Is Oestradiol a Key Player in the Sex Differences in Innate Immunity Through Toll-like Receptor Activation?

Research has shown a sex-specific immune response, with males having a worse prognosis in acute inflammatory diseases. While these disparities were initially attributed to sex hormones, increasing evidence points to a predominant role for X-linked genetic factors. Toll-like receptors and several components of their signaling pathway are encoded on the X chromosome and may contribute to these differences. We investigated whether increase in circulating oestradiol influences TLR-dependent immune response. Sixteen women undergoing controlled ovarian hyperstimulation for in vitro fertilisation were studied. Whole blood collected before treatment, during stimulation and at ovulation triggering was stimulated with ligands targeting TLR2/6, TLR1/2, TLR4 and TLR7/8. TLR2, TLR4 and CD99 expression, intracellular phosphorylated NF-κB p65, ERK1/2 and p38 MAPK, and cytokine production were assessed. Oestradiol levels increased markedly during treatment (48.1 to 1819.5 pg/mL; p < 0.001). Despite this rise, no or minimal impact on TLR2/4 and CD99 expression, intracellular signalling or cytokine release was detected. Only IL-6 and IL-10 in response to TLR2/6 stimulation increased significantly, with IL-6 positively associated with oestradiol variation. These findings indicate that oestradiol exerts a limited influence on TLR-dependent immune responses, supporting our view that sex-based immune differences are driven primarily by genetic rather than hormonal factors.