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Diet interventions may be effective as self-management strategy in women with endometriosis
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Nutrients with anti-inflammatory properties may suppress endometriosis symptoms
Abstract
The success rate of medical and surgical treatment for endometriosis is limited. Empowering patients suffering from endometriosis by giving them opportunities to positively influence their symptoms could result in increased quality of life. Changing diet is one of these self-management activities, but current endometriosis diets are mostly based on limited evidence. In order to gain more insight into the role of nutrients on symptoms in women with endometriosis a systematic review was carried out in which the effect of a nutrient or diet on endometriosis-related symptoms was investigated. PubMed and the Cochrane Database of Systematic Reviews were searched for relevant articles up to 1 March 2019. Search terms included endometriosis, diet, and 26 possible nutrients were identified after assessing available endometriosis diets in the literature and on the internet. Twelve studies were included. Study quality, including risk of bias, was assessed using GRADE criteria and all were of low to very low quality. Intake of additional fatty acids, antioxidants and a combination of vitamins and minerals may have a positive effect on endometriosis-associated symptoms. Future studies are necessary to gain evidence about which food products are effective and in which amounts.
). It is a debilitating disease characterized by dysmenorrhoea, dyspareunia, dyschezia, dysuria and infertility, but there may also be many unspecific complaints like pelvic pain, fatigue, bloating and back pain (
WERF EndoCost Consortium The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross–sectional survey.
). Diagnostic delay is considerable due to a lack of non-invasive reliable diagnostic testing, and to the lack of awareness in medical professionals because of the often non-specific symptoms with which women are presenting to their doctors (
). Because of the delay and the severity of symptoms, costs to society are high due to the (partial) inability to work and to the necessity for psychological support because of pain and infertility (
The pathogenesis of endometriosis has not been fully elucidated. The most widely accepted theory is that of retrograde menstruation. Endometriosis may occur when menstrual debris is transported through the tubes and enters the abdominal cavity, where it can attach and adhere to the peritoneal lining (
). However, retrograde menstruation is seen in 90% of women with patent tubes, whereas symptomatic endometriosis is present in only approximately 10% of women (
). Different genetic, immunological, environmental and hormonal factors may be involved in the development of endometriosis and may explain the difference between the occurrence of retrograde menstruation and the presence of endometriosis (
). However, the exact contribution of these factors is still unknown.
Endometriosis can currently be treated pharmacologically and/or surgically. Treatment is individualized and depends on severity, character and location of symptoms, and on the presence or absence of the wish to conceive. Analgesics may be used to suppress pain symptoms when there is a desire to achieve pregnancy. Anti-inflammatory agents can be prescribed in order to suppress prostaglandin activity. Prostaglandin activity plays a role in the inflammatory reaction, which in turn causes pain in active endometriosis (
). This can be achieved by using oral contraceptives, progestogens or gonadotrophin-releasing hormone (GnRH) analogues. Dysmenorrhoea may be effectively decreased by suppressing the menstrual cycle (
). Moreover, by suppressing oestrogen activity the progress of disease may be prevented, thereby protecting women against future damage caused by endometriosis, including adhesions and infertility (
). Surgical excision of endometriosis lesions may also be effective to treat pain symptoms. However, surgical procedures are often complex and surgical treatment has a risk of complications. Risk of recurrence of symptoms is 40–50% after 5 years (
). To date, there is no definitive cure for endometriosis.
Because of the limited amount of success of treatment and because of the chronic character of endometriosis, many women feel the need to be in control of this disease themselves and they are looking for tools to do so. Empowering patients suffering from chronic diseases, including endometriosis, by giving them opportunities to positively influence their pain could result in decreased feelings of helplessness and increased quality of life (
). Self-management activities may be important empowering tools. According to an Australian national online survey, up to 76% of women with endometriosis use self-management strategies, consisting of diverse self-care and lifestyle choices, such as meditation, exercise and nutrition. Almost half (44%) of the women tried to manage their endometriosis themselves with adaptation of dietary choices, such as a gluten-free or vegan diet. The effectiveness of the dietary choices was rated with a score of 6.4 out of 10 in this online national survey (
Numerous sources can be found on the internet promoting dietary restrictions or full diets for the treatment of endometriosis. These diets are often created by patients themselves and are based on their own experience instead of scientific evidence. Implementing the dietary changes from these diets could result in nutritional deficiencies, as many food products are excluded from the diet and not adequately replaced. Furthermore, adherence to the diet may be costly in both money and time. Finally, women often report feelings of guilt and stress when they do not manage to adhere to the diet. There is little scientific evidence for the effects of nutrition on endometriosis. Most studies about the association between nutrition and endometriosis are case–control studies investigating dietary intake and endometriosis risk instead of the role in treatment. The aim of this review is to provide evidence for the effects of nutrition on symptoms in women with endometriosis. A scientific basis for the benefit of dietary interventions is necessary in order to be able to advise women about the effects of nutrients on the symptoms of endometriosis.
Materials and methods
Eligibility criteria
Inclusion criteria were: study populations investigating women with surgically or magnetic resonance imaging/ultrasound-confirmed endometriosis; studies concerning the effect of a nutrient or diet on endometriosis-related symptoms; studies written in English in a peer-reviewed journal. All study designs using quantitative or qualitative methods were included. Exclusion criteria were: study populations investigating women with unconfirmed endometriosis, animal studies, laboratory studies, narrative review articles and organizational guidelines, in an attempt to focus the review on primary literature. Conference abstracts were also excluded.
Information sources
This systematic review was designed to meet the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A systematic research was conducted to search for relevant articles in which an effect of a nutrient was described on pain, fertility or quality of life associated with endometriosis. PubMed and the Cochrane Database of Systematic Reviews (Cochrane Library) were searched from database inception until 1 March 2019.
Search strategy
First a general search (Search 1) was carried out: ‘endometriosis and diet’. After that a more specific search (Search 2) was done, in which all search terms were converted into ‘MeSH terms’ and corresponding ‘entry terms’. A combination of relevant vocabulary terms together with free-text terms searched in the title or abstract was used. The following 26 search terms were input into PubMed: antioxidants, ascorbic acid, beta carotene, caffeine, carbohydrates, coffee, copper, dietary fibre, dietary product, ethanol, fruit, gluten, Lepidium, lipids, locust bean gum, organic food, soy, sweetening agents, toxin, Triticum, vegetables, vegetarian diet, vitamin A, vitamin D, vitamin E and zinc.
Different combinations with endometriosis were formed by using Boolean operators (AND, OR and NOT) to connect various pieces of information.
From MeSH terms and corresponding entry terms, components were made of an entire search string. Two search strings were used, and for every dietary component a search string was made consisting of three parts (1 = related to endometriosis, 2 = related to dietary component, 3 = related to diet) (see Supplementary data).
Study selection
A two-stage process was used to assess eligibility for inclusion. First, an initial search of the literature was undertaken in which both reviewers (A.N., E.H.) separately assessed all articles on title and abstract in order to select relevant articles potentially meeting the inclusion criteria. Then, reviewers shared their list of studies that needed to be read in full text. The full text of potentially relevant articles was retrieved to assess whether the paper should be included. Full-text articles were reviewed and uncertainties were discussed until consensus was reached among the authors.
Data extraction
Data were extracted into an evidence table in which the following items were described: author and publication date, number of participants, study design, age of participants, type of endometriosis, dietary component, dosage/intervention/duration, end-point of study, result, P-value and quality of evidence (Table 1).
Table 1Summary of data extracted from the included articles
Dosage and intervention: palmitoylethanolamide 400 mg Polydatin 40 mg, twice a day Duration: 3 months
VAS (for chronic pelvic pain, dysmenorrhoea, deep dyspareunia, dyschezia and dysuria) Use of analgesics
Pain scores chronic pelvic pain and dyspareunia decreased after 1 and 3 months No significant difference in dysmenorrhoea, dyschezia, dysuria Reduction in use of analgesics after 1, 2 and 3 months
Pain score chronic pelvic pain: P < 0.0069 after 1 month, no significant further decrease after 2 and 3 months Dyspareunia: P < 0.0132 after 1 month, no significant further decrease after 2 and 3 months Use of analgesics: P < 0.0176 after 1 month, no significant further decrease after 2 and 3 months
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
Randomized double-blind parallel-group placebo-controlled clinical study
24–61
ASRM stage I and II
N-palmitoylethanolamine and transpolydatin
Dosage and intervention: Group A: palmitoylethanolamine + transpolydatin 400 mg + 40 mg twice a day Group B: placebo tablet; unclear how many tablets/day Group C: celecoxib, 200 mg twice a day, 7 days Duration: 3 months
VAS (for pelvic pain, dyspareunia and dysmenorrhoea)
VAS score lower in N-palmitoylethanolamine and transpolydatin compared with placebo. VAS score lower in celecoxib compared with N-palmitoylethanolamine and transpolydatin
Dosage and intervention: 400 mg alpha-lipoic acid, 300 mg PEA, 100 mg myrrh, two tablets a day Duration: 6 months
VAS for dysmenorrhea, pelvic pain and dyspareunia at start and after 3 and 6 months Volume of endometrial ovarian cyst at start, after 3 and 6 months with ultrasound assessment
Chronic pelvic pain and dysmenorrhoea: after 3 and after 6 months significantly lower than at start Dyspareunia after 6 months significantly lower than at start Cyst volume: not changed after 3 and 6 months
Chronic pelvic pain and dysmenorrhoea: P < 0.05 after 3 and after 6 months Dyspareunia: P < 0.05 after 6 months
Dosage and intervention: Group 1: 2 mg DNG once per day and 100 mg DIM three times per day Group 2: 2 mg DNG once per day Duration: 3 months
Endometriosis-associated pelvic pain (EAPP) using VAS after 1, 2 and 3 months Bleeding pattern after 1, 2 and 3 months
Pain: EAPP was lower in DNG group compared with DNG-DIM group at start of study. At the end of study, EAPP was significantly decreased in both groups. EAPP was higher in DNG group than in DNG-DIM group Bleeding pattern: fewer bleeding days and less heavy bleeding in DNG-DIM group as compared with DNG group
Pain: EAPP DNG-DIM vs DNG group P < 0.05 Bleeding pattern: number of days of bleeding DNG-DIM vs DNG alone P < 0.05
Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial.
Vitamin B6, A, C, E; Ca, Mg, Se, Zn, Fe; VSL3 lactic ferments (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus bulgaricus, Streptococcus thermophilus); omega-3 and omega-6 fatty acids
Dosage and intervention: surgical intervention: conservative surgery. Post-surgical treatment: -placebo (n = 110) -GnRH analogue 3.75 mg/month (n = 39) -OC continuously (n = 38) -dietary intervention (n = 35) A different dietary protocol was assigned according to body mass index, physical activity, and job of each woman Duration: 6 months
Pain (VAS score) and QoL (SF36) 18 months after surgery
18 months after surgery: pain and QoL equal in hormonal treatment group and dietary group, but less pain and better QoL in both treatment groups compared with placebo group
Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.
Eur. J. Obstet. Gynecol. Reprod. Biol.2009; 147: 72-77
Vitamin B6, A, C, E; Ca, Mg, Se, Zn, Fe; VSL3 lactic ferments (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus bulgaricus, Streptococcus thermophilus); omega-3 and omega-6 fatty acids
Dosage and intervention: surgical intervention: cystectomy and adhesiolysis Post-surgical treatment: -placebo (n = 60) -GnRH analogue 3.75 mg/month (n = 58) -OC continuously (n = 60) -dietary intervention (n = 62) A different dietary protocol was assigned according to body mass index, physical activity, and job of each woman Duration: 6 months
Recurrence of endometrioma 18 months after surgery
Not described. (Patients had surgically confirmed endometriosis and IBS)
Low FODMAP
Dosage: no FODMAP Intervention: low FODMAP diet Duration: effect was reported after 4 weeks
Response to low FODMAP, defined as >50% improvement of symptoms in women with endometriosis and IBS, compared with response to low FODMAP in patients with IBS alone
Adherence to low FODMAP n = 55 (93%), response to low FODMAP n = 43 (72%)
Response: P = 0.001
Very low
ASRM = American Society for Reproductive Medicine; FODMAP = fermentable oligosaccharides, disaccharides, monosaccharides and polyols; GnRH = gonadotrophin-releasing hormone; IBS = irritable bowel syndrome; QoL = quality of life; VAS = visual analogue scale.
Serious: case series; lack of group of cases using DIM alone
Not serious
No
Serious: use of surrogacy outcome: bleeding pattern; and lack of cases using DIM alone
No
No
Very low quality (downgrade 2 levels due to 1, 4)
Gluten and soy
Chandrareddy, 2008
Low quality (observational study)
Serious: case report
No
No
Serious: small and different characteristics of the cases
No
No
Very low quality
Caserta, 2014
Low quality (observational study)
Serious: case report
No
Serious: unclear what disease caused effect of intervention
Serious: small research group, unclear follow-up
No
No
Very low quality
More than one dietary intervention
Sesti, 2007
High (RCT)
No
No
No
Very serious: heterogeneous diet intervention and heterogeneous surgical interventions, unclear what diet intervention or which surgical therapy causes which effect
No
No
Low quality (downgrade two levels due to 4)
Sesti, 2009
High (RCT)
No
No
No
Very serious: heterogeneous diet intervention, unclear what intervention causes which effect; type of endometriosis varies from ASRM I to IV despite design that says ovarian endometrioma
No
No
Low quality (downgrade two levels due to 4)
Moore, 2016
Low quality (observational study)
No
No
No
Serious: large difference in study population and number of patients in each group
Serious: possible over-interpretation of positive results of diet in subgroup of original study population
No
Very low quality (downgrade two levels due to combination of 4 and 5)
ASRM = American Society for Reproductive Medicine; DIM = diindolylmethane; RCT = randomized controlled trial.
The nature of the evidence retrieved by the literature search was such that meta-analysis was not possible, because a limited number of articles was included, the included studies were small and described very heterogeneous dietary factors. For this reason, a narrative synthesis of data is provided.
Results
Study selection
The search retrieved 454 articles (Search 1 = 111, Search 2 = 343). After reading titles and abstracts, 387 failed to meet the inclusion criteria. The full-text versions of the remaining 67 studies were read in their entirety. Of these 67 studies, 55 were excluded because they did not meet the inclusion criteria. This left 12 included studies (
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial.
Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.
Eur. J. Obstet. Gynecol. Reprod. Biol.2009; 147: 72-77
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial.
). After grading the evidence, the quality of the evidence in this review turned out to be low to very low. Most studies were small, lacked control groups and involved either a heterogeneous patient group or a heterogeneous intervention (Table 1).
Risk of bias of included studies
Imprecision, inconsistency, indirectness and/or publication bias were found in all included studies (Table 2).
Synthesis of results
Effective nutrients
There were no articles meeting the inclusion criteria for all 26 dietary components implemented in the search. In studies meeting the inclusion criteria, effects of vitamin D, fatty acids, antioxidants, gluten, soy, and certain combinations of nutrients were reported. Described below is the effect of the different dietary components per component and per diet.
Vitamin D
Two studies with opposite results were found about vitamin D in relation to endometriosis. No difference was found in pain after surgery for endometriosis between women taking oral vitamin D (cholecalciferol or 1,25-dihydroxyvitamin D3) and placebo in a randomized double-blind trial (
). In another study, a different concept was investigated. Women with endometriosis were treated with a combination of letrozole, norethindrone acetate, calcium citrate and vitamin D. Pain scores as well as American Society for Reproductive Medicine (ASRM) scores were lower after treatment compared with before treatment (
). The vitamin D given in this study was given as add-back therapy together with calcium in order to prevent bone loss. Therefore it was unclear whether vitamin D played a role in the observed effect.
Fatty acids
Four studies were found about fatty acids and their effects on endometriosis (
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
). In three of these studies, with a total study group of 112 women aged 24–61, an intervention with palmitoylethanolamine and transpolydatin was carried out (
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
). In all three studies there was a lower visual analogue scale (VAS) score for endometriosis-related pain in the intervention group as compared with the control group. The fourth study investigated the effect of alpha-lipoic acid, palmitoylethanolamide and myrrh on both the volume of endometriosis cysts and pain in women with these cysts. Cyst volume did not change after the intervention, but chronic pelvic pain and dysmenorrhoea evaluated with VAS score significantly decreased (
In a case series of eight women, treatment with the antioxidant diindolylmethane (DIM) together with dienogest suppressed pain and bleeding in women with endometriosis as compared with treatment with dienogest alone (
). However, it was not clear whether avoiding gluten had a positive effect on the coeliac disease, as was expected, and thereby gave relief of all abdominal complaints, or whether avoiding gluten could also be effective against endometriosis.
Soy
In a small case series, two women with endometriosis became pain-free after a soy-free diet (
). This positive effect of avoiding soy, which is rich in phytoestrogens, on endometriosis-associated pain seems logical because endometriosis is an oestrogen-dependent disease. However, the amount of phytoestrogens present in soy is relatively low, making the effect of avoiding soy on suppressing endometriosis-related symptoms questionable.
Combination of nutrients
Sesti and coworkers investigated the effects of a diet consisting of a combination of vitamins B6, A, C and E, minerals calcium (Ca), magnesium (Mg), selenium (Se), zinc (Zn) and iron (Fe), lactobacilli and omega-3 and -6 fatty acids (
Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial.
Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.
Eur. J. Obstet. Gynecol. Reprod. Biol.2009; 147: 72-77
). Dosages of nutrients were adjusted to a patient's individual parameters including body mass index and physical activity. Following this diet, pain was less and quality of life after surgery for endometriosis was higher compared with women in a placebo group. The effects of diet were equal to the effects of post-surgical hormonal therapy (
Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial.
). Using the same dietary intervention in a group of patients undergoing cystectomy and adhesiolysis because of endometrioma, the authors found no differences in recurrence of endometrioma in women following the diet, women using GnRH analogues and in the placebo group (
Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.
Eur. J. Obstet. Gynecol. Reprod. Biol.2009; 147: 72-77
). The authors speculated that the recurrence risk may reflect successful reseeding, reimplantation and regrowth of the ectopic endometrium.
In another study, the low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet, which was used as a therapy for patients with irritable bowel syndrome, turned out to be effective in women with irritable bowel syndrome (IBS) and endometriosis (
). Women with endometriosis and IBS had a higher response to the low FODMAP diet than patients with IBS alone. FODMAP are short-chain carbohydrates that are poorly absorbed in the small bowel and highly fermentable by gut bacteria. Luminal distension is caused by their osmotic effects and gas production. This causes pain and bloating in patients with visceral hypersensitivity, which is not only found in IBS but also in women with endometriosis. Avoiding FODMAP turned out to decrease pain in women with IBS as well as endometriosis, but it was unclear whether this decrease in pain was specific for endometriosis-associated symptoms.
Discussion
This systematic review provides evidence for the role of nutrients in the management of endometriosis and reports on the positive effects of adding or avoiding certain nutrients on endometriosis-associated symptoms. In nine studies, nutrients were added to patients’ diets, and in seven of these a positive effect was found. In three studies, nutrients were avoided, with positive effects on endometriosis-associated symptoms as well.
Inflammation is thought to be one of the main factors in endometriosis. The immune system plays a pivotal role in the pathophysiology of endometriosis as well as in pain and in subfertility associated with it. Different immune cells are involved in the inflammatory response, including cytokines, neutrophils, granulocytes (including mast cells and macrophages), chemokines and different subsets of T-cells (
). Antioxidants balance oxidative stress, which is present in chronic inflammatory processes. All nutrients that turned out to be effective in suppressing endometriosis-associated pain had anti-inflammatory or antioxidative actions, thereby directly or indirectly suppressing the inflammatory response. Palmitoylethanolamine (PEA) plays a role in controlling inflammation by mast cell activation and has immunosuppressive, analgesic, neuroprotective and antioxidant effects (
). It is found in small quantities in eggs and peanuts. The presence of activated and degranulating mast cells in deep endometriosis, and the close histological relationship between mast cells and nerves, suggests that mast cells may contribute to the development of pain in endometriosis, possibly by an effect on nerve structures (
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
). Polydatin, a natural glucoside of resveratrol, has anti-inflammatory, antioxidant and anti-chemotactic activities and is present in berries, grapes and peanuts (
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
). DIM is an antioxidant that is formed in acidic environments from indole-3-carbinol (I3C) which is present in cabbage, Brussels sprouts, broccoli and cardamom (
Cytostatic effects of 3,3′-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression.
). It has anti-carcinogenic properties, but in oestrogen-sensitive cells it specifically reverses oestrogen effects by inhibiting oestrogen receptor alpha signalling (
). The combination of antioxidant and anti-oestrogen activities makes it especially promising for the treatment of endometriosis. The activity of prostaglandins is involved in generating pain. Omega-3 fatty acids selectively modulate specific prostaglandins, whereas vitamin B6 plays a role in the production of oestradiol prostaglandin (
). By influencing the level of antioxidants and prostaglandins using different dietary components, an environment can be created in which inflammation is suppressed. The combination of different agents with anti-inflammatory actions may result in a synergy of actions, powerful enough to effectively treat endometriosis-related symptoms. It is important to stress that the case series of eight women in which a positive effect of adding antioxidants to the diet was described is too small to draw conclusions about the effectiveness of adding antioxidants to the diet of women with endometriosis.
Nutrients that were avoided with a positive effect on endometriosis-associated symptoms were soy, gluten and FODMAP. Soy is rich in phytoestrogens and may stimulate oestrogen activity, thereby stimulating endometriosis. By avoiding soy, the amount of phytoestrogens in the diet is reduced, with a possible suppression of endometriosis-associated pain. However, this result was described in only one case series including two women and so there is insufficient evidence to advise women with endometriosis to avoid soy. Gluten is the main structural protein component of wheat, consisting of gliadin and glutenin. The intake of wheat may contribute to the manifestation of a chronic inflammatory response as gliadin and wheatgerm agglutinin can both increase intestinal permeability and thereby activate the immune system (
). However, only one case report described a positive effect of avoiding gluten on fertility, concerning a woman who not only suffered from endometriosis, but from gluten intolerance as well. It remains unclear whether avoiding gluten is effective for women with endometriosis-associated symptoms, even more so because wholegrains are part of a healthy diet (
). However, the patients in this study had both IBS and endometriosis, making it difficult to explain the effects of low FODMAP as specific to suppressing endometriosis alone. Therefore, evidence is insufficient to advise endometriosis patients to adhere to a low FODMAP diet. On the other hand, many women with endometriosis report gastrointestinal symptoms, and many women are diagnosed with endometriosis in combination with IBS (
). However, theoretically, dietary vitamin D intake and plasma 25-hydroxyvitamin D [25(OH)D] concentration may influence endometriosis and endometriosis-related symptoms because beyond its role in calcium and bone homeostasis, vitamin D influences the immune function and promotes anti-inflammatory processes (
reported that increased plasma 25(OH)D and higher dairy intake was associated with a decreased risk of developing endometriosis.
This review has a number of strengths. First, the search strategy was broad and thorough, and constructed with an expert librarian. Second, the review has a specific scope. The focus was on the role of diet on symptoms of already established endometriosis, and the research question was formulated accordingly. This was done to find evidence concerning the role of nutrients in active endometriosis, and in order to be able to provide specific dietary advice for women suffering from endometriosis symptoms. For this reason, the search ruled out laboratory and animal studies. Moreover, studies focusing on nutrients that may play a role in the development or in the prevention of endometriosis were not taken into account either.
The narrow scope of the review may also be a limitation. The specific research question may have led to a limited selection of nutrients for which evidence was found for the effect of suppressing endometriosis symptoms. Moreover, only studies in the English language were included, so there may be relevant articles in other languages that have not been taken into account in this review. Finally, the quality of the evidence found was low to very low. Interpretation of the results of the review can only be done with caution and advice for dietary practice may be of limited value. This holds true especially for the effect of adding antioxidants to the diet and of avoiding gluten and soy, because the effects of these interventions were only described in a case series and in two case reports, respectively. Despite the very low numbers of patients in these studies and hence the impossibility of drawing conclusions for the usefulness of the findings in daily practice, it was decided to include these articles in the review, because many women with endometriosis ask questions about the effects on their symptoms of these specific nutrients. By including these articles in the review, the aim was to raise awareness in medical professionals about considering the role of antioxidants, gluten and soy.
In conclusion, nutrients with direct or indirect anti-inflammatory properties may be effective in suppressing endometriosis-associated pain. Hence, it may be speculated that foods that are rich in polyunsaturated fatty acids, certain vitamins and minerals, antioxidants, polydatin (resveratrol) and lactobacilli may be implemented in a diet in order to suppress endometriosis symptoms (Table 3). However, it is too early to develop an endometriosis diet based on the results of this review. More studies are needed in order to collect evidence supporting the speculations.
Table 3Nutrients with a possible positive effect on endometriosis-related symptoms, their sources and their recommended daily amount (
According to the World Health Organization (WHO), a healthy diet comprises a combination of different foods including staples (like cereals, or starchy tubers or roots like potato, yam, taro or cassava), legumes, fruit and vegetables, and foods from animal sources (meat, fish, eggs and milk) (www.who.int/behealthy). Women with endometriosis may decide to combine fatty acids (from fish, seeds, nuts and cereals) with antioxidants (from vegetables and fruit). It is important to stress to these women that they should pay attention to the WHO advice to maintain a healthy diet in order to avoid nutrient deficiencies. A poor diet, including a shift towards a higher n-6:n-3 fatty acid ratio and a high intake of simple sugars, has been implicated as being one of the factors for developing an inflammatory phenotype (
In response to the wishes of patients to be able to control their endometriosis themselves, the role of diet receives a lot of attention and a lot of dietary advice is given by dieticians and doctors and on the internet. Evidence supporting this advice is scarce. Based on this systematic review, nutrients with direct or indirect anti-inflammatory properties might be effective against endometriosis-related pain symptoms but not on recurrence of endometriomas. Combining different agents may provide a synergistic effect.
The quality of the evidence was low in the articles included in this review. High-quality intervention studies in women with endometriosis are necessary in order to improve the quality of the evidence. A research agenda has been developed with topics that need to be investigated in order to gain more knowledge about the role of nutrients in endometriosis-related symptoms (Table 4).
Table 4Research agenda
Type of study
Study question
Goal
Descriptive exploratory study
Do women with endometriosis have a healthy diet according to WHO criteria? What dietary intervention is used by women with endometriosis and what is its perceived effectiveness regarding endometriosis related symptoms?
Finding out whether a healthy diet according to WHO criteria, or changing diet itself is effective against endometriosis related symptoms
Prospective randomized controlled trial
What is the effect on endometriosis-related symptoms of adding or omitting specific (combinations of) nutrients to the diet of women with endometriosis, compared with a normal diet?
Finding out whether adding or omitting single nutrients or a combination of nutrients is effective against endometriosis-related symptoms
Laboratory study
What amount of effective nutrients is present in specific food products?
Finding out which specific food products should be advised in an endometriosis diet and in which amounts per day
Moreover, the majority of nutrients that were studied were administered in tablets or capsules instead of in food products. It is unclear what specific food products may be effective against endometriosis symptoms and in which amounts they should be implemented in daily eating habits. However, patient empowerment is strongest when patients are able to influence their symptoms by changing their lifestyle on their own account. In order to stimulate patient empowerment by changing dietary habits, it is important to gain more evidence about the effectiveness of specific food products and their appropriate dosages. In future studies, the effects of specific food products and specific dosages, identified based on possibly effective nutrients, should be investigated for use in women with endometriosis.
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Gurates B.
Bulun S.E.
Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study.
Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2011; 158: 82-86
Cytostatic effects of 3,3′-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression.
Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial.
Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs. placebo.
Eur. J. Obstet. Gynecol. Reprod. Biol.2009; 147: 72-77
Dr Annemiek Nap, MD, PhD, is initiator of the multidisciplinary team for diagnosis and treatment of endometriosis at Rijnstate Hospital, the Netherlands. She is one of the group leaders of the ESHRE Guideline Development Group ‘Management of women with endometriosis’, and a board member of the World Endometriosis Association.
Key message
Evidence for the effect of dietary interventions on endometriosis-related symptoms was of low quality. Dietary interventions may be potentially useful as a self-management strategy for women with endometriosis. However, the evidence is scarce and more research is necessary to identify useful dietary advice for women with endometriosis.
Article info
Publication history
Published online: May 13, 2020
Accepted:
April 17,
2020
Received in revised form:
March 23,
2020
Received:
December 29,
2019
Declaration: The authors report no financial or commercial conflicts of interest.
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