The aim of this study was to see if masculine traits, which are dependent on androgen levels in foetal and pubertal stages of development, are related to the immune quality in healthy men; it seems they are not

Masculinity and immune system efficacy in men. Judyta Nowak-Kornicka,Barbara Borkowska,Bogusław Pawłowski. PLoS One, December 14, 2020. https://doi.org/10.1371/journal.pone.0243777

Abstract: Masculinity-related morphological traits are supposed to be honest indicators of a man's biological quality. While some studies showed that sexually dimorphic traits are related to various aspects of biological condition such as general health, immunity or fertility, still little is known about the relationship between masculine traits and the effectiveness of innate and adaptive immunity in humans. The aim of this study was to see if masculine traits, which are dependent on androgen levels in foetal and pubertal stages of development, are related to the immune quality in healthy men. The immune quality was evaluated for 91 healthy men aged 19–36 years. Immunity measurements included innate and adaptive parameters. General health status, age, testosterone level, BMI, physical activity, and smoking were controlled. The shoulder-to-hip ratio (SHR), 2D:4D digit ratio and hand-grip strength (HGS) were used as markers of masculinization. The regressions showed that when controlling for confounds, masculinity-related traits were in general not related to innate and adaptive immunity. Only a weak association was observed for right 2D:4D ratio and T-lymphocyte counts (but it becomes non-significant after adjustment for multiple comparisons). Our results do not support the premise that masculinity is a cue for immunological quality in men. However, the positive association between right 2D:4D and T lymphocytes might suggest that further studies are needed to verify if androgen stimulation in prenatal development might be related to immunity in adulthood.

The relationship between masculinity traits and controlled factors

Because HGS was associated with such controlled factors as a participant's age, BMI and body height (see section "IV" in S1 File, the correlation between body height and BMI was weak (R = -0.22)), we also conducted the analyses adjusted for these. The separate models were carried out for each immune function. These analyses also revealed that HGS is not related to any of the analysed immune parameters.

According to the evolutionary hypothesis concerning the biological implications of sexually selected traits which are commonly perceived as attractive (good genes hypothesis), and are also involved in intra-sexual competition and costly to produce (handicap hypothesis), we assumed that masculinity in men aged 19–36 might serve as a signal reflecting an individual's biological quality. The aim of this study was to check if body masculinity of healthy men is related to immune function, which is one of the most important fitness-related characteristics of an organism, determining risk of morbidity and mortality in all life stages. In general, we found no association between masculinization markers and either innate or adaptive immune responses, even when controlling for a participant's age, BMI, free-testosterone levels, smoking status or sport activity.

The finding in the current study of no associations between SHR or HGS and any of the studied immune parameters, indicates that these indirect markers of pubertal or current testosterone do not reflect immune functioning. To the best of our knowledge, there is no study linking SHR with any of the immune-associated biomarkers, and there have only been limited studies testing the relationship between muscle mass and immunity [45], with only one study directly testing CD4+ count and muscle functions itself as measured by strength [65]. This was, however, only in patients with an HIV-associated immune injury. Raso et al. (2013) [65] showed that disease-associated decreases in HGS are associated with a lower CD4+ count. There are also several studies only indirectly linking HGS with immunity-related characteristics, showing that inflammation-associated diseases [66, 67] or autoimmune disorders [68] are related to lower HGS. Our study is the first to demonstrate that a V-shaped upper body, reflected in SHR and muscle function and measured by HGS, is not associated with immunity in healthy men.

Our results investigating the relationship between masculinity, post-vaccination and lymphocyte-proliferation responses are in contrast to the limited human studies testing ICHH in facial masculinity and the strength of antibody or cytokine response after immune stimulation [e.g. 15, 19]. It is worth underlining, however, that in these two studies the authors analysed only facial (and not body) perception and they did not use anthropometry. Furthermore, Rantala et al. (2012) [15] measured immune response against the hepatitis B virus i.e. conservative antigens, whereas we studied immune response to the influenza virus i.e. a fast evolving/mutating antigen. The lack of association between analyzed markers of masculinization and immune reactivity in response to potentially harmful factors may therefore indicate that the immune response can differ depending on the antigen in question. It is also possible that some vaccine-contained antigens and/or in vitro lymphocyte stimulation may be inadequate to reflect general immune quality. Our results also contradict studies that have indirectly measured immunity (e.g. frequency of infection) and its relationship with facial masculinity (rated and/or morphometric) finding that men with more masculine faces (rated and measured) reported a lower frequency of colds and flu [16, 62]. It is therefore possible that facial dimorphism has more signalling significance than body masculinity (or the traits studied in this paper). On the other hand, Foo et al. (2017a) [63] did not find the relationship between rated facial masculinity and various immune functions measured in saliva. Therefore in the future it will be important for studies to include both facial and body traits related to masculinity in order to address this discrepancy in the literature.

Due to the mixed findings in humans, we should also consider that the immunosuppressive role of androgens (the basis of ICHH) is still controversial. It has been suggested that androgens have immunomodulatory rather than immunosupressive properties [18, 21] and this was also observed in a group of participants included in this study (see S3 Table in S1 File). It may also be the case that in contrast to experimental or in-vitro studies which, in accordance to ICHH, expect a negative relationship between immunity and masculinity, in correlational studies (such as ours) the lack of associations might also be interpreted in the framework of the ICHH and good genes hypothesis. This is because testosterone-induced immune suppression in highly masculine men may suppress immunity to a level similar to that observed in men with a lower immune quality. Consequently, more masculine males might only be a little healthier than average [69], and there may be no noticeable difference in immune quality between those with high and low-masculinity observed in correlational studies. In other words, if, in accordance with ICHH, only individuals with a well-functioning immune response bear a cost associated with testosterone-derived immunosuppression, we should expect that men with a higher expression of masculine traits only have a marginally better, or perhaps a very similar level, of immune quality as men with a lower masculinization level.

Our results are also consistent with recent reports showing that physically attractive traits such as male body height [64] or components of men’s facial attractiveness [63] are not related to immune effectiveness–at least in Western, well-fed societies. The Immune Priority Hypothesis (IPH) [64] is another explanation proposed to answer why immune quality might not be reflected by sexually dimorphic traits. IPH suggests that a well-functioning body defence is so crucial for long-lived species, like human beings, who are exposed to many ubiquitous pathogens that immunity cannot be traded for the traits that are not directly related to survival (e.g. body height, SHR or HGS). According to IPH, energy resources should be invested in development of costly morphological signals only when the right amount of energy in creating an optimal immune defence is assured. In this instance, masculine traits instead signal a lack of immune related disorders, and an organism’s ability for sparing additional energy for “luxury” sexual dimorphism. This would mean that despite there being no relationship between immune functions themselves and masculine traits, higher masculinization might still provide information about the biological quality of an organism.

The weak positive association between right 2D:4D (which is a better indicator of prenatal androgenisation than left 2D:4D [70] and lymphocyte T count, might suggest that higher prenatal exposure to androgens is related to lymphocyte count in adults. This result can be partially explained by the organizational action of androgens on the immune system. It was shown that exposure to androgens in early life might permanently affect immunity both in primates [71] and rodents [27], whereas gonadectomy in mature animals does not abolish sex-differences in immune response [72]. This does not mean, however, that testosterone level in adults is not related to immunity. There are several experimental and correlational studies showing that testosterone has a negative impact on lymphocyte T count and/or function [10, 73], and that androgens may increase apoptosis of T cells [74]. It is surprising, however, that our observations concern only the lymphocyte count but not lymphocyte function (the proliferative response). It is also worth noting that our result becomes non-significant after adjusting for multiple comparisons and therefore the obtained relationship between the 2D:4D digit ratio and lymphocyte count should be treated with great caution and further studies are warranted. In general, the lack of associations between masculinity markers and immunity in our study is consistent with the results of a recent meta-analysis that provides no support for immunosuppressive testosterone properties in correlational human studies [18].

There are a few limitations of our study. Since we have studied men from a well-nourished Western population (not a common state in our evolutionary past), one needs to be very cautious with generalizing our results to all ecological conditions humans might have lived in. It is also very likely that a well-nourished urbanized population is not ideal for measuring the masculinity-immune associations due to a relatively low cost associated with immune challenges. Improved living conditions, including hygiene practices, infection prevention (vaccines), and increased access to medications and antimicrobial drugs, have all contributed to the reduction of pathogen exposure and shortening the duration of an infection in these populations. Consequently, the physiological cost associated with the immune system functioning in such a population might be much lower in comparison to a population with a greater pathogen load and a higher risk of infection. Furthermore, the effect size (calculated as a Cohen's f2) showed that the magnitude of associations is small or moderate (see Tables 2 and 3), which is also true for a significant relationship between 2D:4D and T cell (f2 = 0.31). This indicates that in well-nourished western populations the relationship between immune parameters and masculine traits is relatively low. In other words, the results suggest that the difference in immune functioning between men with more and less masculine traits might be too low to have functional immunological consequences.

The final problem to consider is that of the complicated structure of immunity and the interdependencies between immunity and other physiological aspects. It is likely that the measurements of baseline immune functions in men who declared no health problems, had no chronic diseases or ongoing infections and had a normal level of inflammatory markers (both CRP and WBC) are still inadequate for measuring immune quality. It is possible that, to assess an individual's immune quality, the analysis of many immune parameters, activated in response to real/natural pathogen-inducing infection, should be taken into account. The measurement of an immunological response to pathogen stimulation might be more informative than baseline immune parameters (in a "healthy state", without antigen stimulation) or only vaccine-induced antibody production or mitogen-induced proliferation.