Yudu - sportEX medicine - 1999-2010

CONTROVERSIES STEROIDS IN SPORT

testosterone, most notably the androgenic effects. Although these androgenic effects were required for treating hypogonadism, it ultimately precluded the use of these drugs in children and women to treat diseases that would benefit from testosterone’s anabolic effects, such as cachexia, growth disorders and (in women) breast cancer (where, increasingly, testosterone was being used not only for its anabolic effects but also for the anti-cancer effects, which it exerted through antagonising the actions of oestrogen), as it often led to virilisation (the development of male secondary sexual characteristics) (2). Work published in 1942 by Charles Kochakian demonstrated that some androgens had a greater anabolic effect than androgenic effect. This sparked research into the development of a new group of compounds that aimed to retain the anabolic effects of testosterone but dissociate the unwanted androgenic effects, leading to a range of both oral (such as methandrostenolone (Dianabol®) in 1959) and injectable (such as nandrolone decanoate in 1960) compounds that, compared with testosterone, had a significantly increased ratio of anabolic to androgenic activity. Ultimately, however, the dissociation of androgenic effects was realised only partially, and, depending on the type and dose, it was found that all steroids had the potential to induce virilising effects in children and women, thus limiting their use in clinical medicine (in particular to the testosterone esters that were used for replacement therapy in hypogonadism) (2). Despite this, the potential of steroids to enhance

performance did not go unnoticed by those involved in bodybuilding and sport. Indeed, as Wright notes: “various forms of testosterone were being used to increase muscle size by bodybuilders in the late 1940s and early 1950s” (3), which certainly reflected the interest in enhancement by both the medical community – which had been examining the effects in men from 1941 onwards (4) – and testosterone’s leading public proponent of the time, Paul de Kruif (5).

OH 17 17 OH 17 OH The history of steroid use outside of clinical medicine

is largely a synthesis of anecdotal narrative from those involved in bodybuilding and sport at that time. It is sketchy at best and reflects both personal experience and prejudices, along with a good dollop of conjecture (and makes for great reading!). The reader is referred to Dimeo (6) for a detailed critique of this subject. Suffice to say, it appears that by the 1960s steroid use was an accepted practice in UK bodybuilding and weightlifting (7), and that by the 1980s their use was reported as becoming more common within the general population (8).

DO ANABOLIC STEROIDS WORK? Our understanding of the mechanisms by which steroids exert their effects on the body are limited, especially in humans. However, they are governed by a complex function of pharmacokinetics and pharmacodynamics that include dose; absorption; distribution and storage in the body; the degree to which they mimic the action of endogenous testosterone; their ability to act promiscuously through other signalling pathways (such as through the progesterone signalling pathways in the case of some steroids); and individual differences in metabolism. Furthermore, variables such as sex, age, lifestyle and genetic factors are also likely to play a significant role in modulating the effects of these drugs.

For many years there was acrimonious debate over

whether steroids could enhance performance, with many medical, scientific and sporting organisations repudiating their effects based primarily on the results of studies that failed to show unequivocal improvements in strength (9). However, as recognised at the time, the conclusions that could be drawn from these studies were limited by variations in the experimental design, in particular the failure to standardise on type of anabolic steroid (which may have different pharmacodynamic properties) and dose (which mostly failed

OH 17 CH3 OH 17 CH3 OH 17 CH3

The addition of a methyl group (CH3) at C-17! prevents the oxidation of the steroid to a 17-keto steroid (part of the metabolic degradative pathway of testosterone). This protects the steroid from being rapidly degraded by the liver. When given orally, methyltestosterone has a half-life of ~150 minutes compared to ~10 minutes for testosterone. Most orally active steroids have a methyl group at C-17! to enhance bioavailability.

O O O Testosterone Testosterone Testosterone Testosterone

Methyltestosterone (oral 17!-alkylated steroid) O

Methyltestosterone (oral 17 a-alkylated steroid) Methyltestosterone (oral 17!-alkylated steroid)

Testosterone propionate (injectable testosterone ester)

17 17 O O O 17 O

Esterification of testosterone with propionic acid via the C-17b-hydroxyl group makes the steroid more soluble in the lipid (oily) injection vehicle, thereby decreasing the rate of absorbtion from the injection site, and, hence prolonging its action. When released from the injection vehicle and enters the bloodstream the ester group is removed by esterases to leave biologically active free testosterone. Most injectable steroids are esterified at the C-17b-hydroxyl group to enhance bioavailablity. Typically, the longer the ester, the longer the half-life. In case of testosterone propionate, the short length of the ester gives it a relatively short half life.

O O

Figure 1: Testosterone, 17a-methyltestosterone and testosterone propionate Testosterone propionate (injectable testosterone ester)

Testosterone propionate (injectable testosterone ester) O

O www.sportEX.net Testosterone propionate (injectable testosterone ester)

Esterification of testosterone with propionic acid via the C-17"-hydroxyl group makes the steroid more soluble in the lipid (oily) injection vehicle, thereby decreasing the rate of absorption from the injection site, and, hence, prolonging its action. When released from the injection vehicle and enters the bloodstream the ester group is removed by esterases to leave biologically active free testosterone. Most injectable steroids are esterified at the C-17"-hydroxyl group to enhance bioavailability. Typically, the longer the ester, the longer the half-life. In the case of testosterone propionate, the short length of the ester gives it a relatively short half-life.

21 Methyltestosterone (oral 17!-alkylated steroid) The addition of a methyl group CH3 ) at C-17a-prevents the

oxidation of the steroid (part of the metabolic degradative pathway of testosterone). This protects the steroid from being rapidly degraded by the liver. When given orally, methyltestosterone has a half life of 150 minutes compared to 10 minutes for testosterone. Most orally active staroids have a methyl group at C-17a to enhance bioavailability