Are the Previously Reported Risk Factors for Endometriosis Actually Associated With Pain and Infertility Rather Than Endometriosis Itself?

The author has nothing to report.

This work was supported by KARL STORZ.

The potential shared risk factors for endometriposisn dysmenorrhea, chronic pain and infertility are summurised in Table  1 . Findings on the association between age at menarche and endometriosis risk are inconsistent. Two systematic reviews and meta‐analyses [ 21 , 22 ] revealed that an earlier age at menarche is associated with an increased risk of endometriosis. Additionally, a two‐sample Mendelian randomization (MR) analysis provided weak evidence of an association between age at menarche and endometriosis [ 23 ]. However, a large cross‐sectional study found no such association [ 24 ]. Nevertheless, misclassification of endometriosis based on self‐reported medical histories could weaken the true association [ 24 ]. Two cross sectional studies showed that early menarche was a potent determinant of dysmenorrhea [ 25 , 54 ]. A cohort study of postmenarcheal female adolescents showed that early pubertal timing increased the odds of dysmenorrhea by 22%–31% [ 25 ]. A cohort study reported that pubertal timing—indicated by maturation features other than menarche—is also a risk factor for adolescent dysmenorrhea [ 26 ]. By contrast, a multicenter, cross‐sectional study found no independent association between age at menarche and dysmenorrhea [ 27 ]. A cohort study on associations between age at menarche and chronic pain revealed that early menarche is an independent risk factor for pain across a broad spectrum of pain outcomes [ 30 ]. Three population‐based cross‐sectional studies revealed that earlier age at menarche (≤ 11 years) was associated with an increased risk of chronic low back pain (LBP), chronic widespread musculoskeletal pain, and chronic nonspecific pain defined as pain in at least one location not related to any known disease or injury [ 28 , 29 , 31 ]. Findings of the associations between age at menarche and risk of infertility are inconsistent. A potential explanation is that there are multiple causes of female infertility, each of which may have distinct and complex relationships with age at menarche [ 35 ]. Several Studies showed that later age at menarche is associated with the risk of infertility [ 58 , 59 , 60 , 61 , 62 ]. In contrast, a retrospective cohort study of pregnant women who conceived either naturally or with the help of assisted reproductive technologies revealed that both early ( 15 y) menarche are associated with decreased fecundability [ 33 ]. Furthermore, one cohort study [ 32 ] and one case–control study [ 34 ] revealed that an earlier age at menarche (defined as < 12 y) was associated with an increased risk of infertility and reduced fecundability. However, a two‐sample MR study revealed no association between age at menarche and risk of infertility [ 23 ]. These findings suggest that both an earlier and a later age at menarche are associated with an increased risk of subsequent infertility and reduced fecundability. Different causes of infertility and reduced fecundability may be associated with an earlier or later age at menarche. A systematic review [ 8 ] showed that women born with low birthweight (< 2, 500 g) were more likely to be diagnosed with endometriosis. A total‐population register‐based cohort study revealed that lower birthweight and lower birthweight‐for‐gestational age were at higher risk of endometriosis, irrespective of their gestational age at birth [ 9 ]. However, a MR analysis revealed no association between low birth weight and endometriosis risk [ 63 ]. However, because this review did not perform subgroup analyses, it is not clear whether low birth weight is associated with endometriosis patients with infertility, chronic pain, or both. Exposure to DES increased the risk of laparoscopically confirmed endometriosis [ 11 ]. This association was stronger among those with concurrent infertility [ 11 ]. Later, a cross‐sectional study also revealed the association of in utero DES exposure with subsequent risk of endometriosis [ 12 ]. Finding on the associations between low birthweight and subsequent risk of chronic pain is inconsistent. However, a birth cohort study in Norway reported that very low birth weight (VLBW, < 1500 g) and small for gestational age (SGA) are associated with subsequent risk of chronic pain [ 36 ]. Studies showed that the association between very preterm (VP, < 32 weeks' gestation)/VLBW and lower fertility was significant during the late (≥ 30 years) but not early (< 30 years) reproductive window [ 37 , 38 ]. A population‐based registry study revealed that those born with low birth weight (< 2500 g) or preterm (< 37 weeks) were less likely to give birth compared to those with normal birth weight at term [ 64 ]. A long‐term follow‐up of women exposed in utero to DES revealed the association with a high risk of infertility [ 40 ]. These findings suggest that exposure to DES in utero may be a risk factor of infertility, but not for endometriosis. Previous studies have shown a link between childhood sexual abuse and an increased risk of endometriosis [ 17 , 18 ]. However, Harris et al. [ 17 ] found that the association between sexual abuse and endometriosis was only found in the subgroup of patients without infertility, who were likely to have painful symptoms. Bourdon et al. [ 19 ] demonstrated that a history of sexual abuse during childhood and/or adolescence is associated with severe pelvic pain, though not endometriosis. These findings suggest that exposure to sexual abuse during childhood may be a risk factor for severe pelvic pain, but not for endometriosis [ 19 ]. There was an association between the number and severity of ACEs and the risk of dysmenorrhea [ 41 ]. Sexual abuse and posttraumatic stress disorder appeared to be associated with dysmenorrhea, pelvic pain, and dyspareunia [ 41 ]. Studies showed that ACEs are associated with the subsequent risk of chronic pain [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Although only a few studies have investigated this, research has reported a link between ACEs and reduced fertility later in life [ 55 , 56 , 57 ]. The risk of infertility appears to increase with each additional ACE experienced, regardless of the type of ACE [ 55 , 56 , 57 ]. There is a lack of research on the relationship between dietary patterns during childhood and adolescence and subsequent risk of endometriosis, chronic pain, dysmenorrhea, and reduced fertility. However, studies have shown that eating behaviors remain stable over time [ 39 , 65 ], and thus, dietary patterns may persist from childhood into adulthood [ 39 , 65 ]. A prospective cohort study [ 13 ] examined the relationship between dietary habits and endometriosis diagnoses. Adherence to the Alternative Healthy Eating Index, which reflects healthier dietary patterns, was associated with a 13% lower risk of receiving an endometriosis diagnosis, who had never reported infertility and experienced pain at the time of diagnosis [ 13 ]. On the other hand, adherence to a Western dietary pattern characterized by high intake of red meat, processed meat, refined grains, and desserts was associated with a 27% higher risk of receiving an endometriosis diagnosis [ 13 ]. Two cross‐sectional studies [ 14 , 15 ] reported that increased intake of the pro‐inflammatory diet, as a higher dietary inflammatory index (DII) score, was positively associated with endometriosis risk among American adults. However, it is unclear whether a higher DII score was associated with endometriosis patients with pain, infertility, or both [ 14 , 15 ]. However, all of these studies are based on data from American adults [ 13 , 14 , 15 ]. Therefore, the findings cannot be generalized to other populations. A cross‐sectional study showed that an inflammatory diet in adulthood is associated with an increased risk of chronic pain [ 49 ]. A two‐sample MR analysis revealed causal links between specific dietary habits and various types of chronic pain [ 50 ]. A Prospective cohort study showed that BMI at age 18 and current BMI were each significantly inversely associated with endometriosis. Both associations were stronger among infertile women [ 6 ]. A nested case–control study showed that the odds of endometriosis were lower among women who reported having a large versus lean body size at 8 years, at menarche and at ages 20–25 years [ 7 ]. A systematic review and meta‐analysis revealed that being underweight may increase the risk of primary dysmenorrhea [ 51 ]. Being overweight or obese may not be associated with primary dysmenorrhea [ 51 ]. A cross‐sectional study of Sofy app users revealed that those in the normal BMI range reported the lowest prevalence of menstrual pain. A cross‐sectional study of a period tracking application revealed that users with a normal BMI reported the lowest prevalence of menstrual pain. Meanwhile, those who were underweight reported the highest prevalence [ 52 , 53 ]. A cross‐sectional analysis revealed that being underweight or obese during adolescence is a potential risk factor for subsequent infertility [ 52 , 53 ]. Studies have reported that the prevalence of mental health problems such as depression and anxiety is high in patients with endometriosis [ 66 , 67 , 68 ]. A meta‐analysis revealed that symptoms of depression and anxiety occur frequently in endometriosis patients, but no differences were found comparing with other chronic pelvic pain patients [ 66 ]. Depression and anxiety may be associated with chronic pain, rather than endometriosis itself. A retrospective, population‐based study reported that patients with chronic pain with/without endometriosis are around twice as likely to experience anxiety as patients with endometriosis but without chronic pain [ 69 ]. These findings suggest that anxiety might be a risk factor for chronic pain, but not for endometriosis [ 69 ]. Observational studies cannot determine whether endometriosis causes depression or vice versa. However, bidirectional two‐sample MR analyses have clearly shown that depression can cause endometriosis, though endometriosis does not cause depression [ 70 , 71 , 72 , 73 , 74 ] (Table  2 ). Summary of studies on the association between endometriosis, dysmenorrhea, chronic pain and infertility and mental disorders. 208,912 individuals (17,054 cases of endometriosis and 191,858 controls). 500,199 individuals (170,756 cases of depression and 329,443 controls) Neuroticism clusters: depressed affect ( N  = 357,957), “worry” ( N =  348,219), “sensitivity to environmental stress and adversity (SESA)” ( N =  351,827). Endometriosis (15,088 cases, 107,564 controls) Female infertility (13,142 cases, 107,564 controls) PCOS (1,424 cases, 200,581 controls) Uterine fibroma (31,661 cases, 179,209 controls) Genetically predicted depressed affect and worry components of neuroticism significantly increased the risk of infertility and endometriosis. Genetically predicted sensitivity to environmental stress, and adversity (SESA) component of neuroticism increased only the risk of endometriosis The study included only individuals of European ancestry, thereby reducing the generalizability of its findings. No sex‐specific analysis has been reported for genetically distinct neuroticism clusters, resulting in potential bias Depression or dysthymia: 48,847 cases and 225,483 controls. Endometriosis: 15,088 cases and 10,7564 controls Depression 449,414 (13,559 cases and 435,855 controls). Anxiety 210,623 participants (12,513 cases and 198,110 controls). Neuroticism 374,323. Endometriosis 77,257 individuals (8288 cases and 68,969 controls) Genetic predispositions to depression and neuroticism were significantly associated with an increased risk of endometriosis. No causative link was found between genetic susceptibility to anxiety and the occurrence of endometriosis. Reverse MR analysis did not support a bidirectional genetic susceptibility between endometriosis and psychiatric disorders The study sample exclusively comprises individuals from European populations, without considering the potential confounding impact of racial factors on the mediation of endometriosis. It included only individuals of European ancestry, thereby reducing the generalizability of its findings Female self‐reported depression data: N  = 194,153 Female medical‐recorded depression data: N  = 192,680 Endometriosis: N  = 150,350 Endometriosis did not have a genetically informed influence on depression. Depression clearly had a genetically predicted effect on Endometriosis A: European Major depression disorder (MDD): n  = 1,707,656 Pain associated with female genital organs and the menstrual cycle: n  = 3316 B: East Asian: Seen a doctor (GP) for nerves, anxiety, tension, or depression: n  = 430 Pain medicine use during menstruation: n  = 1813 There is a significant causal effect of depression on dysmenorrhea. No evidence was found to support a causal effect of dysmenorrhea on depression. Sleeplessness was revealed to play a mediating role in this relationship It uses data from European and East Asian populations. However, due to the heterogeneity in phenotype definition and the limited power of genome‐wide association study (GWAS) data in East Asian populations, these findings must be interpreted cautiously. Because of the lack of individual‐level data, the mediation analysis relied on summary‐level GWAS data 10 studies 4,691 participants All the included studies were observational designed, either cross‐sectional or case–control trials. Different validation tools were employed for assessing either primary dysmenorrhea or depression in the 10 included studies, which might affect the outcomes among different studies 246,363 cases of self‐reported clinical depression diagnoses. 561,190 controls Depression is a cause of headaches and pain localized in the neck, shoulders, back, and abdomen rather than the face, hips, or knees. Genetically instrumented, multisite chronic pain and headaches have been associated with MDD All pain phenotypes and depression were broadly defined and self‐reported. The participants were of European ancestry. Therefore, the results can only be generalized to European populations. Pain was defined as experienced in the last month. Therefore, it is unclear if the participants had chronic pain. Depression is strongly associated with an increased risk of experiencing pain in multiple areas of the body, including headaches, neck and shoulder pain, back pain, and stomach and abdominal pain. Similarly, these types of pain are associated with an increased risk of depression. Insomnia is causally related to genetic susceptibility to pain in multiple areas, such as the head, neck, shoulders, back, and hips. Similarly, headaches, neck and shoulder pain, back pain, and hip pain increase susceptibility to insomnia This is based on self‐reports from volunteers through questionnaires. This method may be biased because people without medical knowledge may not accurately identify the location of their pain or mistake temporary mood changes for mental illness. All of the participants in this study were UK residents. Therefore, the results of this experiment can only be generalized to populations of European or Western European ancestry Depression: (170,756 cases, 329,443 controls) Chronic widespread pain (CWP): (6,914 cases, 242,929 controls) The chronic widespread pain case‐definition was heterogenous, comprising chronic regional musculoskeletal, chronic widespread pain and/or fibromyalgia. Genome‐wide associations were observed in populations of European ancestry Therefore, the results can only be generalized to European populations Fewer years of schooling, smoking, greater alcohol consumption, and MDD increase the risk of CBP. CBP does not lead to an increased risk of depressive disorder, though it does lead to increased alcohol consumption and smoking The risk factors examined in this study may be subject to bias, which could impact the outcomes of GWAS and MR estimates. All of the participants in this study were UK residents. Therefore, the results of this experiment can only be generalized to populations of European or Western European ancestry This study employed the inverse‐variance weighted (IVW) analysis method, revealing a positive causal relationship between MDD and all back pain outcomes. However, subgroup analyses based on random effects models, as well as those using the MR‐Egger and weighted median methods, did not support a positive causal relationship between MDD and back pain. These results challenge the conclusions of prior MR studies and highlight the necessity of additional relevant MR studies to confirm this relationship. This meta‐analysis demonstrates the positive causal relationship between back pain and BMI, insomnia, smoking, alcohol consumption, and sedentary leisure behaviors Due to the nature of a pooled analysis of individual MR studies, a patient‐level analysis cannot be conducted. There is potential for publication bias Neuroticism clusters: depressed affect ( N =  357,957), “worry” ( N =  348,219), and “sensitivity to environmental stress and adversity (SESA)” ( N =  351,827). Endometriosis (15,088 cases, 107,564 controls) Female infertility (13,142 cases, 107,564 controls) PCOS (1,424 cases, 200,581 controls) UF (31,661 cases, 179,209 controls) Genetically predicted depressed affect and worry components of neuroticism significantly increased the risk of infertility and endometriosis. Genetically predicted sensitivity to environmental stress, and adversity (SESA) component of neuroticism increased only the risk of endometriosis. In the reverse analysis, genetically predicted PCOS was causally associated with an increased risk of the worry component of neuroticism It included only individuals of European ancestry, thereby reducing the generalizability of its findings. No sex‐specific analysis has been reported for genetically distinct neuroticism clusters, resulting in potential bias Anxiety: 462,933 Depression: 462,933 MDD: 462,933 Anorexia nervosa: 14, 477 Attention deficit hyperactivity disorder (ADHD): 32, 102 Bipolar disorder: 337, 159 And other mental disorders (epilepsy, insomnia, Alzheimer's Disease, autism spectrum disorder, Parkinson's disease, schizophrenia) Male infertility (680 cases and 72,799 controls) Female infertility (6,481 cases and 68,969 controls) For females, anorexia nervosa, ADHD and MDD increased risk of infertility. In reverse relationship, female infertility increased the incidence of bipolar disorder Anxiety disorder ( n  = 9897) Broad depression ( n  = 322,580) MDD ( n  = 480,359 and n  = 500,199) Bipolar disorder ( n  = 51,710) Insomnia ( n  = 462,341) Female infertility ( n  = 126,342) MDD was associated with female infertility. Reverse mendelian randomization did not indicate a causal relationship among these disorders Focusing only on the European population, which may impact the generalizability of the results due to genetic variations among ethnic groups; Lack of analysis on the duration of mental disorders Female infertility (112,105 individuals of European ancestry, comprising 11,442 cases and 100,663 controls). Depression (807,553 individuals: comprising 246,363 cases and 561,190 controls). Anxiety (21,763 individuals comprising 7016 cases and 14,745 controls). Bipolar disorder (51,710 individuals comprising 20,352 cases and 31,358 controls). Eating disorders (72,517 individuals comprising 16,992 cases and 55,525 controls) A potential causal relationship between depression and female infertility, with both inverse variance weighting and weighted median methods showing increased infertility risk in depressed patients. No causal relationship was found between female infertility and psychiatric disorders in the opposite direction Depression: 135,458 cases and 344,901 controls Infertility: 6481 cases and 68,969 controls Unmeasured and residual potential confounding factors. The reliance on self‐reported data for infertility diagnoses. The generalizability may be limited, as our study cohort was predominantly of US population MR analyses also revealed that depression can also lead to dysmenorrhea [ 75 ], chronic pain [ 77 , 78 , 79 , 80 , 81 ], and fertility issues [ 76 , 82 , 83 ] (Table  2 ), which are all major clinical problems in patients with endometriosis [ 5 ]. Two‐sample bidirectional MR analyses demonstrated that genetic predisposition to depression or dysthymia [ 72 ], as well as two genetically predicted components of neuroticism (depressed affect and worry, and sensitivity to environmental stress and adversity) [ 71 ], were significantly associated with an increased risk of endometriosis. A two‐sample bi‐directional MR analysis demonstrated that genetic predisposition to depression or dysthymia was associated with an increased risk of developing PCOS, ovarian cysts, abnormal uterine and vaginal bleeding (AUB), and endometriosis [ 71 ]. A bidirectional two‐sample MR revealed that genetic predispositions to depression and neuroticism were significantly associated with an increased risk of endometriosis [ 73 ]. However, no causative link was found between genetic susceptibility to anxiety and the occurrence of endometriosis [ 73 ]. A bidirectional two‐sample MR analysis revealed that endometriosis did not have a genetically informed influence on depression, while depression clearly had a genetically predicted effect on endometriosis [ 74 ]. Reverse MR analysis did not support a bidirectional genetic susceptibility between endometriosis and psychiatric disorders [ 70 , 71 , 72 , 73 , 74 ]. A Systematic Review and Cumulative Analysis showed that primary dysmenorrhea was associated with a significant depressive disorder [ 85 ]. A two‐sample, bidirectional, and multivariate MR analysis confirmed a significant causal effect of depression on dysmenorrhea [ 75 ]. Sleeplessness was revealed to play a mediating role in this relationship [ 75 ]. Conversely, no evidence was found to support a causal effect of dysmenorrhea on depression [ 75 ]. A two‐sample Mendelian randomization study revealed bidirectional evidence of causality between genetically predicted depression and chronic widespread pain (CWP) risk [ 77 , 78 , 79 ]. CWP increases susceptibility to depression, and genetic liability to depression is causally linked to an increased risk of CWP [ 77 , 78 , 79 ]. Another MR analysis revealed that major depressive disorder (MDD) increases the risk of chronic back pain (CBP) [ 80 ]. However, CBP does not lead to an increased risk of MDD [ 80 ]. A meta‐analysis of MR studies using the inverse‐variance weighted (IVW) method showed a positive causal relationship between MDD and back pain [ 81 ]. Nevertheless, subgroup analyses based on random effects models, as well as those using the MR‐Egger and weighted median methods, did not support a positive causal relationship between MDD and back pain [ 81 ]. Two‐sample Mendelian rando [ 71 , 76 , 83 , 84 , 86 ], though female infertility does not appear to cause depression [ 71 , 76 , 83 , 86 ]. Among previously reported risk factors for endometriosis, several factors are also associated with mental health problems, notably depression (Table  3 ). Summary of studies on the association between potential risk factors for endometriosis and mental disorders. 22 studies 87,798 participants 13 observational studies (5 cohorts and 8 cross‐sectional studies) 434,838 participants Most of the studies were conducted in high‐income countries. Publication bias Included studies did not account for confounders consistently and some reported unadjusted effect estimates. Potential publication bias AAM: 252,514 Age at natural menopause (ANM): 201,323 Age at birth (AFB): 418,758 Age at sexual intercourse (AFS): 214,547 Major depression disorder (MDD): 500,199 individuals (170,756 cases and 329,443 controls) The summary‐level data for women's reproductive traits only included women, whereas MDD was tested in both men and women. Data from participants of European descent, so the results cannot be generalized to other ethnicities Low birth weight increased the odds of depression. Premature birth and SGA were not associated with depression 18 studies 13, 655 adolescents (Being born preterm or with low birth weight (PTB) = 8, 813, controls = 4, 852) PTB adolescents exhibit a higher prevalence of developing psychiatric disorders. Girls being more frequently diagnosed with MDD, generalized anxiety disorder, agoraphobia, separation anxiety disorder and social anxiety disorder, but less often with the hyperactive subtype of Attention Deficiet Hyperactivity disorder 76,240 women DES exposure: 1612 (2.2%) women. Self‐reported data Important influencing factors were not adjusted BMI ( N  = 323,298) Depression traits ( N  = 286,052) 183 studies 6 788 834 participants Ascertainment of depression was based on individual's reports. There was variation in the covariates adjusted for in each study. There were considerable differences in research methods, sample size, included age groups and gender, depression screening tools and reported effect sizes 35,407 participants All data collected from the National Health and Nutrition Examination Survey (NHANES) 2005–2018 A U‐shaped relationship between depression and BMI. No such relationship was found among non‐Hispanic blacks The GWAS data were mainly derived from European population. Sex‐stratified analyses were not performed due to sex‐specific GWAS summary statistics were not available Because full summary statistics were unavailable for the East Asian major depression GWAS, the study could not rule out reverse causation, or the possibility that depression influences BMI. Data from participants of East Asian ancestry, so the results cannot be generalized to other ethnicities Depression or dysthymia: 48,847 cases and 225,483 controls. Endometriosis: 15,088 cases and 10,7564 controls Genetic predisposition to depression or dysthymia was associated with an increased risk of developing PCOS, ovarian cysts, abnormal uterine and vaginal bleeding (AUB) and endometriosis No evidence for reverse causality The menstrual disorders severity was self‐reported. The possibility of residual or unmeasured confounders cannot be ruled out. The study did not collect information on symptoms that may be associated with HMB (e.g., endometriosis‐related pain), which could influence or exacerbate depression Retrospective study The study is subject to confounding Foods provided by others (e.g., at school) were not included Food intake was based on maternal report. Dietary intake measured at a single time point was used, which may not represent dietary practices across childhood The findings may not generalize to those from highly disadvantaged backgrounds. Because the study measured the intake of 23 dietary items, the study was unable to generate the well‐used DII 6 studies (4 prospective cohorts and 2 cross‐sectional studies) 49,584 participants The use of various measures of depression, the DII score was computed by self‐report from FFQ or 24 h dietary records, which carries an inherent recall bias. Different cut‐off values of DII score Generalizability of the findings to diverse populations should be taken with caution because most of the analyzed participants were of European descent All included studies were observational in design Potential publication bias was identified. Dietary intake was predominantly assessed through self‐reported tools 54 studies 506,299 participants The heterogeneity of the effect sizes. Only a marginal proportion of included studies reported the exact time duration since parental divorce had happened. Publication bias. Most of the studies used relied on self‐reported measures of mental health Early but not middle childhood father absence was strongly associated with increased odds of offspring depression and greater depressive symptoms at age 24 years. Females had higher trajectories of depressive symptoms compared to males across adolescence and young adulthood Across all ACE scores, those with a history of family mental illness had the highest likelihood of receiving a depression diagnosis. The second strongest association were those with sexual abuse The depression diagnoses variable was self‐reported. ACEs and outcomes are subjective The depression diagnoses variable was self‐reported. ACEs and outcomes are subjective. All nine ACE measures were associated with significantly higher odds of both anxiety and depression. Associations were stronger with depression than with anxiety for almost all ACE categories The study doesn't include questions related to neglect and physical, emotional, or sexual abuse. The report of ACE exposures may be underreported or overreported. Whether the exposure or outcome occurred first cannot be answered with this study ACEs were associated with depression and anxiety in a linear, dose‐dependent manner. Differential impacts of ACES on mental health observed across racial and ethnic groups were observed The associations of ACEs with depression and anxiety were strongest in Black and White participants Data on youth are provided by caregivers. No information regarding the severity of symptoms. The participants were predominantly white (76.5%), with minimal representation from Black (6.9%), Asian (6.14%), and other racial and ethnic minority groups (10.47%). This limited representation restricts the generalizability of the findings Three meta‐analyses revealed that girls who experienced early menarche were significantly more likely to be depressed than those who did not [ 87 , 88 , 89 ]. A two‐sample, multivariable MR study revealed a significant causal effect of an earlier age at menarche on depression risk [ 112 ]. Subsequently, two studies using one‐ and two‐sample MR methods found that an earlier age at menarche is associated with elevated depressive symptoms in early adolescence [ 90 , 91 ]. A systematic review and meta‐analysis revealed that low birth weight increased the odds of adult depression [ 92 ]. A recent systematic review and meta‐analysis revealed that being born preterm or with low‐birth‐weight adolescents exhibit a higher prevalence of developing psychiatric disorders [ 93 ]. A cohort study revealed that a history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed [ 94 ]. Another study showed that prenatal DES exposure was not associated overall with the risk of depression in women or men [ 95 ]. However, in women, exposure in early gestation before 8 weeks' gestation or to a low cumulative dose may be weakly associated with an increased depression risk [ 95 ]. A systematic review and meta‐analysis revealed that both underweight and obesity increase the risk of depression [ 96 ]. More recent observational studies also showed a U‐shaped relationship between BMI and depression [ 10 , 97 ]. A MR analysis showed a bidirectional causal association between depression and BMI, with comparable effect sizes estimated in both directions, in European populations [ 98 ]. In Contrast, two MR analyses revealed that lower BMI was associated with higher odds of depression in individuals of East Asian ancestry [ 86 , 99 ]. Women with severe menstrual disorders including dysmenorrhea, premenstrual syndrome and abnormal uterine bleeding are associated with a higher risk of depressive symptoms in adolescents, adults and older adults, in South Korea [ 97 ]. In South Asia, women with heavy menstrual bleeding are at a higher risk of depression [ 101 ]. A retrospective analysis showed that HMB is associated with depression diagnosis in adolescent females [ 102 ]. A two‐sample bi‐directional MR analysis demonstrated that genetic predisposition to depression or dysthymia was associated with an increased risk of abnormal uterine and vaginal bleeding (AUB), but no evidence for reverse causality [ 71 ]. A 10‐year longitudinal cohort study revealed that a higher inflammatory dietary pattern in childhood is associated with a higher risk of depression in early adulthood, at age 18 [ 103 ]. A cross‐sectional study revealed that inflammatory diet patterns were associated with mental well‐being at ages 11 and 12, as well as in mid‐adulthood [ 104 ]. A meta‐analysis revealed that a pro‐inflammatory diet, as estimated by a higher DII score, is independently associated with an increased risk of depression, particularly in women [ 113 ]. A more recent meta‐analysis revealed that higher DII scores are associated with an increased risk of depression [ 105 ]. A systematic review and meta‐analysis revealed that a significant association existed between parental divorce and every aspect of mental health: Depression, anxiety, suicide attempt, suicidal ideation, distress, alcohol, smoking and drugs [ 106 ]. A UK‐birth cohort study revealed that early but not middle childhood father absence was strongly associated with increased odds of offspring depression and greater depressive symptoms at age 24 years [ 107 ]. There was clear evidence that females had higher trajectories of depressive symptoms compared to males across adolescence and young adulthood [ 107 ]. A large‐scale survey revealed that across all ACE scores, those with a history of family mental illness had the highest likelihood of receiving a depression diagnosis [ 108 ]. The second strongest association was those with sexual abuse [ 108 ]. Another large‐scale survey found that individuals with two or more ACEs were more likely to report a depression diagnosis, irrespective of race/ethnicity [ 109 ]. A cross‐sectional study revealed that all measures of ACEs, spanning nine categories, were significantly associated with increased odds of anxiety and depression [ 110 ]. The associations were stronger for depression than anxiety for almost all ACEs [ 110 ]. A large, cross‐sectional, nationally representative, population‐based study of children and adolescents in the United States revealed that ACEs were associated with depression and anxiety in a linear, dose‐dependent manner [ 111 ]. Differential impacts of ACEs on mental health were observed across racial and ethnic groups [ 111 ].

The author has nothing to report.

Endometriosis affects approximately 10% of women of reproductive age [ 1 ]. To date, several risk factors have been reported through epidemiological studies, including earlier age at menarche, shorter menstrual cycle, and heavy menstrual bleeding [ 2 ]. A woman's exposure to menstruation is increased in the case of early menarche, shorter menstrual cycle, and heavy menstrual bleeding. Consequently, according to the “retrograde menstruation” theory [ 3 ], a young age at menarche, via earlier retrograde menstrual flow exposure, may be responsible for an increased endometrium volume of the pelvic cavity. Therefore, this might participate in enhancing the risk of endometriosis. Nevertheless, no mechanical study has investigated this assumption [ 4 ]. Diagnosis is often delayed due to a lack of noninvasive diagnostic tools and the disease's varied clinical presentation [ 5 ]. Identifying risk factors is crucial for improving diagnosis delay, reducing the disease's impact and earlier effective treatment [ 5 ]. Additionally, studies have shown that low BMI [ 6 , 7 ], low birth weight [ 8 , 9 , 10 ], in utero exposure to diethylstilbestrol (DES) [ 11 , 12 ], an inflammatory diet [ 13 , 14 , 15 ], and adverse childhood experiences (ACEs) [ 16 , 17 , 18 , 19 , 20 ] are associated with an increased risk of endometriosis (Table  1 ). Summary of studies on the potential shared risk factors for endometriosis, dysmenorrhea, chronic pain and infertility. 18 case control studies 3,805 women with endometriosis and 9526 controls There is a small increased risk of endometriosis with early menarche. 11 studies defined early age at menarche as < 12 years old, in four studies, it was defined as ≤ 12 years old 182 416 women of European descent. Endometriosis 8288 cases/68 969 controls The findings may not be generalized to other populations. Women reporting age at menarche (AAM) as  17 years old were excluded Recall bias could be a concern, as most variables were measured by the participants' subjective self‐report. Earlier menarche was defined as ≤ 14 A single‐item dysmenorrhea assessment. Detailed information about gynecological health was not available Self‐reported questionnaire. They were asked about their menstrual features during the last 3 months 32,673 women: 8986 (27.5%) women reported chronic widespread musculoskeletal complaints (WMSC) Chronic nonspecific pain was more prevalent among girls with early menarche compared to girls with either normal, late or no menarche. Headache/migraine was the most common type of chronic nonspecific pain Combined cohort study Tromsø 6 and Tromsø 7 Tromsø 6 ( n  = 6449), Tromsø 7 ( n  = 5681) The possibility of unmeasured confounding of birth weight, a known predictor of age at menarche. Recall bias due to self‐report Self‐reported information Pain intensity was not recorded Self‐reported information. Internet‐based recruitment Retrospective cohort Retrospective Cross sectional An AAM of 15 or older, was associated with an increased risk of polycystic ovary syndrome (PCOS). An AAM of 13, or 12, or younger, was associated with an increased risk of diminished ovarian reserve The relatively small sample size of the case–control studies. Recall bias 628 312 singleton women. During follow‐up, 8262 women received an endometriosis diagnosis AAM: 243,944. Birth weight: 143,677 The body weight datasets obtained contained both males and females, which may lead to collider bias. The genome‐wide association study (GWAS) was obtained only from European individuals; thus, the results are not representative of other races or geographic areas 62 very low birthweight (VLBW; < 1500 g) 67 term small for gestational age (SGA) 87 controls Small sample size. Not all potentially confounding factors in our study database. Self‐reported chronic pain. The participants were young Seven cohorts 931 VP/VLBW and 1363 term‐born young adults Limited age range: The participants were between 23 and 30 years old. Most parents were from high‐income countries. Relevant sociodemographic factors (e.g., the use of assisted reproductive technology) were not collected Inquiries were made about physical abuse in both childhood and adulthood, but not about childhood sexual abuse. Only adult sexual abuse was assessed. Small sample size 60,595 premenopausal women 3394 laparoscopically confirmed endometriosis Early‐life sexual and physical abuse was associated with an increased risk of endometriosis. Greater risk was associated with severity, chronicity, and accumulation of types of abuse. The association between sexual abuse and endometriosis was only found in the subgroup of patients without infertility, who were likely to have painful symptoms An association between a diagnosis of endometriosis and experiences of sexual abuse, emotional abuse, neglect, and inconsistent parenting in childhood. No association was found with physical abuse or neglect, physical abuse of the mother, drug abuse in the family, family members with an intellectual disability, or suicidal ideation in the family No significant association between endometriosis and a history of sexual abuse during childhood and/or adolescence. The presence of at least one severe pelvic pain symptom was associated with a history of sexual abuse 19 studies (17 cross‐sectional 2 case–control) 25,838 participants An association was found between the number and severity ACEs and the risk of dysmenorrhea. Sexual abuse and posttraumatic stress disorder were associated with dysmenorrhea, pelvic pain, and dyspareunia It was unclear whether this relationship was mediated by poorer mental health. The included studies used different definitions of the outcome 11409 participants (61.9% female). having fibromyalgia ( n  = 515) Self‐reporting of fibromyalgia Recall bias Statistically significant association between bullying victimization in childhood and fibromyalgia. The association between bullying and fibromyalgia was not statistically significant when depression was included Self‐reporting of fibromyalgia. Recall bias. Cross‐sectional design with retrospective reports of childhood adversities 4 longitudinal studies. 6,275 participants Unexplained heterogeneity There is potential for reporting and publication biases due to the difficulty of publishing findings that show no connection between bullying victimization and pain Cross‐sectional design with retrospective reports of childhood adversities. Under‐response among younger employees, among those with lower occupational positions and among those with longer sickness absence 85 studies 826,452 adult participants Individuals who were exposed to direct ACEs were significantly more likely to report chronic pain. Individuals who reported experiencing physical abuse during childhood were significantly more likely to report chronic pain. Exposure to any ACEs, either alone or in combination with indirect ACEs, significantly increases the odds of developing chronic painful conditions and experiencing pain‐related disability in adulthood. The risk of chronic pain increased significantly with each additional ACE The terminology and operational definitions of “child abuse and neglect,” as well as the tools used to measure ACEs, vary across studies. The accuracy of self‐reported ACEs is uncertain. Not all studies evaluated the influence of covariates. The majority (84%) of included studies used a cross‐sectional design 68 studies 196,130 participants There are associations between ACEs and chronic pain in adulthood, and this relationship is dose dependent. All types of ACEs should be considered risk factors for chronic pain in adulthood. Poor mental health was found to mediate the detrimental connection between adverse childhood experiences and chronic pain Heterogeneity of terminology. The majority of studies were retrospective. Not all studies evaluated the influence of covariates Cross national from 22 countries The intensity, type, or interference of pain with daily activities could not be examined. Recall bias. Remaining unmeasured confounding Adherence to the Alternative Healthy Eating Index, which reflects healthier dietary patterns, was associated with a 13% lower risk of receiving an endometriosis diagnosis, who had never reported infertility and experienced pain at the time of diagnosis. Adherence to a Western dietary pattern characterized by high intake of red meat, processed meat, refined grains, and desserts was associated with a 27% higher risk of receiving an endometriosis diagnosis The dietary patterns of children and adolescents were not evaluated. Information on diet was self‐reported. Residual or unmeasured confounding by factors that are associated with dietary patterns must be considered. Delay of several years between endometriosis symptom onset among those with pelvic pain and surgical diagnosis The dietary patterns of children and adolescents were not evaluated. Endometriosis diagnoses were self‐reported. Dietary intake was assessed using a single 24‐h recall, which may not fully capture habitual intake The dietary patterns of children and adolescents were not evaluated. Endometriosis diagnoses were self‐reported. Dietary intake was assessed using a single 24‐h recall, which may not fully capture habitual intake The dietary patterns of children and adolescents were not evaluated. A bivariate pain variable was created using relevant yes/no questions from the self‐reported data. The present study also only assessed Black and non‐Hispanic white participants Exposures: 20 different dietary habits; approximately 500,000 participants. Outcomes: Multisite chronic pain (MCP): 387,649 European individuels. MCP is defined as self‐reported pain lasting at least three months in seven distinct bodily regions (head, face, neck/shoulder, back, stomach/abdomen, hip, and knee) Causal associations between various dietary habits and different types of chronic pain. Adhering to an anti‐inflammatory diet may potentially alleviate chronic pain symptoms The dietary patterns of children and adolescents were not evaluated. The GWAS primarily focused on individuals of European ancestry, which may limit their applicability to other populations 12 observational studies. 29 647 participants mean baseline age of 17–45 years Being underweight may be related to the occurrence of primary dysmenorrhea. Being overweight and obesity may not be associated with the development of primary dysmenorrhea Menstrual symptoms were treated as binary variables, limiting the ability to explore the distribution of symptom severity and its relationship with age and BMI in depth. As part of the Sofy app's commitment to user privacy, information on several potential confounding factors was not collected or stored. This study relied on app‐based data collection and self‐reported symptom records Being underweight or obese at adolescence is a potential risk factor for subsequent infertility among Japanese women. In particular, being underweight during adolescence may be a contributing factor to unexplained infertility later in life Information was collected from self‐administered questionnaires. Some might not have remembered the height and weight at 18 years of age, which might have led to misclassification Several risk factors previously reported for endometriosis have also been associated with dysmenorrhea, chronic pain, and fertility issues including earlier age at menarche [ 25 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 54 ], low birth weight [ 36 , 37 , 38 ], in utero DES exposure [ 40 ], inflammatory diet [ 49 , 50 ], low BMI [ 51 , 52 , 53 ] and ACEs [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 55 , 56 , 57 ] (Table  1 ). Dysmenorrhea, chronic pain, and fertility issues are major clinical problems in patients with endometriosis [ 5 ]. These findings raise a question of whether previously reported risk factors for endometriosis are associated with dysmenorrhea, chronic pain, and fertility issues, rather than endometriosis itself.

The author declares no conflicts of interest.