XY Brain: Men's Mental Health

The most obvious genetic characteristic of men is their Y chromosome. Although there are exceptions, women usually have two X chromosomes, and men have one X chromosome (inherited from their mother) and one Y chromosome (from their father). The Y chromosome is the smallest of all human chromosomes, roughly a third of the size of the X chromosome, and whilst the X chromosome has about 900 genes, the Y chromosome has considerably less (estimates range from 55 to 100) (1). 

Until recently, it was assumed that genes on the Y chromosome were only involved in male sex determination, development, and spermatogenesis. However, evolving research suggests that they have broader regulatory effects which could explain differences in disease susceptibility between men and women. For the purpose of this article, we will focus on what we know, which is sufficiently enlightening and enriching to nutritional therapy practice.

The X Factor

Much has been made of the MAOA gene impact on aggression, and the ‘warrior or worrier’ moniker. As the name suggests, the monoamine oxidase (MAO) genes oxidise monoamines such as serotonin, noradrenaline, adrenaline, histamine and dopamine, as well as excess tyramine, found in cheese.

A SNP (941T>G) on the promoter region of the MAOA gene has been consistently associated with differential activity - the (wild) G allele being faster and the T (variant) allele slower. The slower activity T allele is commonly referred to as the ‘warrior’ genotype due to higher levels of serotonin (and possibly other catecholamines). Conversely, the lower serotonin, G allele is classified as the ‘worrier’ (2).

Both MAO (A and B) genes are located on the X chromosome. As females have two X chromosomes, they inherit an allele (base) from each parent and thus a wild, heterozygous or homozygous genotype. However, as males only have a single X chromosome, they have one MAOA allele (inherited maternally). So, according to the ‘warrior or worrier’ hypothesis, as males cannot inherit a ‘balancing’ allele (in other words, cannot be heterozygous (GT)), their MAOA gene must be either fast (G) - ‘worrier,' or slow (T) - ‘warrior’ (3).

Whilst the ‘warrior or worrier’ analogy may be memorable (and is quoted extensively, to promote direct to consumer genetic testing), it is at best over simplistic or, at worst, simply wrong. Alarmingly, this genotype has been used (successfully) in defence of aggression (claiming that aggressive behaviour was due to their genetic make up) in at least two legal cases in the US (4). 

How do we fix these problems? The answer is context! 

The context considers the whole person - what are their symptoms, and their family history? How does nutrition and lifestyle play in to this? And, last, but certainly not least, what about the genes? - noting the plural. 

Whilst it is important to know that the MAOA gene requires vitamin B2 as cofactor, and that curcumin and quercetin inhibit it, no gene exists in a vacuum, and so MAOA should not be looked at in isolation. To understand the potential impact, we do want to know the genotype - likely fast, slow or intermediate (in women), but we also need information about the wider serotonin (and other catecholamine) system(s). For example, the availability of tryptophan (needed to make serotonin) which can be impacted by inflammation (in turn impacted by genes and environmental factors such as infection and diet), and SNPs on the TPH2 gene - which together with insufficiency of cofactors including Vitamin D, can slow the conversion of tryptophan to 5-HTP (precursor to serotonin). In addition, SNPs on receptor genes can impact an individual’s response/ sensitivity to serotonin (5).

Looking at the wider picture, we should also consider noradrenaline and adrenaline, as these are also degraded by MAOA, and related genes such as COMT (which deactivate catecholamines), and environmental factors including methylation (COMT is a methyl transferase gene requiring SAMe, the master methyl donor, as cofactor). These things considered high adrenaline may be a more likely culprit than MAOA (or serotonin) in aggression. Which leads us nicely on to testosterone…

The Big T

Testosterone is the primary male hormone and has many functions and effects including on: skin - hair growth, collagen formation and sebum production; sexual development - of organs, erectile function, spermatogenesis and prostate growth and function; brain - libido, cognition, memory, and (as we will see) HPA balance; muscle - strength, volume and resilience; and bone - linear growth and closure of epiphyses (impacting height) (6).

Once again, there is an over simplistic prevalent assumption that testosterone positively correlates aggression. Although there is research that connects very high testosterone with aggressive behaviour, in fact, lower testosterone is prevalent in many conditions including: metabolic syndrome, infertility, hypertension, lidipaemia, erectile dysfunction, osteoporosis, fatigue, cognitive decline, and mood disorders - including aggressive behaviour (7). 

Under ‘normal’ circumstances, when life is not too stressful, and nutrients and lifestyle are sufficient, cholesterol is converted firstly to pregnenolone, and then to steroid hormones - progesterone, corticosteroids (cortisone and cortisol), testosterone and oestrogen. However, under pressure, genes and environmental factors can tip the balance, in helpful and not so helpful ways. 

In a context of chronic stress, resources are naturally diverted to prioritise cortisol. A SNP on the CYP17A1 gene is associated with up-regulated oxidation of progesterone to 17-OH progesterone the substrate for cortisol. Stress, blood sugar dysregulation (and high insulin) and alcohol are also known to up-regulate this process. In addition, a SNP on the HSD11B1 hydroxysteroid 11-beta dehydrogenase 1) gene confers more rapid conversion of cortisone (inactive) to cortisol, and is stimulated by stress, insulin resistance, and inflammation. High cortisol can worsen acne vulgarisms, increase the risk of hypertension, and shut down natural production of testosterone (8).

Testosterone is aromatised to oestrogen (by CYP19A1) or reduced to more potent 5a-DHT (5alpha-Dihydrotestosterone) by 5aR (5alpha-Reductase). 5aR is naturally higher in males, and conversion to 5a-DHT is favoured over oestrogen. However, SNPs on CYP19A (aromatase) confer higher activity, as do stress and insulin (again!). In males, excess oestrogen can cause symptoms such as gynecomastia (appearance of breasts), erectile dysfunction, and infertility. In this case, natural aromatase inhibitors including indole-3-carbinol (found in cruciferous vegetables), green tea, zinc, vitamin E, resveratrol, flavonoids, can be helpful (9,10).

It’s not the SNP, it’s the wrong environment.

On the other side of the equation, 5aR (5alpha-Reductase) activity can be impacted by SNPs on the SRD5A2 gene. A G allele (coding for valine) at the Val89Leu position confers higher activity, and more 5a-DHT, which can contribute to metabolic dysregulation (including insulin resistance) with BPH (benign prostatic hypertrophy), and premature baldness (in males), whereas the lower activity C allele (leucine) genotype can contribute to low androgen (5a-DHT) symptoms (low libido, fatigue, and depression) (11).

Finally (in the metabolism of testosterone), 3a-HSD (3-alpha hydroxysteroid dehydrogenase), coded by the AKRIC4 gene, reduces 5a-DHT to Adiol (3a-androstanediol) a potent neurosteroid which exerts inhibitory effects via the GABA-A receptor. A SNP (L311V) on the ARK1C4 gene can reduce activity by up to 80% significantly impacting Adiol (neurosteroid) levels (12). Additionally a common SNP on GABRA2 confers weaker binding of neurosteroids and is independently associated with anxiety disorders, and alcohol misuse (13). 

Although having low testosterone in the first place can have downstream effects on 5a-DHT and subsequently Adiol, genetic SNPs can have significant (positive or negative) impacts. Additionally, the reducing agent NADH (a form of vitamin B3), is a cofactor for both 5aR and 3a-HSD. 

Other 3a-HSD activators include calcium, omega 3-fatty acids in particular palmitoylethanolamide (PEA), evening primrose oil, gingko biloba, crocus sativus and some SSRIs, which can all help to support Adiol function. Conversely, if testosterone is high and/ or 5alpha reductase is up-regulated, 5aR inhibitors such as saw palmetto, stinging nettle, quercetin, zinc, flaxseed, EGCG (epigallocatechin gallate in green tea) and soy isoflavones, can be helpful in a context of excess androgenic symptoms (14).

HPA Axis

The hypothalamic–pituitary–adrenal axis (HPA axis) is a major neuroendocrine system that controls responses to stress and regulates stress hormones such as cortisol and adrenaline, and interacts with the HPG axis which regulates sex steroid hormones. Both HPA and HPG axes regulation involves negative and positive feedback loops, which are designed to enable flexibility according to environmental (endogenous and exogenous) conditions (15).

One of the most significant impacts on the HPA axis is the FKBP5 (FK506 binding protein 51) gene, which regulates (inhibits) glucocorticoid receptor (GC) sensitivity. The FKBP5 rs1360780 T allele is associated with increased activity and GC inhibition and prolonged cortisol activation in response to stressors. An increasing body of research has linked this higher activity FKBP5 genotype to diverse phenotypes including anxiety, depression, PTSD, suicidality, aggression, violent behaviours and psychosis (16).

However, this outcome is not determinate. It can be altered, for better or for worse, by other genes and environmental factors - including testosterone. In fact, testosterone plays an important role in anti-anxiety and anti-depressant behaviours at multiple levels of the HPA axis - reducing adrenal sensitivity to ACTH, suppression of ACTH release (from the pituitary) and CRH release from the PVN. This is mediated, perhaps surprisingly by testosterone (and its metabolites) binding with Oestrogen Receptor 2 (ESR2). The lower sensitivity ESR2 1730G>A genotype is less conducive to testosterone (and oestrogen) modulation of HPA activity. Low testosterone can exacerbate the situation increasing the risk of HPA hyperactivity and consequently, high cortisol, metabolic dysregulation, and symptoms of depression (17). The risk is even higher if there are SNPs on adrenaline beta receptors (ADRB1 and ADBR2) which confer increased sensitivity and response to adrenaline (hypertension and glycemic dysregulation), and TCF7L2 and MTNR1B which increase risk of hyperglycaemia due to insulin insufficiency (18,19).

On the other side of the equation (HPA & HPG Axis diagram), the OPRM1 and FAAH genes conduct positive feedback to the HPA, thus enabling a stress response to happen (which is a good thing). SNPs on these genes are associated with blunted HPA and HPG responses with negative affects on fertility (reduced sperm  count in males, and disrupted/ anovulatory cycles in females), and emotional suppression. SNPs on the OPRM1 gene have been specifically linked to alcohol use (perhaps as a means to enable self expression) (20). FAAH is responsible for the inactivation and clearance of fatty acid amides including the endocannabinoid AEA (anandamide). The lower activity FAAH genotype confers less flexible / variable response (cortisol raising and then falling) in response to stressors (21).

Size Isn’t Everything

Men cannot change their chromosomes and genes, but they can learn to understand how they impact their health.Nutrigenomics help us embrace the dynamics between genes (and other genes), nutrition, and lifestyle beyond testosterone's simplified men's health construct. Exploring the steroid metabolic pathways and regulatory mechanisms shows there is more to testosterone than the stereotypical portrayal of physical masculinity and aggression, indeed the opposite is true. The Y chromosome may be small, but men’s health and hormones are just as complex and interesting as women’s, and that’s no bad thing.

By embracing the complexity and the context, and using visualisation techniques to understand it, we can discover how to work with our genes and hormones rather than against them, to optimise Men’s Health.

Our Unique Approach

Lifecode Gx® offers a range of specialist nutrigenomics DNA test panels which inform how inherited health risks can be mitigated through personalised nutrition and lifestyle change.

Genotype results are presented in the context of nutrition and other environmental factors, such as sleep, stress, physical activity and chemicals, that can influence them. Our unique colour-coded pathway diagrams provide easy to digest visual summaries, alongside in-depth insights into the risks or protective potential of each genotype. This enables a deeper and holistic understanding of results and identification of the lifestyle changes that will be most effective. The genes and pathways discussed in this article are included in Lifecode Gx Hormones report (22).

Resources

Practitioner Registration: www.lifecodegx.com/registration

Hormones Report: https://www.lifecodegx.com/hormones-report

Nutrigenomics Training: https://www.lifecodegx.com/training

References

1. Genome.gov. 2021. Y Chromosome. [online] Available at: <https://www.genome.gov/about-genomics/fact-sheets/Y-Chromosome-facts>
2. McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD. Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation. Proc Natl Acad Sci U S A. 2009;106(7):2118-2123. doi:10.1073/pnas.0808376106
3. Delisi, Matt. (2015). The Warrior Gene: MAOA genotype and antisocial behavior in males. https://www.researchgate.net/publication/271385397_The_Warrior_Gene_MAOA_genotype_and_antisocial_behavior_in_males
4. Farahany, N. and Robinson, G., 2021. Criminal defendants still cite a ‘gene for violence.’. The Washington Post, [online] Available at: <https://www.washingtonpost.com/outlook/2021/03/18/genetics-criminal-defense-warrior-violence/>
5. Latsko MS, Gilman TL, Matt LM, Nylocks KM, Coifman KG, Jasnow AM. A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val66Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects. PLoS One. 2016;11(10):e0162585. Published 2016 Oct 3. doi:10.1371/journal.pone.0162585
6. Yourhormones.info. 2021. Testosterone | You and Your Hormones from the Society for Endocrinology. [online] Available at: <https://www.yourhormones.info/hormones/testosterone/>
7. Urologyhealth.org. 2021. Low Testosterone: Symptoms, Diagnosis & Treatment - Urology Care Foundation. [online] Available at: <https://www.urologyhealth.org/urology-a-z/l/low-testosterone> 
8. Farag AGA, Badr EA, Eltorgoman AMA, Assar MF, Elshafey EN, Tayel NR, Aboutaleb HE. Role of 11β HSD 1, rs12086634, and rs846910 single-nucleotide polymorphisms in metabolic-related skin diseases: a clinical, biochemical, and genetic study. Clin Cosmet Investig Dermatol. 2019 Jan 23;12:91-102. doi: 10.2147/CCID.S193156. PMID: 30774405; PMCID: PMC6350638.
9. Alison M. Dunning, Mitch Dowsett, Catherine S. Healey, Louise Tee, Robert N. Luben, Elizabeth Folkerd, Karen L. Novik, Livia Kelemen, Saeko Ogata, Paul D. P. Pharoah, Douglas F. Easton, N. E. Day, Bruce A. J. Ponder, Polymorphisms Associated With Circulating Sex Hormone Levels in Postmenopausal Women, JNCI: Journal of the National Cancer Institute, Volume 96, Issue 12, 16 June 2004, Pages 936–945, https://doi.org/10.1093/jnci/djh167
10. Artigalás, O., Vanni, T., Hutz, M.H. et al. Influence of CYP19A1 polymorphisms on the treatment of breast cancer with aromatase inhibitors: a systematic review and meta-analysis. BMC Med 13, 139 (2015). https://doi.org/10.1186/s12916-015-0373-9
11. LLC, H., 2021. 5a-DHT | Healthmatters.io. [online] Healthmatters.io. Available at: <https://healthmatters.io/understand-blood-test-results/5a-dht>
12. Lord SJ, Mack WJ, Van Den Berg D, et al. Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study. Breast Cancer Res. 2005;7(3):R336-R344. doi:10.1186/bcr999
13. Lieberman R, Kranzler HR, Joshi P, Shin DG, Covault J. GABRA2 Alcohol Dependence Risk Allele is Associated with Reduced Expression of Chromosome 4p12 GABAA Subunit Genes in Human Neural Cultures. Alcohol Clin Exp Res. 2015;39(9):1654-1664. doi:10.1111/acer.12807
14. Ben's Natural Health. 2021. 5 Alpha-Reductase Inhibitors: BPH Treatment - Ben's Natural Health. [online] Available at: <https://www.bensnaturalhealth.com/blog/5-alpha-reductase-inhibitors/> 
15. Acevedo-Rodriguez, A. & Kauffman, Alexander & Cherrington, Brian & Borges, Cibele & Roepke, Troy & Laconi, Myriam. (2018). Emerging insights into Hypothalamic-pituitary-gonadal (HPG) axis regulation and interaction with stress signaling. Journal of Neuroendocrinology. 30. e12590. 10.1111/jne.12590. 
16. Reul JM, Collins A, Saliba RS, et al. Glucocorticoids, epigenetic control and stress resilience. Neurobiology of Stress. 2015 Jan;1:44-59. DOI: 10.1016/j.ynstr.2014.10.001. PMID: 27589660; PMCID: PMC4721318
17. Jurečeková, J., Kmeťová Sivoňová, M., Drobková, H., Híveš, M., Evin, D., Kliment, J., & Dobrota, D. (2021). Association between estrogen receptor β polymorphisms and prostate cancer in a Slovak population. Oncology Letters, 21, 214. https://doi.org/10.3892/ol.2021.12475
18. Ding W, Xu L, Zhang L, et al. Meta-analysis of association between TCF7L2 polymorphism rs7903146 and type 2 diabetes mellitus. BMC Med Genet. 2018;19(1):38. Published 2018 Mar 7. doi:10.1186/s12881-018-0553-5
19. Garaulet M, Gómez-Abellán P, Rubio-Sastre P, Madrid JA, Saxena R, Scheer FA. Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. Metabolism. 2015 Dec;64(12):1650-7. doi: 10.1016/j.metabol.2015.08.003. Epub 2015 Aug 14. PMID: 26440713; PMCID: PMC4856010 
20. Lovallo, W., Enoch, MA., Acheson, A. et al. Cortisol Stress Response in Men and Women Modulated Differentially by the Mu-Opioid Receptor Gene Polymorphism OPRM1 A118G. Neuropsychopharmacol 40, 2546–2554 (2015). https://doi.org/10.1038/npp.2015.101
21. Hill MN, Tasker JG. Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2012;204:5-16. doi:10.1016/j.neuroscience.2011.12.030
22. https://www.lifecodegx.com