Do steroids damage your brain? The science of AAS neurotoxicity

Hey guys, so I thought I’d do a post on whether AAS are neurotoxic. There’s a lot in the community about various AAS and I wanted to address the molecular mechanisms behind why certain compounds seem to be more neurotoxic than others, and indeed, if they even are neurotoxic to begin with. The reason I put so much effort into these posts is because I love talking about this - and I honestly believe that the more information is out there, the more you can be informed if and when you use certain compounds. The more that is hidden just makes everything incredibly murky, and in my mind, more dangerous for young guys than if the science is out there and you can just educate yourself fully rather than when I was growing up where some back-page forum was the only resource.

Please note: nothing in this article is advice or recommending anything, just simply presenting some data for you and for educational purposes.

To start, AAS don’t just act on androgen receptors only, there is evidence that they act on GABA receptors and affect GABAergic transmission. The central region of the medial preoptic area (mPOA), the medial preoptic nucleus (MPN), is characterised by a dense presence of GABAergic neurons and GABAA receptors, as well as high levels of ARs, estrogen receptors (ERs), and aromatase, consistent with the high steroid-affinity of this region:

This area is heavily involved in sexual behaviour and regulates social behaviours and social reward and in studies this area of the brain has been shown to be vastly different in regulating female and male mating behaviour.

With that information, it’s important to understand how androgens act in the brain and how certain androgens can be neurotoxic or not:

PATHWAY 1: APOPTOSIS

Androgens raise calcium ion concentrations involved in nerve transmission, and this seems to be the link between brain neurotoxicity and steroid use. Interestingly, at physiological levels androgens seem to promote neuroprotection, survival and growth - but it is high dose androgens that are the issue.

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Basically, AAS prolong calcium signalling and this can lead to apoptosis (cell death). Neuronal cell death is thus as a result of excessive calcium ion influx through cells - in this study very high levels of testosterone were found to enhance cell death, whereas intermediate/lower levels did not. Interestingly, the researchers also found that estrogen played a protective role in programmed cell death of brain cells.

Further studies have shown that androsterone, nandrolone, dianabol and 17-α-methyltestosterone induced cell death through apoptotic pathways. The researchers detected the appearance of the cleaved and hence active form of caspase 3 (only present once cells are well on the way to death) in neuron-like cells treated with AAS, suggesting cell death may be a programmed response to high concentrations of steroids.

PATHWAY 2: REACTIVE OXYGEN SPECIES

No matter if you’re natty or not, reactive oxygen species (ROS) can contribute to cell death - and there seems to be an interesting split here: treating cells with androgens before exposure to ROS seemed to protect them from death - treating them after exposure to ROS induced significant death - suggesting that androgens are neuroprotective when oxidative stress levels are low, but when oxidative stress levels are elevated, androgens worsen oxidative damage. And further evidence that it is the oxidative stress levels that determine whether AAS are neurotoxic or not is the fact that some studies show that androgens can protect against moderate oxidative stress damage, but not when levels are high. This study backed these findings up: it used hydrogen peroxide to induce oxidative stress in female rat neuronal cells. The purpose of using hydrogen peroxide was to create a condition that mimics the oxidative stress observed in neurodegenerative disorders like Parkinson's disease. Hydrogen peroxide is a reactive oxygen species (ROS) and is commonly used in research to study oxidative stress mechanisms due to its ability to generate oxidative damage in cells. By applying hydrogen peroxide to the N27 cells (neural cells), the researchers could examine how androgens (testosterone or dihydrotestosterone) affected the cells under oxidative stress conditions, allowing them to analyse the dual neuroprotective and neurotoxic roles of androgens in these circumstances.

They found that if androgens were administered AFTER oxidative stress, cell death was increased (for example, the maximum concentration of hydrogen peroxide and testosterone seen as HT100 led to the lowest cell viability compared to hydrogen peroxide [H] alone):

However, interestingly, when cells were pre-treated with androgens, it protected against oxidative stress induced death (T+H outperformed H [hydrogen peroxide] only in terms of keeping cells alive):

Looking deeper, androgens can also have the following effects in the brain:

• They reduce levels of BDNF (Brain-Derived Neurotrophic Factor - a protein that belongs to the neurotrophin family of growth factors, which are crucial for the development, survival, and maintenance of neurons in the nervous system)
• They reduce 5-HT (serotonin: involved in mood, cognitive functioning and sleep amongst a whole host of other things) and dopamine (DA) levels: research found serotonin and dopamine are both reduced in all areas of the brain following stanozolol treatment:
  
  

• Reduces NGF (Nerve Growth Factor, a protein that plays a crucial role in the growth, maintenance, and survival of certain nerve cells. Neurotrophin unbalance has been implicated in behavioural disturbances that can mimic the chemical milieu of depression
• This study found that cell death occurred when cells were treated with Dbol or methyltestosterone (orange/red = cell death):
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So basically, androgens can exert neurotoxic effects via either:

1. Apoptosis (programmed cell death), and/or
2. Oxidative stress (if already present)

However, the research shows it is both concentration-dependent and oxidative-stress dependent, with the neuroprotective effects of androgens seemingly related to the level of oxidative stress already present/not present, which has interesting implications for those guys who have high levels of oxidative stress + are on compounds already.

Thanks so much for reading, see you in the next one guys!