Strong muscles, weak heart: testosterone-induced cardiomyopathy / Sarah Doleeb, Ann Kratz, Monica Salter, Vinay Thohan. - (ESC Heart Failure (2019) 9 July; p. 1-5).
- PMID: 31287235.
- DOI: 10.1002/ehf2.12494

Abstract

Exogenous anabolic androgen steroid use is associated with adverse cardiovascular outcomes. A 53-year-old bodybuilder presented with 3 months of exertional dyspnoea. Physical examination showed tachycardia and pan-systolic murmur; an echocardiogram showed a left ventricular ejection fraction (EF) of 15%. Evaluations included normal coronary angiogram, iron panel and thyroid studies, a negative viral panel (human immunodeficiency virus, Lyme disease, and hepatitis), and urine toxicology. He admitted to intramuscular anabolic steroid use; his testosterone level was 30 160.0 ng/dL (normal 280-1100 ng/dL). In addition to discontinuation of anabolic steroid use, he was treated with guideline-directed heart failure medical therapy. Repeat echocardiogram at 6 months showed an EF of 54% and normalized testosterone level of 603.7 ng/dL. Anabolic steroid use is a rare, reversible cause of cardiomyopathy in young, otherwise healthy athletes; a high index of suspicion is required to prevent potentially fatal side effects.

Strong stuff : the size and seriousness of the doping trade in the Netherlands / Ilse van Leiden, Marjan Olfers, Anton van Wijk, Rebecca Rijnink, Joey Wolsink, Juno van Esseveldt. - 2020

Sterk spul : aard, omvang en ernst van de dopinghandel in Nederland / Ilse van Leiden, Marjan Olfers, Anton van Wijk, Rebecca Rijnink, Joey Wolsink, Juno van Esseveldt. - Bureau Beke; Vrije Universiteit Amsterdam; i.o.v. Ministerie van Volksgezondheid, Welzijn en Sport. - Arnhem : Bureau Beke, 2020. - (Beke reeks)

• ISBN 9789492255402
  
  

Abstract

The use of image and performance enhancing drugs (IPEDs) for cosmetic reasons and in amateur sport has become accepted, a 224 page Report examining the size and seriousness of the doping trade in The Netherlands has highlighted. The Report found that this is in contrast to elite sport, where use of doping substances remains taboo.

The Report concludes that around 2% of the Dutch population uses or has used doping substances, and is fastest increasing amongst noncompetitive athletes who use doping substances to enhance their appearance. In addition, it found that doping is becoming accepted in recreational sport.

The Report found that elite athletes generally come into contact with doping substances through their entourage, which means that they are likely to receive guidance on usage. In contrast, cosmetic and recreational sport users do not receive guidance and gather most of their information from the internet, which puts their health at greater risk.

In elite sport, the Report found that the most common doping agents are anabolic steroids, stimulants, and hormonal and metabolic modulators. It found that there has been a decrease in the number of athletes who are prescribed substances without medical need in an attempt to boost performance since 2015. Micro doping (i.e. using substances in small amounts to avoid detection) is on the increase, as well as utilisation of experimental food (such as ketones).

More shipments of doping substances from outside the EU are being intercepted. From 2016 to 2018, customs seizures tripled with officers intercepting over 8,000 shipments involving medication, including 1,000 that contained doping substances. The most common substances intercepted were stimulants, glucocorticoids, and anabolic agents. Seizures of diuretics, masking agents, beta blockers, and hormonal and metabolic modulators are also increasing.

The Report points out that pharmaceutical companies in Eastern Europe are well known supply chains for the Dutch market. Also, it is impossible to know what substances are being imported into the country from other European Union countries, due to free trade rules. However, it did find that due to stricter regulation on doping substances in recent years, there has been a boost in Underground Laboratories (UGLs) in The Netherlands.

As well as the usual worries about the quality of substances produced in such labs being dangerous to health, the Report found that the increase in UGLs that compete with each other has led to a ‘hardening’ of the market. ‘In the Netherlands, a violent incident is already known where those involved in an UGL were extorted by new players on the market’, it reads.

Doping is not as lucrative as drug trafficking, but the Report did find that criminals are increasingly becoming involved in the doping market. This is because due to the increase in UGLs, the supply of doping substances is no longer dependant on foreign pharmacies. Products can now be produced for export where they can be sold in person or via the internet or dark web.

Doping in sport is not a criminal offence in The Netherlands. However, the Report concludes that the increased intertwining of doping with drug trafficking and the doping trade due to UGLs enabling an international market fo doping products represents a ‘serious problem’.

Source: www.sportsintegrityinitiative.com

Samenvatting:

In de media duiken met enige regelmaat berichten op over het gebruik van doping in de sport. Niet alleen in de topsport, ook daarbuiten worden middelen gebruikt om de (sport)prestaties te vergroten. Maar wat gaat er achter het dopinggebruik en de -handel schuil?

In opdracht van het ministerie van VWS onderzochten wij samen met de Vrije Universiteit Amsterdam de aard, omvang en ernst van dopinghandel in Nederland. In ‘Sterk spul’ komen profielen van gebruikers van dopingmiddelen aan bod en welke risico’s er met het gebruik gepaard gaan. Daarnaast wordt ingegaan op de vraag hoe de handel in dopingmiddelen in elkaar steekt, hoe grootschalig deze handel is en in hoeverre er in Nederland ook dopingmiddelen worden geproduceerd. Een relevante vraag hierbij is wie er bij het produceren, verstrekken en verhandelen van dopingmiddelen betrokken zijn.

Structural brain characteristics of anabolic-androgenic steroid dependence in men / Lisa E. Hauger, Lars T. Westlye, Anders M. Fjell, Kristine B. Walhovd, Astrid Bjørnebekk. - (Addiction 114 (2019) 8 (August); p. 1405–1415). -
- PMID: 30955206.
- DOI: 10.1111/add.14629

Abstract

AIM:
To identify differences in brain morphology between dependent and non-dependent male anabolic-androgenic steroid (AAS) users.

DESIGN:
This study used cross-sectional data from a longitudinal study on male weightlifters.

PARTICIPANTS:
Oslo University Hospital, Norway.

SETTING:
Eighty-one AAS users were divided into two groups; AAS-dependent (n = 43) and AAS-non-dependent (n = 38).

MEASUREMENTS:
Neuroanatomical volumes and cerebral cortical thickness were estimated based on magnetic resonance imaging (MRI) using FreeSurfer. Background and health information were obtained using a semi-structured interview. AAS-dependence was evaluated in a standardized clinical interview using a version of the Structured Clinical Interview for DSM-IV, adapted to apply to AAS-dependence.

FINDINGS:
Compared with non-dependent users, dependent users had significantly thinner cortex in three clusters of the right hemisphere and in five clusters of the left hemisphere, including frontal, temporal, parietal and occipital regions. Profound differences were seen in frontal regions (left pars orbitalis, cluster-wise P < 0.001, right superior frontal, cluster-wise P < 0.001), as has been observed in other dependencies. Group differences were also seen when excluding participants with previous or current non-AAS drug abuse (left pre-central, cluster-wise P < 0.001, left pars orbitalis, cluster-wise P = 0.010).

CONCLUSION:
Male dependent anabolic-androgenic steroid users appear to have thinner cortex in widespread regions, specifically in pre-frontal areas involved in inhibitory control and emotional regulation, compared with non-dependent anabolic-androgenic steroid users.

Structural Brain Imaging of Long-Term Anabolic-Androgenic Steroid Users and Nonusing Weightlifters / Astrid Bjørnebekk, , Kristine B. Walhovd, Marie L. Jørstad, Paulina Due-Tønnessen, Ingunn R. Hullstein, Anders M. Fjell. – (Biological Psychiatry 79 (2016, 30 June) : p. 1-9)

• DOI: 10.1016/j.biopsych.2016.06.017

Contents:

1.) Methods and Materials
A. Participants
B. Doping Analysis
C. Image Acquisition
D. Imaging Analysis
E. Statistical Analyses
2.) Results
A. Demographics and User Characteristics
B. Associations Between AAS Use and Regional Brain Volumetry
C. Associations Between AAS Use and Cortical Thickness
3.) Discussion
A. Thinner and Smaller Cortex Associated With AAS Use
B. Limitations
C. Conclusions
4.) Appendix A. Supplementary material
5.) References

Abstract

Background
Prolonged high-dose anabolic-androgenic steroid (AAS) use has been associated with psychiatric symptoms and cognitive deficits, yet we have almost no knowledge of the long-term consequences of AAS use on the brain. The purpose of this study is to investigate the association between long-term AAS exposure and brain morphometry, including subcortical neuroanatomical volumes and regional cortical thickness.

Methods
Male AAS users and weightlifters with no experience with AASs or any other equivalent doping substances underwent structural magnetic resonance imaging scans of the brain. The current paper is based upon high-resolution structural T1-weighted images from 82 current or past AAS users exceeding 1 year of cumulative AAS use and 68 non–AAS-using weightlifters. Images were processed with the FreeSurfer software to compare neuroanatomical volumes and cerebral cortical thickness between the groups.

Results
Compared to non–AAS-using weightlifters, the AAS group had thinner cortex in widespread regions and significantly smaller neuroanatomical volumes, including total gray matter, cerebral cortex, and putamen. Both volumetric and thickness effects remained relatively stable across different AAS subsamples comprising various degrees of exposure to AASs and also when excluding participants with previous and current non-AAS drug abuse. The effects could not be explained by differences in verbal IQ, intracranial volume, anxiety/depression, or attention or behavioral problems.

Conclusions
This large-scale systematic investigation of AAS use on brain structure shows negative correlations between AAS use and brain volume and cortical thickness. Although the findings are correlational, they may serve to raise concern about the long-term consequences of AAS use on structural features of the brain.

Structure characterisation of urinary metabolites of the cannabimimetic JWH-018 using chemically synthesised reference material for the support of LC-MS/MS-based drug testing / Simon Beuck, Ines Möller, Andreas Thomas, Annika Klose, Nils Schlörer, Wilhelm Schänzer, Mario Thevis. - (Analytical and Bioanalytical Chemistry 401 (2011) 2 (August); p. 493-505)

• PMID: 21455647
• DOI: 10.1007/s00216-011-4931-5

Abstract

As recently reported, the synthetic cannabinoid JWH-018 is the subject of extensive phase I and II metabolic reactions in vivo. Since these studies were based on LC-MS/MS and/or GC-MS identification and characterisation of analytes, the explicit structural assignment of the metabolites was only of preliminary nature, if possible at all. Here, we report the chemical synthesis of five potential in vivo metabolites of JWH-018 derivatives featuring an alkylcarboxy (M1), a terminal alkylhydroxy (M2), a 5-indolehydroxy (M3), an N-dealkylated 5-indolehydroxy (M4) and a 2'-naphthylhydroxy (5) analogue, respectively, and their characterisation by nuclear magnetic resonance spectroscopy. The collision-induced dissociation (CID) patterns of the protonated compounds were studied by high-resolution/high-accuracy tandem mass spectrometry (MS( n )) applying an LTQ Orbitrap with direct infusion and electrospray ionisation of target analytes. An unusual dissociation behaviour including a reversible ion-molecule reaction between a naphthalene cation (m/z 127) and water in the gas phase of the MS was shown to be responsible for nominal neutral losses of 10 u in the course of the CID pathway. LC-MS/MS-supported comparison of synthesised reference standards with an authentic urine sample using an API 4000 QTrap mass spectrometer identified the synthetic JWH-018 analogues M1-M4 as true in vivo metabolites, presuming a chromatographic separation of potentially present regioisomeric analogues. Existing doping control methods were expanded and validated according to international guidelines in order to allow for the detection of the carboxy and the alkylhydroxy metabolites, respectively, as urinary markers for the illegal intake of the synthetic cannabinoid JWH-018. Both metabolites were quantified in authentic doping control urine samples that had been suspicious of JWH-018 abuse after routine screening procedures, and a stable isotope-labelled (13)C(8)-(15)N-carboxy metabolite was synthesised for future analytical applications.

Students’ non-medical use of pharmaceuticals to manage time in everyday life crises / Lea Trier Krøll

• Drugs: Education, Prevention and Policy 26 (2019) 4, p. 339-346
• DOI: 10.1080/09687637.2019.1585760
• Special Issue: Pharmaceutical Cognitive Enhancement

Abstract

This article examines students’ narratives of lived experiences with non-medical uses of prescription pharmaceuticals (NMUP) and analyzes how their experiences of time in everyday life influence the meanings they ascribe to their NMUP. The analysis draws on sociological notions of time and 28 in-depth qualitative interviews with young adults (age 20-30), who have used pharmaceuticals non-medically while enrolled at a university or college in Denmark. The article focuses on how a majority of students associate their NMUP with situations in which they experience urgency and a crisis of temporal agency due to their inability to pursue perceived necessary rhythms of studying or resting. It examines how these students consider NMUP a normative exception yet employ pharmaceuticals to manage their embodied and everyday life rhythms in order to relief senses of urgency and re-gain temporal agency. The article suggests the notion ‘everyday life crises’ to account for how students reflect that the time pressure associated with the experience of urgency relate to their everyday lives’ temporal practices, structures and norms. In conclusion, the article suggests that the analysis of NMUP as a practice embedded in everyday living highlights the relevance of conceptualising NMUP as ‘time work’ and suggests that future prevention campaigns should focus on students’ experiences of temporal conflicts in everyday life.

Studies of the pharmacology of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol, a synthetic anti-inflammatory androstene / Clarence N. Ahlem, Michael R. Kennedy, Theodore M. Page, Christopher L. Reading, Steven K. White, John J. McKenzie, Phaedra I. Cole, Dwight R. Stickney, James M. Frincke. - (International Journal of Clinical and Experimental Medicine 4 (2011) 2 (23 April); 119-135)

• PMID: 21686136
• PMCID: PMC3113500

Abstract

17α-Ethynyl-androst-5ene-3β, 7β, 17β-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3β,7β,17β-triol, a non-glucocorticoid anti-inflammatory metabolite of the adrenal steroid, dehydroepiandrosterone. The pharmacology of HE3286 was characterized in preparation for clinical trials in type 2 diabetes mellitus and other diseases of inflammation. Interactions with nuclear hormone receptors and P450 enzymes were measured in vitro. Drug metabolism was studied preclinically in mice, rats, dogs, and monkeys. Neurological and cardiopulmonary safety and dose-ranging and chronic toxicity studies were conducted in rats and dogs in accordance with FDA guidelines. Pharmacokinetics and metabolites were measured in Phase I clinical trials. HE3286 was differentially metabolized between species. HE3286 and metabolites did not bind or transactivate steroid binding nuclear hormone receptors or inhibit P450 enzymes. There were no adverse effects in safety pharmacology and canine toxicology studies. Although HE3286 did not elicit systemic toxicity in rats, mild estrogenic effects were observed, but without apparent association to hormonal changes. Safety margins were greater than 20-fold in rats and dogs with respect to the most commonly used clinical dose of 10 mg/day. The terminal half-life in humans was 8 hours in males and 5.5 hours in females. HE3286 is the first derivative of the DHEA metabolome to undergo a comprehensive pharmacological and safety evaluation. The results of these investigations have shown that HE3286 has a low potential for toxicity and possesses pharmacological properties generally suitable for use in human medicine. The favorable profile of HE3286 warrants further exploration of this new class of anti-inflammatory agents.

Keywords: HE3286; Toxicology; androstene; metabolism; pharmacokinetics; pharmacology.

Studies on the in Vivo Metabolism of Methylstenbolone and Detection of Novel Long Term Metabolites for Doping Control Analysis / Thomas Piper, Gregor Fusshöller, Wilhelm Schänzer, Andreas Lagojda, Dirk Kuehne, Mario Thevis. - (Drug Testing and Analysis (2019) 16 November); p. 1-25)

• PMID: 31733090.
• DOI: 10.1002/dta.2736

Abstract

The anabolic-androgenic steroid methylstenbolone (MSTEN; 2α,17α-dimethyl-17β-hydroxy-5α-androst-1-en-3-one) is available as a so-called designer steroid or nutritional supplement. It is occasionally detected in doping control samples, predominantly tested and confirmed as the glucuronic acid conjugate of MSTEN. The absence of other meaningful metabolites reported as target analytes for sports drug testing purposes can be explained with the advertised metabolic stability of MSTEN. In 2013, a first investigation into the human metabolism of MSTEN was published, and 2 hydroxylated metabolites were identified as potential targets for initial testing procedures in doping controls. These metabolites were not observed in recent doping control samples that yielded adverse analytical findings for MSTEN, and in the light of additional data originating from a recent publication on the in vivo metabolism of MSTEN in the horse, revisiting the metabolic reactions in humans appeared warranted. Therefore, deuterated MSTEN together with hydrogen isotope ratio mass spectrometry (IRMS) in combination with high accuracy/high resolution mass spectrometry were employed. After oral administration of a single dose of 10 mg of doubly labeled MSTEN, urine samples were collected for 29 days. Up to 40 different deuterated MSTEN metabolites were detected in post-administration samples, predominantly as glucuronic acid conjugates, and all were investigated regarding their potential to prolong the detection window for doping controls. Besides MSTEN excreted glucuronidated, three additional metabolites were still detectable at the end of the study on day 29. The most promising candidates for inclusion into routine sports drug testing methods (2α,17α-dimethyl-5α-androst-1-ene-3β,17β-diol and 2α,17α-dimethyl-5α-androst-1-ene-3α,17β-diol) were synthesized and characterized by NMR.

Study on Doping Prevention : Map of Legal, Regulatory and Prevention Practice Provisions in EU 28 / European Commission. - Luxembourg : European Union, 2014. - ISBN: 9789279435423. - DOI: 10.2766/86776

Abstract

Historically, anti-doping efforts have focused on the detection and deterrence of doping in elite and competitive sport. There is, however, a growing concern that doping is occurring outside the organised sporting system; giving rise to the belief that the misuse of doping agents in recreational sport has become a societal problem and a public health issue that must be addressed.

The EU Commission awarded a contract (EAC/2013/0617) to a Consortium to undertake this Study with the aim of developing the evidence-base for policies designed to combat doping in recreational sport. Fourteen internationally recognised experts shaped the Study which comprised (i) the collection of primary data through a structured survey, and (ii) secondary data through literature searches and website analysis. All 28 Member States participated in the information-gathering process. Specifically, this involved a systematic study of the ethical considerations, legal position, prevention research landscape, and current practise in relation to the prevention of doping in recreational sport.

The Study provides a comprehensive overview of current practice and legislation as it applies to the prevention of doping and promotes and supports the sharing of best practices in the EU regarding the fight against doping in recreational sport. It concludes with seven recommendations for future action that focus on the need for a coordinated response in relation to the problems arising from doping in recreational sport.

Contents

1. Executive Summary
2. Introduction, aims, objectives and methodology of the Study
3. Ethical and philosophical framework for preventative policies regarding anti-doping in recreational sport
3.1. Introduction
3.2. Doping, harm, criminality
3.3. Alternatives to criminalisation
3.4. Privacy
3.5. Conclusion
4. Legal Background
4.1. European legal responses to doping in sport
4.2. Beyond Europe: Harmonisation of legal instruments: World Anti-Doping Agency and the World Anti-Doping Code
4.3. Nature and Structure of National Anti-Doping Organisations (NADOs)
4.4. Definitional problems
5. Perspective of European National Anti-Doping Organisations (NADOs)
5.1. Introduction
5.2. Changes to the 2015 World Anti-Doping Code
5.3. Government Relations
5.4. Education
6. Prevention Landscape Selective Literature Review
7. Presentation of Findings
7.1. Organisations sampled
7.2. Collaborations and networks
7.3. Legislation and political arrangements
7.4. NADO sharing expertise
7.5. Current practice
7.6. Knowledge and Information
7.7. Prevention approach effectiveness
7.8. The role of commercial organisations in doping prevention
7.9. Availability and quality of information
7.10. Expert opinion: Importance of doping prevention
7.11. Expert opinion: Trends in doping prevention
7.12. Expert opinion: Key barriers
8. Conclusions
9. Policy Recommendations

Subject-based steroid profiling and the determination of novel biomarkers for DHT and DHEA misuse in sports / Pieter Van Renterghem, Peter Van Eenoo, Pierre-Edouard Sottas, Martial Saugy, Frans Delbeke. - (Drug Testing and Analysis 2 (2010) 11-12 (November); p. 582-588)

• PMID: 21204290
• DOI: 10.1002/dta.206
• Special Issue: 28th Cologne Workshop: Advances in Sports Drug Testing

Abstract

Doping with natural steroids can be detected by evaluating the urinary concentrations and ratios of several endogenous steroids. Since these biomarkers of steroid doping are known to present large inter-individual variations, monitoring of individual steroid profiles over time allows switching from population-based towards subject-based reference ranges for improved detection. In an Athlete Biological Passport (ABP), biomarkers data are collated throughout the athlete's sporting career and individual thresholds defined adaptively. For now, this approach has been validated on a limited number of markers of steroid doping, such as the testosterone (T) over epitestosterone (E) ratio to detect T misuse in athletes. Additional markers are required for other endogenous steroids like dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA). By combining comprehensive steroid profiles composed of 24 steroid concentrations with Bayesian inference techniques for longitudinal profiling, a selection was made for the detection of DHT and DHEA misuse. The biomarkers found were rated according to relative response, parameter stability, discriminative power, and maximal detection time. This analysis revealed DHT/E, DHT/5β-androstane-3α,17β-diol and 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol as best biomarkers for DHT administration and DHEA/E, 16α-hydroxydehydroepiandrosterone/E, 7β-hydroxydehydroepiandrosterone/E and 5β-androstane-3α,17β-diol/5α-androstane-3α,17β-diol for DHEA. The selected biomarkers were found suitable for individual referencing. A drastic overall increase in sensitivity was obtained. The use of multiple markers as formalized in an Athlete Steroidal Passport (ASP) can provide firm evidence of doping with endogenous steroids.