Aru Na, Yang Congyu, Chen Yuntian, Liu Jiaming
Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
Medicine (Baltimore). 2025 May 30;104(22):e42685. doi: 10.1097/MD.0000000000042685.
Reproductive endocrine diseases (REDs), including polycystic ovary syndrome, endometriosis, and female infertility, are prevalent reproductive disorders that affect a significant number of women worldwide. Recent research has indicated that the inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), in addition to reducing cholesterol levels, may have pleiotropic effects on REDs. However, the impact of PCSK9 and HMCGR inhibitor on REDs is controversial. This study employed drug-target Mendelian randomization to examine the causal relationships between PCSK9/HMGCR inhibitors and REDs, using established coronary heart disease associations as validation controls. Multiple Mendelian randomization methods, primarily inverse-variance weighted (IVW), were implemented alongside sensitivity analyses to verify result reliability. HMGCR inhibitor demonstrated significant protective effects against polycystic ovary syndrome development (IVW OR 0.321, 95% CI 0.136-0.757; P = .009). Correspondingly, PCSK9 inhibitor exhibited favorable associations with endometriosis risk reduction (IVW OR 0.971, 0.688-0.909; P = .001). These observations remained consistent across all sensitivity evaluations, confirming analytical robustness. Our findings support a causal link between HMGCR/PCSK9 inhibitors and REDs, suggesting potential therapeutic implications. However, further mechanistic studies are needed to clarify the biological pathways and clinical relevance of these results.
生殖内分泌疾病（REDs），包括多囊卵巢综合征、子宫内膜异位症和女性不孕症，是普遍存在的生殖障碍，影响着全球大量女性。最近的研究表明，前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的抑制剂，除了降低胆固醇水平外，可能对REDs具有多效性作用。然而，PCSK9和HMCGR抑制剂对REDs的影响存在争议。本研究采用药物靶点孟德尔随机化方法，以已确立的冠心病关联作为验证对照，来检验PCSK9/HMGCR抑制剂与REDs之间的因果关系。实施了多种孟德尔随机化方法，主要是逆方差加权（IVW）法，并进行了敏感性分析以验证结果的可靠性。HMGCR抑制剂对多囊卵巢综合征的发生具有显著的保护作用（IVW比值比0.321，95%可信区间0.136 - 0.757；P = 0.009）。相应地，PCSK9抑制剂与降低子宫内膜异位症风险呈良好关联（IVW比值比0.971，0.688 - 0.909；P = 0.001）。在所有敏感性评估中，这些观察结果均保持一致，证实了分析的稳健性。我们的研究结果支持HMGCR/PCSK9抑制剂与REDs之间存在因果联系，提示了潜在的治疗意义。然而，需要进一步的机制研究来阐明这些结果的生物学途径和临床相关性。
