Elsevier

Toxicology Letters

Volume 165, Issue 2, 20 August 2006, Pages 149-155
Toxicology Letters

17β-Hydroxy-5alpha-androst-1-en-3-one (1-testosterone) is a potent androgen with anabolic properties

https://doi.org/10.1016/j.toxlet.2006.03.001Get rights and content

Abstract

Since the begining of the year 2005, the use of steroid precursors (prohormones) is illegal in the United States; nevertheless, there is still an enormous abuse of such substances. One of the most frequently misused steroids, often declared to be a prohormone, is 1-testosterone (17β-hydroxy-5alpha-androst-1-en-3-one, 1-Testo). In this study, we have characterised molecular mechanisms of its action, determined its tissue specific androgenic and anabolic potency and investigated potential adverse effects. 1-Testo binds highly selective to the androgen receptor (AR) and has a high potency to stimulate AR dependent transactivation. In vivo an equimolar dose of 1-Testo has the same potency to stimulate the growth of the prostate, the seminal vesicles and the androgen sensitive levator ani muscle as the reference compound testosterone propionate (TP). Administration of 1-Testo, in contrast to TP, results in a significant increase of liver weight. Our results demonstrate that 1-Testo, even without being metabolised, is a very potent androgen. It binds selectively to the AR and transactivates AR dependent reporter genes. In vivo it has a high androgenic and anabolic potency and increases liver weight. In summary 1-Testo can be characterised as a typical anabolic steroid. It has to be assumed that consumption of this substance is associated with adverse side effects typical for this class of compounds. Therefore, a strict control of its ban is essential.

Introduction

For more than 20 years so called prohormones have been legally sold as dietary supplements because they consist of compounds that occur naturally in the human body (Ziegenfuss et al., 2002). As per definition, a prohormone is a chemical compound that is a precursor to an actual hormone which is taken in order to boost the body's available hormone supply. These precursors convert to full, active hormones via an enzymatic process that occurs during metabolism. Especially among bodybuilders the use of prohormones has become popular, since the effects can be similar to those of synthetic steroids, including an increase of muscular strength and mass (Delbeke et al., 2002). However, their use remains quite controversial and side effects, especially in woman, are not uncommon (King et al., 1999, Kicman et al., 2003). Since January 2005 the use of steroid precursors is illegal in the United States, nevertheless there is still an enormous misuse of such substances, especially in the bodybuilder scene.

One of the most frequently abused steroids, often declared to be a prohormone, is 1-testosterone (17β-hydroxy-5alpha-androst-1-en-3-one, 1-Testo, Fig. 1) a substance that is chemically closely related to testosterone (Counsell et al., 1961). 1-Testo is listed on the International Standard Prohibited List, and its banned by the declaration of the U.S. Food and Drug Administration (FDA) from January 2005. However, screening the Internet reveals that the use of this substance is still very popular in the bodybuilder scene. On hundreds of pages plenty of information about the potential benefit of this substance, dosing and pseudoscientific mechanistically explanations how it should work, is available. Surprisingly, looking into the literature reveals that scientific information about this substance and its side effects is very limited. Therefore, it was the aim of our study to characterised molecular mechanisms of 1-Testo action and determined its tissue specific androgenic and anabolic potency. We want to clarify if it is a prohormone or an anabolic steroid and identify potential health risks with a misuse of this substance. In order to characterise molecular mechanisms of 1-Testo action in vitro the binding affinity of 1-Testo to different steroid hormone receptors and its ability to transactivate AR dependent reporter gene expression was determined. In order to investigate the tissue specific anabolic and androgenic potency of this substance we determined its ability to stimulate growth of the prostate, the seminal vesicles and the androgen sensitive levator ani (lev. ani) muscle in the castrated rats. In order to identify potential adverse side effects, pathologic changes of liver, prostate and heart weight and liver tyrosine kinase (TAT) expression were investigated.

Section snippets

Substances

1-Testosterone and testosterone proprionate were provided by the Institute of Biochemistry, German Sport University Cologne. Purity of the substances was verified by mass spectroscopy. DHT was obtained by Sigma–Aldrich (Deisenhofen, Germany). R1881 a synthetic androgen with high metabolic stability, aldosterone, dexametasone and progesterone were provided by the Schering AG (Berlin, Germany). For the in vivo investigations testosterone propionate (TP) was chosen as reference substance, because

Receptor binding

Binding of a steroid hormone to its receptor is an important step initiating its action. An important issue, developing new steroids, is the specificity and preference of binding to a receptor. Unspecific binding can result in undesirable side effects and is therefore an exclusion criterion for a pharmacological use. Therefore, we have determined the specific binding affinity of 1-Testo to the AR, PR, MR and GR in correlation to a respective high specific ligand (R1881, progesterone,

Discussion

The aims of our study were to characterise molecular mechanisms of 1-Testo action, determine its tissue specific androgenic and anabolic potency and screen for indicators of adverse effects associated with a consumption of this substance. Our in vitro data clearly demonstrate that 1-Testo has a selective binding affinity to the AR (Fig. 2) and is able to transactivate AR-driven reporter genes in a yeast transactivation assay with a comparable potency like the reference compound DHT (Fig. 3).

Acknowledgments

We thank Perter Muhn, Schering AG Berlin for his support, in conducting the receptor binding assay. We also thank J. Seibel and T. Hertrampf for their assistance performing the animal experiments. This study was funded by the Federal Office of Sports, Magglingen, Switzerland.

References (16)

  • F.T. Delbeke et al.

    Prohormones and sport

    J. Steroid Biochem. Mol. Biol.

    (2002)
  • T. Sugawara et al.

    Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes

    J. Biol. Chem.

    (2003)
  • M.R. Waterman et al.

    Sterol 14 alpha-demethylase, an abundant and essential mixed-function oxidase

    Biochem. Biophys. Res. Commun.

    (2005)
  • L.D. Boada et al.

    Evaluation of acute and chronic hepatotoxic effects exerted by anabolic-androgenic steroid stanozolol in adult male rats

    Arch. Toxicol.

    (1999)
  • R. Counsell et al.

    Anabolic agents derivates of 5a-androst-1-ene

    J. Org. Chem.

    (1961)
  • Friedel, A., Geyer, H., Kamber, M., Laudenbach-Leschowsky, U., Schanzer, W., Thevis, M., Vollmer, G., Zierau, O., Diel,...
  • M. Johansson et al.

    Xenobiotics and the glucocorticoid receptor: additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cells

    Basic Clin. Pharmacol. Toxicol.

    (2005)
  • A.T. Kicman et al.

    Effect of androstenedione ingestion on plasma testosterone in young women: a dietary supplement with potential health risks

    Clin. Chem.

    (2003)
There are more references available in the full text version of this article.

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