Role of sex and gender in autoimmune thyroid diseases: mechanisms and knowledge gaps

Autoimmune thyroid diseases (AITDs), mainly Hashimoto's thyroiditis and Graves' disease, are the most common organ-specific autoimmune disorders and display one of the strongest sex biases in autoimmunity, with a marked female predominance. This review examines how biological sex and gender-related determinants shape AITD susceptibility, expression, and clinical heterogeneity, and their relevance to personalized care. PubMed/MEDLINE and Scopus were searched from inception to June 2026, with Web of Science used for forward citation tracking. Human studies, reviews and meta-analyses, and selected experimental studies addressing sex- and gender-related mechanisms relevant to thyroid autoimmunity were considered. Sexual dimorphism in immune function provides the biological background for the higher autoimmune susceptibility of women, who generally mount stronger innate and adaptive immune responses. Sex hormones modulate immune tolerance and inflammation, while X-chromosome dosage, incomplete or skewed X-chromosome inactivation, X-linked immune genes, and emerging Y-chromosome-related mechanisms further contribute to immune regulation. Epigenetic mechanisms may amplify sex-dependent immune responses. Pregnancy, postpartum immune rebound, reproductive history, and fetal microchimerism highlight the interaction between reproductive biology and thyroid autoimmunity. Environmental exposures, smoking, psychosocial stress, occupational patterns, and healthcare-related determinants add a gender-related dimension, while sex-specific gut microbiota differences may also contribute. However, major knowledge gaps remain. Sex-stratified analyses are often lacking, and AITD-specific evidence on epigenetic profiles, microbiota, and gender-related determinants remains limited. Integrating sex and gender into AITD research and clinical practice may improve risk stratification, diagnosis, prevention, and individualized management, supporting a precision-medicine approach to thyroid autoimmunity.