madman
Super Moderator
Purpose of review
The purpose of this review is to examine the recent evidence regarding the effects of exogenous androgens on the brain. Understanding these effects is of high importance, as the consequences of androgens on the reproductive and endocrine system are well documented, while fewer studies have focused on the neural and cerebral consequences of androgen use.
Recent findings
Supraphysiological doses of androgens have been shown to contribute to neurodegeneration, decreased brain-derived neurotrophic factor, increased inflammation, and decreased neuronal density in animal studies, which may correspond to changes in mood, cognition, and aggression. Findings from human studies suggest that similar behavioral and cognitive deficits may occur as a result of prolonged use of androgens. Additional evidence suggests that androgen use, particularly in high doses, may contribute to brain aging and cerebrovascular problems.
Summary
Findings from recent human and animal studies indicate that androgen use likely contributes to brain alterations, which may cause the frequently observed deficits in cognitive and emotional functioning. Although exogenous testosterone in appropriate doses for therapeutic purposes likely has some neurobiological benefits for certain populations, supraphysiological doses may cause multiple mental and physical health problems, indicating a need for additional large-scale studies in humans.
INTRODUCTION
Testosterone is the primary circulating androgen in men, which is also present in women, though in much lower concentrations. This hormone plays a critical role in regulating bone mass, fat distribution, and sperm production, in addition to mood and cognition [1–3]. Thus, exogenous testosterone can be an important therapy, particularly for patients experiencing symptoms of hypogonadism or low testosterone [3,4]. However, when testosterone is used in supraphysiological doses and without medical supervision, a number of risks arise.
Androgens, or anabolic-androgenic steroids, include testosterone and synthetic derivatives primarily used to increase lean muscle mass and enhance physical appearance and athletic performance. The current global prevalence is estimated to be 3.3%, though this is higher for males (6.4%) [5]. Consistent use of supraphysiological doses of testosterone has been associated with a myriad of physical and psychiatric consequences, including cardiovascular complications, anxiety, and aggressive behavior [6–9]; however, relatively few studies focus on the brain, though this has increased in recent years.
The majority of research investigating neuropsychiatric effects of androgen use has largely focused on behavioral problems, with a significant focus on violence and aggression. Researchers have suggested these behaviors may reflect changes to brain structures often associated with executive function and emotional control, including the prefrontal cortex (PFC), hippocampus, and amygdala. However, the mechanisms by which androgens influence changes to these structures and subsequent behavior are not yet well understood. In recent years, likely as a consequence of a steadily growing population of older androgen users, more studies gained interest in the long-term impact on neuronal and brain health. This review describes the published findings of the last year and a half on the effects of androgen use on the brain, including alterations in neurobiology and neurochemistry, as well as deficits in cognition.
BRAIN HEALTH
Prolonged use of androgens has been found to have deleterious effects on brain health. A number of mechanisms and processes may be implicated, including neurodegeneration via neurotoxicity, increased inflammation and oxidative stress, cardiovascular disease, and impaired neuroplasticity [14].
*Neurodegeneration
*Brain volumes and age
*Cerebrovascular
*Cognition
*Neuroplasticity
THE BRAIN AND AGGRESSION
Behavioral side effects of androgen use, particularly aggression, have been well documented. However, the precise mechanisms underlying these behavioral consequences following androgen use remain somewhat ambiguous [32]. Neuronal activity in the latero-anterior hypothalamus (LAH) has previously been associated with aggressive behavior in animals treated with androgens [33]. Building upon these findings, Morrison et al. [34&&] found that serotonergic factors could be involved as blocking serotonin type-3 receptors in this region increased aggression, but decreased anxious behavior in adolescent Syrian hamsters during androgen withdrawal. Typically, during androgen withdrawal, anxiety increases and aggression declines, suggesting that serotonin neural signaling within the LAH contributes to shifting between these behaviors.
In addition, previous findings suggest that gamma-aminobutyric acid (GABA)-ergic mechanisms in the LAH are involved in androgen-induced aggressive behavior [35–37]. In a recent study, valproate, an anticonvulsant shown to manage pathological aggression and enhance GABA activity in the brain, attenuated androgen-induced aggression in a dose-dependent manner [38]. This effect was reversed following infusion of a GABAA receptor antagonist into the LAH, implying a role of GABA neural signaling within the LAH in androgen-induced aggressive behavior.
Furthermore, additional brain structures are likely implicated in androgen-induced aggression. Previously, a decrease in amygdala volume has been associated with increased aggressive behaviors [39]. However, Tabor et al. [23] found that rats treated with androgens demonstrated increased aggression and enlarged amygdala volumes. Notably, a previous study in humans also identified right amygdala enlargement in androgen users [40], though the sample size of this study was small, and more recent findings have found no differences in amygdala volume between androgen users and controls [41]. In addition, polysubstance use may contribute to aggressive behavior, as rats treated with combined cannabis and nandrolone demonstrated increased aggression, but those exposed to either substance alone did not [16& ]. This may be a result of the increased pro-inflammatory cytokines seen in this treatment group, which have been frequently associated with aggression [42].
Finally, androgen dependence is of growing concern, as those who use androgens for a longer period and in higher doses tend to experience worse side effects. In mice, a single injection of either testosterone or nandrolone strengthened excitatory synaptic transmission in ventral tegmental area dopaminergic neurons, which mediates reward and drug-seeking behavior [43&&]. However, blocking opioid receptors in this region countered two drug-seeking behaviors, suggesting that androgens indirectly stimulate the reward center by activating endogenous opioid signaling, which may mediate the addictive effects of androgens.
*Overall, the findings from studies looking at different aspects of brain health go in the same direction where high-dose, long-term androgen use seems to have a negative impact on brain health.
CONCLUSION
Published findings on the consequences of androgens on the brain from the last 18 months comprise a wide range of areas of interest. The impact of these substances on cognition and behavior is likely brought about by a myriad of alterations to specific brain regions, primarily the cerebral cortex, hippocampus, amygdala, and hypothalamus. Furthermore, high-dose androgen use appears to contribute to increased inflammation and oxidative stress, and impaired neuroplasticity. However, a large portion of these findings come from animal models, with varying species and doses, making it difficult to extrapolate these findings to humans.
The purpose of this review is to examine the recent evidence regarding the effects of exogenous androgens on the brain. Understanding these effects is of high importance, as the consequences of androgens on the reproductive and endocrine system are well documented, while fewer studies have focused on the neural and cerebral consequences of androgen use.
Recent findings
Supraphysiological doses of androgens have been shown to contribute to neurodegeneration, decreased brain-derived neurotrophic factor, increased inflammation, and decreased neuronal density in animal studies, which may correspond to changes in mood, cognition, and aggression. Findings from human studies suggest that similar behavioral and cognitive deficits may occur as a result of prolonged use of androgens. Additional evidence suggests that androgen use, particularly in high doses, may contribute to brain aging and cerebrovascular problems.
Summary
Findings from recent human and animal studies indicate that androgen use likely contributes to brain alterations, which may cause the frequently observed deficits in cognitive and emotional functioning. Although exogenous testosterone in appropriate doses for therapeutic purposes likely has some neurobiological benefits for certain populations, supraphysiological doses may cause multiple mental and physical health problems, indicating a need for additional large-scale studies in humans.
INTRODUCTION
Testosterone is the primary circulating androgen in men, which is also present in women, though in much lower concentrations. This hormone plays a critical role in regulating bone mass, fat distribution, and sperm production, in addition to mood and cognition [1–3]. Thus, exogenous testosterone can be an important therapy, particularly for patients experiencing symptoms of hypogonadism or low testosterone [3,4]. However, when testosterone is used in supraphysiological doses and without medical supervision, a number of risks arise.
Androgens, or anabolic-androgenic steroids, include testosterone and synthetic derivatives primarily used to increase lean muscle mass and enhance physical appearance and athletic performance. The current global prevalence is estimated to be 3.3%, though this is higher for males (6.4%) [5]. Consistent use of supraphysiological doses of testosterone has been associated with a myriad of physical and psychiatric consequences, including cardiovascular complications, anxiety, and aggressive behavior [6–9]; however, relatively few studies focus on the brain, though this has increased in recent years.
The majority of research investigating neuropsychiatric effects of androgen use has largely focused on behavioral problems, with a significant focus on violence and aggression. Researchers have suggested these behaviors may reflect changes to brain structures often associated with executive function and emotional control, including the prefrontal cortex (PFC), hippocampus, and amygdala. However, the mechanisms by which androgens influence changes to these structures and subsequent behavior are not yet well understood. In recent years, likely as a consequence of a steadily growing population of older androgen users, more studies gained interest in the long-term impact on neuronal and brain health. This review describes the published findings of the last year and a half on the effects of androgen use on the brain, including alterations in neurobiology and neurochemistry, as well as deficits in cognition.
BRAIN HEALTH
Prolonged use of androgens has been found to have deleterious effects on brain health. A number of mechanisms and processes may be implicated, including neurodegeneration via neurotoxicity, increased inflammation and oxidative stress, cardiovascular disease, and impaired neuroplasticity [14].
*Neurodegeneration
*Brain volumes and age
*Cerebrovascular
*Cognition
*Neuroplasticity
THE BRAIN AND AGGRESSION
Behavioral side effects of androgen use, particularly aggression, have been well documented. However, the precise mechanisms underlying these behavioral consequences following androgen use remain somewhat ambiguous [32]. Neuronal activity in the latero-anterior hypothalamus (LAH) has previously been associated with aggressive behavior in animals treated with androgens [33]. Building upon these findings, Morrison et al. [34&&] found that serotonergic factors could be involved as blocking serotonin type-3 receptors in this region increased aggression, but decreased anxious behavior in adolescent Syrian hamsters during androgen withdrawal. Typically, during androgen withdrawal, anxiety increases and aggression declines, suggesting that serotonin neural signaling within the LAH contributes to shifting between these behaviors.
In addition, previous findings suggest that gamma-aminobutyric acid (GABA)-ergic mechanisms in the LAH are involved in androgen-induced aggressive behavior [35–37]. In a recent study, valproate, an anticonvulsant shown to manage pathological aggression and enhance GABA activity in the brain, attenuated androgen-induced aggression in a dose-dependent manner [38]. This effect was reversed following infusion of a GABAA receptor antagonist into the LAH, implying a role of GABA neural signaling within the LAH in androgen-induced aggressive behavior.
Furthermore, additional brain structures are likely implicated in androgen-induced aggression. Previously, a decrease in amygdala volume has been associated with increased aggressive behaviors [39]. However, Tabor et al. [23] found that rats treated with androgens demonstrated increased aggression and enlarged amygdala volumes. Notably, a previous study in humans also identified right amygdala enlargement in androgen users [40], though the sample size of this study was small, and more recent findings have found no differences in amygdala volume between androgen users and controls [41]. In addition, polysubstance use may contribute to aggressive behavior, as rats treated with combined cannabis and nandrolone demonstrated increased aggression, but those exposed to either substance alone did not [16& ]. This may be a result of the increased pro-inflammatory cytokines seen in this treatment group, which have been frequently associated with aggression [42].
Finally, androgen dependence is of growing concern, as those who use androgens for a longer period and in higher doses tend to experience worse side effects. In mice, a single injection of either testosterone or nandrolone strengthened excitatory synaptic transmission in ventral tegmental area dopaminergic neurons, which mediates reward and drug-seeking behavior [43&&]. However, blocking opioid receptors in this region countered two drug-seeking behaviors, suggesting that androgens indirectly stimulate the reward center by activating endogenous opioid signaling, which may mediate the addictive effects of androgens.
*Overall, the findings from studies looking at different aspects of brain health go in the same direction where high-dose, long-term androgen use seems to have a negative impact on brain health.
CONCLUSION
Published findings on the consequences of androgens on the brain from the last 18 months comprise a wide range of areas of interest. The impact of these substances on cognition and behavior is likely brought about by a myriad of alterations to specific brain regions, primarily the cerebral cortex, hippocampus, amygdala, and hypothalamus. Furthermore, high-dose androgen use appears to contribute to increased inflammation and oxidative stress, and impaired neuroplasticity. However, a large portion of these findings come from animal models, with varying species and doses, making it difficult to extrapolate these findings to humans.
