Sex hormones and tuberculosis: Implications for immune regulation, susceptibility, and disease pathogenesis

Tuberculosis (TB), caused by Mycobacterium tuberculosis, exhibits pronounced sex differences in incidence and disease progression, with adult males disproportionately affected. Increasing evidence indicates that sex steroid hormones estrogen, progesterone, and testosterone modulate immune responses critical for MTB control. This narrative review synthesizes findings from both human and animal studies using PubMed, ScienceDirect, and Google Scholar. Effective host defense against MTB relies on pro-inflammatory cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, whereas anti-inflammatory cytokines such as IL-4, IL-5, and IL-10 are associated with reduced bacterial control and disease progression. Sex steroid hormones regulate both the magnitude and balance of these immune responses in a dose, stag-, and context-dependent manner. Estrogen enhances Th1-mediated immunity at physiological concentrations but may favor Th2-biased responses at supraphysiologic levels, such as during pregnancy. Progesterone contributes to immune homeostasis at basal concentrations but suppresses dendritic cell function and Th1 immunity at elevated levels. Testosterone consistently attenuates Th1 immunity and enhances anti-inflammatory pathways. Human epidemiologic and clinical studies support these trends, showing adult males are more susceptible to active TB, while women experience increased risk during pregnancy. However, circulating hormone data in TB patients are inconsistent, highlighting the need for longitudinal, hormone-aware studies. Overall, sex hormone mediated immune modulation influences TB susceptibility and pathogenesis, and future research should adopt sex and hormone-dose-aware designs to optimize host-directed therapies.