Abstract
The abuse of anabolic-androgenic steroids (AASs) is associated with high morbidity and mortality rates. The highest incidence of this malpractice documented in males (prevalence rate about 6.4%), a third of which develop adverse reactions. Accordingly, the objective was to review published studies about the neurological complications triggered by the indiscriminate use of AASs, with focus on the pathogenesis of lesions in the nervous system (NS). As a result it was observed that at NS, these stimulants actuate through a complex signaling systems that include the neuroendocrine alteration of the hypothalamic-pituitary-gonadal axis, modification of neurotransmitters and their receptors, as well as the induction of neuronal death by apoptosis in several pathways. These organic neurological alterations can lead to a clinical symptomatology with neurological, mood and sleep disorders. Consequently, varying adverse effects were observed analogous to the class of AAS utilized, how it was administered and time of use. Even though to date, only a few classes were submitted for scientific analyses, on dosages, mode of administration and specific exposure times. Furthermore, the illegal use and production of these drugs does not propitiate their appropriate application, quality control and purity. It was concluded that the abuse of AAS has inimically severe and complex effects, including serious neurotoxic issues.References
Shahidi NT. A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids. Clin. Ther 2001; 23(9) 1355-1390.
Zelleroth S, Nylander E, Nyberg F, Grönbladh A, Hallberg M. Toxic impact of anabolic androgenic steroids in primary rat cortical cell cultures. Neuroscience. 2019; 397: 172- 183.
Evans NA. Current Concepts in Anabolic-Androgenic Steroids. The American Journal of Sports Medicine. 2004; 32 (2): 534-542.
NIDA – National Institute on Drug Abuse. Anabolic Steroids. Accessed on: 2018, November 27. Available at https://www.drugabuse.gov/publications/drugfacts/anabolic-steroids
Kanayama G, Kaufman MJ, Pope HG. Public health impact of androgens. Current Opinion in Endocrinology, Diabetes and Obesity. 2018; 25(3): 218-223.
Coward RM, Rajanahally S, Kovac JR, Smith RP, Pastuszak AW, Lipshultz LI. Anabolic steroid induced hypogonadism in young men. The Journal of urology. 2013; 190(6): 2200-5.
Sagoe D, Molde H, Andreassen CS, Torsheim T, Pallesen S. The global epidemiology of anabolic-androgenic steroid use: a meta-analysis and meta-regression analysis. Annals of epidemiology. 2014; 24(5): 383-98.
Angell PJ, Green DJ, Lord R, Gaze D, Whyte G, George KP. Acute cardiovascular responses to resistance exercise in anabolic steroids users: A preliminary investigation. Science and Sports. 2018; 33(6): 339-346.
Horwitz H, Andersen JT, Dalhoff KP. Health consequences of androgenic anabolic steroids. J Intern Med 2018; doi: 10.1111/joim.12850. [Epub ahead of print]
De Ronde, W. Preventing anabolic steroid abuse; a long way to go. Journal of Internal Medicine. 2018. doi:10.1111/joim.12858
M?dra? M, Brona A, Jó?ków P. The central effects of androgenic-anabolic steroid use. Journal of Addiction Medicine. 2018; 12(3): 184-192.
Mazzeo F. (2018). Anabolic steroid use in sports and in physical activity: Overview and analysis. Sport Mont. 2018; 16(3): 113-118.
Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006; 5: 160-170
Orlando R, Caruso A, Molinaro G. Nanomolar concentrations of anabolic- androgenic steroids amplify excitotoxic neuronal death in mixed mouse cortical cultures. Brain Res. 2007; 1165: 21-29.
Caraci F, Pistara V, Corsaro A. Neurotoxic properties of the anabolic androgenic steroids nandrolone and methandrostenolone in primary neu- ronal cultures. J Neurosci Res. 2011; 89: 592-600.
Pope HGJR, Kanayama G, Hudson JI. Risk factors for illicit anabolic-an- drogenic steroid use in male weightlifters: a cross-sectional cohort study. Biol Psychiatry. 2012; 71: 254- 261
Kanayama G, Brower KJ, Wood RI, Hudson JI, Pope HGJR. Anabolic-androgenic steroid dependence: an emerging disorder. Addiction. 2009; 104: 1966-1978.
Christou MA, Christou PA, Markozannes G, Tsatsoulis A, Mastorakos G, Tigas S. Effects of Anabolic Androgenic Steroids on the Reproductive System of Athletes and Recreational Users: A Systematic Review and Meta-Analysis. Sports Med 2017; 47(9):1869- 1883.
Fortunato RS, Rosenthal D, Carvalho DP. Abuso de Esteróides Anabolizantes e seu Impacto sobre a Func?a?o Tireóidea. Arq Bras Endocrinol Metab. 2007; 51(9): 1417-1424.
Bahrke MS, Yersalis CE, Kopstein AN, Stephens JA. Risk factors associated with anabolic-androgenic steroid use among adolescents. Sports Med. 2000; 29 (6): 397-405.
Silva PRP, Danielski R, Czepielewski MA. Esteroides anabolizantes no esporte. RBME. 2002; 8: 235-243
Ma F, Liu D. 17b-trenbolone, an anabolic-androgenic steroid as well as an environmental hormone, contributes to neurodegeneration. Toxicology and applied pharmacology. 2015; 282(1): 68-76.
Pagonis TA, Angelopoulos NV, Koukoulis GN, Hadjichristodoulou CS. Psychiatric side effects induced by supraphysiological doses of combina- tions of anabolic steroids correlate to the severity of abuse. Eur Psychiatry. 2006; 21: 551-562
Talih F, Fattal O, Malone D Jr. Anabolic steroid abuse: psychiatric and phy- sical costs. Cleve Clin J Med. 2007; 74: 341-344.
Tucci P, Morgese M, Colaianna M, Zotti M, Schiavone S, Cuomo V. Neurochemical consequence of steroid abuse: stanozolol-induced monoaminergic changes. Steroids. 2012; 77: 269-275.
Pomara C, Neri M, Bello S, Fiore C, Riezzo I, Turillazzi E. Neurotoxicity by synthetic androgen steroids: oxidative stress, apoptosis, and neuropathology: a review. Curr Neuropharmacol. 2015; 13 (1):132-145.
Amiaz R, Seidman SN. Testosterone and depression in men. Curr Opin Endocrinol Diabetes Obes. 2008; 15 (3): 278-283
Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract. 2009; 15 (4): 289- 305.
Schwartzer JJ, Ricci LA, Melloni R. Interactions be- tween the dopaminergic and GABAergic neural systems in the lateral anterior hypothalamus of aggressive AAS- treated hamsters. Behav Brain Res. 2009; 203 (1): 15-22
Masonis AE, Mccarthy MP. Effects of the androgenic/ anabolic steroid stanozolol on GABAA receptor function: GABA-stimulated 36Cl- influx and [35S] TBPS binding. J Pharmacol Exp Ther. 1996; 279 (1):186-193
Hughes TK, Rady PL, Smith EM. Potential for the effects of anabolic steroid abuse in the immune and neuroendocrine axis. J Neuroimmunol. 1998; 83 (1-2): 162- 167.
Kindlundh A, Lindblom J, Bergstrom L, Nyberg F. The anabolic-androgenic steroid nandrolone induces alterations in the density of serotonergic 5HT1B and 5HT2 receptors in the male rat brain. Neuroscience. 2003; 119 (1):113-120.
Costine BA, Oberlander JG, Davis MC, Penatti CA, Porter DM, Leaton RN, Henderson LP. Chronic anabolic androgenic steroid exposure alters corticotropin releasing factor expression and anxiety-like behaviors in the female mouse. Psychoneuroendocrinology. 2010; 35 (10): 1473-1485.
Kash Tl, Winder DG. Neuropeptide Y and corticotropin- releasing factor bi- directionally modulate inhibitory synaptic trans- mission in the bed nucleus of the stria terminalis. Neuropharmacology. 2006; 51(5): 1013-1022.
Tasan RO, Bukovac A, Peterschmitt Yn, Sartori Sb, Landgraf R, Singewald N, Sperk G. Altered GABA transmission in a mouse model of increased trait anxiety. Neuroscience. 2011; 183: 71-80.
Pope HG, Katz DL. Psychiatric and medical effects of anabolic-androgenic steroid use. A controlled study of 160 athletes. Arch Gen Psychiatry. 1994; 51 (5): 375- 382.
Pinna G, Agis-Balboa Rc, Pibiri F, Nelson M, Guidotti A, Costa E. Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice. Neurochem Res. 2008; 33 (10): 1990-2007
Ostlund H, Keller E, Hurd YL. Estrogen receptor gene ex- pression in relation to neuropsychiatric disorders. Ann N Y Acad Sci. 2003; 1007: 54-63.
Kanayama G, Hudson JI, Popope J. Long-term psychiatric and medical consequences of anabolic-androgenic steroid abuse: a looming public health concern? Drug Alcohol Depend. 2008; 98: 1-12.
Amsterdam JV, Opperhuizen A, Hartgens F. Adverse health effects of anabolicandrogenic steroids. Regulatory Toxicology and Pharmacology. 2010; 57: 117- 123.
Birgner C, Kindlundh-Hogberg Am, Oreland L, et al. Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone dec- anoate administration. Brain Res. 2008; 1219: 103-110.
Ip EJ, Trinh K, Tenerowicz MJ, Pal J, Lindfelt TA, Perry PJ. Characteristics and behaviors of older male anabolic steroid users. J Pharm Pract. 2015; 28 (5): 450- 456.
Sato SM, Schulz KM, Sisk CL, Wood RI. Adolescents and androgens, receptors and rewards. Horm Behav. 2008; 53 (5): 647-658.
Malone DA, Dimeff RJ, Lombardo JA, Sample RH. Psychiatric effects and psychoactive substance use in anabolic- androgenic steroid users. Clin J Sport Med. 1995; 5 (1): 25-31.
Piacentino D, Kotzalidis GD, Del Casale A, Aromatario MR, Pomara C, Girardi P, Sani G. Anabolic-androgenic steroid use and psychopathology in athletes. A systematic review. Curr Neuropharmacol. 2015; 13 (1): 101-121.
Penatti CA, Costine BA, Porter D. Effects of chronic exposure to an anabolic androgenic steroid cocktail on alpha5-receptor-mediated GABAergic transmission and neural signaling in the forebrain of female mice. Neuroscience. 2009; 161: 526-537.
Oberlander JG, Porter DM, Penatti CA, Henderson LP. Anabolic androgenic steroid abuse: multiple mechanisms of regu- lation of GABAergic synapses in neuroendocrine control regions of the rodent forebrain. J Neuroendocrinol. 2012; 24 (1): 202-214.
Clark AS, Henderson LP. Behavioral and physiological responses to anabolic- androgenic steroids. Neurosci Biobehav Rev. 2003; 27: 413-436
Zitzmann M. Testosterone and the brain. Aging Male. 2006; 9: 195-199
Matrisciano F, Modafferi AM, Togna GI. Repeated anabolic androgenic steroid treatment causes antidepressant-reversible alterations of the hypo- thalamic- pituitary-adrenal axis, BDNF levels and behavior. Neuropharmacology 2010; 58: 1078- 1084
Leibenluft E, Schmidt Pj, Turner Eh, Danaceau Ma, Ashman Sb, Wehr Ta, et al. Effects of leuprolide-induced hypogonadism and testosterone repla- cement on sleep, melatonin, and prolactin secretion in men. J Clin Endocrinol Metab. 1997; 82: 3203-3207
Venancio DP, Tufik S, Garbuio SA. Effects of anabolic androgenic steroids on sleep patterns of individuals practicing resistance exercise. Eur J Appl Physiol. 2008; 102(5):555-60.
Liu PY, Yee B, Wishart SM, Jimenez M, Jung DG, Grunstein RR. The short-term eVects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab. 2003; 88: 3605-3613.
Trenton AJ, Currier GW. Behavioural manifestations of anabolic steroid use. CNS Drugs. 2005; 19: 571-595.
Bjornebekk A, Walhovd KB, Jorstad ML. Structural brain imaging of long- term anabolic-androgenic steroid users and nonusing weightlifters. Biol Psychiatry. 2017; 82: 294-302
Silva DK, Esteves A, Rossi WC, Nogueira DA. Quantidade de Ce?lulas de Purkinje no Cerebelo de Camundongos Sob o Uso de Esteróides Anabolizantes. Rev Neurocienc. 2012; 20 (2): 200-203.
Bueno A, Carvalho FB, Gutierres JM, Lhamas C, Andrade CM. A comparative study of the effect of the dose and exposure duration of anabolic androgenic steroids on behavior, cholinergic regulation, and oxidative stress in rats. PLoS One. 2017; 12 (6): e0177623
Kaufman MJ, Janes AC, Hudson JI. Brain and cognition abnormalities in long-term anabolic-androgenic steroid users. Drug Alcohol Depend. 2015; 152: 47 -56.
Ribeiro CM, Silva DC, Damia?o B, Alves DM, Freitas AC, Ju?nior VCR, Esteves A. Ana?lise quantitativa de ce?lulas de Purkinje em camundongos sob o uso dos esteroides anabolizantes. Rev. Neurocienc. 2014; 22(3): 432-437.
Estrada M, Varshney A, Ehrlich BE. Elevated testosterone induces apoptosis in neuronal cells. J Biol Chem. 2006; 281: 25492-25501.