Long-term anabolic-androgenic steroid use is associated with deviant brain aging
Abstract
Background High-dose long-term use of anabolic-androgenic steroids (AAS) may cause a range of adverse effects, including brain and cognitive abnormalities. We performed age prediction based on brain scans to test whether prolonged AAS use is associated with accentuated brain aging.
Methods T1-weighted MRI (3D MPRAGE) scans were obtained from male weightlifters with a history of prolonged (n=130) or no (n=99) AAS use. We trained machine learning models on combinations of regional brain volumes, cortical thickness, and surface area in an independent training set of 1838 healthy males (18-92 years) and predicted brain age for each participant in our study. Including cross-sectional and longitudinal (mean interval 3.5 years, n=76) MRI data, we used linear mixed-effects (LME) models to compare the gap between chronological age and predicted brain age (the brain age gap, BAG) between the two groups, and tested for group differences in the rate of change in BAG. We tested for associations between apparent brain aging and AAS use duration, the pattern of administration, and dependence.
Results AAS users had higher BAG compared to weightlifting controls, which was associated with dependency and long history of use. Group differences in BAG could not be explained by other substance use, general cognitive abilities, or depression. While longitudinal analysis revealed no evidence of increased brain aging in the overall AAS group, accelerated brain aging was seen with longer AAS exposure.
Conclusions The findings suggest that long-term high dose AAS use may have adverse effects on brain aging, potentially linked to dependency and exaggerated use of AAS.
Introduction
Anabolic-androgenic steroids (AAS) are a family of hormones that comprise testosterone, and hundreds of synthetic derivatives of testosterone (1). Administration of supraphysiological doses of AAS in combination with strength training increases lean muscle mass and strength (2). These are desired effects for athletes and bodybuilders where widespread use was seen from the 1950s before it spread to the general population around the 1980s. AAS use has a range of adverse health and social consequences (3, 4). Yet, the long-term effects on brain health and cognition are understudied, which is paradoxical since sex steroids readily pass the blood-brain barrier and affect the central nervous system (CNS).
The biological action of AAS and their metabolites are primarily mediated via the androgen receptors (AR), however many will also exert physiological effects via estrogen receptor pathways, upon aromatization (5, 6). Sex steroid receptors are widely expressed in the brain, and abundantly in regions such as the brainstem, hypothalamus, amygdala, striatum, hippocampus, and cerebral cortex (7-9). High-dose AAS administration typically involves a complex pattern where testosterone compounds and other AAS are co-administered with doses equivalent to 250-5000 mg/week, which is 5-100 times greater than the natural male production (10). Administration of supraphysiological doses of AAS suppresses the hypothalamic-pituitary-gonadal axis and reduces the endogenous production of testosterone, luteinizing, and follicle-stimulating hormones. The administration typically continues for several weeks or months, separated by drug-free intervals with the intention to allow the hormonal system to recuperate (11). However, it seems that continuous use persisting for years has become more common (12-16), likely to avoid abstinence symptoms that often occur upon cessation (17, 18).
While neuroprotective effects of physiological doses of testosterone have been observed (19, 20), growing evidence suggests that high-dose long-term AAS use harms the brain. Neurotoxic effects of various sorts of AAS in response to high dosages such as those administered by bodybuilders and recreational athletes have been shown (21-26). Moreover, AAS use frequently causes cardiomyopathy (27, 28), atherosclerotic disease (27), prolonged hypogonadism (upon withdrawal) (29, 30), lower LDL cholesterol level (31), impaired insulin sensitivity (32), and occasionally toxicity to liver and kidney (33), with potential implications for brain health (34, 35).
Emerging evidence from field studies suggests that prolonged high-dose AAS use is associated with aberrant brain aging. For instance brain imaging has revealed that long-term AAS-use is associated with structural, neurochemical (36), and functional brain differences (36-38), including smaller gray matter, cortical and putamen volume, and thinner cerebral cortex (37). Also, compared to non-using weightlifters, AAS-exposed weightlifters performed poorer on tests assessing working memory (12, 39, 40), executive functions (12, 40, 41), learning and memory (12, 39, 41), processing speed, and problem-solving (12, 40). Although correlational, such findings have led to the hypothesis that high-dose AAS users are at risk for accelerated brain aging (42, 43).
The effects of AAS use show substantial inter-individual heterogeneity. Some users exhibit little or no symptoms, while others demonstrate multiple psychological and medical consequences following long-term use (11, 44). The range and severity of adverse effects may increase with the burden of use (19) and are particularly pronounced in users fulfilling the criteria for AAS dependence (1, 15, 45). This includes seemingly more pronounced effects on MRI-based measures of cerebral cortical structure (37, 45), self-reported memory problems (12, 41), and impaired executive (40) and memory functions (12, 39) in dependent users. However, group-level differences may disguise substantial individual differences.
Machine learning offers individual predictions based on neuroimaging data (46). For example, training a model to find relationships between brain scans and chronological age allows you to predict the age from unseen brain images with high accuracy (47, 48). The difference between the predicted and chronological age, termed the brain age gap (BAG), serves as a surrogate marker of brain health and individual differences in brain maturation and aging (49, 50). In adults, an older brain age compared to chronological age has been linked with cognitive impairment (51), cardiovascular risk factors (34), mortality (52), dementia (53), and several other common brain disorders, with regionally differing patterns (54). Conversely, a healthy lifestyle has been associated with a younger-looking brain, with correlations between BAG and level of education and physical activity, as indicated by the daily number of flights of stairs climbed (55). Contrary, drug abuse and addiction have been associated with premature brain aging (56-58) and early onset of age-related disease (59). While recent studies have documented associations between cumulative exposure to sex hormones and brain age in middle-aged and elderly women (60), the effects of long-term exposure to supraphysiological doses of testosterone and AAS on brain aging have not been studied.
In a sample of 130 AAS users and 99 weightlifting controls (WLC), we used cross-sectional (n=229) and longitudinal (n=76) data to test the hypothesis of higher relative brain age and higher rates of brain aging in AAS users compared to WLC. We also tested for associations between brain age and AAS use severity, duration, administration (cycling versus continuous use), and dependence.
Discussion
Accumulating evidence suggests that prolonged AAS use harms the brain (12, 36, 37, 39, 42, 43). Using brain scans and brain age prediction based on an independent training set we found evidence of higher relative global, frontal, temporal, occipital, and insular brain age in 130 male AAS users compared to 99 male WLC. Further, among AAS users we found that long-term use and dependence were associated with higher relative brain age. Longitudinal analysis revealed no evidence of accelerated BAG over time in the overall AAS group, however AAS users with more than 10 years of AAS exposure showed accelerated aging compared to WLC, with a significant increase in BAG between the time points in this subgroup. These findings suggest that long-term high dose AAS use may have an adverse effect on brain aging, potentially linked to dependency and exaggerated use of AAS.
*Conclusively, in line with mounting evidence of adverse health effects of AAS use, using brain age prediction we found evidence of increased apparent brain aging in long-term high-dose AAS users, seemingly linked to dependency and exaggerated use of AAS.
