Seized designer supplement named "1-Androsterone": identification as 3β-hydroxy-5α-androst-1-en-17-one and its urinary elimination / Maria K. Parr, Georg Opfermann, Hans Geyer, Folker Westphal, Frank D. Sönnichsen, Josef Zapp, Dorota Kwiatkowska, Wilhelm Schänzer

• Steroids 76 (2011) 6 (May), p. 540-547
• PMID: 21310167
• DOI: 10.1016/j.steroids.2011.02.001

Abstract

New analogues of androgens that had never been available as approved drugs are marketed as "dietary supplement" recently. They are mainly advertised to promote muscle mass and are considered by the governmental authorities in various countries, as well as by the World Anti-doping Agency for sport, as being pharmacologically and/or chemically related to anabolic steroids. In the present study, we report the detection of a steroid in a product seized by the State Bureau of Criminal Investigation Schleswig-Holstein, Germany. The product "1-Androsterone" of the brand name "Advanced Muscle Science" was labeled to contain 100mg of "1-Androstene-3b-ol,17-one" per capsule. The product was analyzed underivatized and as bis-TMS derivative by GC-MS. The steroid was identified by comparison with chemically synthesized 3β-hydroxy-5α-androst-1-en-17-one, prepared by reduction of 5α-androst-1-ene-3,17-dione with LS-Selectride (Lithium tris-isoamylborohydride), and by nuclear magnetic resonance. Semi-quantitation revealed an amount of 3β-hydroxy-5α-androst-1-en-17-one in the capsules as labeled. Following oral administration to a male volunteer, the main urinary metabolites were monitored. 1-Testosterone (17β-hydroxy-5α-androst-1-en-3-one), 1-androstenedione (5α-androst-1-ene-3,17-dione), 3α-hydroxy-5α-androst-1-en-17-one, 5α-androst-1-ene-3α,17β-diol, and 5α-androst-1-ene-3β,17β-diol were detected besides the parent compound and two more metabolites (up to now not finally identified but most likely C-18 and C-19 hydroxylated 5α-androst-1-ene-3,17-diones). Additionally, common steroids of the urinary steroid profile were altered after the administration of "1-Androsterone". Especially the ratios of androsterone/etiocholanolone and 5α-/5β-androstane-3α,17β-diol and the concentration of 5α-dihydrotestosterone were influenced. 3α-Hydroxy-5α-androst-1-en-17-one appears to be suitable for the long-term detection of the steroid (ab-)use, as this characteristic metabolite was detectable in screening up to nine days after a single administration of one capsule.

Selective Androgen Receptor Modulators (SARMs) as Pharmacological Treatment for Muscle Wasting in Ongoing Clinical Trials / Guilherme Wesley Peixoto Da Fonseca, Elke Dworatzek, Nicole Ebner, Stephan Von Haehling. - (Expert Opinion on Investigational Drugs (2020) 18 June; p. 1-11)

• PMID: 32476495
• DOI: 10.1080/13543784.2020.1777275

Abstract

Introduction: Skeletal muscle wasting is a frequent clinical problem encountered in patients with chronic diseases. Increased levels of inflammatory markers play a role in the imbalance between muscle protein synthesis and degradation. Although testosterone has long been proposed as a treatment for patients with muscle wasting, undesirable side effects have raised concerns about prostatic hypertrophy in men as well as virilization in women. Selective androgen receptor modulators (SARMs) have demonstrated similar results like testosterone at improving lean body mass (LBM) with less side effects on androgen-dependent tissue.

Areas covered: This review outlines the ongoing clinical development in the field of SARMs and their effectiveness in improving body composition and physical function. The included articles were collected at pubmed.gov and analyzed integrally.

Expert opinion: There is an unmet clinical need for safe and effective anabolic compounds such as SARMs. Despite the effect on LBM shown by SARMs in phase II clinical trials, results on improved physical function and muscle strength are still lacking and long-term outcomes have to be assessed in these patients. Moreover, there is a need to determine the effect of resistance exercise training and protein intake associated with SARMs in the treatment of patients with muscle wasting.

Selective androgen receptor modulators for the treatment of late onset male hypogonadism / Christopher C. Coss, Amanda Jones, Michael L. Hancock, Mitchell S. Steiner, James T. Dalton. - (Asian Journal of Andrology 16 (2014) 2 (March-April); p. 256-261)

• PMID: 24407183
• PMCID: PMC3955335
• DOI: 10.4103/1008-682X.122339

Abstract

Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs) have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defined clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.

Selective androgen receptor modulators in preclinical and clinical development / Ramesh Narayanan, Michael L. Mohler, Casey E. Bohl, Duane D. Miller, James T. Dalton. - (Nuclear Receptor Signaling (2008) 26 November; p. 1-26)

• PMID: 19079612
• PMCID: PMC2602589
• DOI: 10.1621/nrs.06010

Abstract

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

Selective Androgen Receptor Modulators: An Emerging Liver Toxin / Haseeb Mohideen, Hafsa Hussain, Dushyant Singh Dahiya, Hisham Wehbe

• Journal of Clinical and Translational Hepatology 11 (2023) 1 (28 February), p. 188-196
• PMID: 36479151
• PMCID: PMC9647117
• DOI: 10.14218/JCTH.2022.00207

Abstract

Selective androgen receptor modulators (SARMs) are a class of nonsteroidal drugs that are favored over anabolic androgenic steroids (AASs) for their tissue-selectivity and improved side-effect profile. These drugs have been evaluated for treatment of various diseases including muscle-wasting disorders, osteoporosis, and breast cancer. Despite lacking approval for therapeutic use, SARMs are widely used recreationally as performance enhancing drugs by bodybuilders and athletes. In recent years, cases of drug-induced liver injury (DILI) secondary to SARMs have begun to emerge, but little is known regarding their hepatotoxicity. In this review, we provide current knowledge regarding DILI from SARMs. A literature search was conducted regarding SARMs and liver injury to evaluate relevant cases and information. SARMs have been associated with a cholestatic syndrome congruent with that of DILI from AASs, and it consists of a bland cholestasis in which there is minimal bile duct injury, inflammation, or necrosis. Patients present with an insidious onset of jaundice with marked hyperbilirubinemia and mild hepatic enzyme elevations. No clear treatment exists, although patients typically show improvement with cessation of the offending SARM. Given the novelty of these drugs, further study is necessary to understand diagnosis, management, and complications of SARM-related DILI.

Alaranta A, Alaranta H, Holmila J, Palmu P, Pietilä K, Helenius I.
Int J Sports Med. 2006 Oct;27(10):842-6. Epub 2006 Feb 1.
Division of Social Pharmacy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. anti.alaranta@helsinki.fi

Although athletes' beliefs and values are known to influence whether or not an athlete will use banned drugs, little is known about the athletes' beliefs and attitudes in different sports. The
aim of this study was to clarify the beliefs and attitudes of elite athletes towards banned substances and methods in sports.

A total of 446 athletes (response rate 90.3 %; 446/494) financially supported by the National Finnish Olympic Committee completed a structured questionnaire during their national team camps in 2002. More than 90 % of the athletes reported to believe that banned substances and methods have performance enhancing effects,
and 30 % reported that they personally know an athlete who uses banned substances. Of the male athletes 35 %, and 23 % of females reported they personally know an athlete using banned substances. A total of 15 % of the athletes reported that they had been offered banned substances: 21 % of the speed and power athletes, 14 % of the team sport athletes and of the athletes in motor skills demanding events, and 10 % of the endurance athletes. Stimulants were the most often offered substance group (to 7 % of all the athletes) followed by anabolic steroids (4 %).

Subjects who regarded doping as a minor health risk seemed to be more often associated with doping users than those regarding doping as a significant health risk. Athletes in different sports have a different approach to doping. Risk of doping appears to be highest in speed and power sports and lowest in motor skills demanding sports. Males are at higher risk than females. Controlling doping only by tests is not sufficient. A profound change in the attitudes is needed, which should be monitored repeatedly.

PMID: 16586338 [PubMed - indexed for MEDLINE]

Selling androgenic anabolic steroids by the pound : identification and analysis of popular websites on the Internet
/ F.G. Cordaro, S. Lombardo, M. Cosentino. - (Scandinavian Journal of Medicine & Science in Sports 21 (2011) 6 (December); p. 247-259)

• PMID: 21210860
• DOI: 10.1111/j.1600-0838.2010.01263.x

Abstract

Internet websites offering androgenic anabolic steroids (AAS) were identified and available products were examined. Keywords for the website search were: "anabolic steroids," "anabolic steroids buy," "anabolic steroid purchase." The first 10 websites offering AAS in the first 10 pages of results were considered. At least two AAS-containing products per website were selected. Thirty AAS-selling websites were identified, mainly located in the United States (46.7%) and Europe (30%). Most websites sold other anabolic/ergogenic products (clenbuterol, 76.7%; GH/IGF, 60.0%; thyroid hormones, 46.7%; erythropoietin, 30.0%; insulin, 20.0%) or products for AAS-related adverse effects (mainly: estrogen antagonists, 63.3%; products for erectile dysfunction, 56.7%; 5α-reductase inhibitors, 33.3%; anti-acne products, 33.3%). AAS were sold as medicines (69.6%) or as dietary supplements (30.4%). AAS in medicines were mainly: nandronole (20.4%), methandrostenolone (18.4%), and testosterone (12.2%). Dietary supplements contained mainly DHEA and included several fake compounds. Manufacturers were declared for 97.9% of medicines and 66.7% of dietary supplements; however, several manufacturers were not found on the Internet. Described benefits were usually few adverse effects and no estrogenicity. Toxicity was seldom reported and presented as mild. Recommended doses were two-fourfold higher than current medical recommendations. In conclusion, misleading information and deceiving practices were common findings on AAS-selling websites, indicating their deleterious potential for public health.

Semi-quantitative determination of designer steroids by high-performance liquid chromatography with ultraviolet detection in the absence of reference material / Sarah E. Voelker, Lisa M. Lorenz, Jonathan J. Litzaus

• Drug Testing and Analysis 11 (2019) 3 (March), p. 428-434
• PMID: 30238635
• DOI: 10.1002/dta.2511

Abstract

New designer steroids are continually being encountered in dietary supplements that claim to increase muscle mass, but quantitative analysis of such ingredients is challenging due to the availability, quality, or cost of commercial reference materials. Although standard reference material typically becomes available for these emerging compounds, laboratories often face the challenge of finding properly certified materials from accredited suppliers, due to traceability requirements. Several of these designer steroids have been isolated and identified using multiple structural elucidation tools. Structural characteristics of these compounds of interest were evaluated and molar absorptivity data was collected and compared to several readily available steroid standards using ultraviolet/visible spectroscopy. This approach was used to find suitable compounds for use as surrogate reference materials in the semi-quantitative determination of two designer steroids, 1-dehydroepiandrosterone (1-androsterone) and 6β-chloro-4-androsten-17β-ol-3-one (6β-chlorotestosterone). Laboratory-fortified matrix samples and dietary supplement samples were analyzed using this method for the estimation of 1-androsterone and 6β-chlorotestosterone by HPLC-UV. Assay values obtained for the estimation of 1-androsterone in a dietary supplement sample using a prasterone or dehydroepiandrosterone (DHEA) standard curve were 100% of those obtained using a 1-androsterone reference standard, once it became commercially available. Estimations for 6β-chlorotestosterone in laboratory-fortified matrix samples using a testosterone standard curve were 92%-93% of those obtained using isolated 6β-chlorotestosterone as "reference material."

Sensitive detection of testosterone and testosterone prohormone administrations based on urinary concentrations and carbon isotope ratios of androsterone and etiocholanolone / Thomas Piper, Nadine Haenelt, Gregor Fusshöller, Hans Geyer, Mario Thevis

• Drug Testing and Analysis 13 (2021) 11-12 (November-December), p. 1835-1851
• Special Issue: The 39th Manfred Donike workshop on doping analysis
• PMID: 34648228
• DOI: 10.1002/dta.3168

Abstract

The testing strategy for the detection of testosterone (T) or T-prohormones is based on the longitudinal evaluation of urinary steroid concentrations accompanied by subsequent isotope ratio mass spectrometry (IRMS)-based confirmation of samples showing atypical concentrations or concentration ratios. In recent years, the IRMS methodology focussed more and more on T itself and on the metabolites of T, 5α- and 5β-androstanediol. These target analytes showed the best sensitivity and retrospectivity, but their use has occasionally been challenging due to their comparably low urinary concentrations. Conversely, the carbon isotope ratios (CIR) of the main urinary metabolites of T, androsterone (A) and etiocholanolone (EITO), can readily be measured even from low urine volumes; those however, commonly offer a lower sensitivity and shorter retrospectivity in uncovering T misuse. Within this study, the CIRs of A and ETIO were combined with their urinary concentrations, resulting in a single parameter referred to as 'difference from weighted mean' (DWM). Both glucuronidated and sulfated steroids were investigated, encompassing a reference population (n = 110), longitudinal studies on three individuals, influence of ethanol in two individuals, and re-analysis of several administration studies including T, dihydrotestosterone, androstenedione, epiandrosterone, dehydroepiandrosterone, and T-gel. Especially DWM calculated for the sulfoconjugated steroids significantly prolonged the detection time of steroid hormone administrations when individual reference ranges were applied. Administration studies employing T encompassing CIR common for Europe (-23.8‰ and -24.4‰) were investigated and, even though for a significantly shorter time period and less pronounced, DWM could demonstrate the exogenous source of T metabolites.

Keywords: doping; endogenous carbon isotope ratios; isotope ratio mass spectrometry; steroid concentrations; testosterone.

Sensitivity and specificity of detection methods for erythropoietin doping in cyclists / Jules A.A.C. Heuberger, Peter van Eenoo, Joris I. Rotmans, Pim Gal, Frederik E. Stuurman, Titiaan E. Post, Johannes M.A. Daniels, Herman Ram, Olivier de Hon, Jacobus Burggraaf, Adam F. Cohen. - (Drug Testing and Analysis 11 (2019) 9 (September); p. 1290-1301).
- DOI: 10.1002/dta.2665.
- PMCID: PMC6790592.
- PMID: 31232530

Abstract

Recombinant human erythropoietin (rHuEPO) is used as doping a substance. Anti‐doping efforts include urine and blood testing and monitoring the athlete biological passport (ABP). As data on the performance of these methods are incomplete, this study aimed to evaluate the performance of two common urine assays and the ABP. In a randomized, double‐blinded, placebo‐controlled trial, 48 trained cyclists received a mean dose of 6000 IU rHuEPO (epoetin β) or placebo by weekly injection for eight weeks. Seven timed urine and blood samples were collected per subject. Urine samples were analyzed by sarcosyl‐PAGE and isoelectric focusing methods in the accredited DoCoLab in Ghent. A selection of samples, including any with false presumptive findings, underwent a second sarcosyl‐PAGE confirmation analysis. Hematological parameters were used to construct a module similar to the ABP and analyzed by two evaluators from an Athlete Passport Management Unit. Sensitivity of the sarcosyl‐PAGE and isoelectric focusing assays for the detection of erythropoietin abuse were 63.8% and 58.6%, respectively, with a false presumptive finding rate of 4.3% and 6%. None of the false presumptive findings tested positive in the confirmation analysis. Sensitivity was highest between 2 and 6 days after dosing, and dropped rapidly outside this window. Sensitivity of the ABP was 91.3%. Specificity of the urine assays was high; however, the detection window of rHuEPO was narrow, leading to questionable sensitivity. The ABP, integrating longitudinal data, is more sensitive, but there are still subjects that evade detection. Combining these methods might improve performance, but will not resolve all observed shortcomings.