Sex-related mechanisms underlying female predominance in Hashimoto’s thyroiditis: evidence gaps and implications for sex-aware clinical translation

Hashimoto’s thyroiditis (HT) is markedly female predominant, but evidence for the mechanisms underlying this pattern is heterogeneous. This narrative review examines epidemiology, the clinicopathological spectrum, X-chromosome regulation, sex hormones, thyroid-local T- and B-cell responses, and environmental and life-course modifiers. To prevent disease association from being conflated with an explanation of sex bias, we distinguish (1) human HT studies reporting an explicit sex comparison (2), human HT studies without sex-stratified mechanistic analyses, and (3) non-HT human or experimental evidence used to generate hypotheses. Skewed X-chromosome inactivation has been investigated in female HT case–control studies, whereas sex-dependent downstream TLR7, CD40L and FOXP3 effects within human HT remain incompletely established. Estradiol has potentially opposing actions across immune subsets, progesterone-related tolerogenic findings are not proof of protection in human HT, and HT tissue evidence for B-cell activating factor (BAFF) and its receptor (BAFF-R) does not establish sex-specific therapeutic responsiveness. Clinical translation is therefore more limited than mechanistic plausibility. Established management remains based primarily on thyroid functional status and life-stage context, with levothyroxine as the standard treatment for overt hypothyroidism rather than a sex-specific immune intervention. Large randomized trials in euthyroid TPOAb-positive women have not shown improved live-birth outcomes with routine levothyroxine, while selenium, vitamin D and myo-inositol studies predominantly report biochemical or surrogate outcomes and do not establish sex-specific benefit. Published sex-related differences in TPOAb reference limits are method- and reference-population-dependent and should not be confused with validated HT diagnostic thresholds. Accordingly, sex-aware precision strategies are best viewed as a research framework requiring disease-specific biomarker validation, demonstration of incremental clinical utility, patient-relevant outcomes, and sex-stratified prospective trials before routine implementation.