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

ABSTRACT

Background

Endometriosis is often diagnosed late due to a lack of noninvasive diagnostic tools and the varied presentation of its symptoms. Identifying risk factors for endometriosis is crucial for reducing diagnosis delays, mitigating the disease's impact, and enabling earlier treatment.

Methods

Original and review articles published in English were selected from PubMed and Google Scholar searches up to January 2026. The following keywords were used: endometriosis, pain, infertility, and risk factors. The search was performed using these keywords individually, as well as in combination.

Main Findings (Results)

Several previously reported risk factors associated with endometriosis have also been linked to dysmenorrhea, chronic pain, and infertility. These are all major clinical manifestations of the disease. Additionally, some endometriosis risk factors are associated with depression. Mendelian randomization studies have revealed that depression can cause endometriosis, dysmenorrhea, chronic pain, and infertility. However, few previous studies have conducted subgroup analyses based on clinical manifestations to identify endometriosis risk factors.

Conclusion

It is unclear whether the previously reported risk factors are associated with endometriosis itself or with its specific clinical manifestations, such as pain and infertility. Future epidemiological research evaluating potential risk factors should consider heterogeneous endometriosis populations and include appropriate controls.

1. Introduction

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).

TABLE 1.

Summary of studies on the potential shared risk factors for endometriosis, dysmenorrhea, chronic pain and infertility.

Potential risk factors	Orders	References	Country	Method	No of participants	Summary findings	Limitations
Earlier age at menarche
	Endometriosis
		[21]		Systematic review and meta‐analysis	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	The potential for misclassification of disease in the primary studies
		[22]		Systematic review and meta‐analysis	16 studies	Early menarche (< 12 years) was associated with a significant pooled risk of endometriosis, this risk was higher in low‐income countries	High heterogeneity
		[23]		Two‐sample Mendelian randomization analysis	182 416 women of European descent. Endometriosis 8288 cases/68 969 controls	Weak evidence of an association between age at menarche and endometriosis	The findings may not be generalized to other populations. Women reporting age at menarche (AAM) as < 7 years old or > 17 years old were excluded
		[24]	UK	Cross sectional	250,037 women. 197,714 men	Early age at menarche was not statistically significantly associated with endometriosis risk after multiple test correction	Misclassification of endometriosis based on self‐reported medical histories could weaken the true association
	Dysmenorrhea
		[25]	Pakistan	Cross sectional	600 randomly selected female university students	High levels of stress and early menarche were the potent determinants of moderate/severe dysmenorrhea	Recall bias could be a concern, as most variables were measured by the participants' subjective self‐report. Earlier menarche was defined as ≤ 14
		[26]	USA	Cohort	2588 postmenarcheal female adolescents	Early pubertal timing increased odds for dysmenorrhea by 22%–31%	A single‐item dysmenorrhea assessment. Detailed information about gynecological health was not available
		[27]	Italy	Cross sectional	3782 of Italian girls	No independent association between age at menarche and dysmenorrhea	Self‐reported questionnaire. They were asked about their menstrual features during the last 3 months
	Chronic pain
		[28]	Norway	Cross sectional	32,673 women: 8986 (27.5%) women reported chronic widespread musculoskeletal complaints (WMSC)	There was an association between early age at menarche and chronic WMSC later in life	The self‐reported information used
		[29]	Norway	Cross sectional	3982 aged 13 to 18 years	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	The self‐reported information used
		[30]	Norway	Combined cohort study Tromsø 6 and Tromsø 7	Tromsø 6 (n = 6449), Tromsø 7 (n = 5681)	AAM was significantly associated with chronic pain in the neck, abdomen, and both arms, and chronic widespread pain (CWP)	The possibility of unmeasured confounding of birth weight, a known predictor of age at menarche. Recall bias due to self‐report
		[31]	Norway	Cross sectional	27 697 women with 7300 women reporting low back pain (LBP)	AAM ≤ 11 years was associated with an increased risk of chronic LBP	Self‐reported information Pain intensity was not recorded
	Infertility
		[32]	USA and Canada	Internet‐based preconception cohort study	2,189 female pregnancy planners	Women who reached menarche at < 12 years had reduced fecundability, compared with those who reached menarche at the age of 12–13 years	Self‐reported information. Internet‐based recruitment
		[33]	Norway	Retrospective cohort	67,613 pregnant women	Both early (< 11 years) and late (> 15 years) menarche are associated with decreased fecundability	The study‐population consisted of women pregnant in their second trimester, excluding those with persistent infertility
		[34]	Iran	Cross sectional	488 infertile and 488 fertile women	An earlier age at menarche (< 12 years old) was associated with an increased risk of infertility compared to a later age at menarche (> 16 years old)	The limited number of late‐menarche women (n = 46)
		[35]	China	Retrospective Cross sectional	7,643 infertile women	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	Retrospective study
Low birth weight
	Endometrioisis
		[8]		Systematic review	11 studies	The majority of studies found that women born with low birthweight (< 2.5 kg or < 5.5 lb) were more likely to be diagnosed with endometriosis	The relatively small sample size of the case–control studies. Recall bias
		[9]	Sweden	Total‐population register‐based cohort study	628 312 singleton women. During follow‐up, 8262 women received an endometriosis diagnosis	Lower birthweight and lower birthweight‐for‐gestational age were at higher risk of endometriosis, irrespective of their gestational age at birth	Cases in primary care might be missed
		[10]		Two‐sample multivariable MR	AAM: 243,944. Birth weight: 143,677	No association between low birth weight and endometriosis risk	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
	Chronic pain
		[36]	Norway	Birth cohort study	62 very low birthweight (VLBW; < 1500 g) 67 term small for gestational age (SGA) 87 controls	Children in VLBW and SGA groups had higher odds ratios for chronic pain at age 26	Small sample size. Not all potentially confounding factors in our study database. Self‐reported chronic pain. The participants were young
	Infertility
		[37]		Meta‐analysis	Seven cohorts 931 VP/VLBW and 1363 term‐born young adults	Very preterm birth (VP; < 32 weeks' gestation) or VLBW in high‐income countries is not associated with lower fertility in young adults during their early twenties	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
		[38]	Norway	Prospective, population‐based cohort study	414 participants (212 born VP or with VLBW and 202 term‐born) (52.2% female)	VP and VLBW were significantly associated with lower fertility during the late (≥ 30 years) but not the early (< 30 years) reproductive window	The study did not collect data on additional confounders (e.g., contraceptive use or fertility treatment)
		[39]	Sweden	Population‐based register study.	Women born in Sweden between 1973 and 1993 (n = 1 000 14)	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	Several potential confounders were not available
In utero diethylstilbestrol (DES) exposure
	Endometriosis	[11]	USA	Cohort	84446 women	The rate of endometriosis was also 80% greater among women exposed to DES in utero	It is possible that patients with consistently more frequent utilization of the medical system, those of higher socioeconomic class or greater education
		[12]	USA	Case control	310 endometriosis 727 without	Increased endometriosis risk with maternal use of DES, although the confidence interval included the null	Participant self‐report
	Infertility
		[40]	USA	Combined three cohort study	4653 women exposed in utero to DES and 1927 unexposed controls	Increased endometriosis risk with maternal use of DES	Self‐report
ACEs
	Endometriosis
		[16]	USA	Cross sectional	472 women (Endometriosis n = 190)	No association was observed between either a history of sexual or physical abuse and risk of endometriosis	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
		[17]	USA	Cohort	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	Recall and selection bias
		[18]	Switzerland, Germany, and Austria	A multicenter, retrospective, case–control	421 endometriosis, 421 controls	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	Some of the women in the study may have had asymptomatic endometriosis
		[19]	France	Cohort sudy	168 patients with endometriosis and 103 patients without endometriosis	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	Recall and selection bias
		[20]	Sweden	Cohort	24,311 women with endometriosis; all women born in Sweden from 1974 to 2001	ACEs (Parental substance abuse, parental psychiatric disorder, teenage parent, parental separation, residential instability, receiving public assistance, exposure to violence, parental exposure to violence) were associated with an increased risk of developing endometriosis, in a dose dependent manner	Undiagnosed cases of endometriosis may introduce bias
	Dysmenorrhea, Pelvic pain, Dyspareunia
		[41]		Systematic review	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
	Chronic pain
		[42]	Finland	Cross sectional	11409 participants (61.9% female). having fibromyalgia (n = 515)	Chronic pain was associated with long‐lasting financial difficulties; serious conflicts in the family; parental divorce; serious or chronic illnesses in the family; alcohol problems in the family	Self‐reporting of fibromyalgia Recall bias
		[43]	Finland	Cross sectional	11409 participants (61.9% female) having fibromyalgia (n = 515)	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
		[44]		Systematic review	4 longitudinal studies. 6,275 participants	An increase in pain among those who were victimized by bullying	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
		[45]	Finland	Cross sectional	8140 employees (80% women)	Chronic pain was associated with childhood economic difficulties, illness, parental divorce, parental alcohol problems, and bullying at school or among peers	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
		[46]		Meta‐analysis	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
		[47]		Systematic review	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
		[48]		Cross national from 22 countries	202,898 participants (49% female)	Individuals who experienced parental divorce, lived in a single‐parent household, lost a parent, or suffered financial hardship or abuse during childhood were more likely to report pain later in life	The intensity, type, or interference of pain with daily activities could not be examined. Recall bias. Remaining unmeasured confounding
Inflammatory diet
	Endometriosis	[13]	USA	Cohort	81,997 premenopausal participants of the Nurses' Health Study II, who were followed from 1991 to 2015	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
		[14]	USA	Cross sectional	4149 women from the National Health and Nutrition Examination Survey (NHANES) 2001–2006	Women with endometriosis had higher Dietary Inflammatory Index (DII) scores than those without	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
		[15]	USA	Cross sectional	3410 women from the NHANES 1999–2006	Increased intake of the pro‐inflammatory diet, as a higher DII score, was positively associated with endometriosis risk among American adults	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
	Chronic Pain
		[49]	USA	Cross sectional	16,061 participants (55.4% female)	The Southern dietary pattern is characterized by high consumption of added fats, fried foods, eggs and egg dishes, organ meats, processed meats, refined sugars, and sweetened beverages was associated with a 41% (95% CI: 23, 61%) increase in risk of pain	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
		[50]		Two sample MR	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
Low BMI
	Endometriosis
		[6]	USA	Cohort	116 430 female nurses from September 1989 to June 2011 as part of the Nurses' Health Study (NHS) II cohort	A woman's current BMI and BMI at age 18 are significantly inversely related to the rate of laparoscopically confirmed endometriosis, although the most robust association was observed with BMI at age 18	The NHS II cohort is overwhelmingly Caucasian, which may limit generalizability to more ethnically diverse populations
		[7]	France	Cohort	61 208 included women. 2416 endometriosis cases	The odds of endometriosis were significantly lower among women who reported having a large versus lean body size at 8 years, at menarche and at ages 20–25 years	Body size is based on retrospective self‐report, which may be subject to recall bias
	Dysmenorrhea
		[51]		Systematic and meta‐analysis	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	Potential confounding factors, such as the family history of primary dysmenorrhea, length of menstrual cycle, and dietary habits, could not be completely excluded
		[52]	Japan	Cross sectional	32,556, Japanese female Sofy app users	Participants in the normal BMI range reported the lowest prevalence of menstrual pain, while those who were underweight had the highest prevalence	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
	Infertility
		[53]	Japan	Cross sectional	15,907 married female nurses from the Japan Nurses' Health Study (JNHS) (a large‐scale, ongoing, prospective cohort study conducted across the country among female nurses)	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.

2. Previously Reported Risk Factors for Endometriosis

The potential shared risk factors for endometriposisn dysmenorrhea, chronic pain and infertility are summurised in Table 1.

2.1. Earlier Age at Menarche

2.1.1. Endometriosis

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].

2.1.2. Dysmenorrhea

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].

2.1.3. Chronic Pain

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].

2.1.4. Infertility

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 (< 11 y) and late (> 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.

2.2. Pranatal Factors

2.2.1. Endometriosis

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].

2.2.2. Chronic Pain

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].

2.2.3. Infertility

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.

2.3. ACEs

2.3.1. 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].

2.3.2. Dysmenorrhea and Chronic Pain

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].

2.3.3. Infertility

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].

2.4. Inflammatory Diet  

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].

2.4.1. Endometriosis

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.

2.4.2. Chronic Pain

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].

2.5. Low BMI  

2.5.1. Endometriosis

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].

2.5.2. Dysmenorrhea

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].

2.5.3. Infertility

A cross‐sectional analysis revealed that being underweight or obese during adolescence is a potential risk factor for subsequent infertility [52, 53].

2.6. Mental Health Disorders and Endometriosis

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).

TABLE 2.

Summary of studies on the association between endometriosis, dysmenorrhea, chronic pain and infertility and mental disorders.

Disorders	References	Method	No of participants	Summary findings	Limitations
Endometriosis
	[70]	Bidirectional two‐sample Mendelian randomization (MR) analysis	208,912 individuals (17,054 cases of endometriosis and 191,858 controls). 500,199 individuals (170,756 cases of depression and 329,443 controls)	A causal association between endometriosis and depression and at least one abnormal condition of gastric mucosa.	The study was based on the analysis of data from mainly European ancestry, thereby reducing the generalizability of its findings
	[71]	Bidirectional two‐sample MR analysis	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
	[72]	Bidirectional two‐sample MR analysis	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, but no evidence for reverse causality	The generalizability to diverse ethnic groups with distinct lifestyles and cultural backgrounds is limited, as the study exclusively focused on individuals of European ancestry
	[73]	Bidirectional two‐sample MR analysis	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
	[74]	Bidirectional two‐sample MR analysis	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	The generalizability to diverse ethnic groups with distinct lifestyles and cultural backgrounds is limited, as the study exclusively focused on individuals of European ancestry
Dysmenorrhea
	[75]	Bidirectional two‐sample and multivariate MR analysis	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
	[76]	Systematic Review and Cumulative Analysis	10 studies 4,691 participants	Primary dysmenorrhea was associated with a significant depressive disorder	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
Chronic pain
	[77]	Bidirectional two‐sample MR analysis	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.
	[78]	Bidirectional two‐sample MR analysis	500,000 adult volunteers	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
	[79]	Bidirectional two‐sample MR analysis	Depression: (170,756 cases, 329,443 controls) Chronic widespread pain (CWP): (6,914 cases, 242,929 controls)	CWP is associated with an elevated risk of depression, and vice versa	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
	[80]	Bidirectional two‐sample MR analysis	Chronic back pain (CBP): 78,935 cases. 360,896 controls in UK Biobank	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
	[81]	Meta analysis of MR studies	20 MR studies. Overall, the studies included were of high quality and had a low risk of bias	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
Infertility
	[71]	Bidirectional two‐sample MR analysis	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
	[82]	Bidirectional two‐sample MR analysis	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	It included only individuals of European ancestry, thereby reducing the generalizability of its findings
	[76]	Bidirectional two‐sample MR analysis	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
	[83]	Bidirectional two‐sample MR analysis	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	The generalizability of the findings to other populations is uncertain since all GWAS data used in our analysis are derived from European populations
	[84]	Two‐sample MR analysis	Depression: 135,458 cases and 344,901 controls Infertility: 6481 cases and 68,969 controls	A significant positive causal relationship between genetically predicted depression and infertility	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].

2.6.1. Endometriosis

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].

2.6.2. Dysmenorrhea

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].

2.6.3. Chronic Pain  

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].

2.6.4. Infertility

Two‐sample Mendelian rando [71, 76, 83, 84, 86], though female infertility does not appear to cause depression [71, 76, 83, 86].

2.7. Risk Factors for Endometriosis and Mental Health Disorders

Among previously reported risk factors for endometriosis, several factors are also associated with mental health problems, notably depression (Table 3).

TABLE 3.

Summary of studies on the association between potential risk factors for endometriosis and mental disorders.

Potential risk factors	References	Country	Method	No of participants	Summary findings	Limitations
Earlier age at menarche
	[87]		Systematic review and meta‐analysis	22 studies 87,798 participants	Depression scores and depression incidence were significantly higher in the early menarche group than in the non‐early menarche group	Not all the studies adjusted for these potential confounding factors
	[88]		Systematic review and meta‐analysis	13 observational studies (5 cohorts and 8 cross‐sectional studies) 434,838 participants	Early menarche is associated with significantly higher odds of depression compared to both normative AAM and late AAM	Most of the studies were conducted in high‐income countries. Publication bias
	[89]		Systematic review and meta‐analysis	Eight cohort and three cross‐sectional studies (138,819 participants)	Females with early menarche were more likely to have depression later in life compared with those who had on‐time menarche	Included studies did not account for confounders consistently and some reported unadjusted effect estimates. Potential publication bias
	[90]		Two‐sample univariable and multivariable MR analysis	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)	A multivariable MR revealed significant causal effects of AAM age, AFB and AFS on MDD	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
	[91]		One‐ and two‐sample MR analysis	329,345 post‐pubertal women of European ancestry	An earlier age at menarche causally increases the risk of adolescent depression	The study is based on a predominantly white European cohort
Small birth weight
	[92]		Systematic review and meta‐analysis	14 studies evaluating low birth weight, 9 premature birth and 4 small for gestational age (SGA)	Low birth weight increased the odds of depression. Premature birth and SGA were not associated with depression	The study cannot rule out the possibility that the observed association was due to residual confounding factors relating to intimate partner violence
	[93]		Systematic review and meta‐analysis	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	Heterogeneity in assessment methods and diagnostic criteria
In utero diethylstilbestrol (DES) exposure
	[94]	USA	Cohort study	76,240 women DES exposure: 1612 (2.2%) women.	Women who were exposed to DES in utero had a higher risk of depressive symptoms and use of antidepressants, and that this increase in risk extended into their middle age	Information was self‐reported
	[95]	USA	Cohort study	Women (3,888 DES exposed and 1729 unexposed) and men (1,021 DES exposed and 1042 unexposed)	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	Retrospective and self‐reported depression experiences.
Low BMI
	[63]	China	Cross sectional study	10,686 adults	A U‐shaped relationship between BMI and depression. Both obesity and underweight increased the risk of depression	Self‐reported data Important influencing factors were not adjusted
	[86]		Bi‐directional two samples MR analysis	BMI (N = 323,298) Depression traits (N = 286,052)	Lower BMI was associated with higher odds of depression in individuals of East Asian ancestry	Data from participants of East Asian ancestry, so the results cannot be generalized to other ethnicities
	[96]		Systematic review and meta‐analysis	183 studies 6 788 834 participants	Both underweight and obesity increase the risk of depression	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
	[97]	USA	Cross sectional study	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	Self‐reporting questionnaire may lead to recall bias or reporting bias
	[98]		Bi‐directional two sample MR analysis	Depression (N > 1.3 million) and BMI (N = 806,834)	A bidirectional causal association between depression and BMI, with comparable effect sizes estimated in both directions	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
	[99]		Two sample MR	Depression (with 15,771 cases and 178,777 controls)	Higher BMI was associated with lower odds of depression	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
Heavy menstrual bleeding (HBM)
	[72]		Bidirectional two‐sample MR analysis	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 generalizability to diverse ethnic groups with distinct lifestyles and cultural backgrounds is limited, as the study exclusively focused on individuals of European ancestry
	[100]	Korea	Cross sectional	3,088 premenopausal women	Women with severe menstrual disorders including dysmenorrhea, premenstrual syndrome and AUB are associated with a higher risk of depressive symptoms	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
	[101]	Inde	Cross sectional	3438 adult women	Women with HMB are at a higher risk of depression	Other confounding socioeconomic or clinical variables may drive the observed relationship
	[102]	USA	Retrospective cohort	1168 adolescents (581 with HMB and 87 without HMB)	HMB is associated with depression diagnosis in adolescent females	Retrospective study The study is subject to confounding
Inflammatory diet
	[103]	UK	Cohort	6,939 parents and children with an average age of 8.5 years at baseline	A higher inflammatory dietary pattern in childhood is associated with a higher risk of depression in early adulthood, at age 18	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
	[104]	Australia	Cross sectional	759 aged 11–12 (49% girls) and 1812 parents (88% mothers)	Inflammatory diet patterns were associated with mental well‐being at ages 11 and 12, as well as in mid‐adulthood	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
	106		Systematic review and meta‐analysis	6 studies (4 prospective cohorts and 2 cross‐sectional studies) 49,584 participants	Pro‐inflammatory diet estimated by a higher Dietary Inflammatory Index (DII) score is independently associated with an increased risk of depression, particularly in women	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
	[105]		Systematic review and meta‐analysis	43 studies (11 cohort studies and 32 cross‐sectional studies)	Higher DII scores were associated with an increased risk of depression	All included studies were observational in design Potential publication bias was identified. Dietary intake was predominantly assessed through self‐reported tools
ACEs
	[106]		Systematic review and meta‐analysis	54 studies 506,299 participants	A significant association between parental divorce and every aspect of mental health: Depression, anxiety, suicide attempt, suicidal ideation, distress, alcohol, smoking and drugs	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
	[107]	UK	Birth cohort	8,409 children	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	The possibility of unmeasured and residual confounding
	[108]	USA	Cross sectioanl	52,971 participants	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
	[109]	USA	Cross sectional	127,577 adults	Individuals with two or more ACEs were more likely to report a depression diagnosis, irrespective of race/ethnicity	The depression diagnoses variable was self‐reported. ACEs and outcomes are subjective.
	[110]	USA	Cross sectional	39,929 participants	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
	[111]	USA	Cross sectional	104,205 children aged 0–17	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

2.7.1. Earlier Age at Menarche  

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].

2.7.2. Low Birth Weight

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].

2.7.3. In Utero DES Exposure  

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].

2.7.4. Low BMI  

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].

2.7.5. Heavy Menstrual Bleeding  

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].

2.7.6. Inflammatory Diet  

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].

2.7.7. ACEs  

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].

3. Conclusions

Several risk factors associated with endometriosis that have previously been reported have also been linked to dysmenorrhea, chronic pain, and infertility. These are all major clinical manifestations of the disease. Additionally, some endometriosis risk factors are associated with depression. Mendelian randomization studies have revealed that depression can cause endometriosis, dysmenorrhea, chronic pain, and infertility. However, few previous studies have conducted subgroup analyses based on clinical manifestations to identify endometriosis risk factors; it remains unclear whether these factors are associated with specific clinical manifestations of endometriosis, such as pain and infertility, or with endometriosis itself, regardless of its manifestations.

3.1. Opinions on the Next Steps for the Research

Studies have shown that several non‐genetic factors, including low birth weight, in utero diethylstilbestrol (DES) exposure, an inflammatory diet, and adverse childhood experiences (ACEs), are associated with an earlier age at menarche. These factors are also associated with an increased risk of endometriosis, dysmenorrhea, chronic pain, infertility, and depression. MR analyses revealed that an earlier age at menarche can lead to depression. Depression can cause endometriosis, dysmenorrhea, chronic pain, and fertility issues. These findings suggest the following hypothesis (Figure 1): Several non‐genetic factors, such as low birth weight, in utero DES exposure, an inflammatory diet, and ACEs, may cause an earlier age at menarche in some girls. These exposures may lead to an increased risk of dysmenorrhea, chronic pain, and fertility issues, regardless of the presence of endometriosis. In some girls, depression caused by an earlier age at menarche may mediate these effects. Depression caused by an earlier age at menarche may lead to an increased risk of dysmenorrhea, chronic pain, and fertility issues, regardless of endometriosis presence. Therefore, several previously reported risk factors for endometriosis may be more specific to the subsequent risk of dysmenorrhea, chronic pain, and fertility issues than to endometriosis itself. Further studies are needed to validate this hypothesis.

FIGURE 1.

Diagrams illustrating the hypothesis. For some women, an earlier age at menarche, coupled with several non‐genetic factors, can lead to depression during childhood and adolescence. This depression can increase the subsequent risk of endometriosis, dysmenorrhea, chronic pain, and infertility. For some women, these non‐genetic factors may not result in an earlier age at menarche, but they may cause depression, which increases the risk of these conditions. The solid line shows the causal relationships revealed by Mendelian randomization analyses. The dashed line shows the potential associations identified by observational studies.

To identify true risk factors for endometriosis development, epidemiological investigations and basic research investigating the underlying mechanisms of potential risk factors are necessary. This integrated research approach could provide further insight into the disease's pathophysiology.

Regardless of age at menarche, it is crucial to identify those at risk for depression, as this risk is not limited to children and adolescents with an earlier age at menarche. One risk factor is exposure to ACEs. Identifying and managing children and adolescents exposed to ACEs, as well as diagnosing and treating depression earlier, may prevent dysmenorrhea, chronic pain, and infertility later in life. Further large‐scale prospective clinical studies are needed to confirm this.

The two primary clinical issues experienced by patients with endometriosis are pain and infertility. However, the severity of these issues varies from patient to patient. Furthermore, some patients with endometriosis exhibit heterogeneous, nonspecific symptoms. Nevertheless, many studies have investigated endometriosis patients as a homogeneous population. Few previous epidemiological studies have considered variability in clinical presentations. Therefore, it is unclear whether the previously reported risk factors are associated with endometriosis itself or its specific manifestations. Therefore, it is unclear whether the previously reported risk factors are associated with endometriosis itself or its specific clinical manifestations. MR studies have clearly revealed that depression causes endometriosis. It remains unclear, however, whether depression causes endometriosis with specific symptoms, such as chronic pain and infertility, or if it affects all endometriosis patients, regardless of symptoms. The definition of endometriosis varies among epidemiological studies. Some studies only include patients with a laparoscopic and histological diagnosis, while others include patients diagnosed through imaging analysis and clinical examinations. Misclassifying endometriosis based on self‐reported medical histories could weaken the true association (see Table 1). Additionally, some patients in the control group who experience pain and/or infertility may have undiagnosed endometriosis. Future epidemiological research on endometriosis should clearly define cases, consider heterogeneous populations, and include appropriate controls without endometriosis. Future epidemiological research should consider heterogeneous populations and include appropriate controls to evaluate potential risk factors associated with endometriosis.

However, most of the studies included in this analysis were derived from “WEIRD” (Western, Educated, Industrialized, Rich, Democratic) populations. Although MR analysis is a powerful tool for identifying causal relationships, nearly all of the studies included in this study have focused on European populations. Therefore, it is unclear whether the current findings can be generalized to populations worldwide. Risk factors may differ among different ethnic and cultural groups, so further studies that include a wide variety of these groups are needed to identify true risk factors for endometriosis.

This scientific approach could help identify the true risk factors for endometriosis, improving our understanding of its pathophysiology and enabling earlier diagnosis. It could also optimize patient management in clinical settings.

Funding

This work was supported by KARL STORZ.

Ethics Statement

The author has nothing to report.

Consent

The author has nothing to report.

Conflicts of Interest

The author declares no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.