body mass depended on the amount of dose administered. Although the precise composition of increase lean muscle mass is not established, since AAS has been demonstrated to stimulate protein synthesis, the effects on muscle tissue cannot be established. In recent years, there has been evidence that AAS has muscle building properties. It is also proposed that AAS increase blood volume and water retention (Hartagens et al, 2001, Kuipers et al, 1991).

Scientific studies conducted in animals has shown a decrease in fat mass, so it was concluded that use of AAS will decrease body fat among athletes. However, the research studies have proved inconclusive, and a reduction in body fat percentage was not reduced with the use of AAS. One can conclude though that athletes who use AAS for aesthetic purposes tend to follow a low calorie diet, therefore reducing their body fat (Hartagens et al, 2001, Kuipers et al, 1991, Forbes et al, 1992).

Muscle strength is an effect of AAS that has been investigated fairly extensively. Studies conducted on effects of AAS on muscle strength have been fairly extensive and fairly varied. Studies have been designed using different dosages and with and without strength training programs. The studies concluded that the increases in strength are dependent upon the dose of the AAS, increased doses yielded higher increases in strength. Subjects who were subjected to strength training programs also tended to show a higher increase in muscle strength than subjects who did not have a strength training program administered to them (Bhasin et al, 1996, Bhasin, 2001, Giorgi, 1999).

It is accepted that a relationship between muscle strength and fast twitch, Type II fibers exists. It is, therefore, assumed that AAS affect Type II, fast twitch fibers, more than Type I, slow twitch fibers. In studies conducted to investigate the effect of AAS on Type I muscle fiber, it was concluded that there was a greater increase in Type I muscle fiber in users of AAS than non-users in self-administered long-term use (Kadi et al, 1999, Hartgens et al, 1996, Kuipers, 1993). Other studies have concluded that during short term of multiple AAS administration produced a profound effect on Type II muscle fiber (Hartagens et al. 2002).

A therapeutic use of AAS is the treatment of anemia, since long-term administration of AAS has shown to increase serum hemoglobin concentration. Since there is a relationship between hemoglobin and endurance performance, athletes have started to self-administer AAS. However, the results of scientific studies have been varied. A few studies have demonstrated that that increased serum hemoglobin has lead to increased white blood cells and platelet counts in athletes (Hartgens et al, 1995). However, several studies have also demonstrated that there was no increase endurance performance in athletes who self-administered AAS (Jakob et al, 1988).

It has been theorized that AAS reduce recovery time, but it is difficult to measure this outcome, so studies that have been conducted on recovery focus on indirect parameters that are associated with recovery time (Kuipers et al, 1991, Boone et al, 1990, Rozenek et al, 1989). The investigations conducted on these parameters demonstrated that exercise-induced increments of heart rate and serum lactate levels were delayed and heart rate and lactate levels returned to baseline much faster with the administration of AAS (Keul et al. 1976). Administration of AAS was found to have increased androgen/coritsol ratios and plasma lactate levels in AAS users, which subject the users to lower fatigue after training sessions (Rozeneck et al, 1990).

Neuromuscular changes have also been attributed to use of AAS. It is suggested that neuromuscular changes in athletes was observed in athletes who used AAS compared to athletes who did not. The causal mechanism of neuromuscular changes is not known, but it is theorized that anatomical and biochemical changes in the nervous system (Alen et al, 1984).
Adverse effects of androgenic-anabolic steroids

Androgenic-anabolic steroids have several side effects. The side-effects of AAS can be categorized into subjective and objective. Subjective side-effects are defined as perceived side effects, and are usually self-reported. The undesired health effects are open to objectification.

Subjective side-effects of AAS are usually measured by employing questionnaires. These subjective side effects have been reported both during AAS use, but also after drug withdrawals. The side effects that have been reported include increased sexual drive, occurrence of acne, increased body hair, and an increase in aggressive behavior (Yesalis et al. 1988). Other side effects such as fluid retention, elevated blood pressure (BP), sleeplessness, increased irritability, decreased libido, increased appetite, enhanced transpiration, increased feeling of well-being, depressive mood states, loss of head hair, and the occurrence of gynaecomastia (Yesalis et al, 1988).

Androgenic-anabolic steroids are derived from exogenous testosterone, therefore affecting sex hormones and the reproductive system. AAS suppress the hypothathalamic-pituitary-gonadal axis, which acts as a feedback system. Therefore, exogenous administration of AAS will disturb the endogenous production of testosterone and gonadotrophins. Suppression of gonadotropin production induces testicular atrophy and reduces semen production and quality in males. Serum gonadotrophins levels decrease with the administration of AAS (Torres-Calleja et al, 2001). Long-term administration of AAS may provoke hypogonadotrophic hypogonadism characterized by testicular atrophy, oligo- or azospermia, low serum concentration of luteinising hormone and follicle stimulating hormone and endogenous testosterone and precursors (Martikainen et al, 1986). Another adverse effect of AAS is gynaecomastia in male athletes. Gynaecomastia is the peripheral conversion of AAS to estrogens as a result of huge amounts of exogenous AAS, which results in development of female breast characteristics (Neild, 1995).

The non-medical use of AAS has been linked to acute myocardial infarction, hypertension, enlarged heart, and altered lipid metabolism. Cardiovascular effects of androgens include hypertension and the development of atherogenic lipoprotein profiles. Users of AAS have reported higher systolic blood pressure, but not higher diastolic blood pressure (Nnakwe, 1996). There is also a significant decrease in high-density-lipoprotein cholesterol (HDL-C) and an increase in low-density lipoprotein cholesterol (LDL-C) with uses of AAS. The decrease in HDL-C and increase in LDL-C also causes an increase in blood triglyceride concentration. Use of AAS has also been reported to cause steroid induced hypercholesterolemia and increase in total cholesterol concentration (Nnakwe, 1996).

Liver function disturbances and diseases are some other reported side effects of AAS. Serious liver disorders include subcellular changes of hepatocytes, impaired excretion function, cholestasis, peliosis hepatic and hepatocellular hyperplasia and carcinomas (Soe et al, 1992). These diseases are mainly attributed to 17-α-alkylated steroids, that is, methylestosterone, oxymetholone, fluoxymesterone, norethandrolone and metandienon (Soe et al, 1992). Studies have also noted that there is an increase in alanine aminotransferase with the use of AAS, but returned to normal once AAS use is seceded (Soe et al, 1992).

Psychological changes in behavior have also been noted with AAS use. Studies with athletes using AAS have reported occurrences of schizophrenia, steroid dependence, affective and psychotic symptoms, homicide and near homicide. Administration of AAS also resulted in depression, paranoia, hypomania and psychotic features. Athletes using AAS also tend to have reverse anorexia syndrome and body dysmorphic disorders. People taking AAS also tend to have become addicted to other substances and tend to have addictive personalities (Brower et al, 1990).
Conclusions and Future Direction of Research

Androgenic-anabolic steroids have demonstrated increased strength gains and lean body mass in athletes. AAS are also thought to increase cardiovascular capacity, though that has not been proven. Steroids also have several side effects, from physical to physiological to mental. Research using AAS is very difficult because of ethical concerns, and it is also very difficult to do a scientifically controlled study. Therefore, suggestions for future research include examining the effects of AAS on recent athletes who have admitted to using steroids. A survey study to better understand the side effects and physiological studies examining the physiological effects can be used to better understand the effects of AAS.

Structure of Exogenous Testosterone

Figure 1
(Kochakian, 1993)

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