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Anabolic androgenic steroids AASs represent a large group of synthetic derivatives of testosterone, produced to maximize anabolic effects and minimize the androgenic ones. AAS can be administered orally, parenterally by intramuscular injection and transdermally. Androgens act by binding to the nuclear androgen receptor AR in the cytoplasm and then translocate into the nucleus.
This binding results in sequential conformational changes of the receptor affecting the interaction between receptor and protein, and receptor and DNA. Skeletal muscle can be considered as the main target tissue for the anabolic effects of AAS, which are mediated by ARs which after exposure to AASs are up-regulated and their number increases with body building.
Therefore, AASs determine an increase in muscle size as a consequence of a dose-dependent hypertrophy resulting in an increase of the cross-sectional areas of both type I and type II muscle fibers and myonuclear domains. Moreover, it has been reported that AASs can increase tolerance to exercise by making the muscles more capable to overload therefore shielding them from muscle fiber damage and improving the level of protein synthesis during recovery.
Despite some therapeutic use of AASs, there is also wide abuse among athletes especially bodybuilders in order to improve their performances and to increase muscle growth and lean body mass, taking into account the significant anabolic effects of these drugs. The prolonged misuse and abuse of AASs can determine several adverse effects, some of which may be even fatal especially on the cardiovascular system because they may increase the risk of sudden cardiac death SCD , myocardial infarction, altered serum lipoproteins, and cardiac hypertrophy.
The aim of this review is to focus on deaths related to AAS abuse, trying to evaluate the autoptic, histopathological and toxicological findings in order to investigate the pathophysiological mechanism that underlines this type of death, which is still obscure in several aspects.
The review of the literature allowed us to identify 19 fatal cases between and , in which the autopsy excluded in all cases, extracardiac causes of death. Anabolic androgenic steroids AASs represent a large group of synthetic derivatives of testosterone, produced to maximize anabolic effects and minimize the androgenic ones [ 1 , 2 ].
AASs can be administered orally, parenterally by intramuscular injection and transdermally. This binding results in sequential conformational changes of the receptor affecting the interaction between receptor and protein, and receptor and DNA [ 3 ]. The basic structure of all steroids is a perhydro-cyclopentano phenanthrene ring system that can be modified in order to obtain several designed chemical modifications [ 3 ].
The most important chemical modification, in which the basic structure can undergo, is reported in Fig. The basic structure of steroids can be changed in order to obtain several designed chemical modifications. Skeletal muscle can be considered as the main target tissue for the anabolic effects of AAS, which are mediated by ARs which after exposure to AASs are up-regulated and their number increases with body building [ 5 ]. Therefore, AASs determine an increase in muscle size as a consequence of a dose-dependent hypertrophy resulting in an increase of the cross-sectional areas of both type I and type II muscle fibers and myonucleardomains [ 6 ].
Moreover, it has been reported that AASs can increase tolerance to exercise by making the muscles more capable to overload therefore shielding them from muscle fiber damage and improving the level of protein synthesis during recovery [ 7 ].
Despite some therapeutic use of AASs severe burns, primary or secondary hypogonadism, short stature, HIV wasting syndrome etc. The prolonged misuse and abuse of AASs can determine several adverse effects, some of which may be even fatal especially on the cardiovascular system because they may increase the risk of sudden cardiac death SCD , myocardial infarction, altered serum lipoproteins, and cardiac hypertrophy [ 7 ]. The most frequent cardiovascular adverse effects due to AASs are summarized in Fig.
Some databases, from to June , were searched: A comprehensive flow diagram with inclusion criteria is reported in Fig. Flow diagram with inclusion criteria for the selection of sources for the purpose of the review. The review of the literature using the flow diagram reported in Fig. Of the 19 cases, 17 The age ranged from 18 to 37 years mean age: Among the 19 fatal cases, in 14 bodies.
In none of the cases the BMI was lower than For all cases the autopsy excluded extracardiac causes of death, only in one case a bilateral pulmonary embolism from deep venous thrombus of lower extremities was found Table 2. In the remaining 6 cases in which the toxicological analysis was negative, circumstantial data and evidences reported by relatives and friends of the deceased highlighted a previous prolonged use of AASs. The chronic use of AASs can cause various pathological alterations, which are related to dose, frequency and patterns of use.
Taking into account that numerous organs and apparatus are the target of AASs, several adverse effects can involve the liver, cardiovascular, reproductive, musculoskeletal, endocrine, renal, immunologic and hematological systems as well as some psychological effects; a schematic representation is reported in Fig.
Here 19 fatal cases are reported; although only single case report or small series of cases were included, whereas retrospective studies and other papers that did not fulfill the inclusion criteria were not taken into account, some consideration can be formulated; in all cases the autopsy findings together with the histological examination have highlighted cardiac causes of death.
Only in one case [ 19 ] a mechanical cardiovascular cause of death was found a bilateral pulmonary embolism from deep venous thrombus of lower extremities. In numerous cases [ 16 , 18 , 19 , 22 , 25 ], a common finding was a left ventricular hypertrophy, frequently associated with fibrosis and myocytolisis.
A myocardial hypertrophy was not found in the 4 cases reported by Fineschi et al in two different reports [ 21 , 23 ]. What is the significance that could be attributed to the myocardial hypertrophy? Melchert and Welder [ 29 ] categorized the effects of AAS on the cardiovascular system into four groups of activities: AAS can induce adverse cardiovascular effects such as left ventricular hypertrophy LVH , hypertension, impaired diastolic filling, arrhythmia, erythrocytosis, thrombosis and altered lipoprotein profiles [ 30 ].
Abnormalities in cardio-vascular reflex control of the cardiovascular system [ 31 - 35 ] and in vascular reactivity [ 36 - 40 ] have also been reported. Nandrolone abuse combined with vigorous exercise training may lead to impaired diastolic function and concentric hypertrophy of the left ventricular LV wall [ 43 ]. Vigorous weight lifting itself would also cause LV wall mass and thickness increase but cardiac function would not be affected.
However, when combined with AAS abuse pathological cardiac hypertrophy could be caused [ 44 ]. ND stimulated cardiomegaly that reversed after the end of treatment [ 45 ].
Without a doubt these findings explain the high propensity to the onset and continuance of malignant cardiac arrhythmias. An explanation might be the change of the sympathetic autonomic activity modulated by the renin-angiotensin-system RAS.
Marques Neto et al. Moreover, prolonged QT intervals and ventricular action potential could be explained by the reduced density of the transient outward potassium [ 48 ]. No augmentation in tissue collagen content or in the mRNA expression of types I and III collagens have been shown by histological analysis.
However, Rocha et al. The previously mentioned unconformity could be attributed to the duration of treatment with ND and the age of rats used.
Participation of the potassium K current in the generation of prolonged QT and potential action duration has been noticed. In heart hypertrophic cases I to is down-regulated [ 51 - 53 ].
Low I to density, Kv1. Homogenous distribution of Kv4. These differences may partially explain the up-regulation of Kv4. The expression of KChIP2 is considerably decreased in heart failure and hypertrophy [ 54 , 55 ]. KChIP2 was found to be significant for I to expression in the human heart and the correlation between KChIP2 absence and a total loss of I to together with an increased susceptibility to ventricular arrhythmias in mice has been shown [ 56 ].
According to Riezzo et al. The increase of the heart weight suggested enhanced heart protein synthesis. Lower nuclei suggests a toxic effect of ND which may involve a pro-apoptotic mechanism [ 59 ].
Tanno et al [ 60 ] found that ND treatment whether combined with resistance training or not induced pathological concentric hypertrophy, re-expression of fetal genes, systolic and diastolic function impairment and an incremented myocardial collagen content leading to LVH.
Increased relative left ventricle wall thickness RWT was observed as a consequence of intensive physical training in rats treated with ND compared to the respective non-trained ones.
In addition, the non-trained nandrolone treated group also produced higher RWT compared to the non-trained treated group. Increased interventricular septum thickness in the end-diastole IVSDia was noticed in both the non-trained nandrolone treated and trained vehicle-treated groups, compared to the non-trained vehicle treated rats.
Increment in cardiovascular mortality has been associated to an imbalance of ANS activity [ 54 ]. AASs can acutely inhibit the reuptake of catecholamines into extraneuronal tissue [ 62 ] and consequently the increment of catecholamine concentrations at receptor sites occurs.
Although, the neuronal catecholamine transporter is normally responsible for the reuptake of noradrenaline, it has also been proved responsible for nonexocytotic release of noradrenaline from sympathetic nerve terminals during ischemia. An increased release of noradrenaline has been implicated in ischemia-induced arrhythmia [ 63 , 64 ]. An increased activity of 6-phosphogluconate dehydrogenases and glucosephosphate was observed in rat hearts, also ND activated isocitrate dehydrogenase and malic enzyme, which are other NADP-linked dehydrogenases.
During the same study a significantly increased heart weight was also observed 10 days after nandrolone administration. It was shown that treatment with ND causes small QRS complex extension that might slightly reduce the spreading rate of the action potential through the heart ventricles, possibly because of the greater heart mass.
It is known that administration of doses higher than normal supraphysiological of ND impair exercise-induced cardioprotection in treadmill-exercised rats. It was observed that the hearts of animals treated with nandrolone and having undergone training DT group showed lower glutathione peroxidase GPx , superoxide dismutase SOD and glutathione reductase GR activities compared with controls and trained groups of animals CT.
The latter observation indicates that nandrolone could act through blocking or down regulating the mechanisms implicated in the improvement of antioxidant defenses in DT animals, which might explain the lower percentage of left ventricular developed pressure and augmented infarct size in DT group.
Notwithstanding the strenuous research efforts, the molecular mechanism s involved in exercise-induced cardio protection is still debatable. The numerous studies above reported in animal models, especially in rats, have called into question several pathophysiological mechanisms, which may explain some of the macroscopic and microscopic finding regarding the 19 cases here reported; however, we have to underline that these cases are single case report or small series of cases and not experimental studies.
Moreover, the users of these substances frequently associate numerous steroids, in different forms, singularly and in several temporal combinations and cycles, and commonly, various steroid-accessory drugs are also used.
Therefore, the interpretation of the postmortem findings is particularly difficult and no comprehensive conclusions can be done. Finally, a brief remark must be placed regarding the BMI which was in all cases 12 males and 2 females higher than As a result, some subjects such as highly trained athletes may have a high BMI because of increased muscularity rather than increased body fatness; therefore, these results should be evaluated with caution.
The relationship between AAS abuse, vigorous exercise training, and cardiac death can be evaluated only by the application of an investigative protocol, which must include a rigorous methodology covering:. Moreover, only through a careful examination of all suspicious cases of AAS related deaths with the application of a rigorous investigative protocol, these cases can be identified and they could provide further information and data that may increase the knowledge of this type of deaths.
The authors confirm that this article content has no conflict of interest. National Center for Biotechnology Information , U. Journal List Curr Neuropharmacol v.
Published online Jan. Paola Frati , 1, 2 Francesco P. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License http: This article has been cited by other articles in PMC.
Abstract Anabolic androgenic steroids AASs represent a large group of synthetic derivatives of testosterone, produced to maximize anabolic effects and minimize the androgenic ones. Table 1 AASs most commonly abused oral and injectable formulations. Open in a separate window.
Cardiovascular adverse effects due to a prolonged use of AASs. Table 2 Autoptic, macroscopic and histological findings in 19 AAS related deaths. Contraction band necrosis, lymphocytic infiltration Renal hypertrophy, hepatosplenomegaly Ferenchick G.