Mao Fei, Yang Jihong, Guo Zhihan, Chang Tianqing, Wu Hua, Yang Guangping, Dai Heqi, Feng Ruizhi, Qian Yun
Reproductive Center of Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
FASEB J. 2025 Jul 15;39(13):e70785. doi: 10.1096/fj.202500914R.
The accelerating trend of obesity in women of childbearing age has become a significant issue in personal health, female fecundity, and offspring development. Simvastatin (SV) is a statin commonly prescribed oral agent for lipid-lowering therapy; however, its applicability in reproductively active women remains controversial. In this study, through clinical data analysis, we further confirmed that obesity reduces in vitro fertilization pregnancy success, with significant decreases in the number of retrieved oocytes, mature oocytes, and cleavage embryos. We found SV inhibited follicle development cultured in vitro. Based on our previously reported metabolomics data, mevalonic acid (MVA) was found to be a key metabolite in follicular development. In our in vitro follicle culture system, we demonstrated that the supplement of MVA in SV-added follicles recovered to grow similar to the untreated blank group, indicating the rescue effect of potential reproductive toxicity of SV. Both the downstream metabolites cholesterol and geranylgeraniol partially attenuated SV-induced apoptosis elevation and proliferation suppression in KGN cells. RNA sequencing results suggested that this rescue effect may be mediated through the TNF, PI3K-Akt, and JAK-STAT pathways. Our study shed light upon clinical practice for women of childbearing age who were treated with statins and might contribute to better health management in obesity populations.
育龄女性肥胖率加速上升已成为个人健康、女性生育能力和后代发育方面的一个重大问题。辛伐他汀（SV）是一种常用于降脂治疗的口服他汀类药物；然而，其在有生殖活性的女性中的适用性仍存在争议。在本研究中，通过临床数据分析，我们进一步证实肥胖会降低体外受精的妊娠成功率，同时取出的卵母细胞、成熟卵母细胞和卵裂胚胎数量显著减少。我们发现辛伐他汀会抑制体外培养的卵泡发育。基于我们之前报道的代谢组学数据，发现甲羟戊酸（MVA）是卵泡发育中的关键代谢物。在我们的体外卵泡培养系统中，我们证明在添加辛伐他汀的卵泡中补充MVA后，其生长恢复到与未处理的空白组相似，这表明MVA对辛伐他汀潜在生殖毒性具有挽救作用。下游代谢物胆固醇和香叶基香叶醇均部分减轻了辛伐他汀诱导的KGN细胞凋亡增加和增殖抑制。RNA测序结果表明，这种挽救作用可能是通过TNF、PI3K - Akt和JAK - STAT信号通路介导的。我们的研究为使用他汀类药物治疗的育龄女性的临床实践提供了参考，并可能有助于肥胖人群更好的健康管理。
