{"paper_id":"484e006f-112d-469a-817d-7acad5e13c58","body_text":"Association of sleep traits, physical activity and leisure sedentary behavior with women’s reproductive health: a two-sample Mendelian randomization analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of sleep traits, physical activity and leisure sedentary behavior with women’s reproductive health: a two-sample Mendelian randomization analysis Jiaxin Zhang, Tao Wang, Pusheng Yang, Yaxin Miao, Beilei Ge, Jing Sun This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4419372/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Living habits affect women's endocrine and fertility over time with aging and in certain circumstances, according to which we can promote women's reproductive health by adjusting living habits. Methods: We utilized two-sampleMendelian randomization (TSMR) analysis with summary datasets from genome-wide association study (GWAS) to investigate the causal relationship between sleep traits, leisure sedentary behavior, physical activity and women’s reproductive health-related traits. Exposure genetic instruments were used as variants significantly related to traits. The inverse-variance weighted (IVW) method was used as the main analysis approach, and we also performed MR-Egger and weighted median to supplement the sensitivity test. Then, the horizontal pleiotropy was detected by using MRE intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran’s Q statistics by IVW and MR-Egger. Results: We found evidence that insomnia showed a significant inverse causal association with the endometriosis [OR (95% CI) IVW = 1.80 (1.16, 2.80), P = 0.009], and with the abnormal menstruation [OR (95% CI) IVW = 2.37 (1.34, 4.20), P = 0.003]. What else the sleep duration has the negative relation menopause age (beta IVW = −0.034, P = 0.001), the long sleep duration might be the protective factor of endometriosis [OR (95% CI) IVW = 0.07 (0.01, 0.72), P = 0.024], strenuous sports were also negatively correlated with the female infertility[OR (95% CI) IVW = 0.10 (0.02, 0.68), P = 0.019]. In sensitivity analysis, we observed no sign of horizontal pleiotropy or heterogeneity. Conclusion: Our finding suggested insomnia was an adverse factor of endometriosis and abnormal menstruation, long sleep duration was a protective factor with endometriosis. Therefore, adequate sleep and regular schedule might decrease the risk of endometriosis and abnormal menstruation to guarantee the women reproductive health. Two-sample mendelian randomization analysis insomnia endometriosis abnormal uterine and vaginal bleeding menopause age Figures Figure 1 Figure 2 Introduction Many factors, both genetic and environmental, affect female reproductive health [1] . Multiple lifestyle factors can be modified to enhance overall well-being and they are ultimately under one’s own control, and play a key role in determining reproductive health [2] . Recently, a study has researched about whether sleeping habits, physical activity, and lifestyle affect reproductive health, it is a topic of great concern[3]. In women, sleep interacts with reproductive health, and sleep disorders can emerge within the context of reproductive stages[4]. Woman’s sleep changes over time with changing hormone levels associated with the menstrual cycle and menopause[5]. While there also appears to be a relationship between sleep traits and women’s reproductive health: Poor sleep is associated with menstrual cycle irregularity[6]; Sleep dysregulation may result in infertility; Circadian dysrhythmia is linked to altered secretion of reproductive Hormones[7–9]. It has been proved that reductions in daily physical activity are primary causes of chronic diseases and that physical activity is rehabilitative treatment of inactivity-caused dysfunctions[10]. There is emerging evidence that physical activity and sedentary lifestyle both in female and male can influence reproductive success and assisted reproductive technologies success [11, 12]. Among women, increased physical activity and decreased sedentary behavior may improve fertility through maintenance of body weight and hormone levels[13]. In contrast, high levels of physical activity could inhibit ovulation, leading to decreased fertility, while little is known about whether leisure sedentary behavior causally related to reproductive capacity[14, 15]. Used women’s reproductive health factor as outcome factor, we focused on some common infertility diseases such as polycystic ovarian syndrome (PCOS), endometriosis and female infertility[16]. The study also included some sex hormones (total testosterone (TT), bioavailable testosterone (bio-T), estradiol (E 2 ), and anti-Mullerian hormone (AMH)) and menstrual phenotypes (menopausal age, irregular menstrual cycle/bleeding). Mendelian randomization (MR) utilized single-nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of an exposure on certain outcomes[17]. According to Mendel's law, alleles of genetic variation are randomly separated during gametophytogenesis and fertilization combination, which makes them independent of confounding factors[18]. This allows to bypass possible and potential biases from confounding and reverse causation, and to strengthen causal inference in expose-outcome associations. Previous MR studies have demonstrated the significant impact of smoking initiation and alcohol and coffee consumption on an women’s reproductive health[19]. However, no robust evidence has been provided to support the correlation between sleep traits, leisure sedentary behavior, physical activity and women’s reproductive health-related traits. Herein, we employed a two-sample MR approach to investigate the association of these three lifestyle behaviors with reproductive traits and abnormal menstrual phenotypes, which is beneficial for recommendations to manage women’s reproductive health. Materials and methods Study design In this study sleep traits (sleep duration, long sleep duration, short sleep duration, insomnia), physical activity (Moderate-to-vigorous physical activity (MVAP), vigorous physical activity (VAP) and Strenuous sports) and leisure sedentary behavior (television watching, computer use, driving) were used as exposure factors, single nucleotide polymorphisms (SNPs) loci significantly associated with the above exposure factors were selected as instrumental variables (IVs), and the outcome variable were (PCOS, endometriosis, female infertility, abnormal menstruation, menopause age, bioT, TT, E 2 and AMH), and the causal association analysis between exposure and outcome was performed using a two-sample MR analysis approach based on a publicly available genome wide association study (GWAS) data base of large samples. Table 1 GWAS data pertaining to sleep traits, leisure sedentary behavior and physical activity. GWAS Phenotype Participants Ancestry Year ID Jansen, P. R. Insomnia 1,331,010 European 2019 PMID: 30804565 Dashti, H. S. Sleep duration 446,118 European 2019 PMID: 30846698 Dashti, H. S. Short Sleep duration 106,192 European 2019 PMID: 30846698 Dashti, H. S. Long Sleep duration 34,184 European 2019 PMID: 30846698 Klimentidis, Y. C. MVPA 377,234 European 2018 ebi-a-GCST006097 Klimentidis, Y. C. VPA 98,060 European 2018 ebi-a-GCST006098 Klimentidis, Y. C. Strenuous sports 124,842 European 2018 ebi-a-GCST006100 Van de Vegte Y.J. Television watching 422,218 European 2020 PubMed ID 32317632 Van de Vegte Y.J. Computer use 422,218 European 2020 PubMed ID 32317632 Van de Vegte Y.J. Driving 422,218 European 2020 PubMed ID 32317632 Table 2 GWAS data pertaining to women’s reproductive health-related traits. Phenotype Participants Ancestry Year ID PCOS 118,228 European 2021 finn-b-E4_POCS Endometriosis 68,969 European 2021 finn-b-N14_ENDOMETRIOSIS Female infertility 68,969 European 2021 finn-b-N14_FEMALEINFERT Menopause age 156,364 European 2018 GCST90029037 abnormal menstruation 68,969 European 2021 Finngen-b-N14_ABNORMALBLEED Bio-T 382,988 European 2020 GCST90012104 TT 194,453 European 2020 GCST90012113 E 2 134,323 European 2020 GCST90020091 AMH 3,344 European 2020 GCST007363 Correlation analysis MR analysis relies on three fundamental assumptions[20]: (1) The initial assumption posits a robust correlation between IVs and sleep traits, leisure sedentary behavior and physical activity. (2) The assumption of independence denotes that IVs and the outcome variables, women’s productive health remained uncorrelated with any other confounding factors; (3) IVs can solely impact women’s productive health by modulating these life factors without the involvement of any additional pathways (Fig. 1 ). To identify suitable IVs, we selected SNPs displaying strong associations as IVs, rigorous screening and clumping of the significant SNPs (p < 5e-08) for sleep traits and physical activity, (p < 5e-07) for sedentary behavior[21]. Linkage disequilibrium (LD) LD indicates that genetic variants with genomes in close proximity have a tendency to be inherited in common, resulting in a greater likelihood that alleles from two or more loci will co-occur on a single chromosome than if they occur randomly. The screening criteria were as follows: (1) kb > 10, 000; (2) r 2 < 0.01. Elimination of weak IVs, the F-statistic was employed to assess the strength of an IV. When the F-value is less than 10, it is classified as a weak IV, whereas an F-value greater than 10 designates it as a non-weak IV. The F-value was calculated using the following formula: (beta/se) 2 . R 2 is the proportion of variance explained by SNPs in the exposed database. R 2 = 2×EAF×(1-EAF) ×beta 2 /SD 2 where EAF is the effect allele frequency, beta is the allele effect value, and SD is the standard deviation. MR analysis Main 3 methods were employed to determine the causal relationship between life factors (exposure factor) and the outcome of women’s reproductive health. These methods encompassed inverse variance weighting (IVW), MR-Egger regression and weighted median. The \"Two-Sample MR\" package in the R programming language was utilized to visualize MR results, featuring scatter plots and forest plots, as well as sensitivity analysis plots. Typically, the IVW method’s results are the primary gauge of MR analysis reliability, with a significance threshold of P < 0.05 indicating a positive outcome[22]. For the reliability of the final analysis results, the following screening criteria were used as filters for robust significant causality: (1) IVW was mainly suggested a significant causal relationship. (2) The direction of MR analysis results (beta value) was consistent among all three methods. (3) There is no heterogeneity or horizontal pleiotropy among the IVs. If the IVs meet the assumptions, the results will be unbiased and the standard error will be lesser than with IVW. The main results with causal significance and without heterogeneity or pleiotropy were shown through forest plots, others were displaced in supplement table. Sensitivity analysis IVW and MR-Egger tests were used to assessed the heterogeneity, with a significance level of P < 0.05 stating the presence of heterogeneity in the studies. In cases where the IV influences the outcome through factors other than the exposure variable, it denotes the presence of pleiotropy. Pleiotropy can undermine the assumptions of independence and exclusivity, which was assessed by MR-Egger intercept test. A P -value < 0.05 indicated the presence of pleiotropy in the data. We employed the \"leave-one-out\" method to conduct a sensitivity analysis. This approach entails systematically removing the results associated with individual SNPs, assessing whether they are outliers, and observing the stability of the results after each SNP’s removal. Additionally, funnel plot was utilized to assess the symmetry of SNPs and evaluate the reliability of the results[23]. Results Main results are presented in the text were without neither heterogeneity nor pleiotropy, and the IVW suggested a significant causal relationship. We did not find a significant relationship between leisure sedentary behavior with women’s reproductive health, the physical activity might influence the women sex hormone while there always existed strong heterogeneity and pleiotropy. IV. screening 67 SNPs in \"insomnia\" displayed robust associations with “endometriosis” and “abnormal menstruation”. Moreover, \"long sleep duration\" displayed 10 such SNPs with “endometriosis”, 6 such SNPs between “long sleep duration” and “Menopause age”. Additionally, 6 SNPs in \"strenuous sports\" demonstrated a robust association with female infertile. No weak IVs or confounding factors were detected in our analysis as F-value of the SNPs was calculated by R package \"Mendelian Randomization\". Results of the MR analysis Using IVW, MR-Egger regression and weighted median, we assessed the causal relationship between exposure factors and outcomes. MR results were visualized using the \"Two-Sample MR\" package in the R programming language, which included scatter plots and forest plots. The results showed that insomnia [OR (95% CI) IVW = 1.80 (1.16, 2.80), P = 0.009] was associated with endometriosis (Fig. 2 A), and abnormal menstruation [OR (95% CI) IVW = 2.37 (1.34, 4.20), P = 0.003; OR (95% CI) WM = 2.64(1.24, 5.62), P = 0.012] (Fig. 2 B). In addition, the IVW analysis supported suggestive evidence of a positive association for long sleep duration and endometriosis [OR (95% CI) IVW = 0.07 (0.01, 0.72), P = 0.024; OR (95% CI) WM = 0.02(0.00, 0.30), P = 0.004](Fig. 2 C); The long sleep duration initiation SNP IVW analysis showed potential causality for a positive effect on menopause age [beta (95% CI) IVW= -5.33(0.00, 0.13), P = 0.001; beta WM = 0.02, 95%CI = (0.00, 0.86), P = 0.042](Fig. 2 D); after eliminating two SNP with pleiotropy (rs55938136, rs3785884). The strenuous sports in women had a similar negative causality with female infertility [OR (95% CI) IVW = 0.1 (0.02, 0.68), P = 0.019]; OR (95% CI) WM = 0.04(0.00, 0.37), P = 0.004] (Fig. 2 E Sensitivity analysis We employed MR-Egger regression and IVW to assess the presence of heterogeneity. The results showed P > 0.05 for all datasets, indicating absence of heterogeneity. Subsequently, Egger regression was adopted to study whether directional pleiotropy existed, and the results showed that P > 0.05 of all data sets indicated that directional pleiotropy did not exist. The funnel plot displayed a symmetric distribution of SNPs, underscoring the relative stability of the results. To evaluate the influence of individual SNPs, a leave-one-out approach was employed, and the results demonstrated no significant impact on effect sizes. Table 3 Variation scale and heterogeneity analysis. Exposure Outcome SNP Heterogeneity tests Directional horizontal pleiotropy MR-Egger IVW Insomnia Endometriosis 46 0.070 0.069 0.053 Insomnia Abnormal menstruation 46 0.120 0.120 0.138 Long sleep duration Endometriosis 10 0.255 0.236 0.283 Long sleep duration Menopause age 6 0.912 0.845 0.866 Strenuous sports Female infertility 6 0.146 0.222 0.259 Discussion The objective of this study was to examine the causal relationship between sleep traits, physical activity and leisure sedentary behavior with women’s reproductive health, by utilizing publicly available large-sample GWAS data and conducting MR analysis using the R programming language. Most of the endometriosis concomitant symptoms, including dysmenorrhea, chronic pelvic pain, female infertility, and dyspareunia are well recognized symptoms of endometriosis; however, little attention has been given to insomnia symptoms[9]. It already had some studies provided strong evidence that individuals with symptomatic endometriosis experience higher levels of sleep disturbances compared to those without endometriosis[24, 25]. A significant positive correlation was found between poor sleep quality and the intensity of dysmenorrhea or pelvic pain[26, 27], some speculated chronic pelvic pain, chronic pain, or fatigue could potentially act as a mediating factor with endometriosis and sleep disturbances. In this article a causal relationship between insomnia and endometriosis (OR (95% CI) IVW = 1.80 (1.16, 2.80); P = 0.009) was determined. The insomnia might be the risk factor of endometriosis, this result add weight to a previous study, which revealed a significant association between night shift work, changes in sleep patterns during days off and the risk of endometriosis[28]. What else long sleep duration was a protective factor with endometriosis [OR (95% CI) IVW = 0.07 (0.01, 0.72), P = 0.024]. We all know endometriosis could impair sleep such as increased sleep disturbances and decreased the sleep duration, the long sleep might potentially prevent endometriosis. While it also might be that long sleep duration females were more likely to escape endometriosis. Patients with insomnia are more likely to suffer from endometriosis, meanwhile patients with the endometriosis have higher ratio with sleep disturbances. Collectively, these studies suggest a bidirectional relationship between sleep traits and endometriosis, it possibly because of changes in the immune system or gynecologic endocrine[29]. The chronic estrogen-dependent nature of endometriosis intensifies hormonal changes, which may play a further role in sleep disruption[30]. One study demonstrated that the use of hormonal treatment could improve sleep disturbance but not available for sleep quality, daytime sleepiness and insomnia[31]. While other studies were in contrast with this result. The mechanism of sleep traits between endometriosis needed further study. The association between sleep traits and the menstrual cycle has been scarcely studied. In this study insomnia was determined a positive causal relationship with abnormal uterine and vaginal bleeding (OR (95% CI) IVW = 2.37 (1.34, 4.20), p = 0.003), which is in coincidence with a former systematic review[32]. In a cross-sectional study, sleep duration and irregular menstrual cycles were found to be significantly inversely correlated[33]. One longitudinal study found that those having insomnia increased the risk of menstrual cycle irregularity more than 2 times higher over a year, these associations became more predominant as the Insomnia Severity Index score increased[34]. Persons with sleep disturbances usually do not have regular circadian rhythms, which may be related to irregular synthesis and secretion of female gonadal hormones. Sleep disorders inhibit gonadotropin-releasing hormone reproduction from the pituitary gland, thereby resulting in reduced secretion of gonadal hormones [35, 36]. Lower estradiol levels, lower FSH in relation with lower sleep variation and Luteinizing hormone (LH) pulse frequency inhibited by sleep noted a significant relation between hormone between sleep traits, demonstrated an activation of the HPA axis[37–39]. Consequently, in the activation of the HPA axis, corticotropin-releasing hormone (CRH) inhibits GnRH secretion, and the decrease frequency of GnRH pulsatile secretion lead to hypothalamic amenorrhea[40]. Therefor female reproductive functions such as folliculogenesis, ovulation, menstruation, hormone synthesis and secretion can be hindered by sleep deprivation, sleep disruption, and complex molecular genetics and hormonal pathways play an important role in regulating these relationships[41]. Similarly, sleep problems may exacerbate gynecologic conditions. While we found no relation between short sleep duration and abnormal menstrual cycle, which in contrast with many other study[42, 43]. In this study we did not obtain evidence that rigorous exercise is risk factors for menstrual cycle irregularity[44]. Long sleep duration had the negative causality with the menopause age [beta (95% CI) IVW= -5.33(0.00, 0.13), P = 0.001]. As is known the sleep disturbance is a common condition in menopause transition[45]. Regardless of sex, older adults exhibit poorer sleep consolidation compared with younger adults, while the menopausal transition conveys poor sleep beyond anticipated age effects[46]. One study also found that a short sleep duration was significantly associated with a later onset of menopause[28], the reason might be with the levels of neuroendocrine hormones. Cognitive behavioral therapy represents the first-line treatment of insomnia in the general population, however, when vasomotor symptoms are present, menopausal hormone therapy should be considered[47]. We observed a modest and significant genetic correlation between strenuous exercise and female infertility [OR (95% CI) IVW = 0.1 (0.02, 0.68), P = 0.019]. Physically active females were more likely to be fertile, consistent with a previous observational study reporting that more females with normal fertility engaged in moderate and vigorous activities[14]. However, other conservative studies have revealed that among females, excessive exercise may generally, levels of engagement in physical activity vary across individuals that high levels of physical activity among females could result in an energy deficit, lead to hypothalamic amenorrhea, causing short-term infertility, and ultimately hinder one’s fertility[48]. The strengths of this study can be summarized as follows: (1) It leveraged a large sample of GWAS data, enhancing the reliability of the findings. (2) Potential biases were effectively mitigated through association analysis, LD analysis, elimination of weak IVs, and control for confounding actors. (3) A symmetrical distribution of SNPs was observed in the funnel plot. Furthermore, both the pleiotropy test and the leave-one-out test showed the relative stability of the results. Nevertheless, this study also exhibits several limitations: (1) We acknowledge that heterogeneity may originate from variations in analysis platforms, experimental conditions, pop characteristics, and other IVs even both the MR-Egger regression and IVW methods yielded results with P-values greater than 0.05. Consequently, a more comprehensive investigation into the sources of heterogeneity is warranted. (2) This study primarily centered on the European population, resulting in a paucity of GWAS data pertaining to Asian and African populations. (3) The number of IVs for SNPs within each dataset in this study was relatively modest. Therefore, it necessitates the utilization of large sample datasets to expand the pool of SNPs available as IVs for subsequent analysis. (4) We employed MR to explore the causal relationship between exposure and outcome. It is worth noting that we did not delve into the associated underlying mechanisms in this study. Conclusion Our study suggested that insomnia and endometriosis might were reciprocal causation, long sleep duration was a protective factor with endometriosis. It is also genetically predicted insomnia was risk factor of abnormal uterine and vaginal bleeding. Thus, improving sleep quality and prolong the duration of sleep may be potential intervention targets for preventing endometriosis and abnormal uterine and vaginal bleeding. Declarations Acknowledgements We express our gratitude to the IEU Open GWAS database (https://gwas.mrcieu.ac.uk/) for providing publicly available summary-level GWAS data for our study. Author contributions JXZ designed the research. JZX and TW collected and analyzed the data. JXZ, TW, PSY and YXM, drafted the manuscript. JS and BLG revised the manuscript. All authors contributed to the article and approved the submitted version. Funding This work was supported by grants from the Science and Technology Commission of Shanghai Municipality (22Y11906100) to Jing Sun and Shanghai Outstanding Academic Leaders Plan to Jing Sun (Year 2019). Acknowledgements Not applicable. Competing interests The authors declare no competing interests. Ethics approval and consent to participate The data used in this paper are publicly available, ethically approved, and the subjects have given their informed consent. Consent for publication Not applicable. References Zoe B, Kirsty O, Courtney B, Emily M, Janice B, Yvonne H: Sexual and reproductive health education: Midwives' confidence and practices . Women Birth 2021, 35 (4):360-366. Rakesh S, Kelly R B, Jennifer M F, Ashok A: Lifestyle factors and reproductive health: taking control of your fertility . Reprod Biol Endocrinol 2013, 11 . Yoko U, Miyuki H, Shinnosuke K, Ikumi A, Chihiro T, Yoshiharu N, Aisaku F, Yoshiharu M, Takuya K, Yusuke I et al : Lifestyle and fertility-specific quality of life affect reproductive outcomes in couples undergoing in vitro fertilization . Front Endocrinol (Lausanne) 2024, 15 . Kathryn Aldrich L, Fiona C B: Sleep and Women's Health Across the Lifespan . Sleep Med Clin 2018, 13 (3):xv-xvi. Joyce A W: Women and sleep . Handb Clin Neurol 2010, 98 :639-651. Elin Rosenbek S, Thea Otte A, Agnete Skovlund D, Andreas Kryger J, Christoffer S, Nina la Cour F, Henriette Svarre N, Naja Hulvej R: Night-time smartphone use, sleep duration, sleep quality, and menstrual disturbances in young adult women: A population-based study with high-resolution tracking data . Sleep Adv 2023, 4 (1):zpad013. Meers JM, Nowakowski S: Sleep, premenstrual mood disorder, and women's health . Curr Opin Psychol 2020, 34 :43-49. Kloss JD, Perlis ML, Zamzow JA, Culnan EJ, Gracia CR: Sleep, sleep disturbance, and fertility in women . Sleep Med Rev 2015, 22 :78-87. Ishikura IA, Hachul H, Pires GN, Tufik S, Andersen ML: The relationship between insomnia and endometriosis . J Clin Sleep Med 2020, 16 (8):1387-1388. Booth FW, Roberts CK, Laye MJ: Lack of exercise is a major cause of chronic diseases . Compr Physiol 2012, 2 (2):1143-1211. Leandro Fornias Machado dR, Maurício RL, Juan Pablo R-L, Victor Keihan Rodrigues M, Olinda do Carmo L: Sedentary behavior and health outcomes: an overview of systematic reviews . PLoS One 2014, 9 (8):e105620. Siret L, Francisco B O, Theodora KK, Lana J, Jonatan R R, Julius H, Kjell W, Anneli S-E, Ruth K, Andres S et al : Physical and Sedentary Activities in Association with Reproductive Outcomes among Couples Seeking Infertility Treatment: A Prospective Cohort Study . Int J Environ Res Public Health 2021, 18 (5):2718. Vickà V, Lara S, Dirk A, Tom D, Christophe M, Leonardo G, Roland D, Peter C, Annick B: Dietary intake, physical activity and sedentary behavior and association with BMI during the transition to parenthood: a prospective dyadic study . Front Public Health 2023, 11 :1092843. Brinson AK, da Silva SG, Hesketh KR, Evenson KR: Impact of Physical Activity and Sedentary Behavior on Spontaneous Female and Male Fertility: A Systematic Review . J Phys Act Health 2023, 20 (7):600-615. Dana N J, Shannon W: Stress and the HPA Axis: Balancing Homeostasis and Fertility . Int J Mol Sci 2017, 18 (10):2224. Ling S, Dai Y, Weng R, Li Y, Wu W, Zhou Z, Zhong Z, Zheng Y: Epidemiologic and genetic associations of female reproductive disorders with depression or dysthymia: a Mendelian randomization study . Sci Rep 2024, 14 (1):5984. Stephen B, Adam B, Simon G T: Mendelian randomization analysis with multiple genetic variants using summarized data . Genet Epidemiol 2013, 37 (7):658-665. Christopher J Y, Su Yeon K, Chang Hyun N, Junehawk L, Jung Woo P, Jihyeob M, Seongyeol P, Soyoung L, Boram Y, Kyoung Il M et al : Estimation of intrafamilial DNA contamination in family trio genome sequencing using deviation from Mendelian inheritance . Genome Res 2023, 32 (11-12):2134-2144. Jiang Z, He R, Wu H, Yu J, Zhu K, Luo Q, Liu X, Pan J, Huang H: The causal association between smoking initiation, alcohol and coffee consumption, and women's reproductive health: A two-sample Mendelian randomization analysis . Front Genet 2023, 14 :1098616. Jack B, George DS, Stephen B: Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression . Int J Epidemiol 2015, 44 (2):512-525. Zhang XB, Jiang HH, Zhang LL, Li CJ, Chen C, Xing MZ, Ma YN, Ma YX: Potential causal associations between leisure sedentary behaviors, physical activity, sleep traits, and myopia: a Mendelian randomization study . BMC Ophthalmol 2024, 24 (1):104. Jin T, Huang W, Cao F, Yu X, Guo S, Ying Z, Xu C: Causal association between systemic lupus erythematosus and the risk of dementia: A Mendelian randomization study . Front Immunol 2022, 13 :1063110. Zhu K, Shi J, Yang R, Zhou C, Liu Z: Evidence based on Mendelian randomization: Causal relationship between mitochondrial biological function and lung cancer and its subtypes . Neoplasia 2023, 46 :100950. Pickup B, Coutts-Bain D, Todd J: Fear of progression, depression, and sleep difficulties in people experiencing endometriosis-pain: A cross-sectional study . J Psychosom Res 2024, 178 :111595. Leone Roberti Maggiore U, Bizzarri N, Scala C, Tafi E, Siesto G, Alessandri F, Ferrero S: Symptomatic endometriosis of the posterior cul-de-sac is associated with impaired sleep quality, excessive daytime sleepiness and insomnia: a case-control study . Eur J Obstet Gynecol Reprod Biol 2017, 209 :39-43. Baker F, Driver H, Rogers G, Paiker J, Mitchell D: High nocturnal body temperatures and disturbed sleep in women with primary dysmenorrhea . Am J Physiol 1999, 277 (6):E1013-1021. Dunlap K, Yu L, Fisch B, Nolan T: Polysomnographic characteristics of sleep disorders in chronic pelvic pain . Prim Care Update Ob Gyns 2000, 5 (4):195. Nagata C, Wada K, Yamakawa M, Nakashima Y, Sugino M, Mori T: Sleep duration and the onset of menopause in Japanese women . Menopause 2023, 30 (4):437-440. Facchin F, Buggio L, Roncella E, Somigliana E, Ottolini F, Dridi D, Roberto A, Vercellini P: Sleep disturbances, fatigue and psychological health in women with endometriosis: a matched pair case-control study . Reprod Biomed Online 2021, 43 (6):1027-1034. Wang Y, Nicholes K, Shih IM: The Origin and Pathogenesis of Endometriosis . Annu Rev Pathol 2020, 15 :71-95. Bergqvist A, Theorell T: Changes in quality of life after hormonal treatment of endometriosis . Acta Obstet Gynecol Scand 2001, 80 (7):628-637. Jeon B, Baek J: Menstrual disturbances and its association with sleep disturbances: a systematic review . BMC Womens Health 2023, 23 (1):470. Nam GE, Han K, Lee G: Association between sleep duration and menstrual cycle irregularity in Korean female adolescents . Sleep Med 2017, 35 :62-66. WonYang K, Keun-Ho J, Hyeong-Min L, Ji-Sung A, Won-Ju P: The menstrual cycle associated with insomnia in newly employed nurses performing shift work: a 12-month follow-up study . Int Arch Occup Environ Health 2018, 92 (2):227-235. Karen L G, David R, Carl Hirschie J: Shift work and circadian dysregulation of reproduction . Front Endocrinol (Lausanne) 2013, 4 . Wen-Pei C, Yu-Pei C: Meta-Analysis Comparing Menstrual Regularity and Dysmenorrhea of Women Working Rotating Shifts and Fixed Day Shifts . J Womens Health (Larchmt) 2020, 30 (5):722-730. Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, Kales A, Chrousos GP: Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications . J Clin Endocrinol Metab 2001, 86 (8):3787-3794. Hall JE, Sullivan JP, Richardson GS: Brief wake episodes modulate sleep-inhibited luteinizing hormone secretion in the early follicular phase . J Clin Endocrinol Metab 2005, 90 (4):2050-2055. Sandrine T, Muriel R, Hans B, Enriqueta B, René E: Relationship between sleep and secretion of gonadotropin and ovarian hormones in women with normal cycles . Fertil Steril 2002, 77 (4):738-744. Marshall J: The menstrual cycle and disorders of ovulation . Endocrinology: Adult and Paediatric Eds Philadelphia: Elsevier Saunders Publishing 2016:2231-2241. Zhang Y, Luo Z, Jia Y, Zhao Y, Huang Y, Ruan F, Ying Q, Ma L, Luo J, Zhou J: Development and validation of a predictive model of abnormal uterine bleeding associated with ovulatory dysfunction: a case-control study . BMC Womens Health 2023, 23 (1):536. Lim AJR, Huang Z, Chua SE, Kramer MS, Yong E-L: Sleep Duration, Exercise, Shift Work and Polycystic Ovarian Syndrome-Related Outcomes in a Healthy Population: A Cross-Sectional Study . PLoS One 2016, 11 (11):e0167048. Taeryoon K, Ga Eun N, Byoungduck H, Sung Jung C, Junghun K, Do Hyun E, Sang Woo L, Soon Hong M, Woohyun L, Kyungdo H et al : Associations of mental health and sleep duration with menstrual cycle irregularity: a population-based study . Arch Womens Ment Health 2018, 21 (6):619-626. Jensen T, Scheike T, Keiding N, Schaumburg I, Grandjean P: Fecundability in relation to body mass and menstrual cycle patterns . Epidemiology 1999, 10 (4):422-428. Baker FC, Lampio L, Saaresranta T, Polo-Kantola P: Sleep and Sleep Disorders in the Menopausal Transition . Sleep Med Clin 2018, 13 (3):443-456. Shaver J, Woods N: Sleep and menopause: a narrative review . Menopause (New York, NY) 2015, 22 (8):899-915. Proserpio P, Marra S, Campana C, Agostoni E, Palagini L, Nobili L, Nappi R: Insomnia and menopause: a narrative review on mechanisms and treatments . Climacteric : the journal of the International Menopause Society 2020, 23 (6):539-549. Evenson KR, Hesketh KR: Studying the Complex Relationships Between Physical Activity and Infertility . Am J Lifestyle Med 2016, 10 (4):232-234. Additional Declarations No competing interests reported. Supplementary Files suplementmetarial.zip Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4419372\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":305768090,\"identity\":\"1974dc0f-1507-437e-bafa-9df89d7b264b\",\"order_by\":0,\"name\":\"Jiaxin Zhang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tongji University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jiaxin\",\"middleName\":\"\",\"lastName\":\"Zhang\",\"suffix\":\"\"},{\"id\":305768091,\"identity\":\"9f7aebca-faa7-463b-9855-911ec33e5464\",\"order_by\":1,\"name\":\"Tao Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tongji University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tao\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":305768092,\"identity\":\"a50294da-c899-405f-b9b9-c119120de9a0\",\"order_by\":2,\"name\":\"Pusheng Yang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tongji University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Pusheng\",\"middleName\":\"\",\"lastName\":\"Yang\",\"suffix\":\"\"},{\"id\":305768093,\"identity\":\"5c84d0b8-895e-4a41-be24-ea5a0129d8d6\",\"order_by\":3,\"name\":\"Yaxin Miao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tongji University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yaxin\",\"middleName\":\"\",\"lastName\":\"Miao\",\"suffix\":\"\"},{\"id\":305768094,\"identity\":\"fac85b77-fda2-4012-a319-08c4aa9d9e8a\",\"order_by\":4,\"name\":\"Beilei Ge\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Tongji University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Beilei\",\"middleName\":\"\",\"lastName\":\"Ge\",\"suffix\":\"\"},{\"id\":305768095,\"identity\":\"d0af9202-e346-4d21-8af7-c2fdbd4011d1\",\"order_by\":5,\"name\":\"Jing Sun\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"\",\"institution\":\"Tongji University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Jing\",\"middleName\":\"\",\"lastName\":\"Sun\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-05-14 13:00:01\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-4419372/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4419372/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":57410597,\"identity\":\"52d22dfc-dbc1-430f-b5cd-cc383f47efd3\",\"added_by\":\"auto\",\"created_at\":\"2024-05-30 10:24:05\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":69363,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFlow chart of the two-samples MR analysis\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4419372/v1/dc9e5544c9b52ac8d5ebe441.png\"},{\"id\":57410598,\"identity\":\"55eadd0d-6fb0-4a29-af54-c4ce6ad9b4e7\",\"added_by\":\"auto\",\"created_at\":\"2024-05-30 10:24:05\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":113306,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot of the causal relationship, primarily evaluated using the IVW method. A: insomnia and endometriosis B: insomnia and abnormal menstruation. C: long sleep duration and endometriosis. D: long sleep duration and menopause age. E: strenuous sports and female infertility.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4419372/v1/35f167a9494c1e667263432a.png\"},{\"id\":57860326,\"identity\":\"6980c690-0220-48cc-ab5f-f251862f7c72\",\"added_by\":\"auto\",\"created_at\":\"2024-06-06 14:14:24\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1873245,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4419372/v1/5fb912d4-8251-4e87-9171-b5db5999be28.pdf\"},{\"id\":57410599,\"identity\":\"5bc99c78-07b7-460c-9c8b-ab55565d0d21\",\"added_by\":\"auto\",\"created_at\":\"2024-05-30 10:24:05\",\"extension\":\"zip\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":427005,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"suplementmetarial.zip\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4419372/v1/d3077c6bbd9c8abf22eff1de.zip\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Association of sleep traits, physical activity and leisure sedentary behavior with women’s reproductive health: a two-sample Mendelian randomization analysis\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eMany factors, both genetic and environmental, affect female reproductive health\\u003csup\\u003e[1]\\u003c/sup\\u003e. Multiple lifestyle factors can be modified to enhance overall well-being and they are ultimately under one\\u0026rsquo;s own control, and play a key role in determining reproductive health\\u003csup\\u003e[2]\\u003c/sup\\u003e. Recently, a study has researched about whether sleeping habits, physical activity, and lifestyle affect reproductive health, it is a topic of great concern[3].\\u003c/p\\u003e \\u003cp\\u003eIn women, sleep interacts with reproductive health, and sleep disorders can emerge within the context of reproductive stages[4]. Woman\\u0026rsquo;s sleep changes over time with changing hormone levels associated with the menstrual cycle and menopause[5]. While there also appears to be a relationship between sleep traits and women\\u0026rsquo;s reproductive health: Poor sleep is associated with menstrual cycle irregularity[6]; Sleep dysregulation may result in infertility; Circadian dysrhythmia is linked to altered secretion of reproductive Hormones[7\\u0026ndash;9].\\u003c/p\\u003e \\u003cp\\u003eIt has been proved that reductions in daily physical activity are primary causes of chronic diseases and that physical activity is rehabilitative treatment of inactivity-caused dysfunctions[10]. There is emerging evidence that physical activity and sedentary lifestyle both in female and male can influence reproductive success and assisted reproductive technologies success [11, 12]. Among women, increased physical activity and decreased sedentary behavior may improve fertility through maintenance of body weight and hormone levels[13]. In contrast, high levels of physical activity could inhibit ovulation, leading to decreased fertility, while little is known about whether leisure sedentary behavior causally related to reproductive capacity[14, 15].\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eUsed women\\u0026rsquo;s reproductive health factor as outcome factor, we focused on some common infertility diseases such as polycystic ovarian syndrome (PCOS), endometriosis and female infertility[16]. The study also included some sex hormones (total testosterone (TT), bioavailable testosterone (bio-T), estradiol (E\\u003csub\\u003e2\\u003c/sub\\u003e), and anti-Mullerian hormone (AMH)) and menstrual phenotypes (menopausal age, irregular menstrual cycle/bleeding).\\u003c/p\\u003e \\u003cp\\u003eMendelian randomization (MR) utilized single-nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of an exposure on certain outcomes[17]. According to Mendel's law, alleles of genetic variation are randomly separated during gametophytogenesis and fertilization combination, which makes them independent of confounding factors[18]. This allows to bypass possible and potential biases from confounding and reverse causation, and to strengthen causal inference in expose-outcome associations. Previous MR studies have demonstrated the significant impact of smoking initiation and alcohol and coffee consumption on an women\\u0026rsquo;s reproductive health[19].\\u003c/p\\u003e \\u003cp\\u003eHowever, no robust evidence has been provided to support the correlation between sleep traits, leisure sedentary behavior, physical activity and women\\u0026rsquo;s reproductive health-related traits. Herein, we employed a two-sample MR approach to investigate the association of these three lifestyle behaviors with reproductive traits and abnormal menstrual phenotypes, which is beneficial for recommendations to manage women\\u0026rsquo;s reproductive health.\\u003c/p\\u003e\"},{\"header\":\"Materials and methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy design\\u003c/h2\\u003e \\u003cp\\u003eIn this study sleep traits (sleep duration, long sleep duration, short sleep duration, insomnia), physical activity (Moderate-to-vigorous physical activity (MVAP), vigorous physical activity (VAP) and Strenuous sports) and leisure sedentary behavior (television watching, computer use, driving) were used as exposure factors, single nucleotide polymorphisms (SNPs) loci significantly associated with the above exposure factors were selected as instrumental variables (IVs), and the outcome variable were (PCOS, endometriosis, female infertility, abnormal menstruation, menopause age, bioT, TT, E\\u003csub\\u003e2\\u003c/sub\\u003e and AMH), and the causal association analysis between exposure and outcome was performed using a two-sample MR analysis approach based on a publicly available genome wide association study (GWAS) data base of large samples.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eGWAS data pertaining to sleep traits, leisure sedentary behavior and physical activity.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGWAS\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePhenotype\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eParticipants\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAncestry\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eYear\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eID\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eJansen, P. R.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eInsomnia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1,331,010\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2019\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePMID: 30804565\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDashti, H. S.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSleep duration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e446,118\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2019\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePMID: 30846698\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDashti, H. S.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eShort Sleep duration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e106,192\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2019\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePMID: 30846698\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDashti, H. S.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eLong Sleep duration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e34,184\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2019\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePMID: 30846698\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKlimentidis, Y. C.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMVPA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e377,234\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2018\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eebi-a-GCST006097\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKlimentidis, Y. C.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eVPA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e98,060\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2018\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eebi-a-GCST006098\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKlimentidis, Y. C.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eStrenuous sports\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e124,842\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2018\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eebi-a-GCST006100\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVan de Vegte Y.J.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTelevision watching\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e422,218\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePubMed ID 32317632\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVan de Vegte Y.J.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eComputer use\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e422,218\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePubMed ID 32317632\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVan de Vegte Y.J.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDriving\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e422,218\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePubMed ID 32317632\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eGWAS data pertaining to women\\u0026rsquo;s reproductive health-related traits.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePhenotype\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eParticipants\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eAncestry\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYear\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eID\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePCOS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e118,228\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2021\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003efinn-b-E4_POCS\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEndometriosis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e68,969\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2021\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003efinn-b-N14_ENDOMETRIOSIS\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFemale infertility\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e68,969\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2021\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003efinn-b-N14_FEMALEINFERT\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMenopause age\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e156,364\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2018\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eGCST90029037\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eabnormal menstruation\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e68,969\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2021\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eFinngen-b-N14_ABNORMALBLEED\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBio-T\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e382,988\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eGCST90012104\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e194,453\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eGCST90012113\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eE\\u003csub\\u003e2\\u003c/sub\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e134,323\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eGCST90020091\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAMH\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3,344\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEuropean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2020\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eGCST007363\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCorrelation analysis\\u003c/h2\\u003e \\u003cp\\u003eMR analysis relies on three fundamental assumptions[20]: (1) The initial assumption posits a robust correlation between IVs and sleep traits, leisure sedentary behavior and physical activity. (2) The assumption of independence denotes that IVs and the outcome variables, women\\u0026rsquo;s productive health remained uncorrelated with any other confounding factors; (3) IVs can solely impact women\\u0026rsquo;s productive health by modulating these life factors without the involvement of any additional pathways (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eTo identify suitable IVs, we selected SNPs displaying strong associations as IVs, rigorous screening and clumping of the significant SNPs (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;5e-08) for sleep traits and physical activity, (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;5e-07) for sedentary behavior[21].\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eLinkage disequilibrium (LD)\\u003c/h2\\u003e \\u003cp\\u003eLD indicates that genetic variants with genomes in close proximity have a tendency to be inherited in common, resulting in a greater likelihood that alleles from two or more loci will co-occur on a single chromosome than if they occur randomly. The screening criteria were as follows: (1) kb\\u0026thinsp;\\u0026gt;\\u0026thinsp;10, 000; (2) r\\u003csup\\u003e2\\u003c/sup\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01. Elimination of weak IVs, the F-statistic was employed to assess the strength of an IV. When the F-value is less than 10, it is classified as a weak IV, whereas an F-value greater than 10 designates it as a non-weak IV. The F-value was calculated using the following formula: (beta/se)\\u003csup\\u003e2\\u003c/sup\\u003e. R\\u003csup\\u003e2\\u003c/sup\\u003e is the proportion of variance explained by SNPs in the exposed database. R\\u003csup\\u003e2\\u003c/sup\\u003e\\u0026thinsp;=\\u0026thinsp;2\\u0026times;EAF\\u0026times;(1-EAF) \\u0026times;beta\\u003csup\\u003e2\\u003c/sup\\u003e /SD\\u003csup\\u003e2\\u003c/sup\\u003e where EAF is the effect allele frequency, beta is the allele effect value, and SD is the standard deviation.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eMR analysis\\u003c/h2\\u003e \\u003cp\\u003eMain 3 methods were employed to determine the causal relationship between life factors (exposure factor) and the outcome of women\\u0026rsquo;s reproductive health. These methods encompassed inverse variance weighting (IVW), MR-Egger regression and weighted median. The \\\"Two-Sample MR\\\" package in the R programming language was utilized to visualize MR results, featuring scatter plots and forest plots, as well as sensitivity analysis plots. Typically, the IVW method\\u0026rsquo;s results are the primary gauge of MR analysis reliability, with a significance threshold of \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 indicating a positive outcome[22].\\u003c/p\\u003e \\u003cp\\u003eFor the reliability of the final analysis results, the following screening criteria were used as filters for robust significant causality: (1) IVW was mainly suggested a significant causal relationship. (2) The direction of MR analysis results (beta value) was consistent among all three methods. (3) There is no heterogeneity or horizontal pleiotropy among the IVs. If the IVs meet the assumptions, the results will be unbiased and the standard error will be lesser than with IVW. The main results with causal significance and without heterogeneity or pleiotropy were shown through forest plots, others were displaced in supplement table.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSensitivity analysis\\u003c/h2\\u003e \\u003cp\\u003eIVW and MR-Egger tests were used to assessed the heterogeneity, with a significance level of \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 stating the presence of heterogeneity in the studies. In cases where the IV influences the outcome through factors other than the exposure variable, it denotes the presence of pleiotropy. Pleiotropy can undermine the assumptions of independence and exclusivity, which was assessed by MR-Egger intercept test. A \\u003cem\\u003eP\\u003c/em\\u003e-value\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 indicated the presence of pleiotropy in the data. We employed the \\\"leave-one-out\\\" method to conduct a sensitivity analysis. This approach entails systematically removing the results associated with individual SNPs, assessing whether they are outliers, and observing the stability of the results after each SNP\\u0026rsquo;s removal. Additionally, funnel plot was utilized to assess the symmetry of SNPs and evaluate the reliability of the results[23].\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eMain results are presented in the text were without neither heterogeneity nor pleiotropy, and the IVW suggested a significant causal relationship. We did not find a significant relationship between leisure sedentary behavior with women\\u0026rsquo;s reproductive health, the physical activity might influence the women sex hormone while there always existed strong heterogeneity and pleiotropy.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eIV. screening\\u003c/h2\\u003e \\u003cp\\u003e67 SNPs in \\\"insomnia\\\" displayed robust associations with \\u0026ldquo;endometriosis\\u0026rdquo; and \\u0026ldquo;abnormal menstruation\\u0026rdquo;. Moreover, \\\"long sleep duration\\\" displayed 10 such SNPs with \\u0026ldquo;endometriosis\\u0026rdquo;, 6 such SNPs between \\u0026ldquo;long sleep duration\\u0026rdquo; and \\u0026ldquo;Menopause age\\u0026rdquo;. Additionally, 6 SNPs in \\\"strenuous sports\\\" demonstrated a robust association with female infertile. No weak IVs or confounding factors were detected in our analysis as F-value of the SNPs was calculated by R package \\\"Mendelian Randomization\\\".\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eResults of the MR analysis\\u003c/h2\\u003e \\u003cp\\u003eUsing IVW, MR-Egger regression and weighted median, we assessed the causal relationship between exposure factors and outcomes. MR results were visualized using the \\\"Two-Sample MR\\\" package in the R programming language, which included scatter plots and forest plots. The results showed that insomnia [OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;1.80 (1.16, 2.80), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.009] was associated with endometriosis (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eA), and abnormal menstruation [OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;2.37 (1.34, 4.20), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.003; OR (95% CI) WM\\u0026thinsp;=\\u0026thinsp;2.64(1.24, 5.62), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.012] (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eB).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eIn addition, the IVW analysis supported suggestive evidence of a positive association for long sleep duration and endometriosis [OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;0.07 (0.01, 0.72), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.024; OR (95% CI) WM\\u0026thinsp;=\\u0026thinsp;0.02(0.00, 0.30), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.004](Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eC); The long sleep duration initiation SNP IVW analysis showed potential causality for a positive effect on menopause age [beta (95% CI) IVW= -5.33(0.00, 0.13), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.001; beta WM\\u0026thinsp;=\\u0026thinsp;0.02, 95%CI = (0.00, 0.86), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.042](Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eD); after eliminating two SNP with pleiotropy (rs55938136, rs3785884). The strenuous sports in women had a similar negative causality with female infertility [OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;0.1 (0.02, 0.68), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.019]; OR (95% CI) WM\\u0026thinsp;=\\u0026thinsp;0.04(0.00, 0.37), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.004] (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eE\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSensitivity analysis\\u003c/h2\\u003e \\u003cp\\u003eWe employed MR-Egger regression and IVW to assess the presence of heterogeneity. The results showed \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05 for all datasets, indicating absence of heterogeneity. Subsequently, Egger regression was adopted to study whether directional pleiotropy existed, and the results showed that \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05 of all data sets indicated that directional pleiotropy did not exist.\\u003c/p\\u003e \\u003cp\\u003eThe funnel plot displayed a symmetric distribution of SNPs, underscoring the relative stability of the results. To evaluate the influence of individual SNPs, a leave-one-out approach was employed, and the results demonstrated no significant impact on effect sizes.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eVariation scale and heterogeneity analysis.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eExposure\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eOutcome\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eSNP\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eHeterogeneity tests\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eDirectional horizontal pleiotropy\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eMR-Egger\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eIVW\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInsomnia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEndometriosis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e46\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.070\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.069\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.053\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInsomnia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAbnormal menstruation\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e46\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.120\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.120\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.138\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLong sleep duration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEndometriosis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.255\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.236\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.283\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLong sleep duration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMenopause age\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.912\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.845\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.866\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStrenuous sports\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eFemale infertility\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.146\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.222\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.259\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThe objective of this study was to examine the causal relationship between sleep traits, physical activity and leisure sedentary behavior with women\\u0026rsquo;s reproductive health, by utilizing publicly available large-sample GWAS data and conducting MR analysis using the R programming language.\\u003c/p\\u003e \\u003cp\\u003eMost of the endometriosis concomitant symptoms, including dysmenorrhea, chronic pelvic pain, female infertility, and dyspareunia are well recognized symptoms of endometriosis; however, little attention has been given to insomnia symptoms[9]. It already had some studies provided strong evidence that individuals with symptomatic endometriosis experience higher levels of sleep disturbances compared to those without endometriosis[24, 25]. A significant positive correlation was found between poor sleep quality and the intensity of dysmenorrhea or pelvic pain[26, 27], some speculated chronic pelvic pain, chronic pain, or fatigue could potentially act as a mediating factor with endometriosis and sleep disturbances. In this article a causal relationship between insomnia and endometriosis (OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;1.80 (1.16, 2.80); \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.009) was determined. The insomnia might be the risk factor of endometriosis, this result add weight to a previous study, which revealed a significant association between night shift work, changes in sleep patterns during days off and the risk of endometriosis[28]. What else long sleep duration was a protective factor with endometriosis [OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;0.07 (0.01, 0.72), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.024]. We all know endometriosis could impair sleep such as increased sleep disturbances and decreased the sleep duration, the long sleep might potentially prevent endometriosis. While it also might be that long sleep duration females were more likely to escape endometriosis. Patients with insomnia are more likely to suffer from endometriosis, meanwhile patients with the endometriosis have higher ratio with sleep disturbances. Collectively, these studies suggest a bidirectional relationship between sleep traits and endometriosis, it possibly because of changes in the immune system or gynecologic endocrine[29]. The chronic estrogen-dependent nature of endometriosis intensifies hormonal changes, which may play a further role in sleep disruption[30]. One study demonstrated that the use of hormonal treatment could improve sleep disturbance but not available for sleep quality, daytime sleepiness and insomnia[31]. While other studies were in contrast with this result. The mechanism of sleep traits between endometriosis needed further study.\\u003c/p\\u003e \\u003cp\\u003eThe association between sleep traits and the menstrual cycle has been scarcely studied. In this study insomnia was determined a positive causal relationship with abnormal uterine and vaginal bleeding (OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;2.37 (1.34, 4.20), p\\u0026thinsp;=\\u0026thinsp;0.003), which is in coincidence with a former systematic review[32]. In a cross-sectional study, sleep duration and irregular menstrual cycles were found to be significantly inversely correlated[33]. One longitudinal study found that those having insomnia increased the risk of menstrual cycle irregularity more than 2 times higher over a year, these associations became more predominant as the Insomnia Severity Index score increased[34]. Persons with sleep disturbances usually do not have regular circadian rhythms, which may be related to irregular synthesis and secretion of female gonadal hormones. Sleep disorders inhibit gonadotropin-releasing hormone reproduction from the pituitary gland, thereby resulting in reduced secretion of gonadal hormones [35, 36]. Lower estradiol levels, lower FSH in relation with lower sleep variation and Luteinizing hormone (LH) pulse frequency inhibited by sleep noted a significant relation between hormone between sleep traits, demonstrated an activation of the HPA axis[37\\u0026ndash;39]. Consequently, in the activation of the HPA axis, corticotropin-releasing hormone (CRH) inhibits GnRH secretion, and the decrease frequency of GnRH pulsatile secretion lead to hypothalamic amenorrhea[40]. Therefor female reproductive functions such as folliculogenesis, ovulation, menstruation, hormone synthesis and secretion can be hindered by sleep deprivation, sleep disruption, and complex molecular genetics and hormonal pathways play an important role in regulating these relationships[41]. Similarly, sleep problems may exacerbate gynecologic conditions. While we found no relation between short sleep duration and abnormal menstrual cycle, which in contrast with many other study[42, 43]. In this study we did not obtain evidence that rigorous exercise is risk factors for menstrual cycle irregularity[44].\\u003c/p\\u003e \\u003cp\\u003eLong sleep duration had the negative causality with the menopause age [beta (95% CI) IVW= -5.33(0.00, 0.13), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.001]. As is known the sleep disturbance is a common condition in menopause transition[45]. Regardless of sex, older adults exhibit poorer sleep consolidation compared with younger adults, while the menopausal transition conveys poor sleep beyond anticipated age effects[46]. One study also found that a short sleep duration was significantly associated with a later onset of menopause[28], the reason might be with the levels of neuroendocrine hormones. Cognitive behavioral therapy represents the first-line treatment of insomnia in the general population, however, when vasomotor symptoms are present, menopausal hormone therapy should be considered[47].\\u003c/p\\u003e \\u003cp\\u003eWe observed a modest and significant genetic correlation between strenuous exercise and female infertility [OR (95% CI) IVW\\u0026thinsp;=\\u0026thinsp;0.1 (0.02, 0.68), \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.019]. Physically active females were more likely to be fertile, consistent with a previous observational study reporting that more females with normal fertility engaged in moderate and vigorous activities[14]. However, other conservative studies have revealed that among females, excessive exercise may generally, levels of engagement in physical activity vary across individuals that high levels of physical activity among females could result in an energy deficit, lead to hypothalamic amenorrhea, causing short-term infertility, and ultimately hinder one\\u0026rsquo;s fertility[48].\\u003c/p\\u003e \\u003cp\\u003eThe strengths of this study can be summarized as follows: (1) It leveraged a large sample of GWAS data, enhancing the reliability of the findings. (2) Potential biases were effectively mitigated through association analysis, LD analysis, elimination of weak IVs, and control for confounding actors. (3) A symmetrical distribution of SNPs was observed in the funnel plot. Furthermore, both the pleiotropy test and the leave-one-out test showed the relative stability of the results.\\u003c/p\\u003e \\u003cp\\u003eNevertheless, this study also exhibits several limitations: (1) We acknowledge that heterogeneity may originate from variations in analysis platforms, experimental conditions, pop characteristics, and other IVs even both the MR-Egger regression and IVW methods yielded results with P-values greater than 0.05. Consequently, a more comprehensive investigation into the sources of heterogeneity is warranted. (2) This study primarily centered on the European population, resulting in a paucity of GWAS data pertaining to Asian and African populations. (3) The number of IVs for SNPs within each dataset in this study was relatively modest. Therefore, it necessitates the utilization of large sample datasets to expand the pool of SNPs available as IVs for subsequent analysis. (4) We employed MR to explore the causal relationship between exposure and outcome. It is worth noting that we did not delve into the associated underlying mechanisms in this study.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eOur study suggested that insomnia and endometriosis might were reciprocal causation, long sleep duration was a protective factor with endometriosis. It is also genetically predicted insomnia was risk factor of abnormal uterine and vaginal bleeding. Thus, improving sleep quality and prolong the duration of sleep may be potential intervention targets for preventing endometriosis and abnormal uterine and vaginal bleeding.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe express our gratitude to the IEU Open GWAS database (https://gwas.mrcieu.ac.uk/) for providing publicly available summary-level GWAS data for our study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eJXZ designed the research. JZX and TW collected and analyzed the data. JXZ, TW, PSY and YXM, drafted the manuscript. JS and BLG revised the manuscript. All authors contributed to the article and approved the submitted version.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis work was supported by grants from the Science and Technology Commission of Shanghai Municipality (22Y11906100) to Jing Sun and Shanghai Outstanding Academic Leaders Plan to Jing Sun (Year 2019).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data used in this paper are publicly available, ethically approved, and the subjects have given their informed consent.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eZoe B, Kirsty O, Courtney B, Emily M, Janice B, Yvonne H: \\u003cstrong\\u003eSexual and reproductive health education: Midwives\\u0026apos; confidence and practices\\u003c/strong\\u003e. \\u003cem\\u003eWomen Birth \\u003c/em\\u003e2021, \\u003cstrong\\u003e35\\u003c/strong\\u003e(4):360-366.\\u003c/li\\u003e\\n\\u003cli\\u003eRakesh S, Kelly R B, Jennifer M F, Ashok A: \\u003cstrong\\u003eLifestyle factors and reproductive health: taking control of your fertility\\u003c/strong\\u003e. \\u003cem\\u003eReprod Biol Endocrinol \\u003c/em\\u003e2013, \\u003cstrong\\u003e11\\u003c/strong\\u003e.\\u003c/li\\u003e\\n\\u003cli\\u003eYoko U, Miyuki H, Shinnosuke K, Ikumi A, Chihiro T, Yoshiharu N, Aisaku F, Yoshiharu M, Takuya K, Yusuke I\\u003cem\\u003e et al\\u003c/em\\u003e: \\u003cstrong\\u003eLifestyle and fertility-specific quality of life affect reproductive outcomes in couples undergoing in vitro fertilization\\u003c/strong\\u003e. \\u003cem\\u003eFront Endocrinol (Lausanne) \\u003c/em\\u003e2024, \\u003cstrong\\u003e15\\u003c/strong\\u003e.\\u003c/li\\u003e\\n\\u003cli\\u003eKathryn Aldrich L, Fiona C B: \\u003cstrong\\u003eSleep and Women\\u0026apos;s Health Across the Lifespan\\u003c/strong\\u003e. \\u003cem\\u003eSleep Med Clin \\u003c/em\\u003e2018, \\u003cstrong\\u003e13\\u003c/strong\\u003e(3):xv-xvi.\\u003c/li\\u003e\\n\\u003cli\\u003eJoyce A W: \\u003cstrong\\u003eWomen and sleep\\u003c/strong\\u003e. \\u003cem\\u003eHandb Clin Neurol \\u003c/em\\u003e2010, \\u003cstrong\\u003e98\\u003c/strong\\u003e:639-651.\\u003c/li\\u003e\\n\\u003cli\\u003eElin Rosenbek S, Thea Otte A, Agnete Skovlund D, Andreas Kryger J, Christoffer S, Nina la Cour F, Henriette Svarre N, Naja Hulvej R: \\u003cstrong\\u003eNight-time smartphone use, sleep duration, sleep quality, and menstrual disturbances in young adult women: A population-based study with high-resolution tracking data\\u003c/strong\\u003e. \\u003cem\\u003eSleep Adv \\u003c/em\\u003e2023, \\u003cstrong\\u003e4\\u003c/strong\\u003e(1):zpad013.\\u003c/li\\u003e\\n\\u003cli\\u003eMeers JM, Nowakowski S: \\u003cstrong\\u003eSleep, premenstrual mood disorder, and women\\u0026apos;s health\\u003c/strong\\u003e. \\u003cem\\u003eCurr Opin Psychol \\u003c/em\\u003e2020, \\u003cstrong\\u003e34\\u003c/strong\\u003e:43-49.\\u003c/li\\u003e\\n\\u003cli\\u003eKloss JD, Perlis ML, Zamzow JA, Culnan EJ, Gracia CR: \\u003cstrong\\u003eSleep, sleep disturbance, and fertility in women\\u003c/strong\\u003e. \\u003cem\\u003eSleep Med Rev \\u003c/em\\u003e2015, \\u003cstrong\\u003e22\\u003c/strong\\u003e:78-87.\\u003c/li\\u003e\\n\\u003cli\\u003eIshikura IA, Hachul H, Pires GN, Tufik S, Andersen ML: \\u003cstrong\\u003eThe relationship between insomnia and endometriosis\\u003c/strong\\u003e. \\u003cem\\u003eJ Clin Sleep Med \\u003c/em\\u003e2020, \\u003cstrong\\u003e16\\u003c/strong\\u003e(8):1387-1388.\\u003c/li\\u003e\\n\\u003cli\\u003eBooth FW, Roberts CK, Laye MJ: \\u003cstrong\\u003eLack of exercise is a major cause of chronic diseases\\u003c/strong\\u003e. \\u003cem\\u003eCompr Physiol \\u003c/em\\u003e2012, \\u003cstrong\\u003e2\\u003c/strong\\u003e(2):1143-1211.\\u003c/li\\u003e\\n\\u003cli\\u003eLeandro Fornias Machado dR, Maur\\u0026iacute;cio RL, Juan Pablo R-L, Victor Keihan Rodrigues M, Olinda do Carmo L: \\u003cstrong\\u003eSedentary behavior and health outcomes: an overview of systematic reviews\\u003c/strong\\u003e. \\u003cem\\u003ePLoS One \\u003c/em\\u003e2014, \\u003cstrong\\u003e9\\u003c/strong\\u003e(8):e105620.\\u003c/li\\u003e\\n\\u003cli\\u003eSiret L, Francisco B O, Theodora KK, Lana J, Jonatan R R, Julius H, Kjell W, Anneli S-E, Ruth K, Andres S\\u003cem\\u003e et al\\u003c/em\\u003e: \\u003cstrong\\u003ePhysical and Sedentary Activities in Association with Reproductive Outcomes among Couples Seeking Infertility Treatment: A Prospective Cohort Study\\u003c/strong\\u003e. \\u003cem\\u003eInt J Environ Res Public Health \\u003c/em\\u003e2021, \\u003cstrong\\u003e18\\u003c/strong\\u003e(5):2718.\\u003c/li\\u003e\\n\\u003cli\\u003eVick\\u0026agrave; V, Lara S, Dirk A, Tom D, Christophe M, Leonardo G, Roland D, Peter C, Annick B: \\u003cstrong\\u003eDietary intake, physical activity and sedentary behavior and association with BMI during the transition to parenthood: a prospective dyadic study\\u003c/strong\\u003e. \\u003cem\\u003eFront Public Health \\u003c/em\\u003e2023, \\u003cstrong\\u003e11\\u003c/strong\\u003e:1092843.\\u003c/li\\u003e\\n\\u003cli\\u003eBrinson AK, da Silva SG, Hesketh KR, Evenson KR: \\u003cstrong\\u003eImpact of Physical Activity and Sedentary Behavior on Spontaneous Female and Male Fertility: A Systematic Review\\u003c/strong\\u003e. \\u003cem\\u003eJ Phys Act Health \\u003c/em\\u003e2023, \\u003cstrong\\u003e20\\u003c/strong\\u003e(7):600-615.\\u003c/li\\u003e\\n\\u003cli\\u003eDana N J, Shannon W: \\u003cstrong\\u003eStress and the HPA Axis: Balancing Homeostasis and Fertility\\u003c/strong\\u003e. \\u003cem\\u003eInt J Mol Sci \\u003c/em\\u003e2017, \\u003cstrong\\u003e18\\u003c/strong\\u003e(10):2224.\\u003c/li\\u003e\\n\\u003cli\\u003eLing S, Dai Y, Weng R, Li Y, Wu W, Zhou Z, Zhong Z, Zheng Y: \\u003cstrong\\u003eEpidemiologic and genetic associations of female reproductive disorders with depression or dysthymia: a Mendelian randomization study\\u003c/strong\\u003e. \\u003cem\\u003eSci Rep \\u003c/em\\u003e2024, \\u003cstrong\\u003e14\\u003c/strong\\u003e(1):5984.\\u003c/li\\u003e\\n\\u003cli\\u003eStephen B, Adam B, Simon G T: \\u003cstrong\\u003eMendelian randomization analysis with multiple genetic variants using summarized data\\u003c/strong\\u003e. \\u003cem\\u003eGenet Epidemiol \\u003c/em\\u003e2013, \\u003cstrong\\u003e37\\u003c/strong\\u003e(7):658-665.\\u003c/li\\u003e\\n\\u003cli\\u003eChristopher J Y, Su Yeon K, Chang Hyun N, Junehawk L, Jung Woo P, Jihyeob M, Seongyeol P, Soyoung L, Boram Y, Kyoung Il M\\u003cem\\u003e et al\\u003c/em\\u003e: \\u003cstrong\\u003eEstimation of intrafamilial DNA contamination in family trio genome sequencing using deviation from Mendelian inheritance\\u003c/strong\\u003e. \\u003cem\\u003eGenome Res \\u003c/em\\u003e2023, \\u003cstrong\\u003e32\\u003c/strong\\u003e(11-12):2134-2144.\\u003c/li\\u003e\\n\\u003cli\\u003eJiang Z, He R, Wu H, Yu J, Zhu K, Luo Q, Liu X, Pan J, Huang H: \\u003cstrong\\u003eThe causal association between smoking initiation, alcohol and coffee consumption, and women\\u0026apos;s reproductive health: A two-sample Mendelian randomization analysis\\u003c/strong\\u003e. \\u003cem\\u003eFront Genet \\u003c/em\\u003e2023, \\u003cstrong\\u003e14\\u003c/strong\\u003e:1098616.\\u003c/li\\u003e\\n\\u003cli\\u003eJack B, George DS, Stephen B: \\u003cstrong\\u003eMendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression\\u003c/strong\\u003e. \\u003cem\\u003eInt J Epidemiol \\u003c/em\\u003e2015, \\u003cstrong\\u003e44\\u003c/strong\\u003e(2):512-525.\\u003c/li\\u003e\\n\\u003cli\\u003eZhang XB, Jiang HH, Zhang LL, Li CJ, Chen C, Xing MZ, Ma YN, Ma YX: \\u003cstrong\\u003ePotential causal associations between leisure sedentary behaviors, physical activity, sleep traits, and myopia: a Mendelian randomization study\\u003c/strong\\u003e. \\u003cem\\u003eBMC Ophthalmol \\u003c/em\\u003e2024, \\u003cstrong\\u003e24\\u003c/strong\\u003e(1):104.\\u003c/li\\u003e\\n\\u003cli\\u003eJin T, Huang W, Cao F, Yu X, Guo S, Ying Z, Xu C: \\u003cstrong\\u003eCausal association between systemic lupus erythematosus and the risk of dementia: A Mendelian randomization study\\u003c/strong\\u003e. \\u003cem\\u003eFront Immunol \\u003c/em\\u003e2022, \\u003cstrong\\u003e13\\u003c/strong\\u003e:1063110.\\u003c/li\\u003e\\n\\u003cli\\u003eZhu K, Shi J, Yang R, Zhou C, Liu Z: \\u003cstrong\\u003eEvidence based on Mendelian randomization: Causal relationship between mitochondrial biological function and lung cancer and its subtypes\\u003c/strong\\u003e. \\u003cem\\u003eNeoplasia \\u003c/em\\u003e2023, \\u003cstrong\\u003e46\\u003c/strong\\u003e:100950.\\u003c/li\\u003e\\n\\u003cli\\u003ePickup B, Coutts-Bain D, Todd J: \\u003cstrong\\u003eFear of progression, depression, and sleep difficulties in people experiencing endometriosis-pain: A cross-sectional study\\u003c/strong\\u003e. \\u003cem\\u003eJ Psychosom Res \\u003c/em\\u003e2024, \\u003cstrong\\u003e178\\u003c/strong\\u003e:111595.\\u003c/li\\u003e\\n\\u003cli\\u003eLeone Roberti Maggiore U, Bizzarri N, Scala C, Tafi E, Siesto G, Alessandri F, Ferrero S: \\u003cstrong\\u003eSymptomatic endometriosis of the posterior cul-de-sac is associated with impaired sleep quality, excessive daytime sleepiness and insomnia: a case-control study\\u003c/strong\\u003e. \\u003cem\\u003eEur J Obstet Gynecol Reprod Biol \\u003c/em\\u003e2017, \\u003cstrong\\u003e209\\u003c/strong\\u003e:39-43.\\u003c/li\\u003e\\n\\u003cli\\u003eBaker F, Driver H, Rogers G, Paiker J, Mitchell D: \\u003cstrong\\u003eHigh nocturnal body temperatures and disturbed sleep in women with primary dysmenorrhea\\u003c/strong\\u003e. \\u003cem\\u003eAm J Physiol \\u003c/em\\u003e1999, \\u003cstrong\\u003e277\\u003c/strong\\u003e(6):E1013-1021.\\u003c/li\\u003e\\n\\u003cli\\u003eDunlap K, Yu L, Fisch B, Nolan T: \\u003cstrong\\u003ePolysomnographic characteristics of sleep disorders in chronic pelvic pain\\u003c/strong\\u003e. \\u003cem\\u003ePrim Care Update Ob Gyns \\u003c/em\\u003e2000, \\u003cstrong\\u003e5\\u003c/strong\\u003e(4):195.\\u003c/li\\u003e\\n\\u003cli\\u003eNagata C, Wada K, Yamakawa M, Nakashima Y, Sugino M, Mori T: \\u003cstrong\\u003eSleep duration and the onset of menopause in Japanese women\\u003c/strong\\u003e. \\u003cem\\u003eMenopause \\u003c/em\\u003e2023, \\u003cstrong\\u003e30\\u003c/strong\\u003e(4):437-440.\\u003c/li\\u003e\\n\\u003cli\\u003eFacchin F, Buggio L, Roncella E, Somigliana E, Ottolini F, Dridi D, Roberto A, Vercellini P: \\u003cstrong\\u003eSleep disturbances, fatigue and psychological health in women with endometriosis: a matched pair case-control study\\u003c/strong\\u003e. \\u003cem\\u003eReprod Biomed Online \\u003c/em\\u003e2021, \\u003cstrong\\u003e43\\u003c/strong\\u003e(6):1027-1034.\\u003c/li\\u003e\\n\\u003cli\\u003eWang Y, Nicholes K, Shih IM: \\u003cstrong\\u003eThe Origin and Pathogenesis of Endometriosis\\u003c/strong\\u003e. \\u003cem\\u003eAnnu Rev Pathol \\u003c/em\\u003e2020, \\u003cstrong\\u003e15\\u003c/strong\\u003e:71-95.\\u003c/li\\u003e\\n\\u003cli\\u003eBergqvist A, Theorell T: \\u003cstrong\\u003eChanges in quality of life after hormonal treatment of endometriosis\\u003c/strong\\u003e. \\u003cem\\u003eActa Obstet Gynecol Scand \\u003c/em\\u003e2001, \\u003cstrong\\u003e80\\u003c/strong\\u003e(7):628-637.\\u003c/li\\u003e\\n\\u003cli\\u003eJeon B, Baek J: \\u003cstrong\\u003eMenstrual disturbances and its association with sleep disturbances: a systematic review\\u003c/strong\\u003e. \\u003cem\\u003eBMC Womens Health \\u003c/em\\u003e2023, \\u003cstrong\\u003e23\\u003c/strong\\u003e(1):470.\\u003c/li\\u003e\\n\\u003cli\\u003eNam GE, Han K, Lee G: \\u003cstrong\\u003eAssociation between sleep duration and menstrual cycle irregularity in Korean female adolescents\\u003c/strong\\u003e. \\u003cem\\u003eSleep Med \\u003c/em\\u003e2017, \\u003cstrong\\u003e35\\u003c/strong\\u003e:62-66.\\u003c/li\\u003e\\n\\u003cli\\u003eWonYang K, Keun-Ho J, Hyeong-Min L, Ji-Sung A, Won-Ju P: \\u003cstrong\\u003eThe menstrual cycle associated with insomnia in newly employed nurses performing shift work: a 12-month follow-up study\\u003c/strong\\u003e. \\u003cem\\u003eInt Arch Occup Environ Health \\u003c/em\\u003e2018, \\u003cstrong\\u003e92\\u003c/strong\\u003e(2):227-235.\\u003c/li\\u003e\\n\\u003cli\\u003eKaren L G, David R, Carl Hirschie J: \\u003cstrong\\u003eShift work and circadian dysregulation of reproduction\\u003c/strong\\u003e. \\u003cem\\u003eFront Endocrinol (Lausanne) \\u003c/em\\u003e2013, \\u003cstrong\\u003e4\\u003c/strong\\u003e.\\u003c/li\\u003e\\n\\u003cli\\u003eWen-Pei C, Yu-Pei C: \\u003cstrong\\u003eMeta-Analysis Comparing Menstrual Regularity and Dysmenorrhea of Women Working Rotating Shifts and Fixed Day Shifts\\u003c/strong\\u003e. \\u003cem\\u003eJ Womens Health (Larchmt) \\u003c/em\\u003e2020, \\u003cstrong\\u003e30\\u003c/strong\\u003e(5):722-730.\\u003c/li\\u003e\\n\\u003cli\\u003eVgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, Kales A, Chrousos GP: \\u003cstrong\\u003eChronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications\\u003c/strong\\u003e. \\u003cem\\u003eJ Clin Endocrinol Metab \\u003c/em\\u003e2001, \\u003cstrong\\u003e86\\u003c/strong\\u003e(8):3787-3794.\\u003c/li\\u003e\\n\\u003cli\\u003eHall JE, Sullivan JP, Richardson GS: \\u003cstrong\\u003eBrief wake episodes modulate sleep-inhibited luteinizing hormone secretion in the early follicular phase\\u003c/strong\\u003e. \\u003cem\\u003eJ Clin Endocrinol Metab \\u003c/em\\u003e2005, \\u003cstrong\\u003e90\\u003c/strong\\u003e(4):2050-2055.\\u003c/li\\u003e\\n\\u003cli\\u003eSandrine T, Muriel R, Hans B, Enriqueta B, Ren\\u0026eacute; E: \\u003cstrong\\u003eRelationship between sleep and secretion of gonadotropin and ovarian hormones in women with normal cycles\\u003c/strong\\u003e. \\u003cem\\u003eFertil Steril \\u003c/em\\u003e2002, \\u003cstrong\\u003e77\\u003c/strong\\u003e(4):738-744.\\u003c/li\\u003e\\n\\u003cli\\u003eMarshall J: \\u003cstrong\\u003eThe menstrual cycle and disorders of ovulation\\u003c/strong\\u003e. \\u003cem\\u003eEndocrinology: Adult and Paediatric Eds Philadelphia: Elsevier Saunders Publishing \\u003c/em\\u003e2016:2231-2241.\\u003c/li\\u003e\\n\\u003cli\\u003eZhang Y, Luo Z, Jia Y, Zhao Y, Huang Y, Ruan F, Ying Q, Ma L, Luo J, Zhou J: \\u003cstrong\\u003eDevelopment and validation of a predictive model of abnormal uterine bleeding associated with ovulatory dysfunction: a case-control study\\u003c/strong\\u003e. \\u003cem\\u003eBMC Womens Health \\u003c/em\\u003e2023, \\u003cstrong\\u003e23\\u003c/strong\\u003e(1):536.\\u003c/li\\u003e\\n\\u003cli\\u003eLim AJR, Huang Z, Chua SE, Kramer MS, Yong E-L: \\u003cstrong\\u003eSleep Duration, Exercise, Shift Work and Polycystic Ovarian Syndrome-Related Outcomes in a Healthy Population: A Cross-Sectional Study\\u003c/strong\\u003e. \\u003cem\\u003ePLoS One \\u003c/em\\u003e2016, \\u003cstrong\\u003e11\\u003c/strong\\u003e(11):e0167048.\\u003c/li\\u003e\\n\\u003cli\\u003eTaeryoon K, Ga Eun N, Byoungduck H, Sung Jung C, Junghun K, Do Hyun E, Sang Woo L, Soon Hong M, Woohyun L, Kyungdo H\\u003cem\\u003e et al\\u003c/em\\u003e: \\u003cstrong\\u003eAssociations of mental health and sleep duration with menstrual cycle irregularity: a population-based study\\u003c/strong\\u003e. \\u003cem\\u003eArch Womens Ment Health \\u003c/em\\u003e2018, \\u003cstrong\\u003e21\\u003c/strong\\u003e(6):619-626.\\u003c/li\\u003e\\n\\u003cli\\u003eJensen T, Scheike T, Keiding N, Schaumburg I, Grandjean P: \\u003cstrong\\u003eFecundability in relation to body mass and menstrual cycle patterns\\u003c/strong\\u003e. \\u003cem\\u003eEpidemiology \\u003c/em\\u003e1999, \\u003cstrong\\u003e10\\u003c/strong\\u003e(4):422-428.\\u003c/li\\u003e\\n\\u003cli\\u003eBaker FC, Lampio L, Saaresranta T, Polo-Kantola P: \\u003cstrong\\u003eSleep and Sleep Disorders in the Menopausal Transition\\u003c/strong\\u003e. \\u003cem\\u003eSleep Med Clin \\u003c/em\\u003e2018, \\u003cstrong\\u003e13\\u003c/strong\\u003e(3):443-456.\\u003c/li\\u003e\\n\\u003cli\\u003eShaver J, Woods N: \\u003cstrong\\u003eSleep and menopause: a narrative review\\u003c/strong\\u003e. \\u003cem\\u003eMenopause (New York, NY) \\u003c/em\\u003e2015, \\u003cstrong\\u003e22\\u003c/strong\\u003e(8):899-915.\\u003c/li\\u003e\\n\\u003cli\\u003eProserpio P, Marra S, Campana C, Agostoni E, Palagini L, Nobili L, Nappi R: \\u003cstrong\\u003eInsomnia and menopause: a narrative review on mechanisms and treatments\\u003c/strong\\u003e. \\u003cem\\u003eClimacteric : the journal of the International Menopause Society \\u003c/em\\u003e2020, \\u003cstrong\\u003e23\\u003c/strong\\u003e(6):539-549.\\u003c/li\\u003e\\n\\u003cli\\u003eEvenson KR, Hesketh KR: \\u003cstrong\\u003eStudying the Complex Relationships Between Physical Activity and Infertility\\u003c/strong\\u003e. \\u003cem\\u003eAm J Lifestyle Med \\u003c/em\\u003e2016, \\u003cstrong\\u003e10\\u003c/strong\\u003e(4):232-234.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Two-sample mendelian randomization analysis, insomnia, endometriosis, abnormal uterine and vaginal bleeding, menopause age\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4419372/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4419372/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground:\\u003c/strong\\u003e Living habits affect women's endocrine and fertility over time with aging and in certain circumstances, according to which we can promote women's reproductive health by adjusting living habits.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e We utilized two-sampleMendelian randomization (TSMR) analysis with summary datasets from genome-wide association study (GWAS) to investigate the causal relationship between sleep traits, leisure sedentary behavior, physical activity and women’s reproductive health-related traits. Exposure genetic instruments were used as variants significantly related to traits. The inverse-variance weighted (IVW) method was used as the main analysis approach, and we also performed MR-Egger and weighted median to supplement the sensitivity test. Then, the horizontal pleiotropy was detected by using MRE intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran’s Q statistics by IVW and MR-Egger.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e We found evidence that insomnia showed a significant inverse causal association with the endometriosis [OR (95% CI) IVW = 1.80 (1.16, 2.80), \\u003cem\\u003eP\\u003c/em\\u003e = 0.009], and with the abnormal menstruation [OR (95% CI) IVW = 2.37 (1.34, 4.20), \\u003cem\\u003eP\\u003c/em\\u003e = 0.003]. What else the sleep duration has the negative relation menopause age\\u003cstrong\\u003e \\u003c/strong\\u003e(beta IVW = −0.034, \\u003cem\\u003eP\\u003c/em\\u003e = 0.001), the long sleep duration might be the protective factor of endometriosis\\u003cstrong\\u003e \\u003c/strong\\u003e[OR (95% CI)\\u003cstrong\\u003e \\u003c/strong\\u003eIVW = 0.07 (0.01, 0.72), \\u003cem\\u003eP \\u003c/em\\u003e= 0.024], strenuous sports were also negatively correlated with the female infertility[OR (95% CI) IVW = 0.10 (0.02, 0.68), \\u003cem\\u003eP\\u003c/em\\u003e = 0.019]. In sensitivity analysis, we observed no sign of horizontal pleiotropy or heterogeneity.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion:\\u003c/strong\\u003e Our finding suggested insomnia was an adverse factor of endometriosis and abnormal menstruation, long sleep duration was a protective factor with endometriosis. Therefore, adequate sleep and regular schedule might decrease the risk of endometriosis and abnormal menstruation to guarantee the women reproductive health.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Association of sleep traits, physical activity and leisure sedentary behavior with women’s reproductive health: a two-sample Mendelian randomization analysis\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-05-30 10:24:00\",\"doi\":\"10.21203/rs.3.rs-4419372/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"78262794-b962-47b3-97c1-82cd5764fb31\",\"owner\":[],\"postedDate\":\"May 30th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-06-06T14:06:17+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2024-05-30 10:24:00\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4419372\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4419372\",\"identity\":\"rs-4419372\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}