
==== Front
BMC Pulm Med
BMC Pulm Med
BMC Pulmonary Medicine
1471-2466
BioMed Central London

39227879
3198
10.1186/s12890-024-03198-0
Research
The association between testosterone, estradiol, estrogen sulfotransferase and idiopathic pulmonary fibrosis: a bidirectional mendelian randomization study
Xu Qingying 1
Hu Guangwang 1
Lin Qunying linqyin@126.com

123
Wu Menghang 1
Tang Kenan 1
Zhang Yuyu 1
Chen Feng 1
1 https://ror.org/050s6ns64 grid.256112.3 0000 0004 1797 9307 The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
2 https://ror.org/01kqcdh89 grid.508271.9 0000 0004 9232 3834 Department of Respiratory Medicine, Putian Pulmonary Hospital, Putian, China
3 https://ror.org/00jmsxk74 grid.440618.f 0000 0004 1757 7156 Department of Respiratory Medicine, Affiliated Hospital of Putian University, Putian, China
3 9 2024
3 9 2024
2024
24 4354 2 2024
5 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

The causal relationships between testosterone, estradiol, estrogen sulfotransferase, and idiopathic pulmonary fibrosis (IPF) are not well understood. This study employs a bidirectional two-sample Mendelian Randomization (MR) approach to explore these associations.

Methods

All genetic data utilized in our study were obtained from the IEU Open GWAS project. For the MR analysis, we employed the inverse variance weighted (IVW), MR-Egger, and weighted median methods to assess the causal relationships. We also conducted a multivariate MR (MVMR) analysis, with adjustments made for smoking. To ensure the robustness of our findings, sensitivity analyses were conducted using Cochran’s Q test, MR-Egger regression, the MR-PRESSO global test, and the leave-one-out method.

Results

Genetically predicted increases in serum testosterone levels by one standard deviation were associated with a 58.7% decrease in the risk of developing IPF (OR = 0.413, PIVW=0.029, 95% CI = 0.187 ∼ 0.912), while an increase in serum estrogen sulfotransferase by one standard deviation was associated with a 32.4% increase in risk (OR = 1.324, PIVW=0.006, 95% CI = 1.083 ∼ 1.618). No causal relationship was found between estradiol (OR = 1.094, PIVW=0.735, 95% CI = 0.650 ∼ 1.841) and the risk of IPF. Reverse MR analysis did not reveal any causal relationship between IPF and testosterone (OR = 1.001, PIVW=0.51, 95% CI = 0.998 ∼ 1.004), estradiol (OR = 1.001, PIVW=0.958, 95% CI = 0.982 ∼ 1.019), or estrogen sulfotransferase (OR = 0.975, PIVW=0.251, 95% CI = 0.933 ∼ 1.018). The MVMR analysis demonstrated that the association between testosterone (OR = 0.442, P = 0.037, 95% CI = 0.205 ∼ 0.953) and estrogen sulfotransferase (OR = 1.314, P = 0.001, 95% CI = 1.118 ∼ 1.545) and the risk of IPF persisted even after adjusting for smoking.

Conclusions

Increased serum levels of testosterone are associated with a reduced risk of IPF, while increased levels of serum estrogen sulfotransferase are associated with an increased risk. No causal relationship was found between estradiol and the development of IPF. No causal relationship was identified between IPF and testosterone, estradiol, or estrogen sulfotransferase.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12890-024-03198-0.

Keywords

Idiopathic pulmonary fibrosis
Sex hormones
Testosterone
Estrogen sulfotransferase
Mendelian randomization
the Scientific Research Innovation Special Project from Putian University2019SZP02 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by progressive and irreversible pulmonary fibrosis. The etiology and pathogenesis of IPF are complex and not yet fully understood. Risk factors for IPF include aging, smoking history, genetic factors, environmental exposure, lung microbiota, gastroesophageal reflux, and more [1]. It is currently believed that IPF is caused by persistent or repeated lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation [2]. Persistent myofibroblast expression leads to excessive extracellular matrix deposition, abnormal lung repair, tissue scarring, distortion of alveolar structure, and irreversible loss of lung function [2]. According to a study covering 12 countries, the adjusted incidence and prevalence rates of IPF are 0.09–1.2/10,000 and 0.33–4.51/10,000, respectively [3]. IPF predominantly affects males, with a French multicenter prospective study reporting that 78% of 236 newly diagnosed IPF patients were male, and 22% were female [4]. IPF progresses rapidly and has a poor prognosis. A systematic review and meta-analysis of 63,307 patients from 20 countries showed 3-year and 5-year survival rates of 61.8% (95% CI 58.7 ∼ 64.9) and 45.6% (95% CI 41.5 ∼ 49.7), respectively [5].

Currently, FDA-approved drugs for treating IPF include Pirfenidone and Nintedanib, both of which can slow the progression of IPF but cannot reverse established pulmonary fibrosis and are associated with tolerability issues [6, 7]. Lung transplantation remains the best option for treating IPF, but it is plagued by issues such as donor shortage, surgical risks, infection risk, and rejection reactions. Therefore, exploring new treatment approaches for IPF is imperative.

Sex hormones are a class of biological molecules produced by the endocrine system, primarily including androgens and estrogens. Testosterone and estradiol are the most prominent biologically active forms of androgens and estrogens, respectively [8, 9]. Sex hormones play important roles not only in sexual development and reproductive system function but also in influencing the immune system and metabolism. Estrogen sulfotransferase is the enzyme with the highest affinity for estrogens and is primarily responsible for catalyzing the sulfation of estrogens [10, 11]. Estrogen sulfotransferase has also been found to be involved in the sulfation of dehydroepiandrosterone and thyroid hormones [10].

Sex hormones have been found to participate in the fibrotic processes in multiple organs, including the heart, kidneys, liver, and more [12–16]. However, research on the role of sex hormones in IPF is limited, and some results are contradictory. A case-control study involving 101 male IPF patients and 51 healthy controls found a significant decrease in testosterone levels in the IPF group [17]. Furthermore, Nawa H et al. found that anti-androgen drugs might lead to interstitial pneumonia, possibly by inhibiting the binding of androgens to receptors [18]. Regarding estradiol, Smith LC et al. discovered that estradiol may reduce lung fibrosis occurrence by specifically downregulating the expression of Chloride intracellular channel 3 and Retinol binding protein 7, genes associated with IPF, without affecting the transforming growth factor beta1 (TGF-β1) signaling pathway [19]. Xiao YH et al. discovered that estradiol could inhibit the development of lung fibrosis in mice by upregulating the expression of Caveolin-1 and suppressing the expression of type III collagen [20]. In addition, Solopov P et al. reported that dietary phytoestrogen intake could alleviate lung fibrosis in mice [21]. However, Gharaee-Kermani M et al. arrived at different conclusions, finding that female rats had more severe lung fibrotic responses than male rats, ovariectomy reduced lung fibrosis severity, and estradiol replacement therapy restored fibrotic responses, suggesting a potential pro-fibrotic role of estrogens [22]. Tofovic SP et al. demonstrated that estrogen had an anti-mitotic effect on human lung fibroblasts only at high pharmacological concentrations (5µM) and had no effect on the growth of human lung fibroblasts at a concentration of 10µM [23]. In contrast, 2-methoxyestradiol (an endogenous metabolite of estradiol) inhibited the growth of human lung fibroblasts in a concentration-dependent manner [23]. Currently, research on the role of estrogen sulfotransferase in IPF is still lacking. Therefore, further studies are needed to explore the causal relationships between testosterone, estradiol, estrogen sulfotransferase, and IPF.

Mendelian Randomization (MR) analysis is a research method in genetic epidemiology proposed by Professor Katan. The basic principle of MR is to use genetic variation as instrumental variables (IVs) to infer causality between exposure and outcome [24]. Unlike traditional studies that can only discover associations between variables, MR can provide stronger evidence for causal inference. Furthermore, MR’s greatest advantage is that genetic variation is randomly allocated at conception, reducing the possibility of reverse causation and the influence of confounding factors [25]. Compared to observational studies, which are susceptible to bias and confounding factors, and experimental studies, which are costly and subject to ethical limitations and participant compliance issues, MR offers a robust approach for causal inference. MR must satisfy three core assumptions [24]: the relevance assumption, where IVs must be closely related to the exposure; the independence assumption, where IVs are not influenced by potential confounding factors; and the exclusion restriction assumption, where genetic variation affects the outcome only through the exposure (Fig. 1) .

In this study, our data were derived from a genome-wide association study (GWAS), and we employed a two-sample bidirectional MR approach to investigate the causal relationships between testosterone, estradiol, estrogen sulfotransferase, and IPF.

Methods

Study design

We conducted a two-sample MR study to explore the causal relationships between testosterone, estradiol, estrogen sulfotransferase and IPF. Causal effects were assessed using the IVW method, MR-Egger method, and weighted median method (WME). We also performed Cochran’s Q test to assess heterogeneity and used MR-Egger regression and MR-PRESO method to examine pleiotropy. Additionally, we conducted a leave-one-out analysis to assess the robustness of our findings.

Smoking is more prevalent among males and has been implicated in the etiology of IPF. Hence, we incorporated smoking as a covariate in our multivariate MR (MVMR) analysis.

To assess the causal relationship between IPF and testosterone, estradiol, and estrogen sulfotransferase, we conducted reverse MR analyses employing consistent methods and settings.

Data sources

In this study, genetic data for testosterone, estradiol, estrogen sulfotransferase, and IPF were obtained from the IEU GWAS database (https://gwas.mrcieu.ac.uk/). All data used in this study are in the public domain and do not require additional ethical approval. Study populations were of European ancestry to minimize potential bias due to racial factors. The dataset for testosterone (GWAS ID: ebi-a-GCST90014013) included 353,805 samples and 10,783,644 single nucleotide polymorphisms (SNPs). The dataset for estradiol (GWAS ID: ebi-a-GCST90020092) consisted of 206,927 samples and 16,136,413 SNPs. The dataset for estrogen sulfotransferase (GWAS ID: prot-a-2892) included 3,301 samples and 10,534,735 SNPs. The dataset for IPF (GWAS ID: finn-b-IPF) comprised 198,014 samples and 16,380,413 SNPs. The dataset for ever smoked (GWAS ID: ukb-a-236) comprised 336,067 samples and 10,894,596 SNPs. (Table 1).

Table 1 Information of the exposures and outcome datasets

Phenotype	IEU GWAS id	Sample size	Numbers of SNPs	
Testosterone	ebi-a-GCST90014013	353,805	10,783,644	
Estradiol	ebi-a- GCST90020092	163,985	7,488,193	
Estrogen sulfotransferase	prot-a-2892	3,301	10,534,735	
IPF

Ever smoked

	finn-b-IPF

ukb-a-236

	198,014

336,067

	16,380,413

10,894,596

	
SNP single nucleotide polymorphism

Instrumental variables

IVs are genetic variants associated with the exposure of interest. In this study, the exposure factors are testosterone, estradiol, and estrogen sulfotransferase, with IPF serving as the outcome. To ensure a strong correlation between genetic variation and exposure, we extracted IVs for testosterone, estrogen sulfotransferase with a threshold of P < 5 × 10− 8 and for estradiol with a threshold of P < 5 × 10− 7 (only 2 SNPs were obtained with P < 5 × 10− 8 for estradiol). Furthermore, to mitigate linkage disequilibrium (LD), we set clustering thresholds at r2 < 0.001 and a minimum intergenic distance of > 10,000 kb. We then excluded SNPs with an F-statistic less than 10, calculated using the formula F = R2(n-k-1)/k(1-R2), to avoid weak IVs. Additionally, we ensured data harmonization by removing palindromic SNPs. Subsequently, we employed LDlink (https://ldlink.nci.nih.gov/) to manually curate and eliminate SNPs associated with confounding factors and outcomes. Risk factors linked to IPF encompass occupational exposures (Work-related exposures to inhaled dust, asbestos, metal and/or wood dust), air pollution, gastro-oesophageal reflux disease, obstructive sleep apnoea, and viral infections [26]. Lastly, we performed a global outlier test using MR-PRESO and removed any outliers.

MR analysis

In this study, all statistical analyses were performed utilizing the “TwoSampleMR”,“MR-PRESSO”, and “MVMR” packages and within the R statistical software, version 4.3.2. Causal effects were assessed using the IVW method, MR-Egger method, and WME method. The IVW method estimates the final causal effect by calculating the weighted average of the effect sizes and standard errors of each genetic variant, thereby reducing the impact of genetic variants with larger measurement errors [27]. The MR-Egger method accounts for the presence of an intercept and can be used to assess pleiotropy [28]. The WME method assumes that over half of the IVs are valid, weights each instrumental variable’s effect by its precision, and then calculates the median [29]. IVW is a robust method that fully utilizes all IVs and offers higher statistical power compared to other methods. Therefore, in this study, we adopted IVW as the primary method for evaluating causal effects, with the other methods used for result validation.

Sensitivity analysis

We conducted Cochran’s Q test to assess heterogeneity, used MR-Egger regression and MR-PRESO method to examine pleiotropy, and performed a leave-one-out analysis to assess robustness. A Cochran Q test with P > 0.05 indicates no heterogeneity. If the MR Egger intercept has a P > 0.05, it suggests no horizontal pleiotropy. If the MR-PRESO Global test has P < 0.05, it indicates the presence of horizontal pleiotropy. MR-PRESO also detects outlier SNPs, which we removed before re-conducting MR analysis. The leave-one-out analysis involves systematically removing each SNP and computing the remaining results to assess the impact of the excluded SNP on causal effects.

Results

Obtained instrumental variables

In total, 70 SNPs were employed as IVs for testosterone, while 6 SNPs were utilized for estradiol, and 3 SNPs were selected for estrogen sulfotransferase, all in accordance with the predefined criteria for IVs selection. In the reverse MR analysis, 6 SNPs were utilized as IVs for IPF. Comprehensive details regarding these selected IVs are presented in Supplementary Table S1-6.

MR results and sensitivity analysis for testosterone, estradiol, estrogen sulfotransferase and IPF

Genetically predicted serum testosterone levels were associated with a 58.7% reduced risk of IPF for everyone standard deviation increase (OR = 0.413, PIVW=0.029, 95% CI = 0.187 ∼ 0.912), while genetically predicted estrogen sulfotransferase levels were associated with a 32.4% increased risk of IPF for everyone standard deviation increase (OR = 1.324, PIVW=0.006, 95% CI = 1.083 ∼ 1.618). Leave-one-out analysis for estradiol revealed that rs2345568 had a significant impact on the results and was removed. No causal relationship was found between estradiol and IPF (OR = 1.094, PIVW=0.735, 95% CI = 0.650 ∼ 1.841).

Cochran’s Q test for IVW on testosterone, estradiol, and estrogen sulfotransferase had P-values of 0.24, 0.88, and 0.646, respectively, all greater than 0.05, indicating no significant heterogeneity. MR-Egger intercepts were 0.178, 0.83, and 0.87 for testosterone, estradiol, and MR-PRESO Global test P-values were 0.262 and 0.871 for testosterone and estradiol, respectively, all greater than 0.05. MR-Egger and MR-PRESO methods suggested no evidence of potential horizontal pleiotropy. The Fig. 2 shows the results. Leave-one-out analysis showed no statistically significant differences in the effect estimates for each SNP (Fig. 3). The scatter plots depict the estimated impact of IVs on exposure and outcomes (Supplementary Fig. 1). Forest plots, Funnel plots and Density plots can be found in supplementary Figs. 2–4.

Fig. 1 Three assumptions for IVs in MR analysis

Fig. 2 Forest plot showing results and sensibility analysis from MR study

Fig. 3 The results of leave-one-out analysis for Testosterone, Estradiol, Estrogen Sulfotransferase and IPF in turn

MVMR analysis adjusting for smoking

The MVMR results indicate that the associations of testosterone (OR = 0.442, P = 0.037, 95% CI = 0.205 ∼ 0.953) and estrogen sulfotransferase (OR = 1.314, P = 0.001, 95% CI = 1.118 ∼ 1.545) with the risk of IPF retained statistical significance after adjusting for smoking (Supplementary Table S7).

MR results and sensitivity analysis for IPF in relation to testosterone, estradiol, and estrogen sulfotransferase

No causal relationships were observed between IPF and testosterone (OR = 1.001, PIVW=0.51, 95% CI = 0.998 ∼ 1.004), estradiol (OR = 1.001, PIVW=0.958, 95% CI = 0.982 ∼ 1.019), or estrogen sulfotransferase (OR = 0.975, PIVW=0.251, 95% CI = 0.933 ∼ 1.018).

Cochran’s Q test for IVW on IPF with estradiol and estrogen sulfotransferase had P-values of 0.53 and 0.29, respectively, both greater than 0.05, indicating no significant heterogeneity. However, for IPF and testosterone, the IVW method had a Cochran’s Q test P-value of 0.04, suggesting the presence of heterogeneity. MR-Egger intercepts for IPF and testosterone, estradiol, and estrogen sulfotransferase were 0.78, 0.88, and 0.9, respectively, all greater than 0.05. MR-PRESO Global test P-values for IPF and testosterone, estradiol, and estrogen sulfotransferase were 0.169, 0.673, and 0.419, respectively. MR-Egger and MR-PRESO methods indicated no evidence of potential horizontal pleiotropy. The Fig. 4 shows the results. Leave-one-out analysis showed no statistically significant differences in the effect estimates for each SNP (Fig. 5). The scatter plots depict the estimated impact of IVs on exposure and outcomes (Supplementary Fig. 5). Forest plots, Funnel plots and Density plots can be found in supplementary Figs. 6–8.

Fig. 4 Forest plot showing results and sensibility analysis from reverse MR study

Fig. 5 The results of leave-one-out analysis for IPF in relation to Testosterone, Estradiol, and Estrogen Sulfotransferase in turn

Discussion

Our study employed a two-sample bidirectional MR approach to investigate the associations between testosterone, estradiol, estrogen sulfotransferase levels, and the risk of IPF. We observed that higher serum testosterone levels were associated with a decreased risk of IPF, while an increase in serum estrogen sulfotransferase levels may potentially elevate the risk of IPF. However, no causal relationship was found between estradiol levels and the occurrence of IPF. Further MVMR analysis confirms that the influence of testosterone and estrogen sulfotransferase on the risk of IPF persists even when accounting for smoking. In the reverse MR analysis, we did not find any causal relationships between IPF and testosterone, estradiol, or estrogen sulfotransferase.

Prior studies have suggested a potential role for sex hormones in the development of IPF, but findings have been inconsistent, and the exact mechanisms are still debated. Our MR results contribute new evidence to this ongoing debate. Our findings may shed light on the protective role of testosterone against IPF. Previous studies have reported significantly reduced testosterone levels in IPF patients, with a positive correlation between testosterone levels and telomere length, a common susceptibility factor in sporadic and familial IPF [17, 30]. Liu M et al. discovered a negative correlation between telomere length and the progression of IPF [31], suggesting that the regulation of telomere length may be one of the mechanisms by which testosterone influences IPF. TGF-β plays a crucial role in IPF pathogenesis by stimulating fibroblast activation and proliferation and is one of the targets of the anti-fibrotic drug Pirfenidone [32, 33]. Zhang G et al. demonstrated that testosterone propionate (an exogenous androgen) could improve renal fibrosis in aged rats by inhibiting the TGF-β1/Smad pathway and activating the nuclear factor erythroid 2-related factor 2/antioxidant response element(Nrf2-ARE) signaling pathway [16]. The renin-angiotensin system (RAS) is also involved in the pathogenesis of IPF, with angiotensin-converting enzyme - Angiotensin II - angiotensin type 1 receptor (ACE-AngII-AT1R) promoting tissue fibrosis and angiotensin-converting enzyme 2 - Angiotensin (1–7) - angiotensin type 2 receptor (ACE2-Ang(1–7)-AT2R) antagonizing fibrosis progression [34]. Despite increased AT2R expression in IPF patients, the AT1R pro-fibrotic axis still predominates. Yang X et al. found that testosterone could inhibit Ang II-induced excessive proliferation and collagen synthesis in cardiac fibroblasts by suppressing the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway [15]. From these studies, we can infer that the protective role of testosterone in IPF may be associated with the inhibition of the TGF-β and Ang II pathways. Testosterone also possesses immunomodulatory properties, suppressing inflammation by increasing anti-inflammatory cytokine IL-10 and reducing pro-inflammatory cytokines tumor necrosis factor-alpha(TNFα), interleukin-1 beta(IL-1β), and interleukin-6(IL-6) [35]. IL-6 not only participates in IPF-associated inflammatory responses but also promotes fibroblast proliferation [36]. Furthermore, studies have shown that testosterone can improve mitochondrial function in heart, muscle, and brain tissues [37–39], while mitochondrial dysfunction plays a significant role in IPF pathogenesis [40].

It is noteworthy that IPF predominantly affects males, which seems to contradict the protective role of testosterone against IPF. Several potential explanations for this discrepancy deserve further consideration. Firstly, IPF is more commonly observed in middle-aged and elderly males, a demographic trend that may correlate with the known decline in testosterone levels with increasing age. Secondly, environmental factors such as occupational dust exposure and smoking, which are more prevalent in males, might counteract the protective effects of testosterone.

Mendoza-Milla C et al. found that dehydroepiandrosterone could exert anti-fibrotic effects by affecting fibroblast migration, proliferation, differentiation, and collagen synthesis [41]. Previous Mendelian randomization studies have indicated that hypothyroidism promotes the development of IPF, possibly due to enhanced oxidative stress and impaired mitochondrial function in a hypothyroid state [42, 43]. We speculate that estrogen sulfotransferase sulfonates dehydroepiandrosterone and thyroid hormones, rendering them inactive, may be one of the reasons estrogen sulfotransferase promotes IPF development.

Future studies should deeply investigate the molecular underpinnings of how sex hormones, especially testosterone and estrogen sulfotransferase, interact with the pathophysiological processes of IPF. This encompasses exploring their effects on fibroblast activity and the regulation of immune responses. Clinical trials are essential for evaluating the potential of sex hormone modulation as a therapeutic approach for IPF. Moreover, longitudinal research across various populations should be undertaken to elucidate the prognostic implications of sex hormone levels. Examining sex-specific differences may uncover distinct risk factors and therapeutic targets for each gender. These research pathways are designed to strengthen our understanding of the complex relationship between sex hormones and IPF, which could lead to innovative preventive and therapeutic perspectives for the condition.

This study is the first to utilize the MR method to assess the causal relationships between testosterone, estrogen, and estrogen sulfotransferase levels and the risk of IPF. Our MR analysis was based on large-sample GWAS data from European populations, providing sufficient statistical power for accurate estimation of causal effects. Additionally, our study effectively mitigated the potential for reverse causality and confounding factors.

Limitations

There are some limitations to our study. Firstly, since the GWAS data used in our study were derived from European populations, the generalizability of our findings to other populations may be limited. Therefore, future research should include more diverse populations to validate and extend these findings. Secondly, due to constraints in the original data, our study did not perform detailed stratified analyses by gender and age. Future studies should consider these key demographic variables for a more comprehensive understanding of their impact on genetic risk for IPF.

Conclusions

Our study suggests that genetically predicted higher serum testosterone levels may be associated with a reduced risk of IPF, while an increase in serum estrogen sulfotransferase levels may potentially elevate the risk of IPF. No causal relationship was found between estradiol levels and the risk of IPF. Furthermore, we did not identify any causal relationships between IPF and testosterone, estradiol, or estrogen sulfotransferase.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

We express our gratitude to the IEU Open GWAS database for providing publicly available summary-level GWAS data for our study.

Author contributions

QX and QL conceived and designed the study. QX, GH, MW, KT, YZ, FC conducted data analysis. QX wrote the manuscript and revised the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the Scientific Research Innovation Special Project from Putian University (2019SZP02). This funding body had no influence on the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Data availability

All GWAS data used in this study are available in the IEU Open GWAS Project (https://gwas.mrcieu.ac.uk/).

Declarations

Ethics approval and consent to participate

The data used in this paper are publicly available, ethically approved.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Barratt SL, Creamer A, Hayton C, Chaudhuri N. Idiopathic pulmonary fibrosis (IPF): an overview. J Clin Med 2018:7(8).
2. Mei Q Liu Z Zuo H Yang Z Qu J Idiopathic pulmonary fibrosis: an update on Pathogenesis Front Pharmacol 2021 12 797292 10.3389/fphar.2021.797292 35126134
Mei Q, Liu Z, Zuo H, Yang Z, Qu J. Idiopathic pulmonary fibrosis: an update on Pathogenesis. Front Pharmacol. 2021;12:797292.35126134 10.3389/fphar.2021.797292
3. Maher TM Bendstrup E Dron L Langley J Smith G Khalid JM Patel H Kreuter M Global incidence and prevalence of idiopathic pulmonary fibrosis Respir Res 2021 22 1 197 10.1186/s12931-021-01791-z 34233665
Maher TM, Bendstrup E, Dron L, Langley J, Smith G, Khalid JM, Patel H, Kreuter M. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res. 2021;22(1):197.34233665 10.1186/s12931-021-01791-z
4. Sesé L Nunes H Cottin V Israel-Biet D Crestani B Guillot-Dudoret S Cadranel J Wallaert B Tazi A Maître B Gender differences in idiopathic pulmonary fibrosis: are men and women equal? Front Med (Lausanne) 2021 8 713698 10.3389/fmed.2021.713698 34422868
Sesé L, Nunes H, Cottin V, Israel-Biet D, Crestani B, Guillot-Dudoret S, Cadranel J, Wallaert B, Tazi A, Maître B, et al. Gender differences in idiopathic pulmonary fibrosis: are men and women equal? Front Med (Lausanne). 2021;8:713698.34422868 10.3389/fmed.2021.713698
5. Zheng Q, Cox IA, Campbell JA, Xia Q, Otahal P, de Graaff B, Corte TJ, Teoh AKY, Walters EH, Palmer AJ. Mortality and survival in idiopathic pulmonary fibrosis: a systematic review and meta-analysis. ERJ Open Res 2022, 8(1).
6. Zhao R Xie B Wang X Zhang X Ren Y Wang C Dai H The tolerability and efficacy of antifibrotic therapy in patients with idiopathic pulmonary fibrosis: results from a real-world study Pulm Pharmacol Ther 2024 84 102287 10.1016/j.pupt.2024.102287 38242314
Zhao R, Xie B, Wang X, Zhang X, Ren Y, Wang C, Dai H. The tolerability and efficacy of antifibrotic therapy in patients with idiopathic pulmonary fibrosis: results from a real-world study. Pulm Pharmacol Ther. 2024;84:102287.38242314 10.1016/j.pupt.2024.102287
7. Cash E Goodwin AT Tatler AL Adenosine receptor signalling as a driver of pulmonary fibrosis Pharmacol Ther 2023 249 108504 10.1016/j.pharmthera.2023.108504 37482099
Cash E, Goodwin AT, Tatler AL. Adenosine receptor signalling as a driver of pulmonary fibrosis. Pharmacol Ther. 2023;249:108504.37482099 10.1016/j.pharmthera.2023.108504
8. Baker ME. What are the physiological estrogens? Steroids 2013;78(3):337–40.
9. Burger HG Davis SR The role of androgen therapy Best Pract Res Clin Obstet Gynaecol 2002 16 3 383 93 10.1053/beog.2001.0281 12099669
Burger HG, Davis SR. The role of androgen therapy. Best Pract Res Clin Obstet Gynaecol. 2002;16(3):383–93.12099669 10.1053/beog.2001.0281
10. Yi M, Negishi M, Lee SJ. Estrogen Sulfotransferase (SULT1E1): its molecular regulation, polymorphisms, and clinical perspectives. J Pers Med 2021, 11(3).
11. Wan R, Wang L, Zhu M, Li W, Duan Y, Yu G. Cellular Senescence: a Troy Horse in Pulmonary Fibrosis. Int J Mol Sci 2023, 24(22).
12. Eisa MA Mansour AM Salama SA Elsadek BEM Ashour AA Abdelghany TM Estrogen/estrogen receptor activation protects against DEN-induced liver fibrosis in female rats via modulating TLR-4/NF-kβ signaling Eur J Pharmacol 2023 960 176165 10.1016/j.ejphar.2023.176165 38059444
Eisa MA, Mansour AM, Salama SA, Elsadek BEM, Ashour AA, Abdelghany TM. Estrogen/estrogen receptor activation protects against DEN-induced liver fibrosis in female rats via modulating TLR-4/NF-kβ signaling. Eur J Pharmacol. 2023;960:176165.38059444 10.1016/j.ejphar.2023.176165
13. Kim SE Min JS Lee S Lee DY Choi D Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration Sci Rep 2023 13 1 15461 10.1038/s41598-023-42788-6 37726372
Kim SE, Min JS, Lee S, Lee DY, Choi D. Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration. Sci Rep. 2023;13(1):15461.37726372 10.1038/s41598-023-42788-6
14. Liu H Dai W Cui Y Lyu Y Li Y Potential associations of circulating growth differentiation factor-15 with sex hormones in male patients with coronary artery disease Biomed Pharmacother 2019 114 108792 10.1016/j.biopha.2019.108792 30909145
Liu H, Dai W, Cui Y, Lyu Y, Li Y. Potential associations of circulating growth differentiation factor-15 with sex hormones in male patients with coronary artery disease. Biomed Pharmacother. 2019;114:108792.30909145 10.1016/j.biopha.2019.108792
15. Yang X Wang Y Yan S Sun L Yang G Li Y Yu C Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat Bioengineered 2017 8 1 14 20 10.1080/21655979.2016.1227141 27791460
Yang X, Wang Y, Yan S, Sun L, Yang G, Li Y, Yu C. Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat. Bioengineered. 2017;8(1):14–20.27791460 10.1080/21655979.2016.1227141
16. Zhang G Kang Y Zhou C Cui R Jia M Hu S Ji X Yuan J Cui H Shi G Amelioratory effects of Testosterone Propionate on Age-related renal fibrosis via suppression of TGF-β1/Smad signaling and activation of Nrf2-ARE signaling Sci Rep 2018 8 1 10726 10.1038/s41598-018-29023-3 30013094
Zhang G, Kang Y, Zhou C, Cui R, Jia M, Hu S, Ji X, Yuan J, Cui H, Shi G. Amelioratory effects of Testosterone Propionate on Age-related renal fibrosis via suppression of TGF-β1/Smad signaling and activation of Nrf2-ARE signaling. Sci Rep. 2018;8(1):10726.30013094 10.1038/s41598-018-29023-3
17. Fang C Huang H Zhang Q Wang N Jing X Guo J Ferianc M Xu Z Relation between sex hormones and leucocyte telomere length in men with idiopathic pulmonary fibrosis Respirology 2020 25 12 1265 73 10.1111/resp.13871 32583532
Fang C, Huang H, Zhang Q, Wang N, Jing X, Guo J, Ferianc M, Xu Z. Relation between sex hormones and leucocyte telomere length in men with idiopathic pulmonary fibrosis. Respirology. 2020;25(12):1265–73.32583532 10.1111/resp.13871
18. Nawa H Niimura T Hamano H Yagi K Goda M Zamami Y Ishizawa K Evaluation of potential complications of interstitial lung Disease Associated with antiandrogens using data from databases reporting spontaneous adverse effects Front Pharmacol 2021 12 655605 10.3389/fphar.2021.655605 34177574
Nawa H, Niimura T, Hamano H, Yagi K, Goda M, Zamami Y, Ishizawa K. Evaluation of potential complications of interstitial lung Disease Associated with antiandrogens using data from databases reporting spontaneous adverse effects. Front Pharmacol. 2021;12:655605.34177574 10.3389/fphar.2021.655605
19. Smith LC Moreno S Robertson L Robinson S Gant K Bryant AJ Sabo-Attwood T Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells Respir Res 2018 19 1 160 10.1186/s12931-018-0861-5 30165855
Smith LC, Moreno S, Robertson L, Robinson S, Gant K, Bryant AJ, Sabo-Attwood T. Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells. Respir Res. 2018;19(1):160.30165855 10.1186/s12931-018-0861-5
20. Xiao YH Liang XF Wang Y Xiao Q [Effects of 17beta-estradiol on the expression Caveolin-1 and type III collagen in the mouse lung fibroblast stimulated by SiO2] Sichuan Da Xue Xue Bao Yi Xue Ban 2015 46 1 62 4 25807798
Xiao YH, Liang XF, Wang Y, Xiao Q. [Effects of 17beta-estradiol on the expression Caveolin-1 and type III collagen in the mouse lung fibroblast stimulated by SiO2]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2015;46(1):62–4.25807798
21. Solopov P, Colunga Biancatelli RML, Dimitropoulou C, Catravas JD. Dietary Phytoestrogens Ameliorate Hydrochloric Acid-Induced Chronic Lung Injury and Pulmonary Fibrosis in mice. Nutrients 2021, 13(10).
22. Gharaee-Kermani M Hatano K Nozaki Y Phan SH Gender-based differences in bleomycin-induced pulmonary fibrosis Am J Pathol 2005 166 6 1593 606 10.1016/S0002-9440(10)62470-4 15920145
Gharaee-Kermani M, Hatano K, Nozaki Y, Phan SH. Gender-based differences in bleomycin-induced pulmonary fibrosis. Am J Pathol. 2005;166(6):1593–606.15920145 10.1016/S0002-9440(10)62470-4
23. Tofovic SP Zhang X Jackson EK Zhu H Petrusevska G 2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats Vascul Pharmacol 2009 51 2–3 190 7 10.1016/j.vph.2009.06.002 19540933
Tofovic SP, Zhang X, Jackson EK, Zhu H, Petrusevska G. 2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats. Vascul Pharmacol. 2009;51(2–3):190–7.19540933 10.1016/j.vph.2009.06.002
24. König IR Greco FMD Mendelian randomization: progressing towards understanding causality Ann Neurol 2018 84 2 176 7 10.1002/ana.25293 30014502
König IR, Greco FMD. Mendelian randomization: progressing towards understanding causality. Ann Neurol. 2018;84(2):176–7.30014502 10.1002/ana.25293
25. Davey Smith G Hemani G Mendelian randomization: genetic anchors for causal inference in epidemiological studies Hum Mol Genet 2014 23 R1 R89 98 10.1093/hmg/ddu328 25064373
Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89–98.25064373 10.1093/hmg/ddu328
26. Podolanczuk AJ, Thomson CC, Remy-Jardin M, Richeldi L, Martinez FJ, Kolb M, Raghu G. Idiopathic pulmonary fibrosis: state of the art for 2023. Eur Respir J 2023, 61(4).
27. Slob EAW Burgess S A comparison of robust mendelian randomization methods using summary data Genet Epidemiol 2020 44 4 313 29 10.1002/gepi.22295 32249995
Slob EAW, Burgess S. A comparison of robust mendelian randomization methods using summary data. Genet Epidemiol. 2020;44(4):313–29.32249995 10.1002/gepi.22295
28. Bowden J Davey Smith G Burgess S Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression Int J Epidemiol 2015 44 2 512 25 10.1093/ije/dyv080 26050253
Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–25.26050253 10.1093/ije/dyv080
29. Bowden J Davey Smith G Haycock PC Burgess S Consistent estimation in mendelian randomization with some Invalid instruments using a weighted median estimator Genet Epidemiol 2016 40 4 304 14 10.1002/gepi.21965 27061298
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some Invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14.27061298 10.1002/gepi.21965
30. Alder JK Armanios M Telomere-mediated lung disease Physiol Rev 2022 102 4 1703 20 10.1152/physrev.00046.2021 35532056
Alder JK, Armanios M. Telomere-mediated lung disease. Physiol Rev. 2022;102(4):1703–20.35532056 10.1152/physrev.00046.2021
31. Liu M Luo P Liu L Wei X Bai X Li J Wu L Luo M Immune-mediated inflammatory diseases and leukocyte telomere length: a mendelian randomization study Front Genet 2023 14 1129247 10.3389/fgene.2023.1129247 37139230
Liu M, Luo P, Liu L, Wei X, Bai X, Li J, Wu L, Luo M. Immune-mediated inflammatory diseases and leukocyte telomere length: a mendelian randomization study. Front Genet. 2023;14:1129247.37139230 10.3389/fgene.2023.1129247
32. Ma H Wu X Li Y Xia Y Research Progress in the Molecular mechanisms, therapeutic targets, and Drug Development of Idiopathic Pulmonary Fibrosis Front Pharmacol 2022 13 963054 10.3389/fphar.2022.963054 35935869
Ma H, Wu X, Li Y, Xia Y. Research Progress in the Molecular mechanisms, therapeutic targets, and Drug Development of Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022;13:963054.35935869 10.3389/fphar.2022.963054
33. Moss BJ Ryter SW Rosas IO Pathogenic mechanisms underlying idiopathic pulmonary fibrosis Annu Rev Pathol 2022 17 515 46 10.1146/annurev-pathol-042320-030240 34813355
Moss BJ, Ryter SW, Rosas IO. Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annu Rev Pathol. 2022;17:515–46.34813355 10.1146/annurev-pathol-042320-030240
34. Young ON Bourke JE Widdop RE Catch your breath: the protective role of the angiotensin AT(2) receptor for the treatment of idiopathic pulmonary fibrosis Biochem Pharmacol 2023 217 115839 10.1016/j.bcp.2023.115839 37778444
Young ON, Bourke JE, Widdop RE. Catch your breath: the protective role of the angiotensin AT(2) receptor for the treatment of idiopathic pulmonary fibrosis. Biochem Pharmacol. 2023;217:115839.37778444 10.1016/j.bcp.2023.115839
35. Mohamad NV Wong SK Wan Hasan WN Jolly JJ Nur-Farhana MF Ima-Nirwana S Chin KY The relationship between circulating testosterone and inflammatory cytokines in men Aging Male 2019 22 2 129 40 10.1080/13685538.2018.1482487 29925283
Mohamad NV, Wong SK, Wan Hasan WN, Jolly JJ, Nur-Farhana MF, Ima-Nirwana S, Chin KY. The relationship between circulating testosterone and inflammatory cytokines in men. Aging Male. 2019;22(2):129–40.29925283 10.1080/13685538.2018.1482487
36. Habiel DM Hogaboam C Heterogeneity in fibroblast proliferation and survival in idiopathic pulmonary fibrosis Front Pharmacol 2014 5 2 10.3389/fphar.2014.00002 24478703
Habiel DM, Hogaboam C. Heterogeneity in fibroblast proliferation and survival in idiopathic pulmonary fibrosis. Front Pharmacol. 2014;5:2.24478703 10.3389/fphar.2014.00002
37. do Val Lima PR Ronconi KS Morra EA Rodrigues PL Ávila RA Merlo E Graceli JB Simões MR Stefanon I Ribeiro Júnior RF: testosterone deficiency impairs cardiac interfibrillar mitochondrial function and myocardial contractility while inducing oxidative stress Front Endocrinol (Lausanne) 2023 14 1206387 10.3389/fendo.2023.1206387 37780627
do Val Lima PR, Ronconi KS, Morra EA, Rodrigues PL, Ávila RA, Merlo E, Graceli JB, Simões MR, Stefanon I. Ribeiro Júnior RF: testosterone deficiency impairs cardiac interfibrillar mitochondrial function and myocardial contractility while inducing oxidative stress. Front Endocrinol (Lausanne). 2023;14:1206387.37780627 10.3389/fendo.2023.1206387
38. Tian X Lou S Shi R From mitochondria to Sarcopenia: role of 17β-estradiol and testosterone Front Endocrinol (Lausanne) 2023 14 1156583 10.3389/fendo.2023.1156583 37152937
Tian X, Lou S, Shi R. From mitochondria to Sarcopenia: role of 17β-estradiol and testosterone. Front Endocrinol (Lausanne). 2023;14:1156583.37152937 10.3389/fendo.2023.1156583
39. Yan W Zhang T Kang Y Zhang G Ji X Feng X Shi G Testosterone ameliorates age-related brain mitochondrial dysfunction Aging 2021 13 12 16229 47 10.18632/aging.203153 34139672
Yan W, Zhang T, Kang Y, Zhang G, Ji X, Feng X, Shi G. Testosterone ameliorates age-related brain mitochondrial dysfunction. Aging. 2021;13(12):16229–47.34139672 10.18632/aging.203153
40. Cala-Garcia JD, Medina-Rincon GJ, Sierra-Salas PA, Rojano J, Romero F. The role of mitochondrial dysfunction in idiopathic pulmonary fibrosis: New perspectives for a Challenging Disease. Biology (Basel) 2023, 12(9).
41. Mendoza-Milla C Valero Jiménez A Rangel C Lozano A Morales V Becerril C Chavira R Ruiz V Barrera L Montaño M Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis Eur Respir J 2013 42 5 1309 21 10.1183/09031936.00027412 23143540
Mendoza-Milla C, Valero Jiménez A, Rangel C, Lozano A, Morales V, Becerril C, Chavira R, Ruiz V, Barrera L, Montaño M, et al. Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis. Eur Respir J. 2013;42(5):1309–21.23143540 10.1183/09031936.00027412
42. Zhang Y Zhao M Guo P Wang Y Liu L Zhao J Gao L Yuan Z Xue F Zhao J Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis EBioMedicine 2021 73 103669 10.1016/j.ebiom.2021.103669 34749302
Zhang Y, Zhao M, Guo P, Wang Y, Liu L, Zhao J, Gao L, Yuan Z, Xue F, Zhao J. Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis. EBioMedicine. 2021;73:103669.34749302 10.1016/j.ebiom.2021.103669
43. Zhu J Zhou D Wang J Yang Y Chen D He F Li Y A causal Atlas on comorbidities in Idiopathic Pulmonary Fibrosis: a bidirectional mendelian randomization study Chest 2023 164 2 429 40 10.1016/j.chest.2023.02.038 36870387
Zhu J, Zhou D, Wang J, Yang Y, Chen D, He F, Li Y. A causal Atlas on comorbidities in Idiopathic Pulmonary Fibrosis: a bidirectional mendelian randomization study. Chest. 2023;164(2):429–40.36870387 10.1016/j.chest.2023.02.038
