Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study

Fei Zou; Yaxian Hu; Mengmeng Xu; Su Wang; Zengrong Wu; Feihong Deng

doi:10.3389/fendo.2024.1272746

Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study

Front Endocrinol (Lausanne). 2024 Apr 10:15:1272746. doi: 10.3389/fendo.2024.1272746. eCollection 2024.

Authors

Fei Zou^#^{1

2}, Yaxian Hu^#³, Mengmeng Xu^{1

2}, Su Wang^{1

2}, Zengrong Wu^{1

2}, Feihong Deng^{1

2}

Affiliations

¹ Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Research Center of Digestive Disease, Central South University, Changsha, Hunan, China.
³ Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

^# Contributed equally.

Abstract

Background: Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear.

Method: Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation.

Results: E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046).

Conclusion: Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.

Keywords: Mendelian randomization; estradiol; inflammatory bowel disease; progesterone; sex hormone; testosterone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colitis, Ulcerative / blood
Colitis, Ulcerative / epidemiology
Colitis, Ulcerative / genetics
Crohn Disease / blood
Crohn Disease / genetics
Estradiol / blood
Female
Genome-Wide Association Study*
Gonadal Steroid Hormones* / blood
Humans
Inflammatory Bowel Diseases* / blood
Inflammatory Bowel Diseases* / genetics
Male
Mendelian Randomization Analysis*
Polymorphism, Single Nucleotide
Progesterone / blood
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism
Sex Hormone-Binding Globulin* / analysis
Sex Hormone-Binding Globulin* / genetics
Sex Hormone-Binding Globulin* / metabolism
Testosterone / blood

Substances

Sex Hormone-Binding Globulin
Gonadal Steroid Hormones
SHBG protein, human
Testosterone
Receptors, Estrogen
Estradiol
Progesterone

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China [grant number 81900478].