Association between depression and endometriosis using data from NHANES 2005–2006

Studies on the association between depression and self-reported endometriosis are limited, and further studies are required to investigate this association. Data were collected from the National Health and Nutrition Examination Survey database (2005–2006). Based on the inclusion and exclusion criteria, 100 participants with self-reported endometriosis and 1295 participants without self-reported endometriosis were included, representing a total population of 64,989,430. Depression severity was assessed using the Patient Health Questionnaire 9 (PHQ9). A survey-weighted logistic regression analysis was performed to explore the association between depression and endometriosis. Subgroup analyses were conducted to explore heterogeneity. The prevalence of endometriosis was 7.17%. A significant positive association was found between the PHQ9 score and endometriosis. After adjusting for all covariates, the PHQ9 score positively correlated with endometriosis. Furthermore, compared with the participants without depression, those with moderate depression were more prone to have endometriosis both in unadjusted and fully adjusted model. However, the relationship between severe depression and endometriosis was not significant in all models (P > 0.05). Our findings highlight the influence of depression on the prevalence of self-reported endometriosis. Further studies are required to elucidate the causal relationship between depression and self-reported endometriosis.


Exposure and outcome definitions
PHQ9 is a reliable questionnaire for rating mood based on standard diagnostic criteria for depression 13,14 .The PHQ9 scale consists of nine items rated from 0 to 3, with the total score ranging from 0 to 27 15 .The depression severity of the survey participants was evaluated using PHQ9, administered in an MEC 16 .The depression was defined as a total PHQ9 score ≥ 10 17 .For participants with depression, the degree of depression was further divided into moderate (total PHQ9 score: 10-14) and severe depression (total PHQ9 score ≥ 15) 18 .The grade of depression and PHQ9 score of each participant were then calculated for further analysis.
Self-reported endometriosis was diagnosed based on the "rhq360" questionnaire administered in the MEC.The structured questionnaire comprised the question, "Has a doctor or other health professional ever told you that you have endometriosis?" 19 .Individuals who answered "yes" were categorized into the case group with self-reported endometriosis, and individuals who answered "no" were classified into the control group without self-reported endometriosis.

Potential covariates
Demographic covariates, including age, race, marital status, educational level, and poverty level, were obtained through home interviews.According to the age distribution, the participants were divided into three groups: first (20-29 years), second (30-40 years), and third (41-54 years) tertiles.Marital status was defined as married, divorced, separated, or spinster 20 .The participants' educational level was recorded as less than high school, high school, or college and above 21 .Poverty level was evaluated based on the poverty income ratio (PIR) and classified as follows: low-income (PIR < 1.35), medium-income (1.35 ≤ PIR < 3.0), and high-income (PIR ≥ 3.0) 22 .Health-related covariates, including smoking status and alcohol use, were evaluated in the MEC.According

Statistical analysis
Due to the complex multistage sampling design of the NHANES, all data were merged and weighted using wtmec2yr under the NHANES protocol 26 .The baseline characteristics of the participants were first compared using Student's t-test for continuous variables and the chi-square test for categorical variables 27 .For descriptive statistics, the variables were expressed as weighted means (standard error).Categorical variables were presented as numbers (weighted percentages).Next, weighted univariate and multivariate logistic regression models were used to evaluate the correlation between depression and endometriosis.In the multivariate logistic regression analysis, three models were constructed: (1) Model 1 (no covariate were adjusted), (2) Model 2 (adjusted for variables found to be significant in the univariate logistic regression analysis), and (3) Model 3 (adjusted for all covariates).Finally, the statistical P for interactions between the covariates and the PHQ9 score was calculated, and subgroup analyses were conducted to further clarify these results.The weighted logistic regression and subgroup analysis results are expressed as odds ratios (OR) and 95% confidence intervals (CI).All analyses were performed using R and R studio (version 4.2.1), and P < 0.05 was used to indicate statistical significance.

Population characteristics
Descriptive characteristics of the study participants are presented in Table 1.After a series of screenings, 1395 participants were included from the NHANES database (2005-2006), representing a total population sample of 64,989,430.Of these, 100 (7.17%) individuals had self-reported endometriosis, whereas 1295 (92.83%) did not.Significant differences in age, race, PIR, and the PHQ9 score were found between patients with and without self-reported endometriosis (P < 0.05).

Subgroup analyses
To assess the influence of potential effect modifiers on the prevalence of self-reported endometriosis, P for interaction and subgroup analyses were conducted (Fig. 2).The results showed no significant interactions between the covariates and PHQ9 score (P for interaction > 0.05).The ORs in all subgroups were greater than one, indicating a robust positive relationship between depression and the prevalence of endometriosis.Although the OR was lesser than one in the subgroups with age 20-29 years (OR = 0.88, 95% CI 0.69-1.13,P = 0.296), spinster status (OR = 0.94, 95% CI 0.85-1.05,P = 0.267), and current smoking status (OR = 0.99, 95% CI 0.93-1.05,P = 0.717), the P value was not significant.

Discussion
To explore the relationship between depression and endometriosis, we conducted a cross-sectional study of 1395 NHANES participants, of whom 7.17% had self-reported endometriosis.Multivariate logistic regression analysis was used to assess the relationship between depression and self-reported endometriosis through independent evaluations.Here, we report that the PHQ9 scores positively correlate with endometriosis prevalence.Particularly, participants with moderate depression exhibited a significantly association with the prevalence of endometriosis compared with those without depression.Our results were relatively robust after adjusting for related covariates.Our findings highlight the role of depression in endometriosis prevention.
Although surgical and drug interventions are currently available for the management of endometriosis, these therapies remain insufficient owing to the high rate of recurrence [28][29][30] .Depression is strongly associated with gynecological diseases, including endometriosis 10 .Participants with moderate depression may be prone to self-reported endometriosis, consistent with pathogenic role of PHQ9 reported previously 18 .In certain situations, depression can contribute to disease progression.For example, severe depressive symptoms are closely associated with an elevated risk of cardiovascular disease 31,32 .Notably, women are more likely to experience depression than men 33,34 .In patients with chronic pelvic pain, higher depression scores were observed in the physical, psychological, social, and environmental domains, likely reflecting the negative effects of depression on quality of life 35 .A cross-sectional study showed that depression may postpone menopause by targeting specific biological mechanisms 36 .Our findings highlighted the influence of depression on the prevalence of self-reported endometriosis.www.nature.com/scientificreports/In this study, age and race were identified as independent risk factors for endometriosis.Population-based studies in China suggest that endometriosis is most common in women aged 15-54 years, with the maximum risk found in the 15-24 years age range; the prevalence of endometriosis subsequently decreases continuously with age 37,38 .However, in the United States, the highest incidence of endometriosis is observed in women aged 36-45 years 39 .In the present study, participants aged 41-54 years had a higher prevalence of endometriosis than those in the youngest age group (20-29 years).This may be explained by the chronic-continuous morbidity pattern consistent with endometriosis.Furthermore, we found that Mexican-American participants were less vulnerable to endometriosis than White participants.Overall, White patients have a higher chance of endometriosis diagnosis than non-White patients 40 .However, due to access to good medical conditions, White patients had a better prognosis, accompanied by lower mortality and cost compared with patients of other races 41 .
This study had certain limitations.First, this was a cross-sectional study; thus, causality could not be determined.Therefore, it is worth investigating whether depression and self-reported endometriosis mutually influence each other.Second, due to the characteristic features of PHQ9 and endometriosis, only participants in a 1-year cycle (2005-2006) were enrolled in this study, which may have led to selection bias.Third, given the high loss rate in covariate "diagnosis age of endometriosis, " the results may be subject to a certain margin of bias.Finally, sampling errors inherent in the NHANES data cannot be ruled out.Considering these limitations, large prospective cohort studies are required to confirm our results.
In conclusion, we found a strong positive association between the PHQ9 score and self-reported endometriosis.Moderate depression significantly and positively correlated with the prevalence of self-reported endometriosis.Our study sheds light on the risk of depression in patients with endometriosis.Further studies are required to elucidate a causal relationship between depression and self-reported endometriosis.

Figure 1 .
Figure 1.Flow chart of the screening process from National Health and Nutrition Examination Survey (2005-2006).BMI, body mass index.

Figure 2 .
Figure 2. Subgroup analyses on the effect of interaction between the covariates and Patient Health Questionnaire 9 score on the prevalence of endometriosis.P value was calculated by P for interaction and logistic regression analysis.BMI, body mass index.PIR, poverty income ratio.

Table 2 .
Association between the covariates and odds of endometriosis.Model 1: No covariate were adjusted.Model 2: Adjusted for age, race, and poverty level but not for the covariate itself.Model 3: Adjusted for age, age at menarche, alcohol use, BMI, education level, marital status, poverty level, history of pregnancy, race, and smoking status.P value was calculated by logistic regression analysis.Classification of depression: no (total PHQ9 score < 10), moderate depression (total PHQ9 score 10-14), severe depression (total PHQ9 score ≥ 15).BMI, body mass index; PHQ, patient health questionnaire.