Immune dynamics throughout life in relation to sex hormones and perspectives gained from gender-affirming hormone therapy

Abstract

Biological sex is closely associated with the properties and extent of the immune response, with males and females showing different susceptibilities to diseases and variations in immunity. Androgens, predominantly in males, generally suppress immune responses, while estrogens, more abundant in females, tend to enhance immunity. It is also established that sex hormones at least partially explain sex biases in different diseases, particularly autoimmune diseases in females. These differences are influenced by hormonal, genetic, and environmental factors, and vary throughout life stages. The advent of gender-affirming hormone therapy offers a novel opportunity to study the immunological effects of sex hormones. Despite the limited studies on this topic, available research has revealed that testosterone therapy in transgender men may suppress certain immune functions, such as type I interferon responses, while increasing inflammation markers like TNF-α. Transgender women on estrogen therapy also experience alterations in coagulation-related and inflammatory characteristics. Furthermore, other possible alterations in immune regulation can be inferred from the assessment of inflammatory and autoimmune markers in transgender individuals receiving hormone therapy. Understanding the complex interactions between sex hormones and the immune system, particularly through the unique perspective offered by gender-affirming hormone therapies, may facilitate the development of targeted therapies for infections and autoimmune diseases while also improving healthcare outcomes for transgender individuals. Here we review immune dynamics throughout life in both sexes and provide a summary of novel findings drawn from studies exploring gender-affirming hormone therapy.

Keywords: androgens; autoimmune diseases; estrogens; gender-affirming hormone therapy; immune system; infectious diseases; sex difference.

Figure 1

Summary of the Hypothalamic–pituitary–gonadal axis. It must be noted that androgens and estrogens are produced in both males and females in different tissues, at vastly different concentrations. The figure only describes the primary production pathways in order to emphasize sex-related differences with respect to hormonal production, while also showing the influence of luteinizing hormone (LH) and follicle stimulating hormone (FSH) on the gonads and the production of the respective hormones. GnRH, Gonadotropin-Releasing Hormone.

Figure 2

Early and pubertal differences regarding immune constituents and characteristics between boys and girls. Also, pubertal hormone changes (testosterone and estrogen) and the changes in neutrophil and lymphocyte frequencies are summarized on an arbitrary longitudinal scale. CD4+, Cluster of differentiation 4; CD8+, Cluster of differentiation 8; NK, Natural killer; T regs, T regulatory cells.

Figure 3

The typical impacts of androgens in the immune system (testosterone structure depicted in center). CD4+, Cluster of differentiation 4; CD8+, Cluster of differentiation 8; Th, T helper cells; T reg, T regulatory cells.

Figure 4

The typical impacts of estrogens on the immune system (estradiol structure depicted in center). CD4+, Cluster of differentiation 4; CD8+, Cluster of differentiation 8; Th, T helper cells; T reg, T regulatory cells.