{"paper_id":"ca38b5f3-c78d-4435-b9f9-a5c91503c6a3","body_text":"ABSTRACT\nBackground\nThe etiology of endometriosis is not well understood. Limited evidence suggests that dietary factors influence risk, but prospective data related to carbohydrate, fiber, and gluten consumption are scarce. Despite this, recommendations concerning fiber, gluten intake, and endometriosis are pervasive in the lay literature.\nObjectives\nWe aimed to investigate the associations of carbohydrate quality [glycemic index (GI) and glycemic load (GL)], fiber intake (total, legume, vegetable, cruciferous vegetable, fruit, cereal), and gluten intake with incident laparoscopically confirmed endometriosis.\nMethods\nThis was a prospective cohort study using data collected from 81,961 premenopausal women in the Nurses’ Health Study II (mean age = 36 y in 1991). Diet was assessed with a validated FFQ every 4 y. Cox proportional hazards models were used to calculate rate ratios (RRs) and 95% CIs.\nResults\nA total of 3810 incident cases of laparoscopically confirmed endometriosis were reported over 24 y of follow-up. Women in the highest quintile of GI had 12% (95% CI: 1.01, 1.23; Ptrend = 0.03) higher risk of endometriosis diagnosis than those in the lowest quintile. Total vegetable and cruciferous vegetable fiber intakes were also associated with higher risk (highest compared with lowest quintile RR: 1.13; 95% CI: 1.02, 1.24; Ptrend = 0.004 and RR: 1.17; 95% CI: 1.06, 1.29; Ptrend = 0.02, respectively). Higher intake of fruit fiber was associated with lower risk of endometriosis but the association was not significant after adjusting for the Alternative Healthy Eating Index. Gluten intake was also associated with lower risk (highest compared with lowest quintile RR: 0.91; 95% CI: 0.80, 1.02; Ptrend = 0.01), but these results were not consistent in direction nor statistical significance across sensitivity analyses. No association was observed for GL or total, legume, or cereal fiber intake.\nConclusions\nOur findings suggest that carbohydrate quality and specific types of fiber—total vegetable and cruciferous vegetable fiber—are associated with endometriosis diagnosis in premenopausal women. These results also indicate it is unlikely that gluten intake is a strong factor in the etiology or symptomatology of endometriosis.\nKeywords: endometriosis, diet, fiber, gluten, nutrition\nIntroduction\nEndometriosis is an estrogen-dependent, chronic, inflammatory gynecologic condition characterized by the presence of endometrial-like tissue outside of the uterus. It is estimated to affect ∼10% of reproductive-age women, and is often associated with pelvic pain symptoms that affect physical, mental, and social well-being (1). Although the etiology of endometriosis is not well understood, current evidence indicates that genetic, environmental, immunologic, and inflammatory factors all contribute to disease etiology (1–4). Given the limited treatment options, it is important to understand the role of modifiable risk factors, such as diet, in disease pathogenesis.\nIt is hypothesized that dietary factors may influence risk of endometriosis through hormonal or inflammatory pathways (5–7); however, there is limited literature investigating dietary factors and endometriosis risk, especially using robust nutritional epidemiologic methods. A 2018 literature review reported that higher intake of fruits and vegetables, fish oils, dairy products, and omega (ω)-3 fatty acids was associated with a lower risk of developing endometriosis (3). In contrast, consumption of red meat and trans fats appeared to increase risk.\nInflammation is thought to play a role in endometriosis, including involvement in fibrin deposition and adhesion formation (8–12). In addition, inflammatory factors (e.g., IL-6, IL-1β, TNF-α, C-reactive protein) are elevated in the peritoneal fluid and blood of women with endometriosis (13–17). It is also well established that dietary intake affects inflammatory processes (18–20); intake of refined carbohydrates has previously been associated with higher concentrations of inflammatory markers (21–23), whereas consumption of dietary fiber has been associated with lower concentrations (22, 24, 25). Fiber intake has also been shown to influence estrogen metabolism (26, 27) and multiple studies have found an inverse association between fiber intake and both endometrial cancer (28) and breast cancer (29). Thus, there is reason to believe that fiber and other dietary factors that affect hormones and inflammation may be associated with risk of endometriosis (30, 31). However, to date, no prospective studies have explored this association. There is also limited literature on related nutrients such as gluten in relation to endometriosis risk (32). The objective of this study was to examine the associations of dietary carbohydrate quality and quantity [fiber intake, glycemic index (GI), and glycemic load (GL)] and gluten intake with incident laparoscopically confirmed endometriosis.\nMethods\nStudy population and data collection\nThe Nurses’ Health Study II (NHSII) is an ongoing prospective cohort study in 116,429 female registered nurses aged 25–42 y at enrollment. Since 1989, participants have completed biennial mailed questionnaires about their health, medical history, and exposures to known or potential risk factors for several chronic diseases. Dietary data were collected first in 1991 and every 4 y thereafter. The response rates have been ≥90% throughout the follow-up cycles. From the 97,813 women who returned the 1991 dietary questionnaire, we excluded women who had an implausible total energy intake (<800 or ˃4200 kcal/d) or who left >70 food items blank in the 1991 FFQ (n = 2580), did not report date of birth (n = 16), were diagnosed with endometriosis before June 1991 (n = 5796), had a prior cancer diagnosis other than nonmelanoma skin cancer (n = 1193), or were lost to follow-up (n = 728). Furthermore, we restricted to women who were premenopausal and had intact uteri, because the occurrence of incident endometriosis diagnosis after hysterectomy or in postmenopausal women is rare.\nThis study was approved by the Institutional Review Boards of the Harvard TH Chan School of Public Health and Brigham and Women's Hospital. Implied consent was assumed upon completion and return of each questionnaire.\nCase ascertainment\nStarting with the questionnaire in 1993, participants were asked if they had “ever had physician-diagnosed endometriosis.” If their response was “yes” they were asked to report the diagnosis date and whether it was confirmed by laparoscopy (which is considered the gold standard for endometriosis diagnosis) (33). For each subsequent questionnaire cycle, participants were asked about endometriosis diagnosis in the preceding 2 y. Among women with self-reported laparoscopic confirmation of their endometriosis diagnosis, medical record confirmation was extremely high in 2 validation studies (100% first study, 95% second study) (34).\nThere is a complex association between endometriosis and infertility, such that many women with infertility may have only been diagnosed with endometriosis during an infertility evaluation. In contrast, women with endometriosis without infertility are more likely to have pain as an indication for laparoscopic evaluation. This is evidenced by the fact that the baseline prevalence of infertility (defined as attempting to conceive for >12 mo without success) in this cohort was higher among those with laparoscopically confirmed endometriosis (20%) than among those reporting endometriosis without laparoscopic confirmation (4%). Because women with endometriosis with infertility may have a higher prevalence of asymptomatic disease secondary to other primary causes of infertility, the risk factors for endometriosis with infertility may differ from those for endometriosis without infertility. Therefore, we conducted analyses stratified by fertility status.\nDietary assessment\nDiet was assessed via the semiquantitative FFQ in 1991 and every 4 y thereafter. Women were asked to report their usual intake during the past year on >130 food items. Each question had 9 possible responses, ranging from “never or less than once per month” to “six or more times per day.” Fiber intake was calculated based on the method of the AOAC. Gluten intake was estimated based on the assumption that gluten comprised 75% of the protein content of gluten-containing ingredients (wheat, wheat flour, wheat bran, wheat germ, wheat berries, wheat cream, wheat gluten, rye and rye flour, barley and barley malt flour, cooked cereal, bulgur, couscous, farina, beer, and pasta) (35–39). The validity of the FFQ, fiber intake, and related nutrients has been extensively assessed. In a prior study, the correlation between intake measured by the FFQ and weighted records was 0.66 for total dietary fiber and 0.69 for carbohydrates (40), and ranged from 0.35 (pasta) to 0.79 (cold cereal) for the foods that contributed the most to gluten intake (41).\nThe GI values for foods were obtained from publicly available databases and publications (42–45). The GI value is a numeric score for a particular food item based on how quickly it makes blood sugar rise (46). Each participant's average dietary GI was calculated by summing the products of carbohydrate content per serving for each food item times the average number of servings of that food per day, times its GI value, and divided by the total daily carbohydrate content. Average GI was calculated by dividing the average dietary GL by the total amount of carbohydrate intake (47, 48). The GL of a food captures both how quickly it makes blood sugar rise and how much glucose it delivers per serving (46). The GL values of foods were calculated by multiplying their GI by the amount of carbohydrate in grams. An individual's total dietary GL was calculated by summing the contributions of all foods consumed (42, 44).\nStatistical analyses\nParticipants contributed person-time to the analyses from return of the baseline FFQ (1991) until self-report of laparoscopically confirmed endometriosis, death, diagnosis of cancer (excluding nonmelanoma skin cancer), hysterectomy, menopause (natural or surgical), loss to follow-up, or 1 June, 2015, whichever occurred first.\nWe used Cox proportional hazards with age and questionnaire calendar time-period as the time scale to estimate the incidence rate ratio (RR) of laparoscopically confirmed endometriosis in relation to the lowest quintile of cumulative average intake of different types of fiber (total, legume, vegetable, fruit, cruciferous vegetable, and cereal), carbohydrates, gluten, GI, and GL. Intakes of all nutrients were adjusted for total energy intake using the residual method (49). In our primary analyses, we used cumulative average consumption, in which endometriosis incidence between each 2-y questionnaire cycle is related to the cumulative average of dietary intake calculated from all the preceding dietary measures. For example, to calculate cumulative average intake, the 1991 intake was assigned to follow-up through 1995; the average of 1991 and 1995 intakes was assigned to the 1995–1999 follow-up period; the average of 1991, 1995, and 1999 intakes was assigned to the 1999–2003 follow-up period; and so forth. The cumulative average method captures long-term dietary intake and reduces measurement error due to within-person variation over time (50). Tests for linear trend were conducted by using the median values of intake in each category as a continuous variable.\nTotal energy intake (continuous) was included in both age-adjusted and multivariable models (49). Multivariable models were further adjusted for the following potential confounders that were chosen a priori owing to their association with endometriosis: age at menarche (<10, 10, 11, 12, 13, 14, 15, 16, >16 y), parity (nulliparous, 1, 2, 3, 4 pregnancies lasting >6 mo), length of menstrual cycle (<26, 26–31, 32–50, ≥51 d, and irregular), and BMI (<19, 19–20.4, 20.5–21.9, 22–24.9, 25–29.9, and ≥30 kg/m2). In addition we conducted analyses stratified by fertility status. We examined effect modification by fertility status using likelihood ratio tests comparing models with both the main effects and cross-product term to those with the main effects only.\nTo assess the robustness of the findings we adjusted gluten intake for refined and whole grain intake, fruit fiber intake for total fruit intake, and cruciferous vegetable fiber intake for total cruciferous vegetable intake. These analyses allowed for exploration of whether the effect of the dietary exposure of interest (e.g., fruit fiber intake) could be explained by another dietary component that was concentrated in the food sources (e.g., fruit) from which the dietary exposure variable was derived. In addition, we adjusted for the Alternative Healthy Eating Index (AHEI) as a total measure of diet quality, as well as individual components of the AHEI (red/processed meat, ω-3 fatty acids, PUFAs, trans fats, sugar-sweetened beverages, sodium). We also conducted sensitivity analyses to explore the temporal relation between gluten intake and risk of endometriosis given the potential for modifications in gluten intake due to endometriosis symptoms before clinical endometriosis diagnosis. In addition to assessing cumulative average intake, we also assessed baseline intake and varying lag-time intake. For baseline intake we examined only gluten intake in 1991 in relation to cases reported throughout the follow-up period (1991–2015). We examined lag times of 2–4 y (simple update), 4–6 y, and 6–8 y. In the simple update analysis, 1991 intake was assigned to the 1991–1995 follow-up time period, 1995 intake was assigned to the 1995–1999 follow-up time period, 1999 intake was assigned to the 1999–2003 follow-up period, and so forth. For a lag time of 4–6 y before diagnosis we used gluten intake reported on the 1991 questionnaire for diagnosis from 1995 to 1999, intake from 1995 for diagnosis from 1999 to 2003, and so forth. For a lag time of 6–8 y before diagnosis we used gluten intake reported in 1991 for a diagnosis from 1997 to 2001, intake from 1995 for diagnosis from 2001 to 2005, and so forth. In addition, we conducted analyses to look separately at women diagnosed before and after 2001 to account for societal changes with respect to gluten intake (e.g., popularization of gluten-free and paleo diets) (32, 51). All P values were 2-sided. Analyses were performed in SAS version 9.4 (SAS Institute Inc.).\nResults\nDuring 22 y of follow-up contributed by 81,961 women, 3810 cases of laparoscopically confirmed endometriosis were diagnosed (Supplemental Figure 1). At baseline in 1991, age and infertility status were similar across quintiles of total fiber intake (Table 1). However, women in the highest quintile of total fiber intake were less likely to be overweight or obese, less likely to be current or past smokers, and more likely to be nulliparous.\nTABLE 1.\n| Total fiber intake, g/d | |||||\n|---|---|---|---|---|---|\n| 2.9–14.5 (n = 19,582) | 14.6–16.9 (n = 16,977) | 17.0–19.1 (n = 14,996) | 19.2–22.1 (n = 14,565) | 22.2–144 (n = 15,650) | |\n| Age, y | 35.7 ± 4.7 | 36.1 ± 4.6 | 36.4 ± 4.6 | 36.5 ± 4.5 | 36.9 ± 4.5 |\n| White | 94.6 | 96.3 | 96.1 | 96.0 | 95.1 |\n| BMI, kg/m2 | |||||\n| <25 | 64.1 | 64.6 | 65.5 | 67.1 | 70.9 |\n| 25–29.9 | 19.8 | 20.5 | 21.6 | 20.8 | 19.1 |\n| ≥30 | 16.1 | 14.9 | 12.9 | 12.1 | 9.9 |\n| Smoking status | |||||\n| Never | 62.6 | 66.4 | 67.4 | 67.6 | 67.7 |\n| Past | 19.3 | 21.5 | 22.1 | 23.3 | 24.8 |\n| Current | 18.1 | 12.1 | 10.5 | 9.1 | 7.5 |\n| Age at menarche, y | |||||\n| <12 | 22.1 | 23.3 | 23.8 | 24.9 | 25.9 |\n| 12 | 29.9 | 30.0 | 30.9 | 30.8 | 30.2 |\n| 13 | 28.4 | 28.1 | 27.7 | 27.3 | 26.8 |\n| >13 | 19.5 | 18.5 | 17.6 | 16.9 | 17.1 |\n| Menstrual cycle length at age 18 y, d | |||||\n| <26 | 11.2 | 10.3 | 10.5 | 10.8 | 11.4 |\n| 26–31 | 66.2 | 66.5 | 65.6 | 66.4 | 65.5 |\n| 32–50 | 17.0 | 18.0 | 18.3 | 17.6 | 17.6 |\n| ≥51 or irregular | 5.5 | 5.2 | 5.5 | 5.2 | 5.5 |\n| Ever use of oral contraceptives | 84.8 | 84.7 | 83.9 | 83.7 | 82.0 |\n| Nulliparous | 26.7 | 23.6 | 23.8 | 25.6 | 32.2 |\n| Reported infertility | 5.4 | 5.3 | 5.3 | 5.4 | 5.8 |\n| Total energy intake, kcal/d | 1773 ± 568 | 1805 ± 548 | 1818 ± 540 | 1800 ± 533 | 1778 ± 544 |\n| Alternative Healthy Eating Index score | 39.6 ± 8.4 | 44.3 ± 8.1 | 47.7 ± 8.2 | 51.5 ± 8.2 | 58.6 ± 9.3 |\n| Servings of red meat per day | 1.2 ± 0.7 | 1.1 ± 0.6 | 1.0 ± 0.6 | 0.9 ± 0.6 | 0.6 ± 0.5 |\n| Servings of fruit per day | 0.6 ± 0.5 | 0.9 ± 0.6 | 1.2 ± 0.7 | 1.5 ± 0.9 | 2.0 ± 1.3 |\n| Servings of vegetables per day | 1.7 ± 0.9 | 2.4 ± 1.1 | 2.8 ± 1.2 | 3.4 ± 1.5 | 4.5 ± 2.4 |\nValues are mean ± SD or percentages. Values except for age are standardized to the age distribution of the study population.\nGI was associated with a higher risk of laparoscopically confirmed endometriosis (Table 2). Women in the highest quintile of GI had a 12% (95% CI: 1.01, 1.23; Ptrend = 0.03) higher risk of endometriosis diagnosis than those in the lowest quintile. Total vegetable fiber and cruciferous vegetable fiber intakes were also associated with higher risk (highest compared with lowest quintile RR: 1.13; 95% CI: 1.02, 1.24; Ptrend = 0.004 and RR: 1.17; 95% CI: 1.06, 1.29; Ptrend = 0.02, respectively). When adjusted for cruciferous vegetable intake, the cruciferous vegetable fiber effect estimate was more strongly associated with endometriosis risk (highest compared with lowest quintile RR: 1.28; 95% CI: 1.13, 1.44; Ptrend = 0.003), with a similar pattern observed when total vegetable fiber intake was adjusted for total vegetable intake (highest compared with lowest quintile RR: 1.33; 95% CI: 1.15, 1.54; Ptrend < 0.001).\nTABLE 2.\n| Cases | Person-years | Age-adjusted RR (95% CI) | Multivariable-adjusted2 RR (95% CI) | Reported infertility | Did not report infertility | P interaction 3 | |||\n|---|---|---|---|---|---|---|---|---|---|\n| Cases | RR2 (95% CI) | Cases | RR2 (95% CI) | ||||||\n| Total fiber intake, g/d, range (median) | |||||||||\n| 2.9–14.5 (13.0) | 823 | 205,328 | 1.00 (reference) | 1.00 (reference) | 137 | 1.00 (reference) | 673 | 1.00 (reference) | 0.57 |\n| 14.6–16.9 (15.8) | 780 | 208,014 | 1.00 (0.91, 1.10) | 1.03 (0.93, 1.13) | 120 | 1.09 (0.84, 1.40) | 648 | 1.01 (0.90, 1.13) | |\n| 17.0–19.1 (18.0) | 753 | 206,662 | 1.03 (0.93, 1.13) | 1.04 (0.94, 1.15) | 120 | 1.16 (0.90, 1.51) | 618 | 1.00 (0.90, 1.12) | |\n| 19.2–22.1 (20.5) | 689 | 206,046 | 0.96 (0.87, 1.06) | 0.95 (0.86, 1.06) | 121 | 1.22 (0.94, 1.59) | 557 | 0.91 (0.81, 1.02) | |\n| 22.2–144.1 (24.9) | 765 | 206,875 | 1.07 (0.97, 1.18) | 1.00 (0.91, 1.11) | 135 | 1.23 (0.96, 1.59) | 617 | 0.97 (0.87, 1.08) | |\n| Ptrend4 | 0.31 | 0.64 | 0.08 | 0.24 | |||||\n| Legume fiber intake, g/d, range (median) | |||||||||\n| 0–0.37 (0.13) | 874 | 205,542 | 1.00 (reference) | 1.00 (reference) | 155 | 1.00 (reference) | 700 | 1.00 (reference) | 0.53 |\n| 0.38–0.70 (0.56) | 791 | 215,115 | 0.95 (0.86, 1.05) | 0.98 (0.87, 1.08) | 108 | 0.96 (0.74, 1.25) | 574 | 0.96 (0.86, 1.07) | |\n| 0.71–1.03 (0.88) | 690 | 197,445 | 1.00 (0.90, 1.10) | 1.02 (0.92, 1.13) | 126 | 1.02 (0.79, 1.32) | 654 | 1.01 (0.90, 1.12) | |\n| 1.04–1.60 (1.26) | 715 | 206,401 | 1.06 (0.96, 1.17) | 1.07 (0.96, 1.18) | 127 | 1.29 (1.00, 1.66) | 581 | 1.01 (0.90, 1.13) | |\n| 1.61–29.3 (2.22) | 740 | 208,423 | 1.11 (1.00, 1.23) | 1.04 (0.94, 1.15) | 117 | 1.11 (0.86, 1.44) | 604 | 1.03 (0.92, 1.15) | |\n| Ptrend4 | 0.007 | 0.20 | 0.18 | 0.45 | |||||\n| Vegetable fiber intake, g/d, range (median) | |||||||||\n| 0–4.2 (3.4) | 777 | 206,868 | 1.00 (reference) | 1.00 (reference) | 118 | 1.00 (reference) | 646 | 1.00 (reference) | 0.36 |\n| 4.3–5.4 (4.8) | 705 | 207,017 | 0.97 (0.88, 1.07) | 1.00 (0.90, 1.11) | 105 | 1.11 (0.84, 1.46) | 591 | 0.98 (0.87, 1.10) | |\n| 5.5–6.6 (6.0) | 707 | 206,844 | 0.99 (0.90, 1.10) | 1.02 (0.92, 1.13) | 115 | 1.14 (0.87, 1.50) | 576 | 0.96 (0.86, 1.08) | |\n| 6.7–8.4 (7.4) | 764 | 206,327 | 1.08 (0.97, 1.19) | 1.09 (0.99, 1.21) | 122 | 1.25 (0.96, 1.64) | 633 | 1.05 (0.94, 1.18) | |\n| 8.5–48.9 (10.1) | 857 | 205,870 | 1.17 (1.06, 1.29) | 1.13 (1.02, 1.24) | 173 | 1.39 (1.08, 1.78) | 667 | 1.04 (0.93, 1.16) | |\n| Ptrend4 | <0.0001 | 0.004 | 0.006 | 0.22 | |||||\n| Cereal fiber intake, g/d, range (median) | |||||||||\n| 0–4.0 (3.4) | 884 | 205,500 | 1.00 (reference) | 1.00 (reference) | 154 | 1.00 (reference) | 712 | 1.00 (reference) | 0.32 |\n| 4.1–5.0 (4.6) | 814 | 206,763 | 1.03 (0.94, 1.14) | 1.05 (0.96, 1.16) | 137 | 1.07 (0.84, 1.37) | 665 | 1.03 (0.93, 1.15) | |\n| 5.1–6.1 (5.6) | 733 | 206,672 | 0.96 (0.87, 1.06) | 0.98 (0.89, 1.08) | 122 | 1.15 (0.89, 1.48) | 603 | 0.96 (0.86, 1.07) | |\n| 6.2–7.5 (6.8) | 679 | 207,359 | 0.95 (0.85, 1.05) | 0.95 (0.86, 1.05) | 121 | 1.26 (0.97, 1.63) | 543 | 0.90 (0.80, 1.00) | |\n| 7.6–132.6 (8.9) | 700 | 206,631 | 0.95 (0.86, 1.05) | 0.92 (0.83, 1.02) | 99 | 0.92 (0.70, 1.20) | 590 | 0.94 (0.84, 1.05) | |\n| Ptrend4 | 0.13 | 0.02 | 0.85 | 0.06 | |||||\n| Fruit fiber intake, g/d, range (median) | |||||||||\n| 0–1.7 (1.2) | 873 | 206,690 | 1.00 (reference) | 1.00 (reference) | 155 | 1.00 (reference) | 705 | 1.00 (reference) | 0.64 |\n| 1.7–2.6 (2.2) | 786 | 204,415 | 1.00 (0.91, 1.11) | 1.03 (0.94, 1.14) | 133 | 1.14 (0.89, 1.46) | 636 | 1.01 (0.91, 1.12) | |\n| 2.7–3.5 (3.0) | 709 | 208,824 | 0.90 (0.81, 0.99) | 0.92 (0.83, 1.01) | 108 | 0.88 (0.68, 1.15) | 589 | 0.92 (0.82, 1.03) | |\n| 3.6–4.8 (4.1) | 714 | 206,709 | 0.93 (0.84, 1.02) | 0.93 (0.85, 1.03) | 123 | 1.09 (0.85, 1.41) | 583 | 0.92 (0.82, 1.02) | |\n| 4.9–32.2 (6.0) | 728 | 206,287 | 0.93 (0.84, 1.02) | 0.90 (0.81, 0.99) | 114 | 0.95 (0.73, 1.23) | 600 | 0.91 (0.81, 1.01) | |\n| Ptrend4 | 0.07 | 0.008 | 0.62 | 0.03 | |||||\n| Cruciferous vegetable fiber intake, g/d, range (median) | |||||||||\n| 0–0.39 (0.25) | 711 | 297,906 | 1.00 (reference) | 1.00 (reference) | 118 | 1.00 (reference) | 574 | 1.00 (reference) | 0.64 |\n| 0.40–0.60 (0.50) | 845 | 221,777 | 1.09 (0.99, 1.21) | 1.11 (1.00, 1.23) | 133 | 0.98 (0.75, 1.27) | 705 | 1.14 (1.02, 1.27) | |\n| 0.61–0.88 (0.73) | 677 | 191,179 | 1.17 (1.05, 1.30) | 1.17 (1.05, 1.30) | 106 | 1.21 (0.91, 1.59) | 562 | 1.15 (1.03, 1.30) | |\n| 0.89–1.30 (1.1) | 765 | 210,758 | 1.12 (1.01, 1.24) | 1.12 (1.01, 1.24) | 124 | 1.13 (0.86, 1.48) | 623 | 1.10 (0.98, 1.23) | |\n| 1.31–23.9 (1.7) | 812 | 201,305 | 1.21 (1.10, 1.34) | 1.17 (1.06, 1.29) | 152 | 1.27 (0.98, 1.64) | 649 | 1.13 (1.01, 1.27) | |\n| Ptrend4 | 0.0007 | 0.02 | 0.03 | 0.21 | |||||\n| Glycemic load, range (median) | |||||||||\n| 1.2–107 (99) | 774 | 205,914 | 1.00 (reference) | 1.00 (reference) | 118 | 1.00 (reference) | 638 | 1.00 (reference) | 0.58 |\n| 108–117 (113) | 764 | 206,416 | 1.03 (0.93, 1.14) | 1.07 (0.97, 1.18) | 134 | 1.22 (0.94, 1.59) | 628 | 1.05 (0.94, 1.17) | |\n| 118–126 (122) | 725 | 206,847 | 0.99 (0.90, 1.10) | 1.04 (0.94, 1.15) | 127 | 1.22 (0.93, 1.60) | 582 | 1.00 (0.89, 1.12) | |\n| 127–137 (131) | 736 | 207,118 | 1.01 (0.91, 1.11) | 1.04 (0.94, 1.16) | 120 | 1.10 (0.84, 1.45) | 605 | 1.04 (0.93, 1.16) | |\n| 138–278 (147) | 811 | 206,629 | 1.05 (0.95, 1.16) | 1.04 (0.94, 1.15) | 134 | 1.00 (0.76, 1.31) | 660 | 1.07 (0.96, 1.19) | |\n| Ptrend4 | 0.47 | 0.64 | 0.62 | 0.43 | |||||\n| Glycemic index, range (median) | |||||||||\n| 4.6–51.3 (50.0) | 733 | 205,929 | 1.00 (reference) | 1.00 (reference) | 127 | 1.00 (reference) | 592 | 1.00 (reference) | 0.32 |\n| 51.4–53.0 (52.3) | 717 | 206,933 | 1.00 (0.90, 1.10) | 1.05 (0.95, 1.16) | 113 | 0.97 (0.74, 1.26) | 594 | 1.06 (0.95, 1.19) | |\n| 53.1–54.4 (53.7) | 749 | 207,079 | 1.02 (0.92, 1.13) | 1.10 (1.00, 1.22) | 110 | 0.94 (0.71, 1.23) | 627 | 1.12 (1.00, 1.25) | |\n| 54.5–56.0 (55.2) | 760 | 206,952 | 0.99 (0.89, 1.10) | 1.08 (0.97, 1.20) | 145 | 1.09 (0.85, 1.41) | 614 | 1.07 (0.96, 1.20) | |\n| 56.1–72.1 (57.3) | 851 | 206,032 | 1.02 (0.92, 1.13) | 1.12 (1.01, 1.23) | 138 | 0.90 (0.70, 1.17) | 686 | 1.15 (1.03, 1.28) | |\n| Ptrend4 | 0.77 | 0.03 | 0.65 | 0.04 | |||||\n| Carbohydrate intake, g/d, range (median) | |||||||||\n| 24–203 (190) | 768 | 205,810 | 1.00 (reference) | 1.00 (reference) | 119 | 1.00 (reference) | 637 | 1.00 (reference) | 0.66 |\n| 204–220 (213) | 782 | 206,318 | 1.07 (0.97, 1.18) | 1.11 (1.00, 1.22) | 134 | 1.21 (0.93, 1.58) | 637 | 1.08 (0.96, 1.20) | |\n| 221–234 (228) | 719 | 207,081 | 1.01 (0.92, 1.12) | 1.05 (0.94, 1.16) | 117 | 1.20 (0.91, 1.58) | 589 | 1.02 (0.91, 1.14) | |\n| 235–251 (243) | 764 | 207,596 | 1.07 (0.97, 1.18) | 1.09 (0.98, 1.20) | 136 | 1.24 (0.95, 1.62) | 612 | 1.05 (0.94, 1.17) | |\n| 252–425 (267) | 777 | 206,121 | 1.07 (0.96, 1.18) | 1.02 (0.92, 1.13) | 127 | 1.02 (0.78, 1.33) | 638 | 1.04 (0.93, 1.16) | |\n| Ptrend4 | 0.24 | 0.86 | 0.93 | 0.64 | |||||\n| Gluten intake, g/d, range (median) | |||||||||\n| 0–4.2 (3.4) | 862 | 205,524 | 1.00 (reference) | 1.00 (reference) | 154 | 1.00 (reference) | 691 | 1.00 (reference) | 0.80 |\n| 4.3–5.5 (4.9) | 865 | 206,648 | 1.05 (0.96, 1.16) | 1.11 (1.00, 1.22) | 158 | 1.23 (0.96, 1.56) | 688 | 1.06 (0.95, 1.18) | |\n| 5.6–6.8 (6.2) | 697 | 206,856 | 0.88 (0.79, 0.97) | 0.93 (0.84, 1.04) | 112 | 1.00 (0.76, 1.32) | 577 | 0.92 (0.82, 1.03) | |\n| 6.9–8.4 (7.6) | 696 | 206,941 | 0.87 (0.78, 0.97) | 0.93 (0.84, 1.04) | 109 | 1.02 (0.77, 1.36) | 573 | 0.91 (0.80, 1.02) | |\n| 8.5–33.4 (9.9) | 690 | 206,956 | 0.83 (0.74, 0.94) | 0.91 (0.80, 1.02) | 100 | 1.00 (0.73, 1.36) | 584 | 0.90 (0.79, 1.03) | |\n| Ptrend4 | <0.0001 | 0.01 | 0.61 | 0.02 |\nRR, rate ratio.\nStratified by age in months at start of follow-up and calendar year of current questionnaire cycle and adjusted for age at menarche (<10, 10, 11, 12, 13, 14, 15, 16, >16 y), length of menstrual cycle between ages 18 and 22 y (<26, 26–31, 32–50, ≥51 d), parity (nulliparous, 1, 2, 3, ≥4 pregnancies lasting >6 mo), BMI (<19, 19–20.4, 20.5–21.9, 22–24.9, 25–29.9, ≥30 kg/m2), and total caloric intake (continuous).\nLikelihood ratio test P values, tests for heterogeneity between dietary exposures and fertility status.\nDetermined using category medians.\nHigher intake of fruit fiber was associated with a lower risk of endometriosis (highest compared with lowest quintile RR: 0.90; 95% CI: 0.81, 0.99; Ptrend = 0.008), although adjusting for total fruit intake slightly attenuated this association (highest compared with lowest quintile RR: 0.94; 95% CI: 0.80, 1.10; Ptrend = 0.26). No statistically or clinically significant association was observed for GL, total fiber, legume fiber, or cereal fiber (Table 2). Mutual adjustment for fruit fiber and vegetable fiber did not meaningfully change the results. After adjustment for AHEI, positive associations between intake of vegetable fiber and cruciferous vegetable fiber and endometriosis risk were strengthened, whereas the inverse association with fruit fiber intake was less pronounced and no longer significant (Supplemental Table 1).\nGluten intake was associated with a lower risk of endometriosis diagnosis (highest compared with lowest quintile RR: 0.91; 95% CI: 0.80, 1.02; Ptrend = 0.01) (Table 2). Adjusting gluten intake for AHEI score or whole grain intake did not meaningfully change the results (highest compared with lowest quintile: AHEI-adjusted RR: 0.91; 95% CI: 0.81, 1.03; Ptrend = 0.02, and whole grain–adjusted RR: 0.93; 95% CI: 0.81, 1.05; Ptrend = 0.03), with similar results observed when adjusting for AHEI components rather than the AHEI score itself (red/processed meat, ω-3 fatty acids, PUFAs, trans fats, sugar-sweetened beverages, sodium; individual results not shown). Adjustment for refined grain intake attenuated the gluten intake association (highest compared with lowest quintile RR: 0.97; 95% CI: 0.84, 1.11; Ptrend = 0.20). When examining varying temporal relations, the inverse association between gluten intake and endometriosis risk was strongest in the simple update (highest compared with lowest quintile RR: 0.82; 95% CI: 0.74, 0.91; Ptrend < 0.0001), whereas no association was observed in the 4- to 6-y lag, 6- to 8-y lag, or baseline intake analyses (Table 3). When stratified by time period, the inverse association was limited to women diagnosed with endometriosis in 2001 and earlier (cases = 3339, highest compared with lowest quintile RR: 0.91; 95% CI: 0.80, 1.03; Ptrend = 0.02), and no association was observed among those diagnosed after 2001 (cases = 465, RR: 0.97; 95% CI: 0.68, 1.37; Ptrend = 0.88) (Table 3).\nTABLE 3.\n| Baseline | Cumulative average | Simple update | 4- to 6-y lag | 6- to 8-y lag | Pre-2001 | Post-2001 | ||||||||\n|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|\n| Gluten, g/d, range (median) | Cases | Multivariable-adjusted2 RR (95% CI) | Cases | Multivariable-adjusted2 RR (95% CI) | Cases | Multivariable-adjusted2 RR (95% CI) | Cases | Multivariable-adjusted2 RR (95% CI) | Cases | Multivariable-adjusted2 RR (95% CI) | Cases | Multivariable-adjusted2 RR (95% CI) | Cases | Multivariable-adjusted2 RR (95% CI) |\n| Q1: 0–4.2 (3.4) | 789 | 1.00 (reference) | 862 | 1.00 (reference) | 849 | 1.00 (reference) | 462 | 1.00 (reference) | 347 | 1.00 (reference) | 696 | 1.00 (reference) | 88 | 1.00 (reference) |\n| Q2: 4.3–5.5 (4.9) | 826 | 1.07 (0.97, 1.19) | 865 | 1.11 (1.00, 1.22) | 835 | 0.99 (0.90, 1.09) | 438 | 1.02 (0.89, 1.16) | 318 | 1.00 (0.85, 1.16) | 724 | 1.08 (0.97, 1.20) | 98 | 1.02 (0.76, 1.36) |\n| Q3: 5.6–6.8 (6.2) | 734 | 0.97 (0.87, 1.08) | 697 | 0.93 (0.84, 1.04) | 727 | 0.89 (0.81, 0.99) | 412 | 0.98 (0.86, 1.13) | 301 | 0.97 (0.83, 1.14) | 649 | 0.97 (0.87, 1.09) | 76 | 0.80 (0.58, 1.10) |\n| Q4: 6.9–8.4 (7.6) | 733 | 0.96 (0.85, 1.07) | 696 | 0.93 (0.84, 1.04) | 741 | 0.92 (0.83, 1.02) | 402 | 0.97 (0.84, 1.11) | 280 | 0.91 (0.77, 1.08) | 645 | 0.92 (0.82, 1.03) | 97 | 0.96 (0.70 1.33) |\n| Q5: 8.5–33.4 (9.9) | 728 | 0.94 (0.83, 1.07) | 690 | 0.91 (0.80, 1.02) | 658 | 0.82 (0.74, 0.91) | 394 | 0.94 (0.81, 1.09) | 316 | 1.01 (0.86, 1.20) | 625 | 0.91 (0.80, 1.03) | 106 | 0.97 (0.68, 1.37) |\n| P trend 3 | 0.10 | 0.010 | <0.0001 | 0.30 | 0.90 | 0.02 | 0.88 |\nQ, quintile; RR, rate ratio.\nStratified by age in months at start of follow-up and calendar year of current questionnaire cycle and adjusted for age at menarche (<10, 10, 11, 12, 13, 14, 15, 16, >16 y), length of menstrual cycle between ages 18 and 22 y (<26, 26–31, 32–50, ≥51 d), parity (nulliparous, 1, 2, 3, ≥4 pregnancies lasting >6 mo), BMI (<19, 19–20.4, 20.5–21.9, 22–24.9, 25–29.9, ≥30 kg/m2), and total caloric intake (continuous).\nDetermined using category medians.\nWhen we stratified our analysis by history of infertility, the associations with GI and gluten were only apparent among women who had never reported infertility, and there was no evidence of association among those who had ever reported infertility. However, the interactions were not statistically significant (Table 2) (all P values, test for heterogeneity ≥ 0.32).\nDiscussion\nIn this cohort of premenopausal women, we observed a greater risk of laparoscopically confirmed endometriosis diagnosis for women with diets that included intake of foods with higher GI and higher intake of both total vegetable fiber and cruciferous vegetable fiber. However, we observed that women with higher fruit fiber and gluten consumption had a lower risk of laparoscopically confirmed endometriosis diagnosis, but these results did not remain significant in sensitivity analyses. No significant association was observed with total fiber, legume fiber, cereal fiber, carbohydrates, or GL.\nOnly 1 previously published study has evaluated the association between fiber intake and risk of endometriosis. A hospital-based case-control study in Iran compared recent typical dietary intake between women with laparoscopically confirmed endometriosis (cases) and women who underwent laparoscopy for endometriosis but had no visual evidence of lesions (controls) (30). Women reported their usual food intake during the previous year using a 147-item FFQ. Higher intakes of soluble fiber (OR: 0.33 comparing 5th with 1st quintile; 95% CI: 0.11, 0.99; Ptrend = 0.04) and insoluble fiber (OR: 0.76 comparing 5th with 1st quintile; 95% CI: 0.59, 0.99; Ptrend = 0.04) were associated with lower odds of endometriosis diagnosis. There was no significant association with crude fiber intake or carbohydrates. However, a major limitation of this study is the retrospective collection of dietary data for only 1 y preceding endometriosis diagnosis. This is problematic because women may have altered their diets owing to the symptoms that indicated the need for surgical evaluation, and thus this window of exposure might be reflective of dietary modifications. In addition, this study did not adjust for factors known to be associated with risk of endometriosis such as parity and age at menarche (3, 52).\nIn a previous study within the NHSII cohort, we observed that cruciferous vegetables, particularly cauliflower, cabbage, and Brussel sprouts, were associated with increased risk of endometriosis diagnosis (6). Although cruciferous vegetables are a good source of dietary fiber, some are high in fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs), which can be hard to digest, and which have been reported to exacerbate irritable bowel syndrome (IBS) symptoms (53), including among women with coexisting IBS and endometriosis (54). Gastrointestinal symptoms are common among women with endometriosis, and many women are diagnosed with IBS before a diagnosis of endometriosis is made (55, 56). Presenting with pelvic pain, which can be caused by gastrointestinal symptoms, is often the first step toward obtaining a surgical confirmation of endometriosis (57, 58). Thus, the association we observed between cruciferous vegetable fiber and laparoscopically confirmed endometriosis could be evidence of diagnostic bias, i.e., increased abdominal pain in women consuming higher amounts of cruciferous vegetables led to medical examination that resulted in an endometriosis diagnosis that would not have occurred in the absence of the cruciferous vegetable–related abdominal pain. However, given that the positive association between cruciferous fiber intake and endometriosis was observed in both women who did and women who did not report infertility, it does not appear that the fiber components of cruciferous vegetables explain our previous results.\nWe observed an inverse association between gluten and endometriosis, but it was not statistically significant in baseline or longer time-lagged analyses, nor among women who did not report infertility. The strongest inverse association with gluten intake was observed for consumption during the 2–4 y before endometriosis diagnosis. Given the lengthy delay between clinical symptoms and endometriosis diagnosis, this may indicate that gluten intake affects symptoms that lead to diagnosis more than disease initiation. This finding could also reflect dietary behavior change in response to symptoms. Despite a lack of supporting evidence, there has been a marked increase in the number of individuals following a gluten-free diet in the United States over the past 3 decades due to perceptions that gluten has adverse health effects (32, 39, 59). Thus, it is plausible that women experiencing abdominal pain and other gastrointestinal manifestations of endometriosis modified their diets to reduce or eliminate gluten in an attempt to manage symptoms, before diagnosis. Although an explanation for the inverse association is not clear, these results combined with the sensitivity analyses, which demonstrated no association between gluten intake and endometriosis risk, provide some evidence that eating gluten-containing foods does not increase risk of endometriosis diagnosis.\nWe found that the association between endometriosis and fruit fiber intake was not statistically significant when adjusted for total fruit intake. In conjunction with our previous report of an inverse association between fruit intake and risk of endometriosis in this same cohort (6), this suggests that there may be nutrients in fruit other than fiber that influence endometriosis risk. This is supported by prior observations that intakes of thiamin, vitamin C, folate, and vitamin E from food sources (but not supplements) were associated with a decreased risk of endometriosis diagnosis (60). Further research is needed to understand the underlying mechanisms of these associations.\nThe primary limitation of this study is the potential for error in self-report of both exposure and outcome. However, the FFQ has been extensively validated for a variety of foods and nutrients (40, 41, 61). We also utilized dietary information collected across multiple time points and calculated cumulative average intake, which reduces measurement error due to within-person variation over time (50). In addition, given that our study was prospective, any misclassification of dietary intake due to error in self-report would be nondifferential with respect to future endometriosis diagnosis and thus attenuate any associations toward the null, with the presented effect estimates being conservative under this type of bias. We reduced the potential for outcome misclassification by restricting our case definition to laparoscopically diagnosed endometriosis, which has a high level of validity in this study population (>95%) (34). In addition, although there were likely some undiagnosed endometriosis cases in the non-endometriosis comparison group, among asymptomatic women the prevalence of endometriosis is estimated to be <2% (62), and thus the influence of any undiagnosed cases on our results was likely minimal.\nIn conclusion, our findings suggest that modifiable dietary factors, such as carbohydrate quality measured with GI, and specific types of fiber intake, and gluten are associated with endometriosis diagnosis and some of these associations may vary by fertility status. In conjunction with recent research into FODMAPs, the popularization of gluten-free diets, and the lengthy prodromal period of endometriosis, these results underscore the role of gastrointestinal symptoms in the diagnosis of endometriosis. To our knowledge, this is the first prospective longitudinal study to investigate the associations of different types of fiber and gluten with endometriosis. Future studies that can account for abdominal pain and other gastrointestinal manifestations could provide important insight into these associations.\nSupplementary Material\nAcknowledgments\nThe authors’ responsibilities were as follows—SAM, HRH, and JEC: designed the research; HRH and MCA: performed the statistical analyses; NRMS, HRH, SAM, and JEC: interpreted the data; NRMS and HRH: wrote the manuscript; SAM, MCA, KLT, LVF, SAM, and JEC: edited manuscript drafts; and all authors: read and approved the final manuscript.\nNotes\nSupported by Eunice Kennedy Shriver National Institute of Child Health and Human Development research grants HD48544, HD52473, and HD57210 (to NRMS) and National Institute of Diabetes and Digestive and Kidney Diseases grant P30 DK046200 (to NRMS). The Nurses’ Health Study II is supported by grants U01 CA176726 and U01 HL145386.\nAuthor disclosures: MCA is employed at the Societé des Produits Nestlé SA. SAM has served on Advisory Boards for AbbVie and Roche, as a Statistical Editor for Human Reproduction, and as the Field Chief Editor for Frontiers in Reproductive Health; she currently has research grant awards from the US NIH, the US Department of Defense, the J Willard and Alice S Marriott Foundation, and AbbVie. All other authors report no conflicts of interest.\nSupplemental Figure 1 and Supplemental Table 1 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/.\nSAM and HRH contributed equally to this work.\nAbbreviations used: AHEI, Alternative Healthy Eating Index; FODMAPs, fermentable oligo-, di-, and monosaccharides and polyols; GI, glycemic index; GL, glycemic load; IBS, irritable bowel syndrome; NHSII, Nurses’ Health Study II; RR, rate ratio.\nContributor Information\nNaomi R M Schwartz, CHOICE Institute, Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.\nMyriam C Afeiche, Nestlé Research, Lausanne, Switzerland.\nKathryn L Terry, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.\nLeslie V Farland, Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.\nJorge E Chavarro, Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.\nStacey A Missmer, Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA; Division of Adolescent and Young Adult Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.\nHolly R Harris, Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.\nReferences\n- 1. 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