Effects of Androgens on the Brain

Androgens such as testosterone are generally viewed simplistically as creating aggression, impulsivity and antisocial behaviours. However, androgens influence behaviour in a complex way which includes promoting both pro- and antisocial behaviours, with a behavioural trend to increase social status¹. In a study testing acute effect of testosterone on behaviour, testosterone group was more likely to generously reward perceived good offers in a test whilst also being more harsh in punishing perceived bad offers¹. Furthermore, unknown is that there is evidence to suggest reduced serum androgens such as seen in age progression are a major risk factor for neurodegenerative diseases, and that the effect of the ε4 variant of the ApoE gene in mice (which diminishes memory and spatial learning) is prevented by administration of androgens².

Androgens are steroid hormones which agonise the nuclear androgen receptor and cause the transcription of genes which cause development of male secondary sexual characteristics³. Androgens are formed endogenously through steroidogenesis which is a multi-step process converting cholesterol to various steroid hormones⁴. The notable endogenous steroid hormones with significant agonism of the androgen receptor are testosterone and its metabolite dihydrotestosterone³. Other endogenous androgens are considered weak agonists and are often precursors to the steroidogenesis of testosterone. Testosterone is a substrate for the aromatase enzyme, unlike dihydrotestosterone which is considered a “pure” androgen, through which it is metabolised to the potent estrogen estradiol⁵, so this article will attempt to differentiate the androgenic effects on the mammalian brain from the indirect estrogenic signalling from the metabolism of testosterone.

Estradiol is known to have neuroprotective effects and is being investigated as therapy for Alzheimer‘s disease, but it has also been determined that the androgenic signalling of androgens in physiological concentrations (without metabolism to estrogens) is also neuroprotective⁶. Induced apoptotic effect in cultured human neurones is reduced when co-cultured with testosterone and an aromatase inhibitor, and also when co-cultured with the non-aromatizable androgen mibolerone⁶, suggesting metabolism of testosterone to estradiol is not necessary for its neuroprotective effects. Furthermore, when testosterone is co-cultured with an antiandrogen (flutamide), it no longer has protective effects on human neurones⁶ suggesting androgenic signalling may be neuroprotective.

Administration of high dose (5mg/kg equating to 400mg in an 80kg adult man) androgens (including testosterone propionate and an unspecified ester of dihydrotestosterone) in rats decreases dopamine in the hypothalamus and amygdala, without affecting norepinephrine and serotonin, and with no noted effect on other brain regions⁷. Furthermore, androgens influence behaviour by affecting the mesocorticolimbic system⁸. The mesocorticolimbic system is implicated in reward learning (and therefore addiction), so influences behaviour⁹.

Testosterone administration into the nucleus accumbens of rats causes conditioning to location due to association of the location with reward (comparably, this is also an effect of dopamine releasing drugs)⁸. This response to androgens is eliminated when a dopamine D₁ and D₂ receptor antagonist is co-administered⁸, suggesting testosterone’s influence on dopamine signalling. Young male chicks administered testosterone pecked grains of familiar colour and had more mate seeking persistence unlike placebo treated chicks which showed more flexibility in behaviour⁸. Testosterone seems to inhibit the ability to change response strategy when it is not effective, supported by the persistence-decreasing effect of antiandrogen treatment in the chicks⁸.

Gonadectomised rats had less perseverance in operant conditioning tasks and showed a deficit in working memory when compared to testosterone-treated gonadectomised rats⁸. Furthermore, significantly reducing androgen receptor agonism such as via antiandrogens causes reductions in executive functioning, cognitive control, attention and visuospatial ability, with a concurrent reduction in grey matter in areas of the prefrontal cortex⁸. Dendritic spine density is increased in the limbic system of rats treated with high doses of testosterone. In the medial prefrontal cortex, dihydrotestosterone increases dendritic spine formation⁸, suggesting the importance for androgens in the brain.

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References:

1. Dreher J., Dunne S., et al 2016.  Testosterone causes pro- and antisocial behaviors Proceedings of the National Academy of Sciences (PNAS) Oct 2016, 113 (41) 11633-11638; DOI: https://doi.org/10.1073/pnas.1608085113  

2. Jordan, C. L., & Doncarlos, L. (2008). Androgens in health and disease: an overview. Hormones and behavior, 53(5), 589–595. DOI: https://doi.org/10.1016/j.yhbeh.2008.02.016  

3. Handelsman DJ. Androgen Physiology, Pharmacology, Use and Misuse. [Updated 2020 Oct 5]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279000/  

4. Encyclopedia of Neuroscience, 2009. Steroidogenesis. Available online at https://www.sciencedirect.com/topics/medicine-and-dentistry/steroidogenesis 

5. Synthesis of Best-Seller Drugs, 2016. Aromatase. Available online at https://www.sciencedirect.com/topics/chemistry/aromatase 

6. Hammond J, Le Q, Goodyer C, Gelfand M, Trifiro M, LeBlanc A. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem. 2001 Jun;77(5):1319-26. PMID: 11389183. DOI: https://doi.org/10.1046/j.1471-4159.2001.00345.x  

7. Vermes I, Várszegi M, Tóth EK, Telegdy G. Action of androgenic steroids on brain neurotransmitters in rats. Neuroendocrinology. 1979;28(6):386-93. DOI: https://doi.org/10.1159/000122887  

8. Tobiansky D., Wallin-Miller K., et al 2018. Androgen Regulation of the Mesocorticolimbic System and Executive Function. Front. Endocrinol., 05 June 2018. DOI: https://doi.org/10.3389/fendo.2018.00279  

9. European Commission 2019. CORDIS EU Research Results – Mesocorticolimbic System: functional anatomy, drug-evoked synaptic plasticity & behavioral correlates of Synaptic Inhibition. Available online at https://cordis.europa.eu/project/id/322541 

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