Primary biliary cholangitis (PBC) may be influenced by low testosterone levels that drive a more inflammatory immune response, according to results from a study published recently in JCI Insight. This new research points to testosterone’s role in calming the immune system by directly acting on T cells, offering hope for potential future therapies.
When researchers compared blood samples from 24 cisgender women with PBC to 23 age-matched healthy women, they found significantly lower testosterone levels in those with the disease. These women also had elevated levels of CD4+ T cells producing inflammatory proteins such as TNF and IFN-γ. Laboratory experiments confirmed that testosterone suppressed these proinflammatory responses in T cells collected from healthy women.
To understand how testosterone influences immune activity in a real-world setting, scientists next studied 25 healthy trans men before and after six months of gender-affirming hormone therapy. Treatment with testosterone led to a reduction in inflammatory cytokines and promoted a shift in CD4+ T cells from damaging Th1 and Th17 types toward regulatory T cells that help keep immune responses in check.
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In mouse models engineered to lack androgen receptors in their T cells, the absence of testosterone signaling caused immune cells to become more inflammatory. These mice produced more Th17 cells and fewer regulatory T cells, reinforcing the idea that testosterone directly regulates immune cell behavior through its receptor on T cells.
In one particularly striking case, a trans man with autoimmune hepatitis/primary sclerosing cholangitis variant syndrome experienced clinical improvements while on testosterone therapy. Markers of liver inflammation and bile duct injury, such as alkaline phosphatase and γ-glutamyltransferase, dropped. Liver stiffness also improved, and his immunosuppressive medication was reduced from 125 mg to 25 mg of azathioprine per day without worsening symptoms.
“Future studies should investigate how the interaction of T cells with hepatic parenchymal cells is modulated by sex hormones,” the authors stated. “In addition, longitudinal studies should investigate the effects of GAHT [gender-affirming hormone therapy] in trans men and trans women in more detail and over a longer period of time in order to appreciate the effects sex hormones have on human immunity.”
For patients with PBC and related autoimmune liver diseases, these results highlight the potential of hormone-based strategies to manage immune dysfunction. While more studies are needed, testosterone’s anti-inflammatory effects may offer a path toward more effective and individualized treatments in the future.
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