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Anabolic Androgenic Steroids: Neurobiological Effects of Nandrolone, Testosterone, Trenbolone, and Stanozolol
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology and addiction research)
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

The use of anabolic androgenic steroids (AAS) for recreational purposes is a health concern, as long-term AAS-use in supraphysiological doses is associated with severe physical and psychological adverse effects. Several behavioral and cognitive problems are reported after long-term AAS-use, and alterations in brain morphology as well as neurotransmitter systems have been reported. The AAS-induced negative impact on the brain may depend on the type of AAS used, but the rationale behind the adverse effects observed is still not clear.

The aim of the present thesis was to investigate the neurobiological impact of supraphysiological doses of structurally diverse AAS; testosterone, nandrolone, stanozolol, and trenbolone, as well as of the prodrugs nandrolone decanoate, testosterone undecanoate, testosterone decanoate, and trenbolone decanoate. Wistar rats were used to study the influence on behavior, effects on the brain, and additional somatic effects. Furthermore, in vitro models of immature and mature primary rat cortical cell cultures were used to examine the potential toxic properties of the AAS administered. In the in vitro studies, nandrolone and trenbolone were identified as the most toxic of the AAS investigated, due to their adverse impact on mitochondrial function, membrane integrity, apoptosis, and neurite outgrowth. In vivo, the AAS demonstrated diverse somatic outcomes affecting body weight development, and organ weights to different degrees. In addition, nandrolone decanoate caused a reduced general activity, an effect possibly induced by increased stress vulnerability and alterations in the oxytocinergic system. Furthermore, nandrolone decanoate induced impaired memory in the novel object recognition test. Overall, nandrolone decanoate was identified as the most harmful steroid investigated due to its prominent impact on body weight development, affecting multiple organs, and being the only AAS causing impaired cognitive function. 

In conclusion, the structurally different AAS exerted diverse effects on cell viability, neurite development as well as regarding physical impairments and impact on behavior, suggesting that harmful physiological, neurological, and psychological outcomes may be expected after AAS-use. These findings highlight that the severity and type of adverse effects depend on the type of AAS used, which is valuable information to consider in order to provide good healthcare and treatment options to AAS-users.    

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2022. , p. 87
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 315
Keywords [en]
Anabolic androgenic steroids, testosterone, nandrolone, trenbolone, stanozolol, central nervous system, primary cortical cell cultures, rats, multivariate concentric square field, novel object recognition.
National Category
Basic Medicine
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-480857ISBN: 978-91-513-1560-7 (print)OAI: oai:DiVA.org:uu-480857DiVA, id: diva2:1685624
Public defence
2022-09-23, B42, Biomedical center, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2022-09-02 Created: 2022-08-03 Last updated: 2022-09-02
List of papers
1. Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures
Open this publication in new window or tab >>Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures
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2019 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 397, p. 172-183Article in journal (Refereed) Published
Abstract [en]

The use of anabolic androgenic steroids (AASs) among non-athletes is a public health-problem, as abusers underestimate the negative effects associated with these drugs. The present study investigated the toxic effects of testosterone, nandrolone, stanozolol, and trenbolone, and aimed to understand how AAS abuse affects the brain. Mixed cortical cultures from embryonic rats were grown in vitro for 7 days and thereafter treated with increasing concentrations of AASs for 24 h (single-dose) or 3 days (repeated exposure). Cells were co-treated with the androgen-receptor (AR) antagonist flutamide, to determine whether the potential adverse effects observed were mediated by the AR. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase (LDH) release, and caspase-3/7 activity. Nandrolone, unlike the other AASs studied, indicated an effect on mitochondrial activity after 24 h. Furthermore, single-dose exposure with testosterone, nandrolone and trenbolone increased LDH release, while no effect was detected with stanozolol. However, all of the four steroids negatively affected mitochondrial function and resulted in LDH release after repeated exposure. Testosterone, nandrolone, and trenbolone caused their toxic effects by induction of apoptosis, unlike stanozolol that seemed to induce necrosis. Flutamide almost completely prevented AAS-induced toxicity by maintaining mitochondrial function, cellular integrity, and inhibition of apoptosis. Overall, we found that supra-physiological concentrations of AASs induce cell death in mixed primary cortical cultures, but to different extents, and possibly through various mechanisms. The data presented herein suggest that the molecular interactions of the AASs with the AR are primarily responsible for the toxic outcomes observed.

Keywords
mitochondrial function membrane integrity cell death androgen-receptor flutamide
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-370111 (URN)10.1016/j.neuroscience.2018.11.035 (DOI)000454922800016 ()30500611 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain Foundation
Note

Även finansierat av Kjell och Märta Beijers stiftelse

Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2022-08-03Bibliographically approved
2. Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures
Open this publication in new window or tab >>Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures
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2021 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 210, article id 105863Article in journal (Refereed) Published
Abstract [en]

The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.

Keywords
Anabolic androgenic steroids, Neurite outgrowth, Neurotoxicity, Primary cortical cell culture, Rat
National Category
Basic Medicine Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-439046 (URN)10.1016/j.jsbmb.2021.105863 (DOI)000652020500001 ()33677017 (PubMedID)
Funder
Kjell and Marta Beijer FoundationThe Swedish Brain FoundationSwedish Research Council, 9459
Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2022-08-03Bibliographically approved
3. Nandrolone decanoate and testosterone undecanoate differently affect stress hormones, neurotransmitter systems, and general activity in the male rat
Open this publication in new window or tab >>Nandrolone decanoate and testosterone undecanoate differently affect stress hormones, neurotransmitter systems, and general activity in the male rat
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2022 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 432, article id 113971Article in journal (Refereed) Published
Abstract [en]

Anabolic androgenic steroids (AAS) are frequently used to improve physical appearance and strength. AAS are known to affect muscle growth, but many AAS-users also experience psychiatric and behavioral changes after long-term use. The AAS-induced effects on the brain seem to depend on the type of steroid used, but the rationale behind the observed effect is still not clear. The present study investigated and compared the impact of nandrolone decanoate and testosterone undecanoate on body weight gain, levels of stress hormones, brain gene expression, and behavioral profiles in the male rat. The behavioral profile was determined using the multivariate concentric squared field test (MCSF-test). Blood plasma and brains were collected for further analysis using ELISA and qPCR. Nandrolone decanoate caused a reduction in body weight gain in comparison with both testosterone undecanoate and control. Rats receiving nandrolone decanoate also demonstrated decreased general activity in the MCSF. In addition, nandrolone decanoate reduced the plasma levels of ACTH in comparison with the control and increased the levels of corticosterone in comparison with testosterone undecanoate. The qPCR analysis revealed brain region-dependent changes in mRNA expression, where the hypothalamus was identified as the region most affected by the AAS. Alterations in neurotransmitter systems and stress hormones may contribute to the changes in behavior detected in the MCSF. In conclusion, both AAS affect the male rat, although, nandrolone decanoate has more pronounced impact on the physiological and the behavioral parameters measured.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Anabolic androgenic steroids, Brain gene expression, Multivariate concentric square field test, Nandrolone decanoate, Testosterone undecanoate, Wistar rat
National Category
Neurosciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-480854 (URN)10.1016/j.bbr.2022.113971 (DOI)000860386000008 ()35738337 (PubMedID)
Funder
Kjell and Marta Beijer Foundation
Available from: 2022-07-21 Created: 2022-07-21 Last updated: 2022-10-14Bibliographically approved
4. The decanoate esters of nandrolone, testosterone, and trenbolone induce steroid specific memory impairment and somatic effects in the male rat
Open this publication in new window or tab >>The decanoate esters of nandrolone, testosterone, and trenbolone induce steroid specific memory impairment and somatic effects in the male rat
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2024 (English)In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 161, article id 105501Article in journal (Refereed) Published
Abstract [en]

Long-term use of anabolic androgenic steroids (AAS) in supratherapeutic doses is associated with severe adverse effects, including physical, mental, and behavioral alterations. When used for recreational purposes several AAS are often combined, and in scientific studies of the physiological impact of AAS either a single compound or a cocktail of several steroids is often used. Because of this, steroid-specific effects have been difficult to define and are not fully elucidated. The present study used male Wistar rats to evaluate potential somatic and behavioral effects of three different AAS; the decanoate esters of nandrolone, testosterone, and trenbolone. The rats were exposed to 15 mg/kg of nandrolone decanoate, testosterone decanoate, or trenbolone decanoate every third day for 24 days. Body weight gain and organ weights (thymus, liver, kidney, testis, and heart) were measured together with the corticosterone plasma levels. Behavioral effects were studied in the novel object recognition-test (NOR-test) and the multivariate concentric square field-test (MCSF-test). The results conclude that nandrolone decanoate, but neither testosterone decanoate nor trenbolone decanoate, caused impaired recognition memory in the NOR-test, indicating an altered cognitive function. The behavioral profile and stress hormone level of the rats were not affected by the AAS treatments. Furthermore, the study revealed diverse AAS-induced somatic effects i.e., reduced body weight development and changes in organ weights. Of the three AAS included in the study, nandrolone decanoate was identified to cause the most prominent impact on the male rat, as it affected body weight development, the weights of multiple organs, and caused an impaired memory function.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Anabolic androgenic steroids, Nandrolone decanoate, Testosterone decanoate, Trenbolone decanoate, Rat, Novel object recognition, Multivariate concentric square field, Memory
National Category
Pharmacology and Toxicology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-480856 (URN)10.1016/j.yhbeh.2024.105501 (DOI)001200194000001 ()38368844 (PubMedID)
Funder
Kjell and Marta Beijer Foundation
Available from: 2022-07-21 Created: 2022-07-21 Last updated: 2024-04-23Bibliographically approved

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Output format
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