Chronic Anabolic Androgenic Steroid Research Articles

Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant – a case report

BackgroundSeverely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels.Case ReportWe present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn’s disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency.ConclusionIn summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

Chronic anabolic androgenic steroid administration reduces global longitudinal strain among off-cycle bodybuilders

BackgroundSupra-physiologic doses of anabolic androgenic steroids (AAS) lead to multiple cardiovascular complications. The long-term clinical effect of AAS overuse on cardiac structure and function, which persists during off-cycle periods, remains unclear. MethodsA total of 15 sedentary subjects and 79 bodybuilders (26 AAS non-users and 53 AAS-users), matched for age and male gender, were assessed in a cross-sectional design for echocardiography measures. AAS-users were included during an off-cycle phase, abstained from AAS for at least 1 month. 2D standard M-mode and speckle tracking echocardiography were used to measure cardiac dimensions and functions. ResultsInter-ventricular septum and posterior wall thickness were significantly higher among chronic off-cycle AAS-users compared to AAS non-users and sedentary group. Off-cycle AAS-users showed lower E/A ratio of the diastolic function. Left ventricular systolic function was not affected in terms of ejection fraction, but significant subclinical systolic dysfunction, assessed by GLS, was observed for chronic off-cycle AAS-users compared to AAS non-users (GLS = -16.8% vs. -18.5%, respectively; p = 0.001). Diameter of left atrium and right ventricle were significantly enlarged among off-cycle AAS-user bodybuilders (p = 0.002 and 0.040). TAPSE and RV S′, and cardiac vasculature of aorta were comparable in all groups. ConclusionsThis study demonstrates that during off-cycle phase, AAS-users show long-term impaired GLS, even after considerable AAS abstain, despite normal LVEF. It highlights the importance of following GLS to predict hypertrophy and heart failure events, and not relying on LVEF alone. In addition, the hypertrophic effect of chronic AAS consumption is transitional during AAS washout periods.

NONISCHEMIC CARDIOMYOPATHY AND CARDIAC ARREST ATTRIBUTABLE TO ANABOLIC-ANDROGENIC STEROIDS

NONISCHEMIC CARDIOMYOPATHY AND CARDIAC ARREST ATTRIBUTABLE TO ANABOLIC-ANDROGENIC STEROIDS

MiRNAs as Novel Biomarkers of Chronic Kidney Injury in Anabolic-Androgenic Steroid Users: An Experimental Study.

miRNAs are a family of 20–22 non-coding nucleotides that control gene expression by inhibiting the translation of their target messenger RNAs (mRNAs). Two models have been proposed to elucidate the mechanism of action: they act either hindering mRNA translation or enhancing mRNA degradation. Anabolic-Androgenic Steroids (AASs) represent a class of drugs used to treat several diseases. In the last few years, AASs have frequently been used for aesthetic purposes, indeed, they form part of the larger group called image- and performance-enhancing drugs (IPEDs). Long-term AAS use can lead to serious health consequences. In this regard, the present study aimed to analyze the role of several microRNAs (miRNAs) in renal damage after AAS use, to better understand the underlying mechanisms. For this purpose, two miRNAs (miR-21 and miR-205) were tested in two groups: AAS group (seven males, mean age 33.28 ± 4.68 years; mean body mass index (BMI) 27.04 ± 1.07), and chronic kidney disease (CKD) group (seven males, mean age 66.2 ± 5.4 years; mean BMI 24.75 ± 1.35). Finally, the same miRNAs were tested in the “Control” group (seven males, mean age 44.85 ± 5.75 years; mean BMI 26.5 ± 1.88). Kolmogorov-Smirnov Test was used to determine the normality of data distribution. All variables were normally distributed. Student’s t-test was used for comparisons between two groups. Analyzing the results of the present study, the two tested miRNAs (miR-21 and miR-205) were significantly higher in the CKD group compared to the AAS group, with mir-21 being much more expressed than miR-205. This study represents a pilot study to define if these expression patterns could be studied in other biological samples (plasma, urine) in subjects with different kidney injury linked to chronic kidney diseases and AAS use, to identify reliable biomarkers that could be applied in clinical and forensic diagnostics, as well as a target for toxicological investigations or therapeutic treatments.

Neuroendocrine Whiplash: Slamming the Breaks on Anabolic-Androgenic Steroids Following Repetitive Mild Traumatic Brain Injury in Rats May Worsen Outcomes

Sport-related concussion is an increasingly common injury among adolescents, with repetitive mild traumatic brain injuries (RmTBI) being a significant risk factor for long-term neurobiological and psychological consequences. It is not uncommon for younger professional athletes to consume anabolic-androgenic steroids (AAS) in an attempt to enhance their performance, subjecting their hormonally sensitive brains to potential impairment during neurodevelopment. Furthermore, RmTBI produces acute neuroendocrine dysfunction, specifically in the anterior pituitary, disrupting the hypothalamic-pituitary adrenal axis, lowering cortisol secretion that is needed to appropriately respond to injury. Some AAS users exhibit worse symptoms post-RmTBI if they quit their steroid regime. We sought to examine the pathophysiological outcomes associated with the abrupt cessation of the commonly abused AAS, Metandienone (Met) on RmTBI outcomes in rats. Prior to injury, adolescent male rats received either Met or placebo, and exercise. Rats were then administered RmTBIs or sham injuries, followed by steroid and exercise cessation (SEC) or continued treatment. A behavioral battery was conducted to measure outcomes consistent with clinical representations of post-concussion syndrome and chronic AAS exposure, followed by analysis of serum hormone levels, and qRT-PCR for mRNA expression and telomere length. RmTBI increased loss of consciousness and anxiety-like behavior, while also impairing balance and short-term working memory. SEC induced hyperactivity while Met treatment alone increased depressive-like behavior. There were cumulative effects whereby RmTBI and SEC exacerbated anxiety and short-term memory outcomes. mRNA expression in the prefrontal cortex, amygdala, hippocampus, and pituitary were modified in response to Met and SEC. Analysis of telomere length revealed the negative impact of SEC while Met and SEC produced changes in serum levels of testosterone and corticosterone. We identified robust changes in mRNA to serotonergic circuitry, neuroinflammation, and an enhanced stress response. Interestingly, Met treatment promoted glucocorticoid secretion after injury, suggesting that maintained AAS may be more beneficial than abstaining after mTBI.

Diagnosis and Management of Anabolic Androgenic Steroid Use.

The lifetime prevalence of anabolic androgenic steroid (AAS) use is estimated at 1% to 5% worldwide. AAS use occurs primarily male elite athletes and men who want a muscular appearance. The evidence for effective, safe management of AAS cessation and withdrawal is weak. Key studies were extracted from PubMed (1990-2018) and Google Scholar with reference searches from relevant retrieved articles. The proven adverse effects of AASs include suppression of the gonadal axis and infertility, hirsutism and defeminization in women, and erythrocytosis. Alkylated AASs that are taken orally may cause hepatopathy. There is an association between high-dosage AAS use and increased risk of cardiovascular disease. Clues for AAS use include very low serum high-density cholesterol and sex hormone-binding globulin concentrations and unexplained erythrocytosis. For elite athletes, the biological passport (monitoring of blood or urinary androgen and androgen precursor concentrations after determining the athlete's baseline) is useful for detecting AAS use. For nonelite athletes, the best method to confirm AAS use is to inquire in a nonjudgmental manner. Cessation of chronic AAS use is associated with a withdrawal syndrome of anxiety and depression. Men who use AASs <1 year typically recover normal hypothalamic-pituitary-testicular axis function within 1 year after cessation. Men who have infertility due to high-dosage AAS use ≥1 year might benefit from short-term treatment with clomiphene or human chorionic gonadotropin.

The Impact of Hippocampal Sex Hormones Receptors in Modulation of Depressive-Like Behavior Following Chronic Anabolic Androgenic Steroids and Exercise Protocols in Rats.

The aim of this study was to evaluate alterations in depressive-like behaviors in rats following chronic administration of a supraphysiological dose of anabolic androgenic steroids (AASs) as well as exposure to a prolonged exercise protocol. The role of hippocampal sex hormones receptors in the modulation of depressive-like behavior was also assessed. A total of 48 male Wistar albino rats were divided into six groups: control, exercise (1 h/day, five consecutive days), nandrolone-decanoate (ND, 20 mg/kg/week, in a single dose), exercise plus ND, testosterone-enanthate (TE, 20 mg/kg/week, in a single dose), and exercise plus TE. After the 6-week protocols were complete, the rats underwent behavioral testing in the tail suspension test (TST). Rats were sacrificed for the collection of blood samples, to determine sex hormones levels, and isolation of the hippocampus, to determine [androgen receptors (AR) and estrogen receptors α (ERα)] expression. ND and TE treatment induced significant depressive-like behavior, opposing the antidepressant effect of exercise. Chronic TE administration elevated testosterone (T) and dihydrotestosterone (DHT) serum levels, and this was augmented by exercise. In contrast, ND and exercise alone did not alter T or DHT levels. There were no changes in serum estradiol levels in any of the groups. Immunohistochemical analysis showed that exercise reduced AR immunoreactivity in all hippocampal regions and increased the ERα expression in the CA1, dentate gyrus (DG), and total hippocampal sections, but not in the CA2/3 region. AASs administration increased AR expression in all hippocampal regions, although not the total hippocampal section in the TE group and did not significantly decrease ERα. The hippocampal AR/ERα expression index was lowered while parvalbumin (PV)-immunoreactivity was enhanced by exercise. AASs administration increased the AR/ERα index and reduced PV-immunoreactivity in the hippocampus. The number of PV-immunoreactive neurons negatively correlated with the antidepressant effects and the AR/ERα ratio. Our results suggest a potential role of the numerical relationship between two sex hormones receptors (stronger correlation than for each individual receptor) in the regulation of depressive-like behavior via the hippocampal GABAergic system in rats, which allow better understanding of the hippocampal sex hormones receptors role in modulation of depressive-like behavior.

Administration of anabolic steroid during adolescence induces long-term cardiac hypertrophy and increases susceptibility to ischemia/reperfusion injury in adult Wistar rats

Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hypertrophy and increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Molecular analyses demonstrated that hyperactivation of type 1 angiotensin II (AT1) receptor mediates cardiac hypertrophy induced by AAS and also induces down-regulation of myocardial ATP-sensitive potassium channel (KATP), resulting in loss of exercise-induced cardioprotection. Exposure to AAS during adolescence promoted long-term cardiovascular dysfunctions, such as dysautonomia. We tested the hypothesis that chronic AAS exposure in the pre/pubertal phase increases the susceptibility to myocardial ischemia/reperfusion (IR) injury in adult rats. Male Wistar rats (26day old) were treated with vehicle (Control, n=12) or testosterone propionate (TP) (AAS, 5mgkg−1 n=12) 5 times/week during 5 weeks. At the end of AAS exposure, rats underwent 23days of washout period and were submitted to euthanasia. Langendorff-perfused hearts were submitted to IR injury and evaluated for mechanical dysfunctions and infarct size. Molecular analysis was performed by mRNA levels of α-myosin heavy chain (MHC), βMHC and brain-derived natriuretic peptide (BNP), ryanodine receptor (RyR2) and sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) by quantitative RT-PCR (qRT-PCR). The expression of AT1 receptor and KATP channel subunits (Kir6.1 and SURa) was analyzed by qRT-PCR and Western Blot. NADPH oxidase (Nox)-related reactive oxygen species generation was assessed by spectrofluorimetry. The expression of antioxidant enzymes was measured by qRT-PCR in order to address a potential role of redox unbalance. AAS exposure promoted long-term cardiac hypertrophy characterized by increased expression of βMHC and βMHC/αMHC ratio. Baseline derivative of pressure (dP/dt) was impaired by AAS exposure. Postischemic recovery of mechanical properties was impaired (decreased left ventricle [LV] developed pressure and maximal dP/dt; increased LV end-diastolic pressure and minimal dP/dt) and infarct size was larger in the AAS group. Catalase mRNA expression was significantly decreased in the AAS group. In conclusion, chronic administration of AAS during adolescence promoted long-term pathological cardiac hypertrophy and persistent increase in the susceptibility to myocardial IR injury possible due to disturbances on catalase expression.

The effect of nandrolone treatment with and without enforced swimming on histological and biochemical changes in the heart and coronary artery of male rats

Objective:Chronic anabolic androgenic steroid (AAS) consumption increases incidence of cardiovascular abnormalities in athletes and mechanisms underlying those abnormalities continue to be investigated. This study examines whether nandrolone consumption induced cardiac and coronary artery wall abnormalities via oxidative stress. It was also designed to determine whether enforced swimming augmented possible cardiotoxic effects of nandrolone in rat heart.Methods:Twenty-four male Wistar rats were divided into 3 groups: control, nandrolone, and nandrolone with enforced swimming. Nandrolone group received 10 mg/kg body weight nandrolone 3 times a week for 6 weeks. Nandrolone group with enforced swimming received the same amount of nandrolone and was forced to swim with excess weight of 20% body weight.Results:After 6 weeks of treatment, results indicated proliferation of heart muscle and coronary smooth muscle cells and lipid peroxidation; significant rise in levels of 8-hydroxy-2’-deoxyguanosine (8-OHdG), nicotinamide adenine dinucleotide phosphate oxidase, homocysteine (Hcy), apolipoprotein B, low-density lipoprotein, and cholesterol, as well as severe fibrosis in heart tissue and around coronary arteries of nandrolone and nandrolone with enforced swimming groups compared with control group.Conclusion:These findings strongly support idea that nandrolone intake by sedentary rats and exercised rats induced heart abnormality mediated by oxidative stress, which was manifest in increased lipid peroxidation, Hcy, and 8-OHdG in heart tissue.

The Effect of Chronic Anabolic-Androgenic Steroid Use on Tp-E Interval, Tp-E/Qt Ratio, and Tp-E/Qtc Ratio in Male Bodybuilders.

The chronic consumption of androgenic anabolic steroids has shown to cause atrial arrhythmias. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate repolarization dispersion measured from the 12-lead surface electrocardiogram (including Tp-e interval, Tp-e/QT ratio, and Tp-e/cQT ratio) in bodybuilders who are using anabolic androgenic steroids (AAS). We selected a population of 33 competitive bodybuilders, including 15 actively using AAS for ≥ 2 years (users) and 18 who had never used AAS (nonusers), all men. QT, cQT, QTd, cQTd, JT, and cJT were significantly increased in AAS users bodybulders compared to the nonusers (all P < 0.001). Tp-e interval, Tp-e/QT ratio, and Tp-e/cQT ratio were also significantly higher in AAS user group compared to the nonuser group (all P < 0.001). QRS duration was not different between the groups. There were negative correlation between E(m) and Tp-e, Tp-e/QT ratio, Tp-e/cQT ration (r = -0.657, P < 0.01; r = -0.607, P = 0.02; r = -0.583, P = 0.02; respectively).There were also negative correlation between S(m) and Tp-e, Tp-e/QT ratio, Tp-e/cQT ration (r = -0.681, P < 0.01; r = -0.549, P = 0.03; r = -0.544, P = 0.023; respectively). In conclusion, we have presented a strong evidence suggesting that Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were increased in AAS users, which suggest that there might be a link between AAS use and ventricular arrthymias and sudden death.

Chronic Anabolic Androgenic Steroid Usage Associated with Acute Coronary Syndrome in Bodybuilder

Chronic Anabolic Androgenic Steroid Usage Associated with Acute Coronary Syndrome in Bodybuilder

Sex and exercise interact to alter the expression of anabolic androgenic steroid-induced anxiety-like behaviors in the mouse

Anabolic androgenic steroids (AAS) are taken by both sexes to enhance athletic performance and body image, nearly always in conjunction with an exercise regime. Although taken to improve physical attributes, chronic AAS use can promote negative behavior, including anxiety. Few studies have directly compared the impact of AAS use in males versus females or assessed the interaction of exercise and AAS. We show that AAS increase anxiety-like behaviors in female but not male mice and that voluntary exercise accentuates these sex-specific differences. We also show that levels of the anxiogenic peptide corticotrophin releasing factor (CRF) are significantly greater in males, but that AAS selectively increase CRF levels in females, thus abrogating this sex-specific difference. Exercise did not ameliorate AAS-induced anxiety or alter CRF levels in females. Exercise was anxiolytic in males, but this behavioral outcome did not correlate with CRF levels. Brain-derived neurotrophic factor (BDNF) has also been implicated in the expression of anxiety. As with CRF, levels of hippocampal BDNF mRNA were significantly greater in males than females. AAS and exercise were without effect on BDNF mRNA in females. In males, anxiolytic effects of exercise correlated with increased BDNF mRNA, however AAS-induced changes in BDNF mRNA and anxiety did not. In sum, we find that AAS elicit sex-specific differences in anxiety and that voluntary exercise accentuates these differences. In addition, our data suggest that these behavioral outcomes may reflect convergent actions of AAS and exercise on a sexually differentiated CRF signaling system within the extended amygdala.

Nandrolone attenuates aortic adaptation to exercise in rats

In this study, we investigated the interaction between exercise-induced mitochondrial adaptation of large vessels and the effects of chronic anabolic androgenic steroids (AASs). Four groups of Sprague-Dawley rats were studied: (i) sedentary, (ii) sedentary + nandrolone-treated, (iii) aerobic exercise trained, and (iv) trained + nandrolone-treated. Aerobic training increased the levels of aortic endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) in accordance with improved acetylcholine-induced vascular relaxation. These beneficial effects were associated with induction of mitochondrial complexes I and V, increased mitochondrial DNA copy number, and greater expression of transcription factors involved in mitochondrial biogenesis/fusion. We also observed enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of beclin1 and autophagy-related protein-7 (ATG7). The levels of thiobarbituric acid-reactive substances and protein carbonyls remained unchanged, whereas significant increases in catalase and mitochondrial manganese superoxide dismutase (MnSOD) levels were observed in the aortas of trained animals, when compared with sedentary controls. Nandrolone increased oxidative stress biomarkers and inhibited exercise-induced increases of eNOS, HO-1, catalase, and MnSOD expression. In addition, it also attenuated elevated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitofusin-2 expression, and further up-regulated LC3II conversion, beclin1, ATG7, and dynamin-related protein-1 expression. These results demonstrate that nandrolone attenuates aortic adaptations to exercise by regulating mitochondrial dynamic remodelling, including down-regulation of mitochondrial biogenesis and intensive autophagy.

Brain Nerve Growth Factor Unbalance Induced by Anabolic Androgenic Steroids in Rats

Anabolic androgenic steroids (AAS) are synthetic androgen-like compounds that are abused in sport communities despite their adverse effects. Nerve growth factor (NGF) influences neuronal differentiation and survival, and it also mediates higher brain functions such as learning and memory. Changes in NGF expression have been implicated in neurodegenerative disorders, including Alzheimer disease. Hence, we decided to study the effect of chronic AAS exposure on brain NGF profile, NGF-dependent cholinergic function, and related behavioral performance. Male Wistar rats were injected for 4 wk with either nandrolone or stanozolol at daily doses (5.0 mg·kg(-1), s.c.) that are considered equivalent to those abused by humans. NGF levels and NGF receptor (TrkA and p75NTR) expression were measured in the hippocampus and in the basal forebrain. Choline acetyltransferase expression was evaluated in basal forebrain. Spatial learning and memory were assessed using the Morris water maze. AAS treatment caused region-specific changes in the expression of NGF and its receptors. Both nandrolone and stanozolol increased NGF levels in the hippocampus and reduced NGF levels in the basal forebrain, reduced p75NTR expression in the hippocampus, and failed to affect TrkA expression in the basal forebrain. Finally, AAS treatment reduced the expression of choline acetyltransferase in the basal forebrain and impaired the behavioral performance in the Morris water maze. The evidence that supraphysiological doses of AAS cause neurotrophic unbalance and related behavioral disturbances raises the concern that AAS abuse in humans may affect mechanisms that lie at the core of neuronal plasticity.

Anabolic–androgenic steroid effects on nociception and morphine antinociception in male rats

The purpose of this study was to investigate the effects of acute and chronic administration of anabolic–androgenic steroids (AAS) on nociception and morphine antinociception in acute pain models, as well as on chronic inflammatory nociception. In Experiment 1, adult, gonadally intact male rats were injected s.c. for 28days with either 5mg/kg testosterone (T), dihydrotestosterone (DHT), stanozolol (STAN), or safflower oil vehicle (N=12–25/group). On day 28, rats in each group were tested on acute thermal and mechanical nociceptive assays, before and after morphine treatment. In Experiment 2, rats in each group (N=8–10/group) were injected with mineral oil or complete Freund's adjuvant (CFA) into one hindpaw after 28days of AAS treatment, and then tested for thermal hyperalgesia, mechanical allodynia, inflammation and locomotor suppression intermittently for 28days. Experiment 3 replicated nociceptive measurements in Experiments 1 and 2, but with a single AAS or vehicle injection occurring 3h prior to testing (N=10–12/group). While chronic AAS administration tended to decrease body weight gain and alter reproductive organ weights in the expected manner, it did not significantly alter acute nociception nor attenuate the development of various chronic pain indices after CFA administration. Morphine antinociceptive potency was significantly decreased by chronic DHT on the hotplate test only. Acute AAS administration also did not significantly alter acute or chronic nociception, or morphine antinociceptive potency. Comparisons between acute and chronic AAS administration suggest that steroid tolerance did not occur in rats treated with AAS chronically. Taken together, these data do not support the hypothesis that AAS exposure alters nociception or morphine antinociception in gonadally intact males.

Heart Disease Induced by AAS Abuse, Using Experimental Mice/Rats Models and the Role of Exercise-Induced Cardiotoxicity

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-receptor-second 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).

Chronic anabolic androgenic steroid exposure alters corticotropin releasing factor expression and anxiety-like behaviors in the female mouse

In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit use of these drugs by elite athletes and a growing number of adolescents to enhance performance and body image. As with adults, AAS use by adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. It has been suggested that adolescents, especially adolescent females, may be particularly susceptible to the effects of these steroids, but few experiments in animal models have been performed to test this assertion. Here we show that chronic exposure of adolescent female mice to a mixture of three commonly abused AAS (testosterone cypionate, nandrolone decanoate and methandrostenolone; 7.5 mg/kg/day for 5 days) significantly enhanced anxiety-like behavior as assessed by the acoustic startle response (ASR), but did not augment the fear-potentiated startle response (FPS) or alter sensorimotor gating as assessed by prepulse inhibition of the acoustic startle response (PPI). AAS treatment also significantly increased the levels of corticotropin releasing factor (CRF) mRNA and somal-associated CRF immunoreactivity in the central nucleus of the amygdala (CeA), as well as neuropil-associated immunoreactivity in the dorsal aspect of the anterolateral division of the bed nucleus of the stria terminalis (dBnST). AAS treatment did not alter CRF receptor 1 or 2 mRNA in either the CeA or the dBnST; CRF immunoreactivity in the ventral BnST, the paraventricular nucleus (PVN) or the median eminence (ME); or peripheral levels of corticosterone. These results suggest that chronic AAS treatment of adolescent female mice may enhance generalized anxiety, but not sensorimotor gating or learned fear, via a mechanism that involves increased CRF-mediated signaling from CeA neurons projecting to the dBnST.

Dr. Pope Replies

Back to table of contents Previous article Next article Letters to the EditorFull AccessDr. Pope RepliesHARRISON G. POPE Jr., M.D.,HARRISON G. POPE Jr., M.D.Search for more papers by this author,Published Online:1 Oct 2009https://doi.org/10.1176/appi.ajp.2009.09060846rAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We agree with virtually all of the points raised by Drs. Scally and Tan, except for a minor semantic issue regarding their suggestion that anabolic steroid-induced hypogonadism represents a possible “confounding variable” in the diagnosis of anabolic-androgenic steroid dependence. To explain, we need to carefully define our terms. Anabolic steroid-induced hypogonadism is certainly a common physiologic response to chronic anabolic-androgenic steroid exposure, and it may contribute to anabolic-androgenic steroid withdrawal symptoms. Withdrawal symptoms, in turn, are a cluster of physical and psychological symptoms that may occur after discontinuing a drug that induces physiological dependence. Withdrawal symptoms are only one of the seven DSM-IV criteria for substance dependence and are neither necessary nor sufficient for a DSM-IV diagnosis of substance dependence. With these definitions in mind, then, we would say that anabolic steroid-induced hypogonadism represents simply one underlying mechanism for the etiology of anabolic-androgenic steroid withdrawal symptoms and should not be considered a confounder for making a DSM-IV diagnosis of anabolic-androgenic steroid dependence. As an example, opioid withdrawal is caused in part by abnormal signaling at central opioid receptors (1) . However, this abnormal receptor activity is not a “confounding variable” in diagnosing opioid dependence. Rather, it is one of the underlying mechanisms of opioid withdrawal, and opioid withdrawal, in turn, is a frequent (but not necessary) criterion for diagnosing opioid dependence. Similarly, if an anabolic-androgenic steroid user suppresses his own testosterone production as a result of prolonged exogenous anabolic-androgenic steroid administration and then develops consequent hypogonadal symptoms upon withdrawing (2) , these withdrawal symptoms would legitimately count as one criterion (although not a necessary criterion) for the diagnosis of anabolic-androgenic steroid dependence. On the basis of these considerations, we would agree with Drs. Scally and Tan that anabolic steroid-induced hypogonadism needs to be differentiated from anabolic-androgenic steroid dependence, since not all patients who suffer from anabolic steroid-induced hypogonadism will qualify for a diagnosis of anabolic-androgenic steroid dependence. However, we would suggest that anabolic steroid-induced hypogonadism does not disqualify an individual from a diagnosis of anabolic-androgenic steroid dependence either. Instead, anabolic steroid-induced hypogonadism represents one of the primary mechanisms of anabolic-androgenic steroid withdrawal and physiological dependence.Belmont, Mass.The author’s disclosures accompany the original editorial.This letter (doi: 10.1176/appi.ajp.2009.09060846r) was accepted for publication in July 2009.

Adolescent anabolic-androgenic steroid exposure alters lateral anterior hypothalamic serotonin- 2A receptors in aggressive male hamsters

Chronic anabolic-androgenic steroid (AAS) treatment during adolescence facilitates offensive aggression in male Syrian hamsters ( Mesocricetus auratus). Serotonin (5-HT) modulates aggressive behavior and has been shown to be altered after chronic treatment with AAS. Furthermore, 5-HT type 2 receptors have been implicated in the control of aggression. For example, treatment with 5-HT 2A receptor antagonists suppress the generation of the offensive aggressive phenotype. However, it is unclear whether these receptors are sensitive to adolescent AAS exposure. The current study assessed whether treatment with AAS throughout adolescence influenced the immunohistochemical localization of 5-HT 2A in areas of the hamster brain implicated in the control of aggression. Hamsters were administered AAS (5.0 mg/kg) each day throughout adolescence, scored for offensive aggression, and then examined for differences in 5-HT 2A-immunoreactivity (5-HT 2A-ir). When compared with non-aggressive oil-treated controls, aggressive AAS-treated hamsters showed significant increases in 5-HT 2A-ir fibers in the lateral portion of the anterior hypothalamus (LAH). Further analysis revealed that AAS treatment also produced a significant increase in the number of cells expressing 5-HT 2A-ir in the LAH. Together, these results support a role for altered 5-HT 2A expression and further implicate the LAH as a central brain region important in the control of adolescent AAS-induced offensive aggression.

Behavioral effects of pubertal anabolic androgenic steroid exposure in male rats with low serotonin

The goal of this study was to assess the interactive effects of chronic anabolic androgenic steroid (AAS) exposure and brain serotonin (5-hydroxytryptamine, 5-HT) depletion on behavior of pubertal male rats. Serotonin was depleted beginning on postnatal day 26 with parachlorophenylalanine (PCPA 100 mg/kg, every other day); controls received saline. At puberty (P40), half the PCPA-treated rats and half the saline-treated rats began treatment with testosterone (T, 5 mg/kg, 5 days/week). Behavioral measures included locomotion, irritability, copulation, partner preference, and aggression. Animals were tested for aggression in their home cage, both with and without physical provocation (mild tail pinch). Brain levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined using HPLC. PCPA significantly and substantially depleted 5-HT and 5-HIAA in all brain regions examined. Chronic T treatment significantly decreased 5-HT and 5-HIAA in certain brain areas, but to a much lesser extent than PCPA. Chronic exposure to PCPA alone significantly decreased locomotor activity and increased irritability but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on locomotion, irritability, or sexual behavior but increased partner preference and aggression. The most striking effect of combining T + PCPA was a significant increase in attack frequency as well as a significant decrease in the latency to attack, particularly following physical provocation. Based on these data, it can be speculated that pubertal AAS users with low central 5-HT may be especially prone to exhibit aggressive behavior.