Psychoneuroendocrinology
Date: April 2003
Pages: 317-331

Published by: Elsevier

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Research article
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Neuroendocrine and behavioral effects of high-dose anabolic steroid administration in male normal volunteers

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Abstract

Objective: Despite widespread abuse of anabolic-androgenic steroids (AAS), the endocrine effects of supraphysiologic doses of these compounds remain unclear. We administered the AAS methyltestosterone (MT) to 20 normal volunteers in an in-patient setting, examined its effects on levels of pituitary-gonadal, -thyroid, and -adrenal hormones, and examined potential relationships between endocrine changes and MT-induced psychological symptoms. Method: Subjects received MT (three days of 40 mg/day, then three days of 240 mg/day) or placebo in a fixed sequence with neither subjects nor raters aware of order. Samples were obtained at the ends of the baseline, high-dose MT and withdrawal phases. Potential relationships between hormonal changes and visual analog scale measured mood changes were examined. Results: Significant decreases in plasma levels of gonadotropins, gonadal steroids, sex hormone binding globulin, free T3 and T4, and thyroid binding globulin (Bonferroni t, p<0.01 for each) were seen during high-dose MT; free thyroxine and TSH increased during high-dose MT, with TSH increases reaching significance during withdrawal. No significant changes in pituitary-adrenal hormones were observed. Changes in free thyroxine significantly correlated with changes in aggressiveness (anger, violent feelings, irritability) (r=0.5,p=0.02) and changes in total testosterone correlated significantly with changes in cognitive cluster symptoms (forgetfulness, distractibility) (r=0.52,p=0.02). Hormonal changes did not correlate with plasma MT levels. Conclusions: Acute high-dose MT administration acutely suppresses the reproductive axis and significantly impacts thyroid axis balance without a consistent effect on pituitary-adrenal hormones. Mood and behavioral effects observed during AAS use may in part reflect secondary hormonal changes.

Keywords

Methyltestosterone
;
Anabolic steroids
;
Aggression
;
Thyroid
;
Mood

Introduction

Anabolic-androgenic steroid (AAS) abuse can be accompanied by a range of mood and behavioral disturbances, including irritability and aggression (Bahrke et al., 1990) and hypomania (Pope et al., 2000) and may represent a significant unrecognized public health problem (Pope et al., 2000). Despite an extensive literature on the psychotoxic effects of AAS, the mechanisms underlying these effects remain unknown. Methodologic limitations of previous studies examining hormonal changes during AAS use may have restricted their interpretation and generalization. These limitations include the common employment of outpatient study settings (with resultant potential confounding by poor compliance, exercise, or co-morbid substance use), administration of comparatively low doses of AAS, subject choice (e.g. seriously medically ill subjects), and lack of placebo controls. The widespread abuse of AAS (Yesalis et al., 1993) plus their recent emergence as a potential therapy in such conditions as HIV-related hypogonadism (Rabkin et al., 2000) dictate that we better understand the physiologic consequences of supraphysiologic doses of AAS. Such understanding would also potentially contribute to our knowledge of the biological mechanisms underlying behavioral disturbances accompanying AAS abuse.
While the endocrine effects of androgens are well described, the hormonal effects of the massive doses of anabolic steroids taken by abusers are not clearly defined, and the need for further investigations employing more sophisticated batteries of neuroendocrine measures has recently been emphasized (Pope et al., 2000). AAS use impacts upon several hormonal systems, most notably the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes (Clerico et al., 1981, Alén et al., 1985, Alén et al., 1987, Deyssig and Weissel, 1993). Perturbations in these hormonal axes in association with affective and behavioral changes in other psychiatric conditions are well documented and presumed to be pathophysiologically relevant. Thus, changes in endocrine function secondary to AAS administration could potentially contribute to AAS-induced psychiatric changes. For example, some authors have suggested that AAS-induced adverse behavioral responses may arise partly through their effects on glucocorticoid receptors (Bonsall and Michael, 1989, Ahima and Harlan, 1992) or estrogen levels (Bahrke et al., 1996).
In an effort to more clearly define the hormonal changes that occur during high-dose AAS use and to explore possible mechanisms underlying the accompanying adverse behavioral changes, we carried out a comprehensive battery of neuroendocrine hormone measures during MT administration in our previously described (Su et al., 1993) study group. We studied hormonal axes that are known to potentially influence mood and behavior and that have also been previously reported as changing during AAS use.
Two specific questions were posed in this study. First, what are the acute effects of supraphysiologic doses of MT on circulating levels of HPA, HPT and HPG axes hormones when administered under carefully controlled conditions to healthy volunteers? Second, are MT-induced hormonal changes associated with the behavioral and mood symptoms observed?

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Section snippets

Subjects

Subject selection and protocol are as previously described (Su et al., 1993) and are summarized as follows: 23 medication-free male volunteers aged 18–42 underwent extensive medical screening, including urine testing for illicit drugs; three were excluded due to medical problems or a positive drug screen. The remaining 20 subjects had no significant current or past history of psychiatric disorder or AAS use and were free of any current or recent (past two years) history of alcohol or substance

HPG axis (Table 3)

Significant suppression of plasma levels of reproductive axis hormones was seen during both high-dose MT and withdrawal conditions compared with baseline. Levels of gonadotropins also fell significantly during the high-dose condition, but returned to baseline values during the withdrawal condition.

HPT axis (Table 3)

Significant decreases in the levels of T3, T4 and TBG were seen during both high-dose and withdrawal conditions compared with baseline, while significant increases were seen in FT4 and TSH during the

Discussion

Several limitations of this study are notable. The duration of treatment with AAS was shorter and doses lower than those reported by some abusers (Porcerelli and Sandler, 1998). Steroid abusing athletes may comprise a different biological or biosocial group than healthy volunteers who have never used androgens. The study design, by minimizing potential confounds such as exercise, co-morbid substance abuse, and multiple steroid use, may have reduced the impact of important factors that

Conclusion

High-dose AAS administration acutely and profoundly affects hormonal balance in the pituitary-gonadal and -thyroid axes, with little impact on the HPA axis. When the relationships between changes in hormonal and adverse psychological measures were examined, changes in testosterone and FT4 were associated with the emergence of cognitive, aggressiveness and activation symptoms. These findings suggest that AAS-induced hormonal changes may be associated with, and contribute to, the adverse mood and

Acknowledgements

The authors are grateful to the 4 East patient care unit nursing staff at the Clinical Center, National Institutes of Health, for their help with behavioral measures, data collection, and clinical care; to Christine Ayotte, PhD, for methyltestosterone assay performance; and to Candace Davis for figure preparation.

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