Testosterone is not neuroprotective, estrogen is.
A common myth circulating in the bodybuilding and TRT community is that testosterone is inherently neuroprotective and is unique from all other anabolic steroids in that regard.
The reason why testosterone is neuroprotective is simply because it aromatizes at a rate that provides a sufficient amount of estradiol to balance out the androgenicity in the body.
Data in rodent models using cortical cells suggests this very convincingly by showing how the aromatase inhibitor Anastrozole (Arimidex) completely eliminated the neuroprotective effects of testosterone [R].
Are Synthetic Anabolic Steroids More Dangerous Than Testosterone?
There have been tons of studies published suggesting how much worse synthetic anabolic steroids are in contrast to testosterone for cardiovascular disease, neurotoxicity, and a myriad of other deleterious outcomes.
I believe that a significant amount of this data is exaggerated based on the fact that exogenous estrogen is never co-administered in these studies.
At the end of the day, testosterone is the safest androgen at physiologic dosages.
However, I theorize that many synthetic anabolic steroids are not as dangerous as we are led to believe.
My theory is that some compounds are not inherently significantly more dangerous than testosterone, rather, it is their lack of aromatization, 5-alpha reduction, or differing affinity for off-target receptors that makes them more dangerous.
The effect on estrogen receptors and how potent of a substrate an anabolic steroid is for aromatase is the main factor that impacts how viable a hormone is for consideration in a monotherapy context.
DHT derivatives cannot be converted by the enzyme aromatase into an estrogen like estradiol.
Nandrolone (19-nortestosterone) and its derivatives (19-nors) each have their own individual affinity (or lack thereof) for estrogen receptors and interaction with aromatase, often resulting in subpar estrogen levels (exceptions to this exist such as Trestolone/MENT).
Basically, I believe that some steroids may show to be significantly more cardiotoxic and neurotoxic in the data because they are always used on their own with an insufficient amount of estrogen to balance out the androgenicity in the body.
The Importance Of Sufficient Estrogen Levels
Healthy estrogen levels are needed for libido, erection quality, vasodilation, cardiovascular health, brain health, bone health and several other critical functions.
In women the risk of cardiovascular disease spikes significantly after menopause.
It isn't a coincidence that the majority of women who develop heart disease have it occur after their estrogen production has dropped to sub-male levels.
If you don't have a sufficient amount of estrogen relative to androgen levels in the body, cardiotoxicity and neurotoxicity levels will be significantly higher than they would be if healthy estrogen levels were sustained.
From a bodybuilding perspective, estrogen is needed to optimize muscle growth, fat loss, as well as IGF-1 and growth factor production/cellular signaling.
This is why heavily aromatizing steroids may indirectly result in greater growth potential and are often classified as “bulking” compounds.
Anecdotally, many bodybuilders report that the most they've ever grown was during off-season mass building phases when their estrogen levels were through the roof.
The Point Of A Testosterone Base
Testosterone is not tissue selective and is actually a poor muscle builder milligram for milligram when compared to other synthetic anabolic steroids developed in the years following its discovery.
When it comes to nitrogen retention, on paper it is not superior to many anabolic steroids.
However, it aromatizes into estradiol at a very tightly regulated rate, it is bioidentical, and our body knows exactly what to do with it.
In addition, our body knows how much testosterone to bind up with SHBG, how much to free up and make available to tissues, as well as how much DHT to 5-alpha reduce to antagonize estrogen receptor activation should it get out of control.
From a bodybuilding perspective, testosterone is subpar in many aspects.
However, in an overall health, longevity AND bodybuilding context, testosterone cannot be beat at therapeutic dosages.
By using a testosterone base or a source of sufficient estrogen the shortcomings of other anabolic agents can be attenuated to some extent, hence why testosterone is the base of most steroid cycles.
The Balancing Act Of Testosterone, DHT and Estrogen
Steroidogenesis in the body is carried out like a massive orchestra to regulate countless functions.
It's far more elaborate than simply testosterone, estrogen and DHT production.
Even at a snapshot view, the balancing act of androgens and estrogens in the body is tightly regulated and is carried out to ensure health remains optimized.
This balancing act gets more and more dysfunctional with age, poor lifestyle, poor diet, poor sleep hygiene and numerous other factors.
However, the body still knows exactly what to do with testosterone, how to create an optimal opposing amount of estrogens, and how much testosterone to 5-alpha reduce into DHT to oppose excessive estrogens and support male secondary sex characteristics.
When you compare clinical data on a synthetic anabolic steroid to testosterone in a monotherapy context, you have to consider that these studies are utilizing that synthetic steroid on their own, not with exogenous estrogen or any supplementary hormones that may be needed to balance out its androgenicity, lack of estrogenic activity and/or interaction with aromatase.
Obviously if you take a compound that doesn't aromatize sufficiently to estrogen and compare it head to head with the bioidentical androgen that our body knows how to aromatize and 5-alpha reduce at a perfectly balanced rate, you can just imagine which is going to come out on top in a cardiotoxicity and neurotoxicity context.
Does this mean that a synthetic anabolic steroid compared to testosterone would not potentially be more efficacious than testosterone should those other backend pathways be supplemented to fill the gaps though?
Synthetic Anabolic Steroids With Exogenous Estradiol For HRT
Some individuals have underlying genetic polymorphisms and defects in sex hormone metabolism that may throw off the tightly regulated steroidogenesis pathway in a way that skews too heavily in favor of estrogen, or too heavily in favor of androgens.
There are many cases in which synthetic anabolic steroids may beat out testosterone, despite testosterone on paper being the candidate of choice for most men at therapeutic dosages, and still the candidate of choice for many men at supraphysiological dosages too in a bodybuilding context.
Nandrolone is a great compound to exemplify this in my opinion.
It has a much lower level of androgenicity in the body due to its 5-alpha reduction into DHN, and it is also far less estrogenic than testosterone.
Those who are prone to gyno, hair loss, acne or other common testosterone related side effects typically prefer nandrolone for this reason.
This is why many female oral contraceptives are nandrolone analogs as well.
Unfortunately, your heart and brain don't care if you have hair loss, acne, or gyno, so there can be deleterious outcomes as a result of androgen use without a sufficient amount of unopposed estrogens, or an estrogen excess without sufficient androgen opposition.
In regards to nandrolone, I don't believe it has a sufficient amount of opposing estrogen to balance out its androgenicity.
It activates estrogen receptor alpha (ERα) a bit via its inherent estrogenicity and it can aromatize to estrone, which can then convert to estradiol, but the amount of overall estrogenic activity it provides does not appear to be sufficient to offset its neurotoxicity or cardiotoxicity.
I believe this is why most of the data found in nandrolone studies shows how horrible it is for the brain and the heart.
Nandrolone is always evaluated on its own without a sufficient amount of estrogen present to provide cardiovascular and neurological support.
If you shut down your natural endogenous testosterone production with an exogenous steroid, you will also shut down your natural endogenous estrogen production.
Any estrogen production (or lack thereof) would then be derived from whatever exogenous steroids are being administered.
This is why some synthetic steroids may not necessarily be as dangerous as we once thought, as the data we use to review their safety profiles are skewed by their lack of estrogenic support in the tissues that would otherwise be supported by testosterone aromatizing into estradiol.
In the presence of sufficient estrogen, it is entirely possible that the deleterious effects of certain synthetic steroids in the body may be attenuated to some extent.
The Neurotoxicity Of Testosterone, Nandrolone And Winstrol
Comparing the effect of testosterone with that of 19-nortestosterone (nandrolone) and stanozolol (Winstrol) on neurotoxicity we can clearly see that estrogen is what protects neurons in the brain, not testosterone itself.
In this study, a physiologic dosage of testosterone was neuroprotective [R].
Testosterone only amplified neurotoxicity at supraphysiological dosages.
The neuroprotective effect of a physiologic dosage of testosterone was completely eliminated when the aromatase inhibitor anastrozole (Arimidex) was co-administered, suggesting that the intrinsic toxicity of testosterone as an androgen is only counterbalanced by its aromatization into 17β-estradiol.
As opposed to testosterone, nandrolone does not appear to aromatize sufficiently into estrogen, and Winstrol does not interact with aromatase at all.
As you would expect, nandrolone and Winstrol were both neurotoxic at every single dose evaluated regardless of Arimidex being co-administered or not.
The anti-androgen flutamide was able to attenuate the neurotoxicity of all three androgens, thus further reinforcing that physiologic dosages of androgens without a sufficient amount of opposing estrogens, or supraphysiological dosages of androgens may facilitate neuronal death.
None of the anabolic androgenic steroids in this study were toxic in the absence of NMDA, therefore suggesting that the mechanism by which unopposed androgens facilitate neuronal death is by increased vulnerability to excitotoxic insults.
Neuroprotective Effect Of Testosterone At Physiologic Dosages Without Arimidex
At physiologic dosages without an aromatase inhibitor present, testosterone has shown to have a neuroprotective effect.
Neuroprotective Effect Of Testosterone At Physiologic Dosages Is Eliminated By Arimidex
It is often assumed that the androgen itself (testosterone) is what protects the brain.
However, the aromatase inhibitor Arimidex completely eliminated all neuroprotective effects of testosterone at that same physiologic dosage.
Arimidex (anastrozole) exacerbated neurotoxicity at every single testosterone dosage when it was co-administered.
This suggests that testosterone is not a unique androgen that is more neuroprotective than all other steroids, rather, it is its aromatization into estrogen that is neuroprotective.
Neurotoxicity Of Testosterone At Suraphysiological Dosages With And Without Arimidex
At supraphysiological dosages, testosterone has shown to exacerbate neurotoxicity.
While its aromatization into estrogen still prevents a significant amount of neuronal death, we can clearly see that supraphysiological testosterone concentrations exacerbate neurotoxicity regardless, and supraphysiological estrogen levels will not provide dose-dependent increases in neuroprotection.
What is the takeaway from this?
The data suggests that physiologic concentrations of testosterone facilitate neuroprotection in the brain via aromatization into estrogen, but there is a threshold to that neuroprotection, and supraphysiological concentrations will still be unhealthy.
Neurotoxicity Of Nandrolone Regardless Of Arimidex Use
Nandrolone exacerbated neurotoxicity at all dosages, regardless if it was a low concentration or a high concentration being evaluated.
In addition, co-administering Arimidex had no impact on how neurotoxic nandrolone was in this model at any dosage.
This suggests that nandrolone does not aromatize into a sufficient amount of estrogen, or activate estrogen receptors on its own at an amount satisfactory to provide the neuroprotective effects of healthy estrogen levels.
A source of estrogen would likely be necessary to co-administer with nandrolone for it to be considered a viable monotherapy alternative in a HRT context, or as a “healthy” cycle.
Neurotoxicity Of Winstrol Regardless Of Arimidex Use
Winstrol exacerbated neurotoxicity at all dosages, regardless if it was a low concentration or a high concentration being evaluated.
In addition, co-administering Arimidex had no impact on how neurotoxic Winstrol was in this model at any dosage.
We already know that Winstrol does not aromatize into estrogen at all.
This data suggests that a source of estrogen would be necessary to co-administer with Winstrol for it to even be considered as a viable monotherapy alternative in a HRT context, or as a “healthy” cycle.
Anti-Androgens Attenuate The Neurotoxicity Of Anabolic Androgenic Steroids
Unopposed androgens with an insufficient amount of estrogen present will be cardiotoxic and neurotoxic.
This is why Flutamide (an anti-androgen) was able to eliminate the neurotoxicity of nandrolone and Winstrol.
Anti-androgens have a dose-dependent response just like anabolic androgenic steroids, so there will be androgen receptor (AR) competition occurring between anti-androgens and androgens for AR binding and activation.
Anti-androgens will act as competitive antagonists for AR, or as makeshift synthetic steroids themselves, albeit with significantly reduced androgenicity.
Basically, depending on the anti-androgen used, they will work either by suppressing endogenous androgen production, and/or by competing for androgen receptors.
How effective the anti-androgen will be at inhibiting androgens from binding to AR will be based on binding affinity, binding constant, half-life, the dosage used, and a myriad of other factors.
Flutamide is non-steroidal and acts as a selective, competitive, silent antagonist of the AR.
It is a primitive and subpar anti-androgen relative to more recent developments in medicine, however, it is still effective at preventing androgens from binding to androgen receptors.
This is why flutamide was able to eliminate all of the neurotoxicity of nandrolone and Winstrol at all dosages.
By preventing nandrolone and Winstrol from binding to androgen receptors, they are no longer able to transcribe their effects in tissues.
The flutamide and Arimidex data reinforces the fact that nandrolone does not produce enough estrogen to provide the neuroprotection needed to stave off neuronal death.
With or without an aromatase inhibitor, nandrolone exacerbates neurotoxicity just the same.
Without an aromatase inhibitor but with an anti-androgen, the neurotoxicity of Nandrolone is eliminated entirely.
I suspect that the same applies for the inherent cardiotoxicity of nandrolone as well.
Expectedly, the same applies for Winstrol as it is not a substrate for aromatase at all.
This is where all the studies showing how terrible nandrolone is for the heart and brain come into question, as those negative outcomes found in the data may not have been so drastic if an exogenous source of estrogen was co-administered.
The same dosage of flutamide was unable to fully offset the neurotoxicity of testosterone at supraphysiological dosages without Arimidex present.
Once testosterone dosages exceed physiologic concentrations, the vulnerability to neurotoxicity and cardiotoxicity skyrockets.
Too much of anything in the body is going to be bad, and testosterone is not exempt from this just because its the bioidentical hormone we naturally produce and aromatize into estrogen.
The Aromatization Of Androgens Into Estrogen Is What Regulates Neurotoxicity
Reflecting on the data with and without an aromatase inhibitor we can see quite clearly that estrogen is what facilitates neuroprotection, not testosterone.
Many assume that testosterone is a unique androgen that binds to AR in some special way that's going to protect the brain and other steroids are going to destroy the brain.
I don't think it's as cut and dry as that.
I think it's pretty clear in the data that with anastrozole co-administered the neuroprotective effect is wiped out, and without anastrozole there is a neuroprotective effect.
What is the difference between aromatase being inhibited and aromatase not being inhibited?
It is the estrogen level in the body.
If you have a sufficient amount of estrogen to balance out androgens in the body, you get a good stable level of neuroprotection, which is reflected in how our body regulates endogenous androgen aromatization as is.
But, if you have a supraphysiological level of androgens, or inhibit aromatase from providing the estrogen needed to carry out necessary functions in the body, neurotoxicity spikes up regardless of the fact that it is testosterone being evaluated, not a non-bioidentical synthetic anabolic steroid.
This all circles back to the rationale behind using a testosterone base on cycle, or having a sufficient source of exogenous estrogen if you are deficient.
It also reinforces that aromatase inhibitors are horrible for you if used unnecessarily.
My Stance On Aromatase Inhibitors
You would be well served by doing whatever you can to avoid using aromatase inhibitors.
If you even need an aromatase inhibitor in the first place you're likely either using too much testosterone to begin with (or other aromatizing steroids), you're too fat (more fat = more aromatase), your diet sucks, your lifestyle choices are poor, or you're injecting too infrequently.
Or you might have a genetic polymorphism that results in subpar sex hormone metabolism.
At the end of the day, the likelihood that you would need an AI to handle a truly therapeutic dose of testosterone if you've optimized everything is extremely low.
In a bodybuilding context at supraphysiological dosages, I also think that in most cases using an AI just so you can use “too high” of a testosterone dose is a poor strategy.
Should You Take Exogenous Estrogen To Prevent Neurotoxicity And Cardiotoxicity
Just because estrogen is what provides neuroprotection, not testosterone, it absolutely does not mean that you should start popping your girlfriend's birth control pills like candy.
Unopposed estrogen in the body is carcinogenic.
There is a reason why the first go to treatments for breast cancer are SERMs and aromatase inhibitors.
Also, estrogen does not provide neuroprotection in a dose dependent manner.
There is a sweet spot for everything in the body, and too much of anything is going to be bad.
A 4-day pretreatment with low concentrations 0.01 μM (10 nM) of 17β-estradiol was substantially neuroprotective against NMDA toxicity.
However, you can clearly see that there was not a dose dependent decrease in neurotoxicity in this study.
Neuroprotection was significantly lower with 1 μM 17β-estradiol than with the much lower dosage of 0.01 μM 17β-estradiol.
More is not better with anything in the body.
The body has a tightly regulated system in place whereby a certain amount of estrogen is needed for physiologic functions.
Too much estrogen without enough androgens can result in cancer development, gynecomastia (gyno), and a myriad of other issues.
Too little estrogen and excessive androgens can result in cardiovascular disease, neuronal death, and a myriad of other issues.
So, if you are using an androgen without a sufficient amount of opposing estrogen to balance it out, you will not only be inhibiting muscle growth and fat loss, but you will be putting your body in an even more quickly deteriorating state of health than you would have already been in regardless simply as a result of supraphysiological androgen levels.
If you are using a TRT dose of testosterone, you would be best served by not unnecessarily inhibiting aromatase.
Also, if you are using an anabolic steroid that is not a potent substrate for aromatase, you would be best served by adding a testosterone base or a source of adequate estrogen to your cycle.
The interesting thing to evaluate would be whether all of the anabolic steroids previously described by the literature as horrendous for the heart and brain would still be described as such if an adequate dosage of exogenous estrogen was used in conjunction with them in the corresponding studies.
It certainly opens the mind up to potential hormone replacement therapy alternatives, hence my experimentation in the past with Trestolone monotherapy, low dose Nandrolone with exogenous estradiol, and SARMs with exogenous estradiol.