STEROIDS

Source: dotpharmacy.co.uk

Anabolic-androgenic steroids

Anabolic steroids, or more correctly, anabolic-androgenic steroids (AAS), are synthetic derivatives of the male sex hormone, testosterone. This hormone has two basic physiological effects: 

- an androgenic effect ­ leads to the development of male features, eg facial and body hair growth,      deepening of the voice, development of the testes and penis

- an anabolic effect ­ refers to its ability to build skeletal muscle tissue.

AAS are used by body builders and weightlifters to increase both lean muscle mass and strength and to decrease body fat, whereas athletes use AAS to increase erythropoiesis and thus enhance the oxygen-carrying capacity of blood to allow them to run faster.

Testosterone was first synthesised in 1935 and is said to have been used to increase the aggressiveness of German soldiers in the Second World War. The use of testosterone by athletes can be traced to the 1954 world weight-lifting championships in Vienna, where it was reported that a Soviet Union coach informed the US coach, Dr John Ziegler, that the Soviets were using testosterone. On returning home, Dr Ziegler began using testosterone with weightlifters and it is believed that AAS use increased among Olympic athletes over the next 40 years. 

AAS have been used medically in the treatment of aplastic anaemia, as well as to offset the protein catabolism that occurs after prolonged corticosteroid therapy and to promote weight gain, eg after surgery, chronic infections or severe trauma. The main current use, however, has been in the treatment of hypogonadal men, though there is much current interest in the use of AAS as a means of promoting weight gain in HIV patients. 

The androgenic side effects of testosterone, especially in women and children, led to the development of synthetic steroids which, while retaining the anabolic properties, were less androgenic. In 1953, 19-nortestosterone (nandrolone) ­ a derivative of testosterone ­ was discovered and found to have three to five times the muscle building effects of testosterone. It became the first compound to be called an 'anabolic' steroid. All of the synthetic AAS that were subsequently developed were derivatives of testosterone or 19-nortestosterone. 

While many of the testosterone derivatives are more anabolic than androgenic, there are no AAS that are purely anabolic or androgenic. Whether an anabolic or androgenic effect occurs will depend on the dosages used, though it should be stressed that all AAS are capable of producing androgenic effects if used in sufficiently high doses. It is worth noting that while AAS and glucocorticoids, such as cortisol and prednisolone, are chemically similar, they have opposite effects. Examples of oral and injectable AAS are shown in Table 1. 

Mode of action

The exact mode of action which leads to an increase in muscle mass and strength remains unclear, but is probably a combination of increased protein synthesis and an anti-catabolic effect. During heavy resistance training (such as weightlifting), stress exerted on muscles induces the release of hormones such as cortisol, and prolonged release can cause skeletal muscle breakdown (hence the use of AAS after corticosteroid therapy). It is thought that AAS can inhibit the negative effects of cortisol, although exactly how this occurs is unknown.

Evidence for action

Two comprehensive reviews of the AAS literature published in 1984 and 1991 concluded that the drugs can increase lean muscle mass and decrease body fat, if used as part of a programme that includes structured training and an adequate intake of protein. As a result, many AAS users consume large amounts of protein in the form of amino acid supplements, although there is little evidence that overloading with such supplements increases muscle mass. 

One of the problems in assessing the efficacy of AAS in many of the published studies is that several of the important variables such as protein intake, diet, length of training experience of the athletes, dosages employed, drug combinations used and whether or not the studies were blinded, were not always controlled. Many studies have also been criticised for having a small number of subjects. 

There appears to be only two well designed, controlled studies which use dosages of AAS that are six times the therapeutic dose. The first of these studies demonstrated that AAS use in experienced body builders produced gains in lean body mass that were maintained for at least three months after discontinuation of drug treatment. Also all adverse effects, such as alterations in the level of HDL cholesterol, returned to normal six weeks after cessation of drug use. The second study used testosterone 600mg per week and assigned the subjects into one of four groups: placebo with no exercise, testosterone with no exercise, placebo with exercise and finally testosterone with exercise. All of the subjects had previous experience of weight training and the results showed that those in the 'testosterone with exercise' group had greater increases in muscle size and fat-free mass than those in both groups who did not exercise, and greater increases in strength than the non-exercising groups. It was also reported that there were no effects on mood or behaviour in any of the groups. 

Psychological effects

Mood changes One study of AAS-using athletes found that 23 per cent of users reported major mood syndromes, eg mania, hypomania or major depression in association with their drug use. 

One commonly reported psychological adverse effect is the so-called '[ste]roid rage'. While increased levels of aggression in laboratory animals can be correlated with higher plasma levels of testosterone, the evidence from human studies is less conclusive. Other varying factors, such as original mental state, drug doses, drug combinations, duration of use and even the type and purity of the drugs, may also influence the development of mood disorders. 

Interestingly, the authors of a study using testosterone enanthanate 200mg per week for up to 20 weeks, as a potential male contraceptive, concluded that the data ''suggests that concerns of adverse effects of exogenous testosterone on male sexual and aggressive behaviour have perhaps been overstated". 

Dependence

There has also been the suggestion that AAS are in some way addictive. The basis for this is that once AAS are discontinued, muscle mass is lost and this can lead to feelings of depression and a desire to continue to use them. Muscle mass occurs because once the exogenous testosterone is removed, the testes, which have often undergone some degree of atrophy, are no longer producing sufficient testosterone to sustain the increased muscle mass.

The concept of a steroid addiction hypothesis was first reported in 1989, when it was suggested that a high proportion of anabolic steroid users might develop a form of anabolic steroid dependence. In addition, results from a year long study of AAS users attending a clinic found that many users reported feeling dysphoric once they stopped taking their drugs. In 1995, Zoe Warwick, a former champion body builder and campaigner against the use of AAS, committed suicide and was diagnosed as suffering from exogenous androgenic misuse syndrome. Despite this unfortunate case, there have been no reports of AAS dependence in women or children or even among patients who have been prescribed high doses of these drugs in the treatment of anaemia. 

Physical side effects

The adverse effects of AAS have been greatly emphasised by the sporting authorities and used as a means of discouraging the wider use of the drugs, but the whole subject has attracted much controversy. 

There are potentially many side effects of using AAS (see Table 2) but most of these resolve once the drug is discontinued, although many of the effects in women appear to be irreversible. In 1997, it was reported that an East German female shotputter, Heidi Krieger, underwent a sex change operation which she claimed was a result of the AAS she was forced to take during training in 1982. Krieger claimed that the AAS had made her develop facial hair and an enlarged Adam's apple, and she suffered severe psychological problems. Similar changes were reported by Christiane Knacke-Sommer, a former East German Olympic swimmer. Several coaches and doctors have been put on trial in Berlin. 

There are many single reports in the literature that have been used as a basis for the case against AAS use and these have been reviewed elsewhere. As shown in Table 2, for instance, AAS can elevate liver function tests and this can lead to the development of liver tumours. However, there are very few (no more than four) cases of tumours associated with AAS use by athletes. One such case report describes how a user took 700mg of oxymetholone a week continuously for five years. In contrast, a study using oxymetholone at 150 mg/day (normal dose being 1-5 mg/kg) for 30 weeks in patients with HIV did not produce any adverse effects on the liver. 

The frequency with which the possible side effects occur will depend on factors such as the combinations of drugs used (see Table 3), dosages employed, length of cycles and the individual response to the drug. In addition, many AAS are counterfeits and while some preparations will contain nothing more than the oil base itself, others will have varying mixtures of different agents and analysed samples have shown wide variation in composition. It is this unknown factor that poses the risk. Since there are many variables to consider, making meaningful predictions of the adverse effects is more difficult. One possible solution to the problems posed to AAS users might be to allow GPs to prescribe the drugs themselves and some success has already been achieved with this approach. In Australia, from 1987 to 1991, a group of anabolic steroid users were prescribed courses of methenolone 140mg per week for seven weeks. 

There are, unfortunately, no large long-term observational studies of body builders and weightlifters from the 1950s and 1960s, which would provide valuable insight into the lasting adverse effects of these drugs. 

Drug regimens

AAS are often used in fairly complicated regimes or cycles. During a cycle, it is not unusual for several different agents to be taken together continuously for up to 12 weeks at differing doses. This is followed by a rest period and the cycle is repeated two or three times per year. If the AAS are delivered via a depot injection, the drugs are held in the fat stores and released slowly over several months, which can create problems for athletes who might use the drugs when not competing, but still test positive several months later. 

The dosages of AAS used are often well in excess of the recommended medical dosages. For example, the therapeutic dose of methandienone (Dianabol) is 5mg daily, whereas body building athletes might use up to 40mg daily. Similarly, testosterone enanthate is used in the treatment of hypogonadism at between 50 and 400mg every two to four weeks, whereas body builders might use up to 800mg per week. 

Drug testing

Testing for AAS was introduced in 1976 using assays based on gas-chromatography and mass spectrometry (GC-MS) and this technique is now used routinely. Tests involve the detection of excessive anabolic steroid metabolites in urine as confirmation of the presence of exogenous AAS. Blood testing is permitted, but not used routinely. 

The most commonly used procedure involves determining the ratio of testosterone to epitestosterone. Normally, the ratio of the two steroids in urine is 1:1 and so if additional testosterone is taken, the ratio increases. Since training can increase the natural levels of testosterone, there is a permitted maximum ratio of the two steroids of 6:1. 

Since the main method of testing is urine, in an attempt to avoid detection, many athletes have resorted to a number of different methods ranging from direct substitution with another person's urine, use of diuretics (see Table 3) and use of blocking agents, such as probenecid, which prevents the excretion of AAS. However, diuretics, blocking agents and use of epitestosterone (to maintain the 1:1 ratio) have all been included on the sports authorities list of banned substances. 

Recently, there has been an increase in the number of athletes testing positive for nandrolone, although many of them are adamant that they have not taken the substance. A steroid precursor to nandrolone is present in some food supplements taken by athletes and there is some evidence that nandrolone can be produced in the body in trace amounts. Since the GC-MS can detect substances at the nanogram level, there is a risk that athletes can test positive even when they have not knowingly used nandrolone and they therefore need to play close attention to their diets. 

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