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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.
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, fluvoxamineSNRIs: duloxetine, venlafaxine, desvenlafaxineTCAs: amitriptyline, amoxapine, imipramineSARIs: trazodone, nefazodoneMAOIs: 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.
References
References
Yale University. (2006, September 27). Elevated Testosterone Kills Nerve Cells. ScienceDaily. Retrieved January 18, 2023 from Elevated Testosterone Kills Nerve Cells — ScienceDaily
Willson C. Opinion: Misadventures in Toxicology: Concentration Matters for Testosterone-Induced Neurotoxicity. Toxics. 2023.
Cai Z, Li H. An Updated Review: Androgens and Cognitive Impairment in Older Men. Front Endocrinol (Lausanne). 2020;11:586909. Published 2020 Nov 13. doi:10.3389/fendo.2020.586909
Safarinejad MR. Evaluation of endocrine profile and hypothalamic-pituitary-testis axis in selective serotonin reuptake inhibitor-induced male sexual dysfunction. J Clin Psychopharmacol. 2008 Aug;28(4):418-23. doi: 10.1097/JCP.0b013e31817e6f80. PMID: 18626269.
Pavlidi P, Kokras N, Dalla C. Antidepressants’ effects on testosterone and estrogens: What do we know? Eur J Pharmacol. 2021 May 15;899:173998. doi: 10.1016/j.ejphar.2021.173998. Epub 2021 Mar 4. PMID: 33676942.
Torre DL, Falorni A. Pharmacological causes of hyperprolactinemia. Ther Clin Risk Manag. 2007 Oct;3(5):929-51. PMID: 18473017; PMCID: PMC2376090.
Grattan DR. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis. J Endocrinol. 2015 Aug;226(2):T101-22. doi: 10.1530/JOE-15-0213. Epub 2015 Jun 22. PMID: 26101377; PMCID: PMC4515538.
Xu ZH, Pan D, Liu TY, Yuan MZ, Zhang JY, Jiang S, Wang XS, Guan Y, Zhao ST. Effect of prolactin on penile erection: a cross-sectional study. Asian J Androl. 2019 Nov-Dec;21(6):587-591. doi: 10.4103/aja.aja_22_19. PMID: 31044754; PMCID: PMC6859666.
Ajmal A, Joffe H, Nachtigall LB. Psychotropic-induced hyperprolactinemia: a clinical review. Psychosomatics. 2014 Jan-Feb;55(1):29-36. doi: 10.1016/j.psym.2013.08.008. Epub 2013 Oct 18. PMID: 24140188.
Park YM. Serum Prolactin Levels in Patients with Major Depressive Disorder Receiving Selective Serotonin-Reuptake Inhibitor Monotherapy for 3 Months: A Prospective Study. Psychiatry Investig. 2017 May;14(3):368-371. doi: 10.4306/pi.2017.14.3.368. Epub 2017 May 16. PMID: 28539956; PMCID: PMC5440440.
Coker F, Taylor D. Antidepressant-induced hyperprolactinaemia: incidence, mechanisms and management. CNS Drugs. 2010 Jul;24(7):563-74. doi: 10.2165/11533140-000000000-00000. PMID: 20527996.
Buvat J. Hyperprolactinemia and sexual function in men: a short review. Int J Impot Res. 2003 Oct;15(5):373-7. doi: 10.1038/sj.ijir.3901043. PMID: 14562140.
von Bardeleben U, Steiger A, Gerken A, Holsboer F. Effects of fluoxetine upon pharmacoendocrine and sleep-EEG parameters in normal controls. Int Clin Psychopharmacol. 1989 Jan;4 Suppl 1:1-5. PMID: 2536765.
Ljung T, Ahlberg AC, Holm G, Friberg P, Andersson B, Eriksson E, Björntorp P. Treatment of abdominally obese men with a serotonin reuptake inhibitor: a pilot study. J Intern Med. 2001 Sep;250(3):219-24. doi: 10.1046/j.1365-2796.2001.00881.x. PMID: 11555126.
McIntyre RS, Mancini D, Eisfeld BS, Soczynska JK, Grupp L, Konarski JZ, Kennedy SH. Calculated bioavailable testosterone levels and depression in middle-aged men. Psychoneuroendocrinology. 2006 Oct;31(9):1029-35. doi: 10.1016/j.psyneuen.2006.06.005. Epub 2006 Sep 5. PMID: 16908107.
Schlösser R, Wetzel H, Dörr H, Rossbach W, Hiemke C, Benkert O. Effects of subchronic paroxetine administration on night-time endocrinological profiles in healthy male volunteers. Psychoneuroendocrinology. 2000 May;25(4):377-88. doi: 10.1016/s0306-4530(99)00065-7. PMID: 10725614.
Nadeem HS, Attenburrow MJ, Cowen PJ. Comparison of the effects of citalopram and escitalopram on 5-Ht-mediated neuroendocrine responses. Neuropsychopharmacology. 2004 Sep;29(9):1699-703. doi: 10.1038/sj.npp.1300475. PMID: 15127082.
Punjani N, Kang C, Flannigan R, Bach P, Altemus M, Kocsis JH, Wu A, Pierce H, Schlegel PN. Impact of duloxetine on male fertility: A randomised controlled clinical trial. Andrologia. 2021 Nov;53(10):e14207. doi: 10.1111/and.14207. Epub 2021 Aug 9. PMID: 34374108; PMCID: PMC8487983.
Tanrikut C, Feldman AS, Altemus M, Paduch DA, Schlegel PN. Adverse effect of paroxetine on sperm. Fertil Steril. 2010 Aug;94(3):1021-6. doi: 10.1016/j.fertnstert.2009.04.039. Epub 2009 Jun 10. PMID: 19515367.
Ostad Haji E, Hiemke C, Pfuhlmann B. Therapeutic drug monitoring for antidepressant drug treatment. Curr Pharm Des. 2012;18(36):5818-27. doi: 10.2174/138161212803523699. PMID: 22681162.
Trenque T, Herlem E, Auriche P, Dramé M. Serotonin reuptake inhibitors and hyperprolactinaemia: a case/non-case study in the French pharmacovigilance database. Drug Saf. 2011 Dec 1;34(12):1161-6. doi: 10.2165/11595660-000000000-00000. PMID: 22077504.
Ajmal A, Joffe H, Nachtigall LB. Psychotropic-induced hyperprolactinemia: a clinical review. Psychosomatics. 2014 Jan-Feb;55(1):29-36. doi: 10.1016/j.psym.2013.08.008. Epub 2013 Oct 18. PMID: 24140188.
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