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False negative results in testosterone doping in forensic cases: Sensitivity of the urinary detection criteria T/E and T/LH
Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
Swedish Doping Control Laboratory, Karolinska University Hospital, Stockholm, Sweden.
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2021 (English)In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. n/a, no n/aArticle in journal (Refereed) Published
Abstract [en]

At the Swedish national forensic toxicology laboratory, a measured testosterone/epitestosterone (T/E) ratio?≥?12 together with testosterone/luteinizing hormone (T/LH) in urine?>?400?nmol/IU is considered as a proof of exogenous testosterone administration. However, according to the rules of the World Anti-Doping Agency (WADA), samples with T/E ratio?>?4 are considered suspicious and shall be further analysed by gas chromatography?combustion?isotope ratio mass spectrometry (GC-C-IRMS) to confirm the origin of testosterone and its metabolites. The aim of this study was to investigate the possibility of false negative results and to estimate the frequency of negative results using the current criteria for detection of abuse of testosterone in forensic investigations. Urine and serum samples were collected by the police at suspected infringement of the doping law in Sweden. Fifty-eight male subjects were included in the study. Urinary testosterone was determined by gas chromatography?mass spectrometry (GC?MS), serum testosterone and LH?by immunoassay. The origin of testosterone and its metabolites was confirmed by means of GC-C-IRMS. Twenty-six of the 57 analysed subjects tested positive for exogenous testosterone using the criteria T/E?≥?12 combined with T/LH?>?400?nmol/IU. The IRMS analyses confirmed 47 positives; thus, 21 were considered false negatives. Negative predictive value was 32% (95% confidence interval [CI]: 16%?50%) and sensitivity 55%. No false positive subjects were found. The number of false negative cases using the current criteria for the detection of testosterone abuse and hence the low sensitivity indicates a need to discuss introduction of new strategies in forensic doping investigations.

Place, publisher, year, edition, pages
John Wiley & Sons, Ltd , 2021. Vol. n/a, no n/a
Keywords [en]
doping, GC-C-IRMS, LH, T/E, testosterone
National Category
Forensic Science
Identifiers
URN: urn:nbn:se:liu:diva-178310DOI: 10.1002/dta.3125ISI: 000674047600001OAI: oai:DiVA.org:liu-178310DiVA, id: diva2:1585518
Conference
2021/08/17
Note

Funding agencies: Strategic Research Area in Forensic Science (2019), Sweden

Available from: 2021-08-17 Created: 2021-08-17 Last updated: 2022-06-17Bibliographically approved
In thesis
1. Testosterone Use and Abuse: Methodological Aspects in Forensic Toxicology and Clinical Diagnostics
Open this publication in new window or tab >>Testosterone Use and Abuse: Methodological Aspects in Forensic Toxicology and Clinical Diagnostics
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Abuse of anabolic androgenic steroids (AAS) is widespread in society and is today a major public health problem, associated with mental and somatic adverse effects and risk behavior, such as use of other illicit drugs and criminality. Testosterone, the most important endogenous male androgen, is therapeutically used in replacement therapy but is also extensively used as a doping agent. Traditionally, testosterone abuse is detected in urine in forensic cases and in serum in clinical diagnosis and monitoring, and free bioavailable serum testosterone is calculated by formulas. Salivary testosterone is however an attractive biomarker, as testosterone in saliva is supposed to reflect free testosterone in serum. 

The aim of this thesis was to investigate the abuse of AAS from a forensic perspective, particularly focusing on testosterone and methodological problems and potential alternative matrices for measurements of testosterone in forensic and clinical assessments. 

In the first study the toxicological findings in individuals suspected of doping offences, registered in the Swedish national forensic toxicology database were investigated (paper I). In paper II, testosterone levels in serum, saliva, and urine in clinical patients during replacement therapy with testosterone undecanoate (Nebido®) were studied. Further, the sensitivity of the current procedure for detection of testosterone abuse was investigated by method comparison using isotope ratio measurement (paper III) and a quantitative LC-MS/MS method for testosterone in serum and saliva was developed and presented (paper IV). 

It was found that testosterone was most frequently detected in the forensic cases and co-abuse of narcotics was common among AAS abusers. Methodological problems in detection of testosterone abuse using the present procedures was identified, indicating a need for new analytical strategies. A sensitive and highly specific LC-MS/MS method was developed for determination of testosterone in serum and saliva, which was shown suitable for analysis of forensic and clinical samples. Salivary testosterone was shown to correlate well with free serum testosterone in both male and female, and a sensitive marker in testosterone therapy, especially in females. In conclusion, it was found that saliva might have a potential as an alternative matrix for detection of illicit administration of testosterone and for diagnosis and monitoring of androgenic status. 

Abstract [sv]

Missbruket av anabola androgena steroider (AAS) är idag utbrett i samhället och är ett betydande folkhälsoproblem, associerat med fysisk och psykisk ohälsa och riskbeteende, såsom bruk av andra illegala droger och kriminalitet. Testosteron, det viktigaste manliga könshormonet används medicinskt vid klinisk substitutionsbehandling, men missbrukas även omfattande som dopningsmedel. Traditionellt detekteras missbruk av testosteron i urin i forensiska fall och i serum i klinisk diagnostik och monitorering och fritt biotillgängligt testosteron beräknas utifrån olika formler. Salivtestosteron är emellertid en attraktiv biomarkör, då testosteron i saliv anses spegla den fria fraktionen testosteron i serum. 

Denna avhandling syftade till att studera missbruket av anabola androgena steroider utifrån ett forensiskt perspektiv, speciellt med fokus på testosteron och metodologiska problem och möjligheten att använda alternativa biomarkörer för detektion och mätning av testosteron i forensiska och kliniska frågeställningar. 

I det första delarbetet studerades de toxikologiska fynden hos individer misstänkta för brott mot den svenska dopinglagen, registrerade i Sveriges nationella databas för forensisk toxikologi. I delarbete II studerades nivåerna av testosteron i serum, saliv och urin hos patienter vid substitutionsbehandling med testosteronundekanoat (Nebido®). Vidare studerades känsligheten för detektion av missbruk av testosteron med befintlig metod genom jämförelser med analyser med isotop ratio (delarbete III) och en kvantitativ LC-MS/MS metod för testosteron i serum och saliv utvecklades och presenterades (delarbete IV). 

Testosteron detekterades frekvent i de forensiska fallen, och ett blandmissbruk av AAS och narkotiska preparat var vanligt förekommande. Metodologiska problem identifierades med den nuvarande proceduren för detektion av testosteronmissbruk, vilket indikerar ett behov av nya analytiska strategier. En känslig och högst specifik LC-MS/MS metod för bestämning av testosteron i serum och saliv utvecklades, vilken visade sig lämplig för analys av forensiska och kliniska prover. Salivtestosteron korrelerade med fritt testosteron i serum hos både män och kvinnor, och visade sig vara en känslig markör vid testosteronbehandling, speciellt hos kvinnor. Slutsatsen är att saliv kan ha potential som en alternativ matris för detektion av missbruk av testosteron och för diagnosticering och monitorering av androgent status.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2021. p. 76
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1762
National Category
Forensic Science
Identifiers
urn:nbn:se:liu:diva-173146 (URN)10.3384/diss.diva-173146 (DOI)9789179297510 (ISBN)
Public defence
2021-03-05, Belladonna, Building 511, Campus US, Linköping, 09:00 (Swedish)
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Note

Funding agencies: The National Board of Forensic Medicine,Department of Endocrinology, University Hospital, Linköping, Medical ResearchCouncil of Southeast Sweden and Strategic Research Area in Forensic Science,Linköping University.

Available from: 2021-02-04 Created: 2021-02-04 Last updated: 2021-12-28Bibliographically approved

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Lood, YvonneAardal, ElisabethJosefsson, MartinAhlner, Johan

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