Sex-related mechanisms underlying female predominance in Hashimoto’s thyroiditis: evidence gaps and implications for sex-aware clinical translation
13 affiliations
- 1Affiliated Central People's Hospital, China Three Gorges University
- 2Department of Endocrinology, Yichang Central People's Hospital
- 3Department of Pathology, Shantou University Medical College
- 4Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University
- 5Department of Biliary-Pancreatic Center, The Affiliated Hospital, Southwest Medical University
- 6Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital, Southwest Medical University
- 7The Third Affiliated Hospital, Qiqihar Medical University
- 8Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University
- 9Nuclear Medicine and Theranostics Key Laboratory of Sichuan Province
- 10Institute of Nuclear Medicine, Southwest Medical University
- 11Heilongjiang University of Chinese Medicine
- 12School of Basic Medical Sciences, Qiqihar Medical University
- 13Department of Oncology, Yichang Central People's Hospital
Abstract
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.
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BibTeX
@article{hou2026sexrelated,
title = {{Sex-related mechanisms underlying female predominance in Hashimoto’s thyroiditis: evidence gaps and implications for sex-aware clinical translation}},
author = {Yiwei Hou and Yu Yang and Qiuyi Peng and Ye Liang and Li Yi and Ru Zheng and Zhenjie Yang and Zan Zhou and Dexiang Sha and Pengfei Liu and Shengyu Tang and Xiangyu Liao and Wufei Zhu},
journal = {Frontiers in Endocrinology},
year = {2026},
month = nov,
doi = {10.3389/fendo.2026.1924753},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1924753/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sex-related mechanisms underlying female predominance in Hashimoto’s thyroiditis: evidence gaps and implications for sex-aware clinical translation
AU - Yiwei Hou
AU - Yu Yang
AU - Qiuyi Peng
AU - Ye Liang
AU - Li Yi
AU - Ru Zheng
AU - Zhenjie Yang
AU - Zan Zhou
AU - Dexiang Sha
AU - Pengfei Liu
AU - Shengyu Tang
AU - Xiangyu Liao
AU - Wufei Zhu
PY - 2026
DA - 2026/11/05
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1924753
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1924753/full
AB - 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.
SN - 1664-2392
ER -