Full length articleBrain and cognition abnormalities in long-term anabolic-androgenic steroid users
Introduction
Illicit anabolic-androgenic steroids (AAS) use poses a growing public health problem worldwide, with 2.9–4.0 million individuals in the US alone having used these drugs (Pope et al., 2014). Virtually all of these users are male (Kanayama et al., 2007). Although used by elite athletes since the 1950s, AAS did not spread widely to the general population until the 1980s (Kanayama et al., 2008). Thus, even the oldest AAS users, who initiated AAS use as youths in the 1980s, are mostly under age 50 today. As the leading edge of this AAS-user population passes through middle age, adverse general health effects of long-term AAS exposure are becoming increasingly apparent (Pope et al., 2014).
AAS are known to cause acute psychiatric effects such as aggression (Copeland et al., 2000, Perry et al., 2003, Pope et al., 2014), violence, including increased partner violence (Beaver et al., 2008, Choi and Pope, 1994, Middleman et al., 1995, Pope and Katz, 1990, Skarberg et al., 2010, Thiblin and Parlklo, 2002), and impulsive behaviors including risky sexual and other behaviors (Hildebrandt et al., 2014, Middleman et al., 1995, Midgley et al., 2000). We (Kouri et al., 1995, Pope et al., 2000) and others (Su et al., 1993, Yates et al., 1999) have documented such effects in controlled human studies. AAS also increase aggressive behaviors in adolescent and adult rodents (Kalinine et al., 2014, Melloni and Ferris, 1996), which may be associated with reduced glutamate uptake and increased N-methyl-d-aspartate (NMDA) receptor activity (Kalinine et al., 2014).
AAS also may cause chronic cognitive effects. Recently, we reported (Kanayama et al., 2013) that long-term AAS users exhibited deficits on two tests of visuospatial memory from the widely used CANTAB battery (Cambridge Cognition, 2015), and the severity of these deficits was associated with lifetime dose of AAS used. One of these tests, Paired Associates Learning, has previously been shown to predict the development of dementia (Swainson et al., 2001). Consistent with our human findings, rodent studies have shown that AAS exposure can impair performance on the Morris water maze test of spatial learning and memory (Magnusson et al., 2009, Novaes Gomes et al., 2014, Pieretti et al., 2013, Tanehkar et al., 2013). Impaired inhibitory control and attention also were recently reported in men actively taking AAS, with greater impairment found in adolescent-than adult-onset AAS users (Hildebrandt et al., 2014).
While the human brain substrates for these AAS effects have yet to be elucidated, the findings reviewed above suggest that attentional regions of the brain associated with threat reactivity and regulation, such as the amygdala, the hippocampus, and the dorsal anterior cingulate cortex (dACC), may be particularly vulnerable to chronic AAS use. The amygdala is involved in threat processing and aggression (Siever, 2008). The rat amygdala is androgen-sensitive (Cooke et al., 1999, Lynch and Story, 2000) and androgen administration to male rats induces amygdala neurogenesis and neuronal soma and astrocyte volume and complexity increases (Fowler et al., 2003, Cooke et al., 1999, Johnson et al., 2008, Johnson et al., 2012). Functional MRI (fMRI) studies in healthy men report positive associations between amygdala reactivity to angry or fearful faces and levels of the endogenous AAS testosterone (Derntl et al., 2009). Similarly, testosterone administration to healthy men acutely increased amygdala reactivity to angry faces (Goetz et al., 2014). Further, amygdala volume increases have been associated with aggressive behavior among substance users (Schiffer et al., 2011). Collectively these findings suggest that AAS could increase amygdala volume and possibly catalyze or enable aggression behaviors. The hippocampus is involved in spatial memory processes (Squire, 1992). In rats, AAS induce hippocampal apoptosis (Ma and Liu, 2015, Tugyan et al., 2013), and inhibit hippocampal neurogenesis (Brannvall et al., 2005, Novaes Gomes et al., 2014), suggesting that AAS could reduce hippocampal volume, which could be a basis for the AAS-associated spatial memory impairments observed in human and animal studies. The dACC is a cognitive control region involved in attentional processes (Bush and Shin, 2006), which as noted above are abnormal in human AAS users (Hildebrandt et al., 2014). Abnormal dACC activation has been documented in alcohol-dependent subjects performing a spatial working memory fMRI task (Vollstädt-Klein et al., 2010), suggesting that visuospatial dysfunction among AAS users could be related to dACC dysfunction.
Although case reports have documented cerebrovascular problems associated with human AAS use (Akhter et al., 1994, Shimada et al., 2012), no systematic neuroimaging studies have yet assessed human brain effects of long-term AAS use. Accordingly, we acquired from long-term AAS users and nonusers 3 T structural magnetic resonance imaging (MRI), resting state functional connectivity (rsFC) MRI (which maps brain regions thought to be functionally coupled and inherently organized at rest (Greicius, 2008)), and proton magnetic resonance spectroscopy (MRS, which evaluates neurochemistry). We also administered the two computerized tests of visuospatial memory revealing deficits in AAS users in our prior study (Kanayama et al., 2013). Because it is technically challenging to acquire high-quality 3 T MRS spectra from the small, irregularly-shaped amygdala and hippocampus, due in part to partial volume effects (contamination by adjacent structures), we acquired MRS spectra from the dACC, from which MRS data be more reliably acquired. Also, as discussed above, this region may contribute to deficits associated with AAS use. We used MRI to determine whether long-term AAS use is associated with abnormal amygdala and hippocampal volumes and connectivities. Also, given rodent studies suggesting that AAS may enhance the effects of glutamate neurotransmission (Kalinine et al., 2014, Orlando et al., 2007), we used MRS to determine whether long-term AAS use is associated with dACC glutamate abnormalities.
Section snippets
Participants
Study participants were drawn from a pool of about 150 experienced male weightlifters aged 35–55 who had been evaluated in 2011–2014 in a large ongoing study of the cardiac effects of long-term AAS use (Weiner et al., 2013). Since virtually all AAS users are weightlifters, we initially recruited these men by advertising in gymnasiums frequented by AAS users and nonusers (Kanayama et al., 2003, Pope et al., 2012). Participants received a comprehensive interview covering athletic, medical, and
Demographic measures and cognitive test findings
The groups were well matched on demographic variables (Table 1). AAS users reported usage patterns similar to those of long-term AAS users evaluated in our prior studies (Kanayama et al., 2003, Pope et al., 2012, Pope and Katz, 1994; see Table 1), involving about 80% injectable AAS (e.g., testosterone, nandrolone, boldenone) and 20% oral preparations (e.g., methandienone, methenolone, stanozolol). Some participants reported current use of prescription psychoactive medications, including 3 AAS
Discussion
In this brain imaging study, long-term AAS users showed (1) markedly increased right amygdala volumes; (2) markedly decreased right amygdala rsFC, and (3) reduced dACC gln/glu and scyllo-inositol levels compared to nonusers. We also found group differences approaching statistical significance on a visuospatial memory test. To our knowledge, these data represent the first report of brain structural and functional effects of long-term human AAS use.
Role of funding source
The sponsors did not have any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
All authors made: (1) substantial contributions to the conception and analysis and interpretation of data; (2) drafting the article and revising it critically for important intellectual content; and (3) gave approval of the version to be published.
Drs. Pope and Kanayama and Mr. Kerrigan oversaw subject recruitment and screening. Drs. Pope, Kanayama, Kaufman, Jensen, and Mr. Kerrigan oversaw data acquisition and management. Drs. Hudson, Pope, and Janes oversaw statistical analyses. Drs. Kaufman,
Conflict of interest
Dr. Pope has testified approximately once per year in legal cases involving anabolic-androgenic steroids. Dr. Hudson has received grant support from Genentech and Shire; and has received consulting fees from Genentech, Roche, and Shire. All other authors declare that they have no conflicts of interest.
Acknowledgements
Funding for this study was provided in part by NIDA grants R01 DA-29141 (to Drs. Hudson, Kanayama, and Pope) and K01 DA-029645 (to Dr. Janes), and by NIMH grant K23 MH-092397 (to Dr. Brennan).
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