Stress Response, Sex and Immunity: the Female Superiority

Stress Sex and Immunity Female Superiority
Stress, sex an immunity

A recent perspective published in Science Signaling outlines the gender-specific differences in the stress response and the actions of glucocorticoids, and the female superiority in terms of dealing with stress and infections.

Sexual dimorphism in immunity, i.e. the differences in males and females in their immunological responses and immune function is well-known.

The sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases. For example, women have a lower risk of infections but are more susceptible to autoimmune/inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid diseases.

Stress activity and responsiveness, however, also display sexual dimorphism or gender differences. It appears that here both the Hypothalamic-Pituitary-Adrenal (HPA) axis responsiveness and the stress responsiveness of the brain noradrenergic system are involved. Hypertension, aggressive behavior, and drug abuse is known to be higher in men, but depression and anxiety disorders are more prevalent in women. These sex differences have been explained, at least in part, by differences in the stress activity and responsiveness.

In the Science Signaling perspective George Chrousos discusses these gender differences from an evolutionary perspective, including gene network evolution and steroid molecular actions, as well as sexual dimorphism even in the absence of estrogens and androgens.

The author provides a concise and contemporary view on the multilevel interactions between the stress, reproductive and immune systems and how they may determine gender-specific stress and immune responses.

In terms of clinical implications, Chrousos goes further, discussing how stress response and immune and inflammatory reactions are more potent in women than in men.

This may explain the former’s higher prevalence of stress-related behavioral syndromes, such as anxiety, depression, psychosomatic and eating disorders, and autoimmune inflammatory or allergic disorders, such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, or asthma, respectively.

Source: Sci Signal, 2010 Oct 12; 3(143):pe36. doi: 10.1126/scisignal.3143pe36
Read more: Science Signaling


A 2017 study published in the Journal of Neuroscience Research examined gender differences in neural correlates of online stress-induced anxiety response in men and women with commensurable levels of the State-Trait Anxiety Inventory (STAI) anxiety and perceived stress. The study reports gender-specific neural correlates of anxiety during stress provocation, mainly in the medial prefrontal and parietal cortices, with opposite patterns of associations in men and women.

Specifically, gender interaction from whole-brain regression analyses was observed in the dorsomedial prefrontal cortex, left inferior parietal lobe, left temporal gyrus, occipital gyrus, and cerebellum, with positive associations between activity in these regions and stress-induced anxiety in women, but negative associations in men, indicating that men and women differentially utilize neural resources when experiencing stress-induced anxiety. The observed neural difference indicates that men and women differentially utilize neural resources when experiencing anxiety during stress.

A 2022 review indicates that here are multiple phenotypic differences between the immune systems of men and women. In general, men are more vulnerable to infectious diseases, and women are more prone to autoimmune diseases. These differences are typically attributed to the stronger female immune response. The weaker male response to pathogens may allow the invader to cause more damage, whereas the strong and persistent female response reduces pathogen-induced damage but may eventually trigger autoimmune processes and cause chronic damage.

Sexual dimorphism in the immune system and its mechanisms have been extensively reviewed in the context of autoimmunity, immune responses, cancer, the response to vaccination, and transplant rejection. The proportions and phenotypes of some of the immune cells are different between the sexes at baseline and may contribute to the higher inflammatory response and better survival of females with infectious diseases. Female peritoneal and plural cavities have higher numbers of T cells, B cells, and macrophages. Female peritoneal macrophages show higher expression levels of genes of the complement system, of the interferon (IFN) signaling pathways, and toll-like receptors (TLRs).

Whereas high estrogen levels increase the risk and worsen the symptoms of inflammatory bowel disease (IBD), rheumatoid arthritis, and systemic lupus erythematosus (SLE), estrogen has a protective effect in multiple sclerosis. Contraceptive pills, which contain female sex hormones and are in direct contact with the digestive system, increase the risk for IBD in genetically susceptible women. With the hormonal drop at menopause, there is a peak in RA, which can be controlled by hormonal replacement.

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