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Review
. 2025 Aug;26(4):679-692.
doi: 10.1007/s11154-025-09974-5. Epub 2025 Jun 9.

Pregnancy-associated thyroid disorders: the role of genetic, epigenetic, and oxidative stress factors

Angelika Buczyńska  1 , Iwona Sidorkiewicz  2 , Justyna Hryniewicka  3 , Monika Zbucka-Krętowska  4 , Janusz Dzięcioł  5 , Małgorzata Szelachowska  3 , Adam Jacek Krętowski  6   3
Affiliations
Review

Pregnancy-associated thyroid disorders: the role of genetic, epigenetic, and oxidative stress factors

Angelika Buczyńska et al. Rev Endocr Metab Disord. 2025 Aug.

Abstract

Thyroid inflammation during pregnancy, particularly Hashimoto's thyroiditis (HT) and postpartum thyroiditis (PPT), has a strong genetic and epigenetic basis. Susceptibility to these conditions is associated with specific HLA haplotypes (HLA-DR3, DR4, DR5) and immune-regulatory genes, including CTLA-4, PTPN22, FOXP3, as well as thyroid-specific genes such as TSHR, TG, and TPO. CTLA-4 polymorphism (CT60) is linked to increased thyroid autoantibody production, while PTPN22 R620W variant disrupts immune tolerance, exacerbating autoreactive lymphocyte activation.Epigenetic modifications play a crucial role in HT and PPT pathogenesis. Dysregulation of microRNAs (miRNAs), including miR-146a, miR-142, miR-301, and miR-155, affects immune pathways by modulating T-cell responses and inflammatory cytokine production. Aberrant DNA methylation in genes regulating immune function, such as FOXP3 and CTLA-4, contributes to altered immune tolerance and disease progression.Oxidative stress further modulates disease severity by inducing DNA damage and enhancing inflammatory responses, particularly in pregnancy. Reactive oxygen species (ROS) promote thyroid autoimmunity by affecting placental function and fetal neurodevelopment. Understanding the interplay between genetic susceptibility, epigenetic regulation, and oxidative stress is essential for developing personalized management strategies. This review highlights the molecular mechanisms underlying HT and PPT and the potential of epigenetic biomarkers for early diagnosis and targeted therapies.

Keywords: CTLA-4; DNA methylation; FOXP3; HLA-DR3/DR4/DR5; Hashimoto’s thyroiditis; Oxidative stress; PTPN22; Postpartum thyroiditis; Pregnancy; TG; TSHR; miR-146a; miR-155.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests. Institutional review board: Not applicable. Informed consent: Not applicable. Conflict of interest: The authors declare no conflicts of interest. Consent to publish: Not applicable. Not applicable. Clinical trial number: Not applicable.

Figures

Fig. 1
Fig. 1
Oxidative Stress Pathomechanisms in HT and PPT CTLA-4 – Cytotoxic T-Lymphocyte Antigen 4; PTPN22 – Protein Tyrosine Phosphatase Non-Receptor Type 22; FOXP3 – Forkhead Box P3; TSHR – Thyroid-Stimulating Hormone Receptor; TG – Thyroglobulin; TPO – Thyroid Peroxidase; miR-146a – microRNA-146a; miR-155 – microRNA-155; HT – Hashimoto’s Thyroiditis; PPT – Postpartum Thyroiditis
See this image and copyright information in PMC

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