Mini Reviews in Medicinal Chemistry - Volume 11, Issue 5, 2011

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.....

Anabolic Androgenic Steroids (AASs) are chemical and pharmacological derivatives of the male hormone testosterone which are widely used for increasing burst and sprinting activities in sports. Although AASs are thought to be transversal to the plurality of sports disciplines, they are principally misused by bodybuilders, weightlifters, shot, hammer, discus or javelin throwers, rugby and American football players as well as by swimmers and runners. AAS exert a kaleidoscope of effects on human biology, principally through the 5-α-reductase-mediated conversion into dihydrotestosterone, the aromatase-mediated conversion into female sex hormones, a competitive antagonism to the glucocorticoid receptors, the potential stimulation of erythropoietin secretion as well as psychoactive effects on the brain. The influence of AASs on physical performance is still undefined, since the large number of studies published so far have described discordant and often contradictory outcomes. Nevertheless, animal and human investigations support the hypothesis that the administration of AASs might increase lean body mass, muscle mass, and maximal voluntary strength especially in men, so that they would represent an appealing form of doping for increasing power capacity, sustaining intensive training periods and, last but not least, as a cosmetic muscle makeover. The aim of this article is to review the biochemistry, physiology and the ergogenic effects of AASs.

Anabolic - androgenic steroids (AAS) were originally developed to promote growth of skeletal muscle. AAS abuse is commonly associated with bodybuilders, weightlifters, and other athletes. The issue of AAS toxicity is not yet completely understood since the adverse effects outline a varied scenario with side effects reported affecting many organs and systems in humans. The true incidence of AAS related medical problems is not known, due to several drawbacks in human studies. The entity of side effects 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. 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. AAS are often used in combination with other dugs or substances, so it is difficult to separate their toxic effects from those caused by the other drugs abused. Hence experimental studies conducted on animal models are mandatory to investigate the mechanisms underlying to AAS toxicity and the organ alterations due to these substances. Finally, clinicians should be aware of the complex and varied pattern of toxicity so as to be able to perform correct diagnoses and treatments.

Increasing evidence suggests that nongenomic effects of testosterone and anabolic androgenic steroids (AAS) operate concertedly with genomic effects. Classically, these responses have been viewed as separate and independent processes, primarily because nongenomic responses are faster and appear to be mediated by membrane androgen receptors, whereas long-term genomic effects are mediated through cytosolic androgen receptors regulating transcriptional activity. Numerous studies have 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. In cardiac cells, testosterone elicits voltage-dependent Ca2+ oscillations and IP3Rmediated Ca2+ release from internal stores, leading to activation of MAPK and mTOR signaling that promotes cardiac hypertrophy. In neurons, depending upon concentration, testosterone can provoke either physiological Ca2+ oscillations, essential for synaptic plasticity, or sustained, pathological Ca2+ transients that lead to neuronal apoptosis. We propose therefore, that Ca2+ acts as an important point of crosstalk between nongenomic and genomic AAS signaling, representing a central regulator that bridges these previously thought to be divergent responses.

The abuse of anabolic androgenic steroids (AAS) is relatively widely spread and epidemiological studies in the western countries report a prevalence between 1-5 % among males. The impact of these steroids on the strength and muscle mass as well as many of the adverse physical effects that have been observed are well described. Several reports have also revealed severe psychological effects as results of the administration of AAS. Effects such as irritability, aggressiveness, anxiety and depression are reported to be associated with AAS abuse. The mechanistic rationales behind these effects are not well understood. Several systems are likely to be involved, including the monoamine and peptidergic systems. The aim of this review is to highlight the potential role of the neuropeptide systems in the brain with focus on how these systems are affected by repeated administration of AAS.

The anabolic-androgenic steroids (AAS) are all synthetic derivates of testosterone and are commonly used as sport performance enhancers in athletes. The heart is one of the organs most frequently affected by administration of anabolic steroids. A direct myocardial injury caused by AAS is supposed to determine marked hypertrophy in myocardial cells, extensive regional fibrosis and necrosis. A number of excellent studies, using animal models, were performed to evaluate the cardiac effects of AAS. It is known that exogenous administration induced cardiac hypertrophy in vitro and in vivo, and when combined with exercise, anabolic steroid use has been shown to change exercise-induced physiological cardiac hypertrophy to pathophysiological cardiac hypertrophy. However the molecular mechanisms are still poorly understood. It's described that sudden cardiac death, myocardial infarct; ventricular remodelling and cardiomyopathy do to AAS is related to apoptosis and oxidative stress when associated with exercise. Mechanical stimuli and circulating humoral factors (TNF-α, HSP-70, IL-1β) released by the heart and peripheral organs are responsible. Testosterone and derivates can work through genomic (activation of specific androgen receptor, interaction with coactivators and co-repressors transcription factors, gene regulation) and non-genomic mechanism (membrane-receptorsecond messenger cascades). Chronic AAS abuse results in different patterns of pathologic alterations, which depend on type, dose, frequency, and mode of use. The difficulty in interpreting experimental data on animals (mice and rats) lies in the diversity of experiments (the diversity of substances, which show different properties, different mice / rats by sex and age, duration of treatment with AAS, dosages used, type, scope and exercise duration).

Anabolic-androgenic steroids (AAS) are synthetic testosterone derivatives developed to maximise anabolic activity and minimise androgenic activity. AAS abuse is widespread among both athletes and non-athletes at fitness centres and is becoming a public health issue. In addition to their atherogenic, thrombogenic and spastic effects, AAS have direct cardiotoxic effects by causing hypertrophy, electrical and structural remodelling, and contractile dysfunction and by increasing the susceptibility to ischemic injuries. All of these factors contribute to an increased risk of ventricular arrhythmias and sudden cardiac death.

In the athletes the wide use of Anabolic Androgenic Steroids (AAS) cause series damage in various organs, in particular, analyzing the liver, elevation on the levels of liver enzymes, cholestatic jaundice, liver tumors, both benign and malignant, and peliosis hepatis are described. A prolonged AAS administration provokes an increase in the activities of liver lysosomal hydrolases and a decrease in some components of the microsomal drug-metabolizing system and in the activity of the mitochondrial respiratory chain complexes without modifying classical serum indicators of hepatic function. Liver is a key organ actively involved in numerous metabolic and detoxifying functions. As a consequence, it is continuously exposed to high levels of endogenous and exogenous oxidants that are by-products of many biochemical pathways and, in fact, it has been demonstrated that intracellular oxidant production is more active in liver than in tissues, like the increase of inflammatory cytokines, apoptosis and the inhibitors of apoptosis NF-κB and Heat Shock Proteins.

Anabolic androgenic steroids (AAS) are artificial substances, acting through androgen receptors and were primarily developed for the treatment of hypogonadism, tumors, hypercalcemia, hypercalcuria and other chronic diseases. The discovery, in the early 1930s that these substances may have other benefits related to improvement in physique and athletic performance, has encouraged extensive use of these substances by amateur and professional athletes and members of the general public. The range of AAS used can be classified as either endogenous or exogenous. When used for ergogenic or recreational purposes the dosage is more often higher than the recommended dosage, and at supraphysiological levels, AAS can cause a number of serious side effects including liver dysfunction, myocardial infarction and potentially stroke, due to its ability to increase platelet and platelet aggregation. Furthermore, these high dosages may or can affect other physiological systems including the immune system. Hence, this paper reviews the current research on the effects of a number of specific AAS in the immune system.

Chronic use of anabolic adrogenic steroids (AAS) has been known to cause serious adverse effects. While the effects of AASs on cardiovascular system are well known, toxicity on other organs has received less attention. A doserelated nephrotoxic effect has been proposed and a wide variety of morpho-functional damages have been observed, but , the exact pathophysiological mechanism of action is still not well known. In the present minireview, we highlight the remaining issues through an analysis of the pertinent literature. As with HSPs toxic agents their overexpression could be considered a protective reaction against AAS abuse however, comprehensive studies concerning the whole range of Hsps/chaperones expressions in all organs after long term use of AAS are needed.

A survey on the main analytical challenges related to the analysis of Androgen Anabolic Steroids (AASs) is reported. AASs analysis is an issue regarding antidoping analyses as well as forensic toxicology applications. This paper reports an overview of the more recent literature regarding various aspects of sample preparation, analytical techniques and interpretation of results for AASs identification in biological samples. New analytical approaches, mainly for their application to the antidoping field, are reported. The application of AASs analysis in forensic cases is also described, taking into consideration mainly the different biological samples that can be analysed for forensic purposes. Particular attention was played on the application of hair analysis as alternative biological specimen for the determination of AASs abuse.