Li Shuyue, Zhang Lina, Li Wanqiong, Qin Jiaying, Qi Lingbin, Xiao Xi, Xue Zhigang, Xue Jinfeng, Ji Yazhong
Reproductive Medical Center, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Stem Cell Research Center, School of Medicine, Tongji University, Shanghai, China.
Front Cell Dev Biol. 2025 May 30;13:1610694. doi: 10.3389/fcell.2025.1610694. eCollection 2025.
Hypothyroidism is a common endocrine disorder in women, which could lead to ovulation disorders and infertility, however, the effects of adult-onset hypothyroidism on ovarian development and gene expression characteristics need further study.
Here we conducted an adult-onset hypothyroidism rat model by using the methimazole (MMI) induction, then the hormone level changes and ovarian development were evaluated, furthermore, the effects of gene expression of granulosa cells and oocytes were detected by using single-cell RNA sequencing.
Our results showed that, in addition to a decrease in thyroid hormones, the body weight was significantly reduced, while the estrus cycle was prolonged in the hypothyroidism group. Although the ovary/body weight ratio was not changed, the adult-onset hypothyroidism disrupted follicle development, primarily manifested by an increased number of atretic follicles and a decreased number of corpora lutea. Serum sex hormone levels were also imbalanced, with elevated LH, FSH, and PRL, while E2 and P were decreased. By combining single-cell RNA sequencing and the validation experiments, we found that adult-onset hypothyroidism promoted apoptosis in granulosa cells of antral follicles and induced oxidative stress in oocytes. Notably, we found significant heterogeneity in mitochondrial ROS in the control group, indicating differences in the redox status of different normal oocytes, which disappeared after hypothyroidism promoted oxidative stress.
In conclusion, adult-onset hypothyroidism interferes with normal follicle development and impairs fertility by promoting apoptosis in granulosa cells of antral follicles and inducing oxidative stress in oocytes.
甲状腺功能减退是女性常见的内分泌疾病，可导致排卵障碍和不孕，然而，成人期甲状腺功能减退对卵巢发育和基因表达特征的影响尚需进一步研究。
本研究通过甲巯咪唑（MMI）诱导建立成年期甲状腺功能减退大鼠模型，评估激素水平变化和卵巢发育情况，此外，采用单细胞RNA测序检测颗粒细胞和卵母细胞的基因表达影响。
我们的结果表明，除甲状腺激素水平降低外，甲状腺功能减退组体重显著减轻，发情周期延长。虽然卵巢/体重比未改变，但成年期甲状腺功能减退破坏了卵泡发育，主要表现为闭锁卵泡数量增加和黄体数量减少。血清性激素水平也失衡，LH、FSH和PRL升高，而E2和P降低。通过结合单细胞RNA测序和验证实验，我们发现成年期甲状腺功能减退促进了窦状卵泡颗粒细胞的凋亡，并诱导了卵母细胞的氧化应激。值得注意的是，我们发现对照组线粒体ROS存在显著异质性，表明不同正常卵母细胞的氧化还原状态存在差异，甲状腺功能减退促进氧化应激后这种差异消失。
总之，成年期甲状腺功能减退通过促进窦状卵泡颗粒细胞凋亡和诱导卵母细胞氧化应激，干扰正常卵泡发育并损害生育能力。
