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.