Harris HR, Eke AC, Chavarro JE, Missmer SA. Fruit and vegetable consumption and risk of endometriosis. Hum Reprod. 2018;33(4):715-727.
To identify associations between consumption of fruits and vegetables and risk of laparoscopically confirmed endometriosis
Prospective cohort study using data collected from women who were enrolled in the Nurses’ Health Study II from 1991 to 2013
This study analyzed data collected from 70,835 premenopausal women aged 25 to 42 years. All women included in the study had an intact uterus. The following were criteria for exclusion: total energy intake <800 or >4,200 kcal per day; more than 70 food items blank on questionnaire; diagnosis of endometriosis; history of infertility; history of cancer (other than non-melanoma skin cancer).
Study Parameters Assessed
Diet was assessed in 1991, 1995, 1999, 2003, 2007, and 2011 using a food frequency questionnaire (FFQ) listing over 130 food items.
Primary Outcome Measures
Analyzed separately from vegetable consumption, total fruit consumption was associated with a lower endometriosis risk, up to 3 servings per day, after which there was no longer association with reduced risk (P=0.005). There was no association between total vegetable consumption and endometriosis risk regardless of number of servings per day.
When looking at specific fruit groups, citrus fruits were associated with a lower risk of endometriosis. Eating 1 serving or more of citrus fruit per day was associated with a 22% reduction in risk compared to eating less than 1 serving per week (P [trend]=0.004). This reduction in risk was only observed among women who had laparoscopic confirmed endometriosis but had never reported infertility and was strongest among ever-smokers. When this association was further narrowed by specific citrus fruit, oranges had the strongest associated reduction in risk.
When looking at specific vegetables types, 1 or more servings of cruciferous vegetables per day had a 13% higher risk of endometriosis (P [trend]=0.03). More specifically, Brussels sprouts (P=0.02), cauliflower (P=0.03), and raw cabbage (P=0.02) were related to higher endometriosis risk. Lima beans/peas and corn were also associated with higher risk of endometriosis and romaine/leaf lettuce was associated with lower risk.
Somewhat perplexing is the 13% increase of endometriosis with daily consumption of cruciferous vegetables.
Of the singular nutrients that were assessed, only the highest quintile for consumption of the carotenoid β-cryptoxanthin was associated with lower endometriosis risk (P=0.02).
Adjustment for intake of trans fat and omega-3 fatty acids did not influence the results.
A 22-year prospective cohort study of nurses’ diets has been evaluated for dietary associations with endometriosis, revealing some surprising trends. The Nurses’ Health Study II’s (NHSII) became the first prospective cohort study to examine many associations of nutrition with women’s health, including endometriosis.1 Endometriosis affects about 10% of women of reproductive age, often in the third and fourth decades of life. A significant theory for the spread of endometrial tissue is retrograde menstruation through the fallopian tubes. That theory is challenged by data suggesting that retrograde menstruation happens quite often in menstruating women,2 occurring in 76% to 90% and so considered a “universal phenomenon.”3 It is most likely that endometriosis is a multifactorial condition, with oxidative stress4 and inflammation5 as key players, and diet has a significant influence.
Dietary antioxidants such as vitamins E and C have been shown to decrease endometriosis pain,6 and other antioxidant nutrients may have similar effects on pain7 and even the pathogenesis.8 When Harris and her team evaluated the dietary patterns in the NHSII, they were looking for associations with antioxidants, especially carotenoids (retinol activity equivalents such as alpha-carotene, beta-carotene, β-cryptoxanthin, lutein/zeaxanthin, and lycopene), and to determine if those associations were modified by smoking.
Higher consumption of total fruits and vegetables was associated with reduced endometriosis risk up to approximately 5 total servings per day, after which point there was no risk reduction but rather reversal of trends in risk reduction. Daily intake of citrus fruits (oranges, grapefruit, orange juice, grapefruit juice) was associated with a 22% lower risk of endometriosis. In women who had a history of smoking, the associated decrease in risk was even stronger. Citrus fruits contain significant carotenoids, especially β-cryptoxanthin, considered the most common carotenoid in human blood. It has been suggested that β-cryptoxanthin is better absorbed from its major food sources than are other common carotenoids.9 In preclinical data, β-cryptoxanthin reduced markers of oxidative stress10 and decreased inflammatory markers (liver necrosis factor [NF]-κB and tumor necrosis factor [TNF]-α expression).11 Such mechanisms may explain how this particular carotenoid was associated with reduced endometriosis incidence in the study reviewed here.
Somewhat perplexing is the 13% increase of endometriosis with daily consumption of cruciferous vegetables. While cruciferous vegetables are known for their ability to promote proper metabolism of estrogen due to constituents such as indole-3-carbinol,12 this study found their consumption to be correlated with an increased diagnosis of endometriosis. Intake of corn and peas/lima beans was also associated with a higher diagnosis rate. All of these foods contain fermentable food constituents that are linked to gastrointestinal (GI) inflammation. Specifically, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs),13 which can cause gas, bloating, and/or GI discomfort, are found in cruciferous vegetables as well as in corn and lima beans. Inflammation in the gut is correlated with an increased risk for endometriosis, a relationship that has been observed for years.14 Irritable bowel syndrome (IBS) and endometriosis are both characterized by chronic, low-grade inflammation and mast cell involvement.11 Supplementation with the probiotic strain Lactobacillus gasseri has been found to increase the production of the cytokine interleukin (IL)-12 and significantly decrease menstrual pain and dysmenorrhea in women with endometriosis,3 further supporting the hypothesis that inflammation beginning in the gut contributes to the pathogenesis of endometriosis.
Another possibility, as proffered by the authors of the study, is that the nonspecific symptoms of GI distress, such as gas and bloating associated with FODMAP foods, may prompt more gynecological referrals. The increase in workups may lead to higher rates of endometriosis diagnoses.
Lastly, the participants in this study were exclusively nurses, who may have begun eating more cruciferous vegetables after their diagnosis of endometriosis. The timing of the diagnosis relative to ingestion was not reported, so the truth of this hypothesis is not possible to discern.
Past reports indicated that the time between onset of symptoms and diagnosis of endometriosis could be as long as 12 years.15 Although recent reports indicate the time lag has shortened to approximately 4 to 5 years, adolescents still have a longer time to diagnosis.16 One recommendation suggests that women with suspected IBS who have a family history of endometriosis should be evaluated for the condition.17 We hope to gain more clarity about dietary associations from studies similar to the study reviewed here, but the cruciferous connection is something to watch.
Although cohort studies are considered midlevel in the evidence pyramid,18 they demonstrate associations and can make for intriguing intervention study designs. Going forward, an intervention study to determine if given foods correlate with repeat endometriosis diagnoses seems one way to tease out this counterintuitive trend of crucifers with endometriosis diagnosis.
- Chavarro JE, Rich-Edwards JW, Gaskins AJ, et al. Contributions of the Nurses' Health Studies to reproductive health research. Am J Public Health. 2016;106(9):1669-1676.
- Parasar P, Ozcan P, Terry KL. Endometriosis: epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34-41.
- Itoh H, Uchida M, Sashihara T, et al. Lactobacillus gasseri OLL2809 is effective especially on the menstrual pain and dysmenorrhea in endometriosis patients: randomized, double-blind, placebo-controlled study. Cytotechnology. 2011;63(2):153-161.
- Iwabuchi T, Yoshimoto C, Shigetomi H, Kobayashi H. Oxidative stress and antioxidant defense in endometriosis and its malignant transformation. Oxid Med Cell Longev. 2015;2015:848595.
- Kobayashi H, Higashiura Y, Shigetomi H, Kajihara H. Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation (Review). Mol Med Rep. 2014 Jan;9(1):9-15.
- Santanam N, Kavtaradze N, Murphy A, Dominguez C, Parthasarathy S. Antioxidant supplementation reduces endometriosis-related pelvic pain in humans. Transl Res. 2013;161(3):189-195.
- Lete I, Mendoza N, de la Viuda E, Carmona F. Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study. Eur J Obstet Gynecol Reprod Biol. 2018 Jul 6;228:221-224.
- Taylor RN, Kane MA, Sidell N. Pathogenesis of Endometriosis: Roles of Retinoids and Inflammatory Pathways. Semin Reprod Med. 2015 Jul;33(4):246-56. doi: 10.1055/s-0035-1554920. Epub 2015 Jul 1. Review. PubMed PMID: 26132929; PubMed Central PMCID: PMC4745121.
- Burri BJ, La Frano MR, Zhu C. Absorption, metabolism, and functions of β-cryptoxanthin. Nutr Rev. 2016;74(2):69-82.
- Kobori M, Ni Y, Takahashi Y, et al. β-Cryptoxanthin alleviates diet-induced nonalcoholic steatohepatitis by suppressing inflammatory gene expression in mice. PLoS One. 2014;9(5):e98294.
- Sahin K, Orhan C, Akdemir F, et al. β-Cryptoxanthin ameliorates metabolic risk factors by regulating NF-κB and Nrf2 pathways in insulin resistance induced by high-fat diet in rodents. Food Chem Toxicol. 2017;107(Pt A):270-279.
- Auborn KJ, Fan S, Rosen EM, et al. Indole-3-carbinol is a negative regulator of estrogen. J Nutr. 2003;133(7 Suppl):2470S-2475S.
- Varjú P, Farkas N, Hegyi P, et al. Low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet improves symptoms in adults suffering from irritable bowel syndrome (IBS) compared to standard IBS diet: a meta-analysis of clinical studies. PLoS One. 2017;12(8):e0182942.
- Viganò D, Zara F, Usai P. Irritable bowel syndrome and endometriosis: new insights for old diseases. Dig Liver Dis. 2018;50(3):213-219.
- Santos TM, Pereira AM, Lopes RG, Depes Dde B. Lag time between onset of symptoms and diagnosis of endometriosis. Einstein (Sao Paulo). 2012 Jan-Mar;10(1):39-43. PubMed PMID: 23045824.
- Soliman AM, Fuldeore M, Snabes MC. Factors associated with time to endometriosis diagnosis in the United States. J Womens Health (Larchmt). 2017;26(7):788-797.
- Moore JS, Gibson PR, Perry RE, Burgell RE. Endometriosis in patients with irritable bowel syndrome: specific symptomatic and demographic profile, and response to the low FODMAP diet. Aust N Z J Obstet Gynaecol. 2017;57(2):201-205.
- MacGill M. What is a cohort study in medical research? Medical News Today. https://www.medicalnewstoday.com/articles/281703.php. Updated February 21, 2018. Accessed June 3, 2018.