Beyond the Human Binary: Decoding Hormone-Immune Plasticity in Transgender Health

Sex- and gender-based immune differences have often been interpreted through a male-female biological binary, overlooking how endocrine signaling dynamically shapes immune function. Gender-affirming hormone therapy (GAHT) offers a unique physiological model to disentangle the effects of sex steroids from chromosomal background and examine immune plasticity in contexts relevant to reproductive health. This hormone-informed framework proposes that estradiol and testosterone regulate immune set-points across innate, adaptive, metabolic, and mucosal compartments. Through genomic and non-genomic signaling via androgen and estrogen receptors (AR, ERα/β), these hormones drive distinct immune outcomes: testosterone dampens type I interferon responses in plasmacytoid dendritic cells and reshapes monocyte inflammatory profiles, while estradiol promotes macrophage polarization and enhances T helper1 (Th1) responses. Hormonal effects are closely coupled to cellular metabolism: androgen signaling acts as a "metabolic brake" on Th17 cells by limiting glutaminolysis, a process reinforced by epigenetic remodeling, and is reflected in shifts in the circulating metabolome, positioning metabolomics as a sensitive tool for monitoring hormone-driven immune adaptation. Regardless, hormones also reshape mucosal barriers and reproductive microbiome composition. GAHT alters vaginal and gut microbial communities and their metabolism, influencing mucosal immunity, local inflammation, and reproductive tract homeostasis, with potential implications for fertility preservation, susceptibility to reproductive tract infections, and long-term genital mucosal health. Collectively, this evidence underscores that human immunity is highly responsive to endocrine context. This review synthesizes evidence linking endocrine trajectories, tissue microenvironments, reproductive biology, and social determinants of health, aiming to advance understanding of immune plasticity and contribute to a more inclusive framework of human immune diversity.