Breaking News: Testosterone and Antidepressants

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The Latest Drug Science

Does testosterone kill brain cells? Do antidepressants turn you into a eunuch? Let’s dig into the real science.

This is Your Brain on Testosterone

Both lay press articles and scientific journals have recently implicated testosterone as a potential neurotoxic agent. However, there are major problems with the studies. Here’s the CliffsNotes version of my journal article on the subject:

In Vitro Data

When scientists want to isolate a given effect for a molecule in a particular tissue, in vitro studies are useful. However, when these studies’ limitations aren’t considered, it often leads to ill-supported conclusions.

Here’s what a Science Daily article claimed, based on one such in vitro study:

“A Yale School of Medicine study shows for the first time that a high level of testosterone, such as that caused by the use of steroids to increase muscle mass or for replacement therapy, can lead to a catastrophic loss of brain cells.”

Sounds pretty frightening right? Unfortunately, the concentration used in this study was 1 µmol, equivalent to around 28,843 ng/dl, a concentration that even those juicing would have difficulty reaching consistently.

The highest overdose ever documented in a man self-administering testosterone enanthate was only 11,400 ng/dl. Classifying testosterone as “neurotoxic” based on this concentration is like calling water a potential rat poison while leaving out that the amount of water required to act as a “poison” would require you to drown the rat.

This isn’t even addressing the fact that we’re only considering total testosterone levels in the blood, as opposed to only the portion that isn’t bound by sex hormone binding globulin (SHBG), which is the portion considered available to reach the brain. It gets worse if we consider tissue distribution.

Distribution to Brain Tissue

Once we consider how unlikely it is for testosterone levels in the blood to reach concentrations such as 1 µmol (one-millionth of a mole), we can see how unlikely it is for concentrations to reach damaging levels in the brain. After all, testosterone levels in the blood are 3-10 times higher than those in the brain.

What about those studies showing that guys who abuse steroids are more likely to have brain damage?

Those studies were observational, retrospective studies. The major issue with them is not only the fact that they can’t demonstrate cause-effect, but that they’re also vulnerable to several major confounders.

These include:

  • Participants consuming other drugs, both legal and illegal
  • Having pre-existing psychiatric and psychological conditions that would explain these differences in brain structure/function, which would make them more prone to use and abuse anabolic steroids and suffer from addiction.
  • A lower IQ and issues with memory and recall when it comes to self-reported data.

Here’s What You Need to Know

Using testosterone for TRT may cause some adverse effects (just as with any pharmaceutical), and abusing testosterone will increase the likelihood of experiencing various adverse effects, some of which may be serious.

However, the available data is fairly weak that testosterone use will increase your risk of dementia or any form of neurological dysfunction or disease. On the contrary, maintaining testosterone levels in the normal range may be helpful when it comes to brain health.

Antidepressants
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Do Antidepressants Decrease Testosterone?

While most side effects of antidepressants are well known, the question of whether they affect testosterone levels hasn’t been addressed very often.

First, let’s clarify what we mean when we talk about antidepressants. We’ve got tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin antagonist-reuptake inhibitor (SARIs). Here are examples of each class:

SSRIs: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, fluvoxamine
SNRIs: duloxetine, venlafaxine, desvenlafaxine
TCAs: amitriptyline, amoxapine, imipramine
SARIs: trazodone, nefazodone
MAOIs: tranylcypromine, isocarboxazid, phenelzine, selegiline

Some of these drugs may be further delineated into other subgroups, and there are also more groups for drugs that were previously considered unclassifiable, not to mention the newest generation of drugs (e.g., serotonin modulators). Regardless, the drugs listed above are the main groups we’ll consider for this discussion.

What’s the Evidence?

There’s some limited evidence that antidepressants with serotoninergic effects can potentially decrease testosterone in some individuals. The serotoninergic action is thought to inhibit dopamine’s inhibitory effect on prolactin release. This increase in prolactin may decrease testosterone by decreasing the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus.

However, some have argued that the potential effects on testosterone are independent of prolactin, noting decreased testosterone with no changes in prolactin.

In any case, keep in mind that these are not absolute effects. Using serotoninergic antidepressants may not have much, if any, effect on prolactin in most people. Furthermore, even if prolactin rises in some, this doesn’t necessarily mean that testosterone levels will decline significantly.

Inconsistencies in Studies

The few studies that examined the effect of some antidepressants on testosterone have shown mixed results. Some studies show a decline in testosterone only in some individuals, while some show little change, and some actually show an increase in testosterone.

Part of the difficulty in examining the issue is that depression itself may decrease testosterone levels, so therapeutic effects from serotoninergic drugs may reverse or attenuate this decrease. The studies with the strongest design (randomized, controlled trials) often have one or more limitations (small doses, limited duration, and limited sample sizes) that make it difficult to capture change that only a small percentage of subjects experience.

However, some have still reported a small and transient decrease in testosterone and an elevation of estradiol at certain time points. Prolactin, however, wasn’t influenced. Additionally, the substantial inter-individual variation in the pharmacokinetics and pharmacodynamics of these medications can also explain the inconsistent results.

Potential Solutions

Since the main proposed mechanism involved in antidepressant-related decreases in testosterone is due to serotoninergic effects with a lack of dopaminergic activity, which in turn raises prolactin, the SSRI sertraline may, hypothetically at least, be less likely to raise prolactin and reduce testosterone levels, although the evidence is mixed.

In addition, antidepressants such as bupropion, which acts through noradrenergic and dopaminergic activity rather than serotoninergic activity, might be something to explore as an alternative or as an add-on therapy.

Some may not want to switch from their current treatment and may instead want to discuss testosterone replacement therapy (TRT) with their physician.

However, the first step, if you suspect your testosterone levels may have declined due to the antidepressant you’re taking, is to have your testosterone (and potentially prolactin) levels assessed.

If you have historical measurements of your hormone levels (a baseline reading) prior to taking antidepressants, that would be helpful for comparison. If you happen to be one of the unlucky ones whose T levels have declined while on antidepressants, discuss trying other options with your doc.

Here’s What You Need to Know

  • Some antidepressants may decrease testosterone levels, presumably by raising prolactin, although the exact mechanism isn’t clear.

  • Based on available evidence, decreased testosterone only occurs in a relatively small number of people.

  • The response with respect to antidepressants and the effect on testosterone is highly variable, likely due to genetic and non-genetically influenced inter-individual differences in pharmacokinetics and pharmacodynamics.

  • If you suspect your testosterone levels have declined, discuss evaluating your hormone levels and potential options with your healthcare provider.

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References

References

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TRT isn’t AAS

There is a huge difference between 100mg per week abd 700mg test 700mg tren, some mast thrown in for good measure etc

Anabolic steroids most certainly are neurotoxic when used in high dosages.

Testosterone replacement isn’t neurotoxic. Likely neuroprotective.

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SSRI’s are pure poison.

Check out PSSD

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I’m in agreement that the doses utilized for TRT are unlikely to be neurotoxic. I’m not as certain that neurotoxicity occurs even with large supraphysiologic doses of testosterone as the concentrations utilized in vitro are much higher than anyone could likely reach even with abuse. Regarding other androgens aside from testosterone, their potential neurotoxicity is also largely based upon less convincing evidence. The concentrations utilized in vitro showing neurotoxicity are often in the high micromolar range which is unlikely to be reached in the human brain. In addition, the animal model data use rodents which are not a good model for humans both in terms of androgen metabolism and sensitivity; monkeys are considered the gold-standard. Last, there is the observational data that has been published recently showing evidence of brain structure/function alterations in long-term androgen abusers. These studies, aside from not being able to demonstrate causation, are prone to major confounding that is difficult to control for. One of the more recent studies showed evidence of deviant brain aging in dependent (but not in those not dependent) anabolic steroid users compared to weight lifting controls but there was no difference between previous users (i.e., those who had ceased using at least 6 months prior) and the weight lifting controls, despite previous users having used nearly just as large of quantities as the dependent users for several years. The authors speculate that this might indicate recovery of these changes, but I find that an unlikely explanation considering the findings in other papers. I believe they’re merely finding associations between well-known differences in brain regions that occur in those prone to and suffering from addiction/dependence (the authors themselves concede this amongst several limitations of their work). The fact that longitudinal data failed to find evidence of increased brain aging supports this.

I think androgens certainly have the potential for adverse effects but the body of evidence for neurotoxicity isn’t particularly strong, especially compared to say cardiovascular effects.

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Hey,

Really interesting article, even leaving aside the silly study that prompted it.

I assume when we’re referring to neuro toxicity, it’s Testosterone acting negatively (associated with cell death) on dopamine receptors? Or, is there a more direct negative connection?

Do you rate neurotransmitter tests at all, or are snapshots completely useless? Or a more direct question, how would you know if TRT was having such a negative effect (if indeed it does).

I take a dopamine agonist to stop my brain being completely useless, which in turn seems to be causing iron saturation issues. On my 4th week of TRT and finding a link between it and death of dopamine receptors is making me curious.

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From another study;

The observation that testosterone did not induce apoptosis in the nondopaminergic GT1-7 cell line suggests that dopaminergic N27 cells are more sensitive to the neurotoxic effects of androgens. One inherent property of dopamine cells is a high degree of ROS formation and oxidative stress due to the catabolism of dopamine itself

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No, the proposed neurotoxicity from testosterone is a direct effect but to be clear, the concentrations required are extremely high.

I wouldn’t be concerned about TRT causing neurotoxicity as even those publishing in this area acknowledge that the concentrations experienced with TRT are, if anything, likely neuroprotective. The concentrations required for potential neurotoxicity with testosterone are far higher than TRT would ever achieve.

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