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  Mini-Reviews in Medicinal Chemistry

Volume 11 Issue 5
ISSN: 1389-5575

   All Titles

Editorial [Hot Topic:Anabolic Androgenic Steroids (AAS) as Doping Agents: Chemical Structures,Metabolism, Cellular Responses, Physiological and Pathological Effects (Guest Editor: V. Fineschi)]
pp.359-361 (3) Author: Vittorio Fineschi

This special issue is dedicated to the effects of Androgenic Anabolic Steroids (AAS), what AAS are, the mechanisms of action as well as the untoward effects on health status in athletes.

Androgenic anabolic steroids (AAS) are used worldwide to help athletes gain muscle mass and strength. They are beneficial in athletic competition and are particularly beneficial for power lifters, bodybuilders, student athletes, and fitness enthusiasts. The real incidence is difficult to evaluate, but a recent study indicated that more than more 1 million Americans are current or former users. The true incidence of AAS related medical problems is not known, due to several drawbacks in human studies. The entity of AAS side effects, in fact, depends on the sex, the dose, the duration of treatment, whether they are taken during exercise training or under sedentary conditions, and the susceptibility of the individuals themselves to androgen exposure partly depending on genetic factors. Both the acute and the chronic effects can lead to toxicity, but generally the serious and even fatal effects depend on the time and the duration of AAS administration, the most serious being observed when AAS are used in high dose and over prolonged time and the milder and more frequently seen side effects disappearing upon discontinuation of use. A limitation of human studies is represented by the fact that information about the intake of steroids are, generally, self reported and it is hardly possible to assess the exact dosage in an objective way. Four of all available AAS seemed to be more used than others; testosterone, nandrolone, methandrostenolone and stanozolol. AAS can be bought legally in some parts of the world, whereas in other countries AAS are classified as illegal narcotic substances. Furthermore AAS are often used in combination with other dugs or substances at high dosage, so it is extremely difficult to separate the toxic effects of AAS from those caused by the other drugs abused.

The fact remains, as Maravelias said, that the abuse of androgenic anabolic steroids (AAS) is a remarkably prevalent problem in competitive and non-competitive athletes. The goal of this special issue is to summarize the clinically relevant data regarding AAS abuse, including mechanism of action, efficacy and adverse effects.

Although there are three typical forms of AASs intake (i.e., oral pills, injection, and skin patches), oral administration is by far the most common and convenient. Oral testosterone is rapidly absorbed but it is rapidly converted into inactive metabolites, so that nearly 15% of it persists in active form. As such, testosterone derivatives are alkylated at the position 17 (e.g., methyltestosterone and fluoxymesterone) to reduces liver catabolism and ultimately enhance bioavailability. No differential effects in increasing sport performances have however been reported according to the different patter of administration. The activity of androgens is mediated by a specific receptor, which belongs to the nuclear receptor superfamily, as Lippi and collaborators explain in detail. It is composed by a DNA binding domain and two transcriptional activation domains, AF-1 and AF-2. Androgen receptor transcriptional activity is mainly mediated by the N-terminal AF-1 domain. When the hormone reach the target cells, it binds to the receptor ligand-binding domain. Then, the receptor is dissociated from protein chaperones and becomes active, moving from cytoplasm to nucleus. Activated receptors interact as homodimers with the androgen response element on the chromatin, which triggers the formation of a transcription complex. Co-activator and co-repressor complexes for nuclearreceptor- mediated transcriptional regulation are present in cells, generally inducing gene activation, transcription of the gene, translation and a resultant alteration in cell function, growth or differentiation.

Lavandero and collaborators focalized their paper about the numerous studies demonstrated increases in intracellular Ca2+ in response to AAS. These Ca2+ mediated responses have been seen in a diversity of cell types, including osteoblasts, platelets, skeletal muscle cells, cardiac myocytes and neurons. The versatility of Ca2+ as a second messenger provides these responses with a vast number of pathophysiological implications. Classically, anabolic androgenic steroids (AAS) act through binding to androgen receptors (AR), which once bound by their ligands, function as nuclear transcription factors promoting the expression of genes under the control of steroid-response elements (SRE). This programmed gene expression is achieved within a time course of hours after AAS binding to ARs. More recently, however, it has been described that steroidal hormones including AAS can also provoke faster responses, which do not involve gene expression. These effects have been termed as ‘nongenomic’, and they cover a wide range of intracellular processes such as the activation of membrane bound receptors, triggering of downstream pathways that involve protein kinases and phosphatases, mobilization of intracellular Ca2+, as well SREindependent changes in transcription. The origin of these responses has been attributed to AR-AAS complexes present in caveolin-enriched zones of the plasma membrane, however, recent studies identify orphan candidates for membrane-bound AR that after binding to AAS, trigger activation of intracellular second messengers.

The Impact of AAS on Neuropeptide Systems is the targeted review treated by Hallberg.

Although the impact of AAS on neuropeptide systems has been the main focus for this review it should be emphasized that it is known that AAS administration to rats also effect other systems with high relevance for the altered behaviors attributed to AAS abuse. These include AAS impact on e.g. the serotonin, dopamine and glutamate systems. It should also be emphasized that the high doses and accumulated levels of nandrolone could lead to activation also of other related steroid receptors such as estrogen, progesterone and mineralcorticoid, as well as glucocorticoid receptors. Furthermore, activation of membrane bound steroid receptors or neurosteroid receptors, e.g. GABAA and NMDA receptors, could all contribute to the observed alterations of the neuropeptide systems. AAS or their sulfate conjugates could also interact with neurosteroid receptors or alternatively AAS could indirectly modulate levels of endogenous neurosteroids.

The conclusions drawn from Riezzo and others, based on data about experimental animal studies, support the hypothesis that the combined effects of vigorous weight training, anabolic steroids abuse and stimulation of the sympathetic nervous system, may predispose to myocardial injury (myocardial disarray, contraction band necrosis, interstitial fibrosis, apoptosis) and subsequent cardiac failure (colliquative myocytolysis) mediated by oxidative stress. These cardiovascular effects of AAS are mediated by genomic (intracellular androgen receptors nuclear transcription gene expression) and non-genomic mechanisms.

Cardiac hypertrophy is a leading predictor of progressive heart disease which often leads to heart failure and to a loss of cardiac contractile performance associated with profound alterations in intracellular calcium handling.....

Affiliation: Department of Forensic Pathology School of Medicine University of Foggia Ospedale Colonnello D'Avanzo, Via degli Aviatori 1 71100 Foggia Italy.

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