Causal effects between different sub-phenotypes of endometriosis and female infertility: a bidirectional Mendelian randomization study

WANG Ye; ZHONG Wei; SHANG Wei; WANG Wei

doi:10.16016/j.2097-0927.202505029

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Causal effects between different sub-phenotypes of endometriosis and female infertility: a bidirectional Mendelian randomization study

Clinical Medicine | 更新时间：2025-08-25

- Causal effects between different sub-phenotypes of endometriosis and female infertility: a bidirectional Mendelian randomization study
- Journal of Army Medical University Vol. 47, Issue 16, Pages: 1962-1969(2025)
- 作者机构：
  
  1.中国人民解放军总医院第七医学中心生殖医学科，北京
  2.首都医科大学附属北京妇产医院/北京妇幼保健院产前诊断中心，北京
- 作者简介：
  
  WANG Wei， E-mail： 906281879@qq.com
- 基金信息：
  
  the Key Project of Science and Technology Development of Chinese Association of Rehabilitation Medicine in 2024(KFKT-2024-KY-019)
- DOI：10.16016/j.2097-0927.202505029
  CLC： R195.4;R711.6;R711.71
- Received：13 May 2025，
  
  Revised：22 July 2025，
  
  Published：30 August 2025
- 稿件说明：
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王业，钟威，商微，等.子宫内膜异位症亚型与不孕症的因果关系：双向孟德尔随机化研究［J］.陆军军医大学学报，2025，47（16）：1962-1969.DOI：10.16016/j.2097-0927.202505029.

WANG Y，ZHONG W，SHANG W，et al.Causal effects between different sub-phenotypes of endometriosis and female infertility： a bidirectional Mendelian randomization study［J］.J Army Med Univ，2025，47（16）：1962-1969.DOI：10.16016/j.2097-0927.202505029.
王业，钟威，商微，等.子宫内膜异位症亚型与不孕症的因果关系：双向孟德尔随机化研究［J］.陆军军医大学学报，2025，47（16）：1962-1969.DOI：10.16016/j.2097-0927.202505029. DOI：

WANG Y，ZHONG W，SHANG W，et al.Causal effects between different sub-phenotypes of endometriosis and female infertility： a bidirectional Mendelian randomization study［J］.J Army Med Univ，2025，47（16）：1962-1969.DOI：10.16016/j.2097-0927.202505029. DOI：

摘要

目的

本研究旨在通过孟德尔随机化（Mendelian randomization， MR）探讨不同亚型的子宫内膜异位症与女性不孕症之间的双向因果关系。

方法

采用两样本MR方法，数据来源于公共数据库全基因组关联研究的子宫内膜异位症和不孕症队列。为每种亚型选择满足MR假设的工具变量（instrumental variables， IVs），主要方法为逆方差加权（inverse variance weighting， IVW）。通过Cochran’s Q检验、MR-Egger回归和留一法等敏感性分析验证结果的稳健性，统计显著性设定为

0.01（Bonferroni校正），但当

0.05时定义为潜在的显著性。

结果

在不同部位的子宫内膜异位症中，卵巢（IVW：

=1.26， 95%

： 1.17~1.35，

0.001）、盆腔腹膜（IVW：

=1.26， 95%

： 1.20~1.33，

0.001）、直肠阴道隔（IVW：

=1.11， 95%

： 1.06~1.16，

0.001）、子宫腺肌症（IVW：

=1.16， 95%

： 1.07~1.25，

0.001）和其他部位的子宫内膜异位症（IVW：

=1.10， 95%

： 1.03~1.17，

=0.004）与不孕症显著相关。输卵管和肠道子宫内膜异位症未显示出显著关联（

0.05）。反向因果分析表明，不孕症可能会导致输卵管子宫内膜异位症（IVW：OR=1.46， 95%

： 1.11~1.93，

=0.007），并与卵巢（IVW：

=1.56， 95%

： 1.27~1.93，

0.001）、盆腔腹膜（IVW：

=1.34， 95%

： 1.11~1.62，

=0.003）、直肠阴道隔（IV

W：

=1.46， 95%

： 1.11~1.93，

=0.007）、其他部位的子宫内膜异位症（IVW：

=1.61， 95%

： 1.21~2.13，

=0.001）相关。不孕症促进子宫腺肌病的发生具有潜在的统计显著性（IVW：

=1.16， 95%

： 1.07~1.25，

0.05）。还不能证明不孕症可以导致肠道子宫内膜异位症（

0.05）。敏感性分析证实了结果的稳健性。

结论

不同亚型的子宫内膜异位症与不孕症之间存在双向因果关系。即本研究应用MR方法验证了子宫内膜异位症可导致不孕症这一临床观察现象，同时还探索性的提出了不孕症本身也可能引发子宫内膜异位症这一重要结论。其中，卵巢子宫内膜异位症对不孕症的影响最大。

Abstract

Objective‍　‍To investigate the bidirectional causal relationship between different subtypes of endometriosis and female infertility using Mendelian randomization (MR). Methods‍　‍A two-sample MR analysis was performed on the data sourced from publicly available genome-wide association study (GWAS) of endometriosis and infertility. For each subtype of endometriosis

instrumental variables (IVs) satisfying MR assumptions were selected

with inverse variance weighting (IVW) as primary method. Sensitivity analyses

including Cochran’s

test

MR-Egger regression

and leave-one-out analysis

were conducted to verify the robustness of the results. Statistical significance was set at

0.01 (Bonferroni correction)

and

0.05 was considered as suggestive significance. Results‍　‍Among different locations of endometriosis

ovary (IVW:

=1.26

95%

: 1.17~1.35

0.001)

pelvic peritoneum (IVW:

=1.26

95%

: 1.20~1.33

0.001)

rectovaginal septum (IVW:

=1.11

95%

: 1.06~1.16

0.001)

adenomyosis (IVW:

=1.16

95%

: 1.07~1.25

0.001)

and other types of endometriosis (IVW:

=1.10

95%

: 1.03~1.17

=0.004) were significantly associated with infertility. But no such association was observed in fallopian tube and intestinal endometriosis with infertility (

0.05). Reverse causality analysis indicated that infertility might lead to fallopian tube endometriosis (IVW:

=1.46

95%

: 1.11~1.93

=0.007)

and was associated with ovarian (IVW:

=1.56

95%

: 1.27~1.93

0.001)

pelvic peritoneal (IVW:

=1.34

95%

: 1.11~1.62

=0.003)

rectovaginal (IVW:

=1.46

95%

: 1.11~1.93

=0.007)

and other types of endometriosis (IVW:

=1.61

95%

: 1.21~2.13

=0.001). Suggestive significance was observed statistically in infertility promoting adenomyosis (IVW:

=1.16

95%

: 1.07~1.25

0.05). It had not been proven yet that infertility could lead to intestinal endometriosis (

0.05). Sensitivity analyses confirmed the robustness of the results. Conclusion‍　‍Bidirectional causal relationships exist between different subtypes of endometriosis and infertility. Our findings based on MR analysis validate the clinical observation that endometriosis can lead to infertility

and we exploratively propose an important conclusion that infertility itself may also induce endometriosis. However

due to limited data

the causal relationships between intestinal/tubal endometriosis and infertility require further investigation.

关键词

Keywords

references

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