Detection of formestane abuse by mass spectrometric techniques

16 Dec 2014

Detection of formestane abuse by mass spectrometric techniques / Xavier de la Torre, Cristiana Colamonici, Davide Curcio, Daniel Jardines, Francesco Molaioni, Maria Kristina Parr, Francesco Botrè. - (Drug Testing and Analysis 6 (2014) 11-12 (November-December); p. 1133-1140)

  • PMID: 25516450
  • DOI: 10.1002/dta.1759

Abstract

Formestane (4-hydroxy-androstenedione) is an aromatase inhibitor prohibited in sports and included, since 2004, in the list of prohibited substances updated yearly by the World Anti-Doping Agency (WADA). Since the endogenous production of formestane has been described, it is mandatory for the anti-doping laboratories to use isotope ratio mass spectrometry (IRMS) to establish the exogenous origin before issuing an adverse analytical finding. The described IRMS methods for formestane detection are time-consuming, requiring usually two consecutive liquid chromatographic sample purifications in order to have final extracts of adequate purity before the mass spectrometric analysis. After establishing a procedure for the determination of the origin of formestane by IRMS without the need of derivatization, and integrated in the overall analytical strategy of the laboratory for pseudo-endogenous steroids, a mass spectrometric analysis by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) of formestane metabolites was carried out in order to investigate whether other biomarkers of formestane abuse could be integrated in order to avoid time-consuming and expensive IRMS confirmations for formestane. From the metabolic studies performed, the inclusion of 3β,4α-dihydroxy-5α-androstan-17-one (4α-hydroxy-epiandosterone) in the routine GC-MS procedures has demonstrated to be diagnostic in order to reduce the number of unnecessary confirmations of the endogenous origin of formestane.

Serum insulin-like factor 3 levels are reduced in former androgen users suggesting impaired Leydig cell capacity

9 Mar 2021

Serum insulin-like factor 3 levels are reduced in former androgen users suggesting impaired Leydig cell capacity / Jon Jarløv Rasmussen, Jakob Albrethsen, Mikkel Nicklas Frandsen, Niels Jørgensen, Anders Juul, Caroline Kistorp. - (The Journal of Clinical Endocrinology & Metabolism (2021) 9 March)

  • PMID: 33693710
  • DOI: 10.1210/clinem/dgab129


Abstract

Background: Illicit use of anabolic androgenic steroids (AAS) is frequently observed in men and is associated with subsequent testosterone deficiency although the long-term effect on gonadal function is still unclear. Serum insulin-like factor 3 (INSL3) has been suggested to be a superior biomarker of Leydig cell secretory capacity compared to testosterone. The objective of this study was to investigate serum INSL3 concentrations in AAS users.

Methods: This community-based cross-sectional study included men aged 18 - 50 years, involved in recreational strength training and allocated to one of three groups: never-AAS users as controls (n=44), current (n=46) or former AAS users (n=42) with an average duration since AAS cessation of 32 (23;45) months.

Results: Serum INSL3 was lower in current AAS users and former AAS users than in controls, median (IQR), 0.04 (ND - 0.07) and 0.39 (0.24 - 0.62) versus 0.59 (0.45 - 0.72) µg/L, P<0.001. Former AAS users exhibited lower serum INSL3 levels than controls in a multivariate linear regression even after adjusting for serum total testosterone and other relevant confounders, (B) (95%CI), -0.16 (-0.29;-0.04) µg/L, P=0.011. INSL3 and total testosterone were not associated in the model, P=0.821. Longer accumulated AAS duration (log2) was associated with lower serum INSL3 in former AAS users, (B) (95%CI), -0.08 (-0.14;-0.01), P=0.022. Serum INSL3, but not inhibin B or testosterone, was associated with testicular size in a multivariate linear regression, (B) (95%CI); 4.7 (0.5 ; 8.9), P=0.030.

Conclusions: Serum INSL3 is reduced years following AAS cessation in men, independently of testosterone, suggesting persistently impaired Leydig cell capacity.

Medicinal Use of Testosterone and Related Steroids Revisited

15 Feb 2021

Medicinal Use of Testosterone and Related Steroids Revisited /  Jan Tauchen, Michal Jurášek, Lukáš Huml, Silvie Rimpelová. - (Molecules 26 (2021) 4 (15 February); p. 1-20)

  • PMID: 33672087
  • PMCID: PMC7919692
  • DOI: 10.3390/molecules26041032


Abstract

Testosterone derivatives and related compounds (such as anabolic-androgenic steroids-AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.

Urinary steroid profiles in doping testing: in relation to natural variation and drug administration

23 Mar 2018

Urinary steroid profiles in doping testing : in relation to natural variation and drug administration / Jenny Mullen. - Stockholm : Karolinska Institute, 2018

  • ISBN 9789176769720


Abstract

To detect doping with endogenous steroids, such as testosterone, biomarkers in urine are measured. These biomarkers include testosterone and some metabolically related steroids. The measured steroids are combined into ratios and together they make up the steroid profile. This steroid profile is followed over time in the Steroid Module of the Athlete Biological Passport. The software used for the passport, calculates individual reference ranges based on the previous results and gives atypical findings if one or more biomarker goes outside of the reference ranges.

All passports are evaluated by experts and all atypical findings are assessed. Evaluating steroidal passports is however difficult since factors, other than doping, can affect the biomarkers of the steroid profile. In this thesis, we evaluated natural variations of the steroid profile, including variations during the menstrual cycle and pregnancy, as well as how certain drugs, such as hormonal contraceptives and testosterone, affect the steroid profile.

In a study of over 11 000 steroid profiles we have seen that intra-individual variation in the steroid profile is large (16-27% in men and 23-40% in women), but that inter-individual variation is larger (49-76% in men and 55-84% in women). Some of this variation could be explained by annual and diurnal variation, with time of day having a larger impact on makers of the steroid profile. Another confounder to consider when evaluating passports is if the urine was collected in competition or not, a factor that could explain over 6% of the total interindividual variation of some ratios. We have also seen that the menstrual cycle affect biomarkers of the steroid profile and that hormonal contraceptives can give patterns on the steroid passports similar to micro-doping with T. Pregnant women also show great differences in their steroid profiles as compared to non-pregnant women.

We have seen that doping with as low as 125 mg T enanthate and 100 mg T gel can be detected with the ABP. However, it is possible that the large natural variation as well as confounding factors, such as permitted drugs, will conceal the effect of doping.

The goal of studying confounding factors in steroid profiling is to provide the scientists evaluating the passport with sharper tools, not only to select the profiles suspicious of doping, but also to be able to reject and not spend unnecessary time and resources on profiles showing atypical results due to natural causes. The ultimate goal is to be able to proceed with a passport case, where the steroidal passport is the only evidence of doping

Budesonide use and misuse in sports: Elimination profiles of budesonide and metabolites after intranasal, high-dose inhaled and oral administrations

2 Dec 2019

Budesonide use and misuse in sports: Elimination profiles of budesonide and metabolites after intranasal, high-dose inhaled and oral administrations / Sergi Coll, Núria Monfort, Xavier Matabosch, Katerina Papakonstantinou, Clara Pérez-Mañá, Julian A. Mateus, Rosa Ventura. - (Drug Testing and Analysis 12 (2020) 5 (May); p. 629-636)

  • PMID: 31306564
  • DOI: 10.1002/dta.2678


Abstract

Budesonide (BUD) is a glucocorticoid (GC) widely used in therapeutics. In sports, the World Anti-doping Agency (WADA) controls the use of GCs, and WADA-accredited laboratories use a reporting level of 30 ng/mL for 6β-hydroxy-budesonide (6βOHBUD) to detect the systemic administration of BUD. In the present work, we examined the urinary excretion profile of 6βOHBUD, BUD, and 16α-hydroxy-prednisolone (16αOHPRED) after intranasal (INT), inhaled (INH) (at high doses) and oral administrations in male and female volunteers. BUD was administered to healthy volunteers using INT route (256 μg/day for three days, n = 4 males and 4 females), INH route (800 μg/day for three days, n = 4 males and 4 females, and 1600 μg/day for three days, n = 4 males) or oral route (3 mg, n = 8 females). Urine samples were collected before and after administration at different time periods, and were analyzed by liquid chromatography-tandem mass spectrometry. 6βOHBUD and BUD concentrations were very low after INT treatment (0.0-7.1 and 0.0-8.1 ng/mL, respectively), and higher after INH treatments (0.0-35.4 and 0.0-48.3 ng/mL, respectively). For 16αOHPRED, elevated concentrations were detected after INT and INH treatments (2.6-66.4 and 3.4-426.5 ng/mL, respectively). Concentrations obtained following oral administration were higher than after therapeutic administrations (2.8-80.6, 1.5-36.1, and 10.4-532.2 ng/mL for 6βOHBUD, BUD, and 16αOHPRED, respectively). After all administrations, concentrations were higher in males than in females. Results demonstrated that 6βOHBUD is the best discriminatory marker and a reporting level of 40 ng/mL was found to be the best criterion to distinguish allowed from forbidden administrations of BUD.

The Probenecid-story - A success in the fight against doping through out-of-competition testing

2 Dec 2019

The Probenecid-story - A success in the fight against doping through out-of-competition testing / Peter Hemmersbach. - (Drug Testing and Analysis 12 (2020) 5 (May); p. 589-594)

  • PMID: 31797550
  • DOI: 10.1002/dta.2727


Abstract

The effectiveness of doping control in sport has been improved continuously during the past 50 years. One of the major steps forward was the introduction of unannounced and targeted out-of-competition testing in order to control the misuse of anabolic-androgenic steroids (AAS), mainly during the end of the 1980s. It also led to the misuse of masking agents in case a surprise control was performed. Athletes tried to be "prepared", when the doping control officer showed up. The disclosure of the masking agent probenecid in 1987 is a perfect example of a memorable finding, of a suspected and purported case of performance manipulation. Probenecid and its metabolites were identified in five urine samples collected from Norwegian athletes in an out-of-competition test, while they were staying and training in the USA. Probenecid is a drug that reduces the urinary excretion of AAS from the body. It was the first time that it had showed up in a doping control sample. The athletes were sanctioned for hampering the analysis of their urine sample, although probenecid was not yet specified on the Prohibited List. Its detection was the result of a successful collaboration of laboratories and investigative diligence and enthusiasm following up suspicious observations in the actual samples. Immediately afterwards probenecid was added to the Prohibited List for 1988 as well as including the manipulation of doping control samples.

If you play with fire, you may get burned

30 Oct 2019

If you play with fire, you may get burned / Jordi Segura, Rosa Ventura, José Antonio Pascual, Rafael de la Torre. - (Drug Testing and Analysis 12 (2020) 5 (May); p. 582-587)

  • PMID: 31667995
  • DOI: 10.1002/dta.2718


Abstract

This article reports an interesting doping case in the late 1990s involving the physical tampering of a urine sample containing a prohibited substance, by adding an alcoholic beverage. The regulations and knowledge available at that time allowed consideration of the case as a sanctioned manipulation and the prohibited substance as an additional element that explained the reasons for it. The development of the case involved some aspects that appeared for the first time in doping control. These include, among others, the participation of an enologist as part of the B sample confirmation, forensic inspection of the sample container, the early development of gas chromatography/combustion/isotopic ratio mass spectrometry (GC/C/IRMS), and the first public hearing by the Court of Arbitration for Sport (CAS), which allowed a wide following of the developments of the case. The information was especially interesting for the general public as the athlete had had, at that time, great Olympic success.

Urine manipulation with liquid soap: A case report

15 Feb 2020

Urine manipulation with liquid soap : A case report / Günter Gmeiner, Thomas Geisendorfer. - (Drug Testing and Analysis 12 (2020) 5 (May) ; p. 575-578)

  • PMID: 32061174
  • DOI: 10.1002/dta.2780


Abstract

Among the various strategies to enhance performance by the use of doping substances or methods, sample manipulation to cheat common detection strategies is prohibited by the World Antidoping Agency. Two cases of urine sample adulteration with surfactants are presented in this article, as well as an easy strategy for the detection of this sort of sample manipulation.

Effect of acute and chronic xenon inhalation on erythropoietin, hematological parameters, and athletic performance

26 Nov 2019

Effect of acute and chronic xenon inhalation on erythropoietin, hematological parameters, and athletic performance / Katrin A. Dias, Justin S. Lawley, Hannes Gatterer, Erin J. Howden, Satyam Sarma, William K. Cornwell 3rd, Christopher M. Hearon Jr, Mitchel Samels, Braden Everding, Allan Shuo-Wen Liang, Max Hendrix, Thomas Piper, Mario Thevis, Richard K. Bruick, Benjamin D. Levine. - (Journal of Applied Physiology 127 (2019) 6 (December); p. 1503-1510)

  • PMID: 31414957
  • DOI: 10.1152/japplphysiol.00289.2019


Abstract

This study aimed to assess the efficacy of acute subanesthetic dosages of xenon inhalation to cause erythropoiesis and determine the effect of chronic xenon dosing on hematological parameters and athletic performance. To assess the acute effects, seven subjects breathed three subanesthetic concentrations of xenon: 30% fraction of inspired xenon (FiXe) for 20 min, 50% FiXe for 5 min, and 70% FiXe for 2 min. Erythropoietin (EPO) was measured at baseline, during, and after xenon inhalation. To determine the chronic effects, eight subjects breathed 70% FiXe for 2 min on 7 consecutive days, and EPO, total blood, and plasma volume were measured. Phase II involved assessment of 12 subjects for EPO, total blood volume, maximal oxygen uptake, and 3-km time before and after random assignment to 4 wk of xenon or sham gas inhalation. FiXe 50% and 70% stimulated an increase in EPO at 6 h [+2.3 mIU/mL; 95% confidence interval (CI) 0.1-4.5; P = 0.038] and at 192 h postinhalation (+2.9 mIU/mL; 95% CI 0.6-5.1; P = 0.017), respectively. Seven consecutive days of dosing significantly elevated plasma volume (+491 mL; 95% CI 194-789; P = 0.002). Phase II showed no significant effect on EPO, hemoglobin mass, plasma volume, maximal oxygen uptake, or 3-km time. Acute exposure to subanesthetic doses of xenon caused a consistent increase in EPO, and 7 consecutive days of xenon inhalation significantly expanded plasma volume. However, this physiological response appeared to be transient, and 4 wk of xenon inhalation did not stimulate increases in plasma volume or erythropoiesis, leaving cardiorespiratory fitness and athletic performance unchanged.

NEW & NOTEWORTHY This is the first study to examine each element of the cascade by which xenon inhalation is purported to take effect, starting with measurement of the hypoxia-inducible factor effector, erythropoietin, to hemoglobin mass and blood volume and athletic performance. We found that acute exposure to xenon increased serum erythropoietin concentration, although major markers of erythropoiesis remained unchanged. While daily dosing significantly expanded plasma volume, no physiological or performance benefits were apparent following 4 wk of dosing.

Tainted toothpaste - Analytical investigation into an unusual adverse finding

7 Jan 2020

Tainted toothpaste - Analytical investigation into an unusual adverse finding / Wilhelm Schänzer, Hans Geyer, Mario Thevis. - (Drug Testing and Analysis 12 (2020) 5 (May) ; p. 570-572)

  • PMID: 31910320
  • DOI: 10.1002/dta.2761

 

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