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Doping in Sport Symposium Proceedings |
Department of Medicine, University of Manchester, Manchester M13 9WL, UK. Fax 0041 161 273 1389; e-mail Frederick.Wu{at}man.ac.uk
Abstract
Understanding of the mechanism of androgen action has been enhanced by advances in knowledge on the molecular basis of activation of the androgen receptor and the importance of tissue conversion of circulating testosterone to dihydrotestosterone and estradiol. New evidence supports the view that supraphysiological doses of anabolic steroids do have a definite, positive effect on muscle size and muscle strength. However, the nature of the anabolic action of androgens on muscle is currently unclear and may involve mechanisms independent of the androgen receptor. The dose–response relationships of anabolic actions vs the potentially serious risks to health of androgenic-anabolic steroids (AAS) use are still unresolved. Most of the adverse effects of AAS are reversible but some are permanent, particularly in women and children. The reported incidence of acute life-threatening events associated with AAS abuse is low, but the actual risk may be underrecognized or underreported; the exact incidence is unknown. The long-term consequences and disease risks of AAS to the sports competitor remain to be properly evaluated.
Key Words: indexing terms: androgen receptor • abused drugs • sports medicine
In the last 40 years, use of anabolic steroids has become much more widespread but has nevertheless remained covert and intermittent, involving an increasing number of agents. Consequently, clinical information concerning the effects of anabolic steroids has continued to be derived from isolated case reports. These uncontrolled anecdotal observations make it difficult to draw unequivocal conclusions. The virtual absence of long-term prospective data also makes judgments on safety rather uncertain. Here, I compare and contrast the principles and practice behind the abuse of androgenic-anabolic steroids (AAS) with the legitimate clinical therapeutic use of androgens, in order to discuss how the use of AAS by athletes fits into our current understanding of androgen physiology and the clinical practice of endocrinology.
physiology of androgen action
Androgens are required life-long in males—from the heterogametic sexual differentiation in utero, through secondary sexual development during puberty (where they are the major determinants of extragenital sexual dimorphism), to the establishment and the maintenance of adult sexual function and fertility. Not only are the physiological functions of androgens spread out temporally, they also act on a large number of reproductive and nonreproductive target tissues, including bone, adipose tissue, skeletal muscle, brain, prostate, liver, and kidney (stimulating production of erythropoietin). It is therefore somewhat surprising that the extremely diverse biological actions of androgens are mediated by only one molecular species of androgen receptor with a singular mode of action, i.e., through transcriptional activation of androgen response elements in different target genes (1).
Some aspects of the tissue specificity of androgen action can be
accounted for by the local conversion of testosterone to more-active or
specific metabolites, including dihydrotestosterone (DHT) and
estradiol. From the clinical syndromes of androgen (2) and
estrogen resistance (3), and 5
-reductase
(4) and aromatase deficiency (5), we can
deduce that testosterone itself is adequate for in utero
masculinization of the internal genitalia and postnatal skeletal muscle
development as well as the activation of sexual behavior during
adolescence and young adult life. DHT, on the other hand, is required
for the fetal development of external genitalia, prostate and seminal
vesicles, and adult secondary hair growth. Aromatization of
testosterone to estradiol is necessary for sexual differentiation of
the brain, bone mass accretion, and fusion of the epiphyses at the end
of puberty. In other words, testosterone is a target hormone itself as
well as a circulating prohormone for several target tissues that
possess the converting enzymes 5-reductase and aromatase. Hence not
all actions of androgens are mediated through the androgen receptor.
dose–response relationships of androgen action
The rationale of using anabolic steroids in competitive sports is based on the following considerations: (a) the clear differential in athletic performance between males and females, on average, the lean body mass being 30% higher in men than in women; (b) obvious anabolic effects resulting from the physiological increase in testosterone during pubertal development; (c) production of undoubted anabolic and ergogenic effects by physiological doses of testosterone in hypogonadal patients; (d) the assumption that use of supraphysiological doses of testosterone or more potent synthetic androgenic analogs would increase muscle bulk and improve performance in eugonadal adult men; and (e) the assumption that anabolic effects can be separated from virilizing effects by use of "pure anabolic" agents.
The steep and linear dose–response relationship for both the
virilizing and anabolic actions of testosterone, ranging from the
concentrations in childhood and in females (<2 nmol/L) to the normal
adult male physiological range (10–35 nmol/L), is indisputable (Fig. 1
). Whether androgen responses can be stimulated by increasing
doses of testosterone beyond the physiological range is at present
unclear. There may also be significant differences in the
dose–response characteristics between individual androgen-dependent
actions and target tissues. Thus, although administration of AAS to
women and children clearly stimulates hypertrophy and perhaps
hyperplasia of skeletal muscle, whether these effects can be
extrapolated beyond the physiological into the pharmacological range is
not clear. Some sports competitors use extremely high doses of
testosterone, producing plasma concentrations two or three orders of
magnitude greater than that found in healthy men. At these
nonphysiological concentrations of hormones, the receptors would
already have been saturated and any biological response may well have
reached a plateau, while at the same time atypical actions can be
induced. It is therefore important to know whether any actual or
perceived gains of AAS administrations are countered by undesirable
side effects.
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do aas improve athletic performance?
Reviews and metaanalyses of literature addressing this question over the last 30 years have determined that many of the previous studies were flawed in their experimental design and, not surprisingly, results were equivocal (6)(7). Some of the reported enhancement in performance may have been due to the effects of AAS in increasing aggression and competitiveness, differences in intensity of training or dietary intake, and important placebo effects. Studies generally did not mimic the dose and variety of drugs that athletes tend to use, a process known as "stacking," or the changes in doses during cycles of steroid administration, i.e., a pyramid program. The inherent polymorphism and individual variations in terms of innate ability and motivation tend to further blur any significant differences between controls and subjects. Practically, true double-blinding is difficult because clinical evidence of side effects such as greasiness of the skin and acne betray which groups—control or treated—the subjects belong to.
To overcome some of the pitfalls of previous investigations, a recent study (8) has been designed to control for the independent effects of testosterone, training, and diet while the dose of testosterone approached that commonly used in AAS abuse. The treated volunteers received 600 mg of testosterone enanthate intramuscularly weekly for 10 weeks. The 43 volunteers with some weightlifting experience were divided into one of four groups: placebo with no exercise, testosterone with no exercise, placebo plus exercise, and testosterone plus exercise. Muscle size, strength, and fat-free mass increased with testosterone without exercise, but exercise itself increased muscle strength. With testosterone administration and exercise together, all of these variables increased in an additive manner. This important study showed unequivocally for the first time that supraphysiological doses of androgens do have an anabolic effect on muscle mass and strength in eugonadal men, which can be further amplified by physical training.
how do aas work?
After puberty, the androgen receptor in striated muscle is
down-regulated (9); the androgen receptor in skeletal
muscle is therefore virtually saturated with the physiological
concentrations of testosterone present. Because there is little
5-reductase activity in skeletal muscle (10),
testosterone and possibly circulating DHT appear to be the key hormones
for androgen action. In vitro studies have demonstrated that the
dose–response relationship of testosterone on growth of skeletal
muscle reaches a plateau once the physiological concentration is
exceeded (11). With supraphysiological doses of
testosterone, the anabolic effects may therefore be evoked through a
separate mechanism independent of the androgen receptor, e.g., an
anticatabolic effect based on an antiglucocorticoid action
(12).
Some indirect evidence supports an anticatabolic effect of androgens. AAS can displace glucocorticoids bound to the glucocorticoid receptor. Antagonists of glucocorticoid action can prevent the muscle atrophy that follows orchidectomy, and urinary free cortisol increases with administration of large doses of AAS. Clinical evidence can be derived from patients who have the androgen insensitivity syndrome as a result of inactivating mutations in the androgen receptor gene. In a recent case study (13), a patient with androgen insensitivity syndrome resulting from a single amino acid substitution (Arg-608 to Lys) in the DNA-binding domain of the androgen receptor received pharmacological doses of testosterone enanthate (5 mg/kg per day for 10 days). Although there were no treatment effects that suppressed gonadotropin and sex-hormone-binding globulin or sebum excretion, testosterone administration resulted in a positive nitrogen balance of 3 g/24 h, similar to that in healthy adult men. Hence, these data indirectly support the hypothesis that the effect of supraphysiological doses of testosterone on muscle is probably mediated through an antiglucocorticoid action independent of the androgen receptor.
adverse effects of aas
Even though different mechanisms may mediate the action of AAS,
the unwanted androgenic effects cannot be completely dissociated from
the anabolic effects (14). The adverse effects of AAS
abuse depend on the age and sex of the individual, the duration and
total dose of exposure, and the type of steroid used (15).
These effects may be differentiated into androgenic (Table 1
) or toxic effects (Table 2
). Whereas the former are amplifications of
the physiological effects of androgens, the latter can be regarded as
the more serious consequences encountered mainly with prolonged usage
of pharmacological doses of AAS.
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The unwanted consequences of AAS abuse are most damaging in females and adolescents: irreversible virilization and stunting of linear growth, respectively. Suppression of the hypothalamic–pituitary–gonadal axis that results in disturbances in menstrual function and infertility is, in contrast, reversible. Stimulation of the sebaceous glands appears to be dose-related: Increasing testosterone beyond the physiological range in normal men results in further increases in the sebum excretion rate. Consequently AAS users tend to suffer from severe acne.
One of the more serious problems associated with anabolic steroid abuse
is the invariable decrease in circulating HDL-cholesterol because of
the action of androgens in suppressing hepatic endothelial lipase
activity. This may have long-term consequences in increasing the risk
to ischemic heart disease, but is probably unrelated to the
cardiomyopathy, cerebral vascular accident, or pulmonary embolism
associated with AAS use—which may be independent effects of androgens
on the vasculature and hemostasis. Possible adverse effects on the
prostate gland arising from prolonged administration of anabolic
steroids have not been fully elucidated, the data consisting of
isolated and infrequent case reports. Data from male contraceptive
trials, where volunteers have received testosterone enanthate 200 mg
weekly for up to 18 months, showed no change in plasma concentrations
in prostate-specific antigen, and the prostatic transverse diameter
increased by only 14% (16). The serious hepatic
abnormalities are virtually always associated with the orally active
17-alkylated androgens such as methyltestosterone,
methandrostenolone, oxandrolone, and stanozolol. Users of anabolic
steroids have exhibited changes in behavior ranging from increased
aggression to the so-called "roid rage" and psychosis
(17). Some evidence suggests that androgen users become
addicted and suffer withdrawal symptoms (17). Withdrawal
effects are probably also related to the slow recovery of endogenous
production of testosterone after cessation of exogenous use.
Although individual case reports are extant in the literature, the
exact incidence of serious or fatal adverse effects is unknown. It
therefore remains difficult to assess accurately just how dangerous the
use of AAS is. Intuitively, one can deduce that there is probably
substantial underreporting of AAS use. Nevertheless, the overall
incidence of serious and fatal complications is probably low. These
isolated cases of pathology may represent idiosyncratic responses of
susceptible individuals to the pharmacological doses used in AAS
abusers; as a rule, however, the reported effects cannot be
extrapolated to indicate a systematic generic/class effect of
androgens—with the important exception of the 17-alkylated
compounds, the most harmful of the anabolic agents. It is sometimes
claimed that the intermittent style of using anabolic steroids probably
ameliorates the long-term side effects and that using anabolic steroids
may not be as dangerous to well-being or as addictive as the use of
other forms of recreational drugs. In the absence of any supporting
data, however, such assertions should not be generally accepted at
present.
References
The following articles in journals at HighWire Press have cited this article:
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  T. Kvorning, M. Andersen, K. Brixen, and K. Madsen Suppression of endogenous testosterone production attenuates the response to strength training: a randomized, placebo-controlled, and blinded intervention study Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1325 - E1332. [Abstract] [Full Text] [PDF]
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 B. L. Jones, P. J. Whiting, and L. P. Henderson Mechanisms of anabolic androgenic steroid inhibition of mammalian {varepsilon}-subunit-containing GABAA receptors J. Physiol., June 15, 2006; 573(3): 571 - 593. [Abstract] [Full Text] [PDF]
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 A M Smith, K M English, C J Malkin, R D Jones, T H Jones, and K S Channer Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina Eur. J. Endocrinol., February 1, 2005; 152(2): 285 - 291. [Abstract] [Full Text] [PDF]
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 C.J. Malkin, P.J. Pugh, T.H. Jones, and K.S. Channer Testosterone for secondary prevention in men with ischaemic heart disease? QJM, July 1, 2003; 96(7): 521 - 529. [Full Text] [PDF]
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 S. Basaria, J. T. Wahlstrom, and A. S. Dobs Anabolic-Androgenic Steroid Therapy in the Treatment of Chronic Diseases J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5108 - 5117. [Abstract] [Full Text] [PDF]
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 J. C. Jorge-Rivera, K. L. McIntyre, and L. P. Henderson Anabolic Steroids Induce Region- and Subunit-Specific Rapid Modulation of GABAA Receptor-Mediated Currents in the Rat Forebrain J Neurophysiol, June 1, 2000; 83(6): 3299 - 3309. [Abstract] [Full Text] [PDF]
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 B. T. Ameredes, J. F. Watchko, M. J. Daood, J. F. Rosas, M. P. Donahoe, and R. M. Rogers Growth Hormone Improves Body Mass Recovery with Refeeding after Chronic Undernutrition-Induced Muscle Atrophy in Aging Male Rats J. Nutr., December 1, 1999; 129(12): 2264 - 2270. [Abstract] [Full Text]
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 B. T. Ameredes, J. F. Watchko, M. J. Daood, J. F. Rosas, M. P. Donahoe, and R. M. Rogers Growth hormone restores aged diaphragm myosin composition and performance after chronic undernutrition J Appl Physiol, October 1, 1999; 87(4): 1253 - 1259. [Abstract] [Full Text] [PDF]
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 D. A. Cowan and A. T. Kicman Doping in Sport: Misuse, Analytical Tests, and Legal Aspects Clin. Chem., July 1, 1997; 43(7): 1110 - 1113. [Full Text] [PDF]
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