A recent study published on February 1, 2025, has unveiled the underlying mechanisms linking thyroid hormone receptor dysfunction to female infertility. Researchers from the National Cancer Institute revealed how mutations in the TRα1 gene can lead to significant reproductive issues, particularly endometrial metaplasia and fibrosis, resulting from reduced expression of the KLF9 gene and abnormal levels of the cytokine IL-33.
Thyroid hormones are integral to various physiological processes, including female reproduction. Thyroid hormone receptors (TRs) mediate the genomic actions of these hormones, and their dysfunction is associated with reproductive abnormalities. Previous research has indicated the involvement of TRs in menstrual irregularities, infertility, and other gynecological disorders. Yet, the molecular pathways by which thyroid dysfunction impacts reproductive health have remained poorly understood.
This study utilized mouse models, particularly those genetically modified to express mutations of the TRα1 gene known as Thra1PV/+ mice. These mice exhibited notable phenotypic changes, including progressive uterine atrophy and endometrial squamous metaplasia. The research team conducted rigorous histological analyses to validate the structural abnormalities within the endometrium, illustrating the replacement of columnar epithelium with squamous cells and the extensive loss of endometrial glands.
The investigators employed RNA sequencing and gene expression profiling, which identified KLF9, a transcription factor linked to squamous differentiation, as significantly downregulated in the endometrial tissue of Thra1PV/+ mice. The loss of KLF9 signaling correlated with the observed squamous metaplasia and indicative changes leading to endometrial fibrosis.
Importantly, the study demonstrated how the abnormal differentiation of endometrial cells serves as the source of ectopic IL-33 expression. This elevation of IL-33 is significant as it plays roles not only as a cytokine but also as a transcription factor involved in inflammatory responses, thereby impacting the immune environment within the uterus—further contributing to reproductive dysfunction.
The findings from this research not only clarify the involvement of thyroid receptor mutations but also highlight the complex interplay between thyroid hormone signaling, endometrial health, and infertility. “Decreased Klf9 signaling led to transcriptional perturbations and resulted in abnormal uterine differentiation,” the study concludes.
Future research directions could explore therapeutic avenues for addressing thyroid-related infertility using insights gained from this study, potentially opening new pathways for women facing reproductive challenges linked to thyroid hormone dysfunction.