by Shu‘ayb Simmons

Graphic design by Michie (Xingyu) Wu

Introduction: Disparities in Illness Across Sex

Disparities in disease incidence across males and females are well established. Here, the word ‘disparity’ serves to denote the unequal incidence of illness manifestation across sex. In general, males are more susceptible to infectious diseases whereas females are more prone to autoimmune diseases.¹ There equally exist illnesses that affect only one sex or one sex in the majority. For example, only females attain certain autoimmune diseases, such as Turner Syndrome, and are more likely to manifest conditions such as Chronic Fatigue Syndrome (CFS).² Males, on the other hand, are more likely to attain illnesses such as stomach cancer, abdominal aortic aneurysms, tuberculosis, esophageal cancer, and liver cancer. So why do these disparities in illness incidence occur across sex exist? They can be attributed mainly to variations in the immune system across sex due to factors like high testosterone levels and chromosomal differences.

A Key Distinction: Sex vs. Gender

The operative words in this article are female and male (i.e., sex) and not woman and man (i.e., gender). Sex and gender are not analogous nor interchangeable. Sex denotes one’s biological chromosome makeup (male = XY, female = XX, etc.). Contrarily, gender refers to the social role one chooses to adopt. This is an important distinction to highlight as the crux of this article focuses on sex.

The Immune System & Sex

Threats to one’s health are not few and far between; bacteria, toxins, and viruses can all cause illness and potentially death. So how exactly do we humans defend ourselves from these serious threats? The immune system is the first common biological defence that pathogens (i.e., illness-causing substances) meet. The immune system is incredibly complicated. In simplified terms, it is a series of cells that aim to conquer the threat (i.e., the antigen) to maintain the host’s health (i.e., the human). The immune system is capable and consists of two components. The first is innate immunity, which can be considered the general immune response. The second is adaptive immunity and mounts a pre-programmed immune response to similar antigens that once invaded the host body, providing the host with a more specific immune defence. The immune system, however, is not infallible and proves virtually useless against specific predators like Naegleria fowleri (the brain-eating parasite). The immune system is also not universal, and its efficacy can be largely determined by the environment and the individual in question. Additionally, the human immune system is ‘sexually dimorphic,’ a million-dollar phrase meaning that the immune response is different across sex. 

The Big T: Testosterone

Hormones are chemical signals of the endocrine system and are secreted by the endocrine glands. Hormones can be divided into two broad classes: steroid or peptide hormones.³ Hormones and behaviour are bidirectional; hormones influence behaviour, and, in turn, behaviour influences hormones. Testosterone (The Big T) is a cholesterol-derived steroid hormone and is one of four androgens. It is synthesized by the ovaries and adrenal glands in females and by the Leydig cells and adrenal glands in males.⁴ Testosterone is present in both females and males, although at a much higher quantity in males, and is critical for developing male characteristics.⁴ Testosterone also boasts immunosuppressive (i.e., immune system weakening)¹ and analgesic (i.e., pain-relieving) qualities, indicating that it can lower the immune system’s efficacy and make pain more bearable. Granted, not all research supports this theory. Nowak and colleagues (2018) did not find a positive relationship between testosterone and immunosuppression.⁵ However, this finding was only significant when considering body mass index (BMI) and age as covariates in their model, suggesting that these are potential confounders. There has been an equal query as to whether testosterone promotes aggressive behaviour since it is marginally beneficial in bouts of human aggression,⁶ however, further research is required to assess the robustness of this relationship due to the paucity of research on the matter. 

Additional Key Players & Conclusion

Testosterone is not the only key player in the sexual dimorphism of the immune response and its consequent effect on the immune system. Factors such as one’s genetic makeup also play a role. Males possess XY chromosomes, whereas females have XX chromosomes. The haploidy (i.e., the singular appearance of X) of the male chromosome is costly; it renders males more susceptible to infectious diseases and diminishes immune system efficacy. Experimental studies in autoimmune encephalitis mice assessing the effect of sex chromosomes on illness have found that mice with XX chromosomes experienced worsened disease progression compared to XY mice.¹ Difference in lifestyles across sex (e.g.., differences in engaged behaviour, thus changing one’s environment) is another potential key player in the disparities of the immune system between sex. Although–immunologically speaking–the Big T may sometimes cost the win, it’s a fascinating hormone with a fascinating immune system interplay. I doubt anyone could imagine a world without testosterone.

References

1. Klein, S. L., & Flanagan, K. L. (2016). Sex differences in immune responses. Nature Reviews. Immunology, 16(10), 626–638. https://doi.org/10.1038/nri.2016.90
2. Faro, S. et al. (2016). Gender Differences in Chronic Fatigue Syndrome. Reumatología Clinica (Barcelona), 12(2), 72–77. https://doi.org/10.1016/j.reumae.2015.05.009
3. Simmons, S. (2021). Diurnal Variation in Male White-Faced Capuchin (Cebus imitator) Faecal Glucocorticoids, Testosterone and Dihydrotestosterone [Unpublished Undergraduate Thesis]. York University.
4. Jordan-Young, R., & Karkazis, K. (2019). Testosterone: An Unauthorized Biography (pp.1-23). Harvard University Press, https://doi.org/10.4159/9780674242647
5. Nowak, P. et al. (2018). No evidence for the immunocompetence handicap hypothesis in male humans. Scientific Reports, 8(1), 7392–11. https://doi.org/10.1038/s41598-018-25694-0
6. Book, S. et al. (2001). The relationship between testosterone and aggression: a meta-analysis. Aggression and Violent Behavior, 6(6), 579–599. https://doi.org/10.1016/S1359-1789(00)00032-X