Long term perturbation of endocrine parameters and cholesterol metabolism after discontinued abuse of anabolic androgenic steroids

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Abstract

Aims

To study the long-term impact of anabolic androgenic steroid (AAS) abuse on the cholesterol profile, and the potential to suppress endocrine activity in men working out at gym facilities. To study the relation between urinary biomarkers for testosterone and nandrolone abuse and the UGT2B17 genotype and time profile.

Experimental design

Subjects (N = 56) were recruited through Anti-Doping Hot-Line. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), plasma levels of low density lipoprotein (LDL), high density lipoprotein (HDL) and urinary steroid profile were regularly measured for a period of up to one year after cessation of intramuscular AAS abuse.

Results and discussion

A sustained suppression of LH, and FSH was observed for several months. The nandrolone urinary biomarker 19-NA was detectable several months after the last nandrolone intake and was correlated to the levels of LH and FSH. Testosterone abuse on the other hand was detectable only for a few weeks, and some of the testosterone abusers did not test positive due to a genetic deletion polymorphism of the UGT2B17. Significantly increased levels of HDL and decreased levels of LDL were observed for 6-months after cessation of AAS abuse.

Conclusion

Some individuals had a sustained suppression of LH and FSH for a period of 1 year whereas the cholesterol profile was normalized within 6 month. The long term consequences of these findings remain to be established.

Highlights

► 1 year follow-up study in androgenic anabolic steroids abusers. ► Compromised hypothalamic–pituitary–adrenal axis in all volunteers. ► Main urinary nandrolone metabolite is detected up to 12 months after abuse cessation. ► HDL increased and LDL decreased observed until 6 month after abuse cessation. ► Long term consequences might be expected.

Introduction

Anabolic androgenic steroids (AAS) including testosterone, other endogenous androgenic hormones and synthetic compounds structurally related to these compounds are the most frequently detected doping agents in sports. They accounted for about 59% of adverse analytical findings in 2008 in accredited doping laboratories around the world (WADA 2008 Adverse Analytical Findings and Atypical Findings reported by accredited laboratories, Montreal, 2009 (http://www.wada-ama.org)). However, the abuse of these agents for cosmetic purposes among non-competitive recreational body-builders and non-athletes is a major societal concern. In fact, AAS abuse has become a growing public health problem [5], [11], [24].

The current test to detect abuse of testosterone is based on determination of the urinary testosterone glucuronide/epitestosterone glucuronide ratio (T/E). When the T/E is above 4.0, doping in sports is suspected (WADA Technical document TD2004EAAS, reporting and evaluation guidance for testosterone, epitestosterone, T/E ratio and other endogenous steroids, Montreal, 2004 (http://www.wada-ama.org)) and such samples must be subject to further analyses for determination of the origin of testosterone. The major enzyme responsible for testosterone glucuronidation is UGT2B17 [9]. We have shown that the T/E ratio after a single dose of testosterone is highly dependent on the UGT2B17 deletion polymorphism [23] and that there are large inter ethnic differences in the distribution of this trait [9].

In order to detect nandrolone intake, the urinary nandrolone metabolites 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE) are used as markers. These metabolites can be endogenously produced at low levels in some cases [15]. When the urine concentration exceeds the threshold of 2 ng/ml, additional investigations are required to avoid a competitive athlete being wrongly subjected to disciplinary proceedings (WADA Technical document TD2010NA, Harmonization of analysis and reporting of 19-norsteroids related to nandrolone, Montreal, 2010 (http://www.wada-ama.org)).

The side effects related to the abuse of these steroids and other AAS are based on empirical observations, so the potential of serious and persisting health risks associated with the abuse of these steroids is still largely unexplored. Reported endocrine adverse reactions to AAS-abuse include acne, gynecomastia, testicular atrophy and decreased secretion of the pituitary hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [3], [17], [18], [20]. Moreover, cardiovascular side effects such as disturbances in the cholesterol profile, i.e. increased low density lipoproteins (LDL) and decreased high density lipoprotein (HDL) have been reported (reviewed by [1], [28]). However, the time course and possible reversibility of these alterations following abuse of AAS is not known. In the present study we addressed these issues in a 12 months follow-up study in AAS abusers that were recruited to the study at cessation of their abuse. We also studied the impact of the UGT2B17 deletion polymorphism on the T/E ratio and the urinary excretion of 19-NA in AAS abusers.

Section snippets

Subjects

Fifty-six men between 18 and 57 years old were recruited to the project between 1998 and 2002. A few were referred from colleagues working in emergency medicine, but most were asked to participate when contacting the Anti-Doping Hot-Line, a free telephone counseling service for individuals affected by or people concerned with abuse of anabolic androgenic steroids [5]. A genuine desire to give up using AAS was a prerequisite to be included. Participation was commenced after informed consent, and

Characteristics of the AAS-abusers

Three individuals were positive for narcotics and were subsequently excluded from the study. Of the 53 individuals that showed up for the first visit, 35 tested positive for nandrolone, testosterone and/or stanozolol (see Fig. 1). Among the volunteers tested positive to 19-NA, two individuals did not claim to have abused nandrolone. This might be due to nandrolone contamination of steroid preparations or memory default in a multiple steroid abuse pattern. Thus, one of these individual was

Discussion

Interestingly, the urinary nandrolone metabolite 19-NA remained detectable for a long period of time. For some of the individuals, the 19-NA was detected up to one year after their last injection of nandrolone decanoate. This finding is in agreement with a previous study showing that exogenous 19-NA could be detected for 6 months in some individuals after a single dose of 150 mg nandrolone decanoate [4]. In a case report, 19-NA and 19-NE levels in urine were detectable for 8 months [12]. It is

Acknowledgements

Supported by grants from Stockholm County Council and the World Anti-Doping Agency and Swedish National Centre for Research in Sports. This work was also supported in part by a grant from the Swiss National Science Foundation (project no.: 129016). C. Möller, J. Börjesson, A.C. Eklöf, A.M. Thurelius are gratefully acknowledged for valuable contributions to the clinical handling of the participants.

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