Association between vitamin D and endometriosis among American women: National Health and Nutrition Examination Survey

Endometriosis is a common inflammatory condition characterized by tissue resembling the endometrium growing outside the uterus and on the pelvis and other organs. This condition affects 176 million women globally, with 5–10% of those who are fertile experiencing pelvic pain and infertility [ 1 ]. Endometriosis is 40–60% more common in women with dysmenorrhea, 21–47% more common in women with subfertility, and 71–87% more common in women with pelvic pain [ 2 ]. Women with endometriosis have direct healthcare costs more than twice as high as women without the condition [ 3 ]. Endometriosis is classified as a public health issue because of its extreme prevalence [ 4 ]. The idea of retrograde menstruation is the leading etiopathogenetic theory. Additionally, endometriosis has been related to other etiological variables such as immunological dysfunction, hereditary factors, environmental elements [ 2 ], and behavior risks like caffeine and alcohol consumption. Despite its significant detrimental impact on healthcare costs and quality of life, little is known about modifiable risk factors that can prevent endometriosis [ 5 ]. Vitamin D is a necessary mineral owing to its skeletal and non-skeletal activities, including anti-inflammatory, antiproliferative, anti-oxidative, and immunomodulatory properties [ 6 ]. Serum vitamin D levels are influenced by diet, sun exposure, and lifestyle. Owing to its therapeutic importance, the level of serum 25-hydroxyvitamin D3 (cholecalciferol, [25(OH)D]) is usually regarded as a marker of short-term vitamin D status [ 7 ]. Agic et al. were the first to show that endometriotic tissues express vitamin D receptors (VDR) and vitamin D enzymes [ 8 ]. Following the confirmation of the presence in the young cycling endometrium by Vigano et al. [ 9 ], Vienonen et al. [ 10 ] recorded VDR protein in the healthy endometrium of older women. Women with endometriosis have VDR in their endometrium [ 8 ]. Whether vitamin D is related to the existence and severity of illness remains debatable; studies have reported positive and negative correlations [ 11 ]. Low levels of vitamin D have been shown to be associated with infertility [ 12 ]. These low vitamin D levels in patients with endometriosis may suggest that proliferative and inflammatory processes can be unchecked by vitamin D deficiency [ 13 ]. Recent studies have some flaws, such as low sample numbers, a focus on 25(OH)D3 levels rather than total 25(OH)D levels, inconsistent definitions of vitamin D deficiency, and inadequate correction of several important variables (e.g., dietary factors, lifestyle factors including physical activity, and comorbidity). Additionally, it is unknown whether smoking, obesity, or other factors affect this association. This cross-sectional study aimed to investigate the association of vitamin D and endometriosis among American women aged 20–54 years, utilizing a large sample size (4,232 participants). Our findings should provide new insights into strategies for endometriosis prevention.

Our study included 3,232 patients, of whom 257 (7.95%) had endometriosis. Serum 25(OH)D levels were, on average, 21.36 ± 10.01 ng/mL; 46.44% of patients had insufficient vitamin D (< 20 ng/mL), and 53.56% had adequate vitamin D (≥ 20 ng/mL). Table 1 shows the baseline characteristics of the participants based on the serum 25(OH)D level. Higher 25(OH)D concentrations were associated with younger age, cohabitation, no smoking, higher educational attainment, higher family income, greater physical activity, and lower BMI. Data are presented as mean(SD) or n (%). The univariate analysis revealed that age, smoking status, family income, and educational level were associated with endometriosis ( Table 2 ). We developed three multivariate logistic regression models to investigate the role of serum 25(OH)D levels in endometriosis. After multivariate adjustment that considered smoking status, age, family PIR, physical activity, education level, marital status, BMI, calories consumed, and carbohydrate intake, ORs and CIs in women with adequate vitamin D compared with insufficient vitamin D was 0.73 (0.54–0.97) ( Table 3 ). OR, odds ratio; CI, confidence interval; Ref: Reference. Model 1 was adjusted for sociodemographic variables (age, education level, marital status, family PIR). Model 2 was adjusted for sociodemographic (age, education level, marital status, family PIR), smoking status, BMI. Model 3 was adjusted for sociodemographic (age, education level, marital status, family PIR), smoking status, BMI, vigorous activity, moderate activity, carbohydrate consumption, protein consumption, Calorie consumption, Vitamin C intake and Vitamin E intake. A stratified analysis was performed in several subgroups to evaluate the potential effect of alterations on the association between 25(OH)D concentration and endometriosis. In various subgroups stratified by age, smoking status, marital status, educational attainment, family income, and BMI, the benefits of serum 25(OH)D concentration on endometriosis were comparable ( Fig 1 ). Each stratification factor was altered for all variables other than the stratification component itself (smoking status, physical activity, BMI, calorie consumption, protein consumption, carbohydrate consumption, Vitamin C consumption and Vitamin E consumption). A total of 3,283 people were eligible for our study after participants with extreme energy intake, consuming 5,000 kcal per day, were considered. The relationship between serum 25(OH)D concentration and endometriosis remained stable. The ORs and CIs in women with adequate vitamin D compared with insufficient vitamin D was 0.73 (0.54–0.97) ( S1 Table ).

We found that higher serum 25(OH)D concentrations were associated with a decreased incidence of endometriosis in a representative sample of American women with endometriosis. These results lend credence to the possible advantages of maintaining sufficient vitamin D levels to prevent endometriosis.

The National Center for Health Statistics, which uses a nationally representative stratified sample based on interviews and physical examinations, and the National Health and Nutrition Examination Survey (NHANES), a population-based cross-sectional survey, were used to collect the data for this study. A single data collection was created from three 2-year NHANES cycles completed between 2001 and 2006. The reproductive health questionnaire was completed by women who participated in the examination component and were eligible for our analyses. A total of 4,232 women were recruited. Exclusion criteria included those with missing endometriosis-related information and those 54 years old since questions about these two gynecologic conditions were not asked. Our final sample comprised 3,232 women, of whom 257 had endometriosis and 2,975 did not. A total of 767 pregnant women were excluded, along with 181 with no information on their serum 25(OH)D values, 42 with calorie consumption 5000 kcal/day. All methods were performed in accordance with the relevant guidelines and regulations. The National Center for Health Statistics Ethics Review Committee authorized the NHANES, and all participants provided written informed consent before participation. Secondary analyses did not require additional Institutional Review Board approval. The DiaSorin RIA kit (Stillwater, MN, USA) measured serum 25(OH)D concentrations in the NHANES 2001–2006. Regression methods were used to correct assay drifts. This converts the RIA data of the 25(OH)D concentrations to equivalent 25(OH)D measurements in the standardized liquid chromatography-tandem mass spectrometry method, allowing researchers to use and evaluate 25(OH)D concentrations. In accordance with the Centers for Disease Control and Prevention recommendations, the analysis was carried out using the aforementioned technique. According to serum 25(OH)D concentrations and the 2011 United States Institute of Medicine guidelines [ 14 ], a vitamin D level < 20 ng/mL is defined as insufficient, and ≥ 20 ng/mL is considered adequate. One inquiry was made regarding the diagnosis of endometriosis: “Has a doctor or other health professional ever told you that you had endometriosis?” Patients who provided affirmative responses were defined as participants. According to the literature [ 15 – 17 ], potential covariates included age, marital status, education level, family income, smoking status, physical activity, body mass index (BMI), calorie intake, protein intake, carbohydrate intake, and vitamin C and E intake. Living with a partner or living alone were the two marital status categories. The categories for educational achievement were 12 years. The poverty income ratio (PIR) divides family income into three categories ranging from 1.3 to 3.5. This was used by the U.S. Government’s Agriculture Report [ 18 ] to classify family income into low, medium, and high categories. Smokers and never-smokers (those who smoked < 100 cigarettes) were the two categories used to define smoking status in previous studies. Physical activity was divided into three categories: inability to perform physical activity, moderate (defined as at least 10 min of movement within the last 30 days that resulted in light perspiration or a mild-to-moderate increase in respiration or heart rate), and vigorous (at least 10 min of activity within the last 30 days, resulting in profuse sweating or an increase). Before the mobile examination center(MEC) interview, participants underwent a dietary recall interview to acquire their 24-hour nutritional data, including total calories consumed, protein, carbohydrates, vitamin C, and vitamin E intake. This is a secondary analysis of freely available datasets. Continuous variables were characterized by the mean (standard deviation) or median (interquartile range), and proportions (%) were used to represent categorical variables. One-way analysis of variance (normal distribution), Kruskal–Wallis tests (skewed distribution), and chi-square tests were used to compare group differences (categorical variables). Odds ratios (OR) and 95% confidence intervals (CIs) for the association between vitamin D levels and endometriosis were calculated using logistic regression models. Age, education level, marital status, and family PIR were all considered while adjusting Model 1. Model 2 was modified to account for sociodemographic details and variables using univariate analysis (p values < 0.05). Model 3 was completely adjusted, considering all sociodemographic factors (age, education level, marital status, and family PIR), smoking status, BMI, vigorous activity, moderate activity, calorie consumption, protein consumption, and vitamin C and E intake. The following factors were also evaluated for their potential to alter the relationship between serum 25(OH)D concentration and endometriosis: age (40, 40–50, and > 50 years), family PIR (low, medium, and high), marital status (living with a partner vs. living alone), BMI (25, 25–30, and > 30) and education level (9, 9–12, and > 12 years). Multivariate logistic regression was used to evaluate the heterogeneity of the subgroups, and likelihood ratio testing was used to investigate any interactions between the subgroups and serum 25(OH)D levels. No a priori statistical power estimations were performed because the sample size was chosen based on the available data. R 3.3.2 ( http://www.R-project.org , The R Foundation, Shanghai, China) is a statistical software program used for all analyses (accessed on January 10, 2023). In addition, Free Statistics Software 1.5 was used [ 19 ]. A descriptive study was conducted on all individuals. Using two-tailed analysis, a p-value of < 0.05 was deemed significant.

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