Loss of vitamin D receptor induces premature ovarian insufficiency through compromising the 7-dehydrocholesterol-dependent anti-aging effects

Haiyun Chen, Qiuyi Wang, Yi Zhang, Lingfei Shangguan, Luxi Shangguan, Zhengquan Zhu, Huan Zhang, Zou Xiang, Xiang Zou, Qinghe Geng, Yanting Wen, Daojuan Wang, Yong Wang
In: Frontiers in Cell and Developmental Biology · 2025 · vol. 13 , pp. 1545167 · doi:10.3389/fcell.2025.1545167 · PMID:40276652 · W4409344782
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

Loss of the vitamin D receptor in mice impairs ovarian follicle maturation and hormone secretion by accelerating granulosa cell aging due to reduced 7-dehydrocholesterol antioxidant effects.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

Using vitamin D receptor (VDR) global knockout (Vdr−/−) mice and transcriptome analysis of ovaries from vitamin D–deficient diet mice, the study assessed ovarian morphology, follicle development, hormone secretion, and granulosa-cell function, with granulosa cells also modeled by CRISPR-Cas9 Vdr knockout in KGN cells. VDR loss caused reduced ovary size, decreased primordial follicles and increased atretic follicles, disrupted estrous cyclicity, lower estrogen levels, reduced granulosa-cell proliferation, and downregulation of genes involved in estrogen/androgen biosynthesis and ovarian reserve (including Amh/Amhr2), alongside disrupted redox balance via decreased Nrf2/HO-1/SOD signaling that accelerated ovarian/granulosa-cell senescence; a limitation is that the antioxidant/anti-aging mechanistic rescue was demonstrated primarily in vitro (KGN cells) with 7-dehydrocholesterol (7-DHC). Mechanistically, VDR loss repressed Hmgcr and decreased de novo cholesterol synthesis, reducing 7-DHC’s antioxidant/anti-aging effects, while 7-DHC supplementation lowered reactive oxygen species and alleviated aging phenotypes in VDR-deficient KGN cells. This paper is centrally about endometriosis and/or adenomyosis only tangentially via its broader relevance to reproductive aging and ovarian function, but it does not explicitly discuss endometriosis or adenomyosis.

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Abstract

Vitamin D has the potential to therapeutically affect the endocrine parameters of premature ovarian insufficiency (POI) patients. Previous research has indicated that serum vitamin D levels tend to decline with age and in individuals with POI. However, the precise impact of vitamin D deficiency on female fertility, especially their ovarian function, remains unclear. Vitamin D receptor (VDR) deficiency mice provide a model to investigate the possible effect of vitamin D on female reproduction. In this study, we observed abnormal follicular development in the Vdr deficiency mice. This anomaly is associated with reduced expression of anti-Mullerian hormone (AMH) and disrupted aromatase expression that disrupts the hormone secretion. Moreover, our findings indicate that Vdr deficiency disturbs redox balance, resulting in oxidative stress in the ovary, which further suppresses granulosa cell function and accelerates ovarian aging. Mechanistically, loss of Vdr inhibits de novo cholesterol synthesis by transcriptional repression of Hmgcr , and the antioxidant and anti-aging effects of the intermediate product 7-dehydrocholesterol (7-DHC) are also decreased. Treatment with 7-DHC effectively reduces ROS levels and alleviates aging in KGN cells deficient in Vdr . In conclusion, our results show that Vdr deficiency impairs follicle maturation and hormone secretion by accelerating granulosa cell aging, as a result of the reduced antioxidant and anti-aging effect of 7-DHC.

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