Causal association between lipid-lowering drugs and female reproductive endocrine diseases: a drug-targeted Mendelian randomization study

Front Endocrinol (Lausanne). 2023 Nov 10:14:1295412. doi: 10.3389/fendo.2023.1295412. eCollection 2023.


Purpose: The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs.

Methods: In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility.

Results: PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea.

Conclusion: The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.

Keywords: Mendelian randomization; drug-target; eQTL; female reproductive endocrine diseases; lipid-lowering drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Coronary Disease*
  • Female
  • Genome-Wide Association Study
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / adverse effects
  • Hypolipidemic Agents
  • Infertility* / chemically induced
  • Lipids
  • Mendelian Randomization Analysis
  • Menorrhagia* / chemically induced
  • Oligomenorrhea
  • PCSK9 Inhibitors
  • Polycystic Ovary Syndrome* / chemically induced
  • Polycystic Ovary Syndrome* / drug therapy
  • Polycystic Ovary Syndrome* / genetics
  • Proprotein Convertase 9 / genetics


  • PCSK9 protein, human
  • Proprotein Convertase 9
  • PCSK9 Inhibitors
  • Hypolipidemic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipids

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was funded by the Scientific Research Foundation of the Hebei Health Commission (NO. 20200754 and NO.20220862).