Definition and Etiology
Endometriosis is a gynecological condition associated with abnormal proliferation of endometrial tissue outside the uterus. The etymology of the name is derived from a combination of three Greek words: endos (inside); metra (womb) and osis (disease). Some population-based studies cite an incidence for endometriosis of just 1% (Eisenberg, Weil, Chodick, & Shalev, 2018), while others have indicated rates as high as 10% (Giudice, 2010).
The cause of endometriosis remains unknown, but several mechanisms have been proposed. Retrograde menstruation (RM) is the longstanding hypothesis that may reveal a large portion of the etiology. Associated with an increase in intrauterine pressure, endometrial tissue is forced backwards into the fallopian tubes and is eventually refluxed into the peritoneal cavity. There, the tissue attaches to the uterus, ovaries and other surrounding structures such as the bladder or rectum (Vercellini, Viganò, Somigliana, & Fedele, 2014). Since endometrial lining contains receptors for sex hormones (even outside the uterus), the high hormone phase of menses stimulates the extrauterine tissue to grow and form adhesions.
The increase in pressure leading to tissue migration may originate from dysregulated uterine contractions. Buletti et al. (2002) found endometriosis sufferers experienced contractions twice as often (22.73 vs. 11.09/contractions/10 min) and up to three times as severe as controls (20.82 vs. 6.77 mmHg). Eicosanoids derived from Arachidonic Acid reportedly play a regulatory role in uterine contractions (Jabbour, Sales, Smith, Battersby, & Boddy, 2006). Some research has suggested that an overexpression of cyclooxygenase-2 (COX-2) and series 2 prostaglandins (PGE2) alter the timing and intensity of rhythms, which result in the rearward movement of tissue (Bulun, Zeitoun, Takayama, & Sasano, 2000; Ota, Igarashi, Sasaki, & Tanaka, 2001).
RM is not an abnormal occurrence, however. Buletti et al. (2002) explain that the uterus normally experiences retrograde contractions early on in the menstrual cycle in order to facilitate the movement of sperm towards the ovum. As menses approaches, however, the direction of contractions reverses in order to drive atrophied endometrial tissue out of the body through the vagina. If RM becomes dysregulated and occurs later in the cycle, tissue which should be expelled may instead be pushed backwards and eventually deposit in the peritoneum.
A more recent theory which could compliment the RM hypothesis is endotoxin mediated inflammation stemming from dysbiosis (Khan et al., 2018). Gram negative lipopolysaccharide (LPS) containing bacteria such as E. coli reportedly translocate from the GI Tract to the menstrual fluid. Toll Like Receptors (TLR’s) are then stimulated by LPS leading to the activation of macrophages. Tumor Necrosis Factor alpha (TNFa), interleukin (IL)-6, and vascular endothelial cell growth factor (VEGF) are released by the immune system to combat the infiltration. This process results in a high degree of inflammation in the immediate as well as the surrounding tissues. Vascularization induced by VEGF also leads to the abnormal proliferation of tissue and the formation of adhesions. RM may further augment this process by allowing bacterial endotoxin (LPS) increased access to the peritoneal cavity.
Contributing factors to endometriosis include oxidative stress (Szczepańska, Koźlik, Skrzypczak, & Mikołajczyk, 2003; Van Langendonckt, Casanas-Roux, & Donnez, 2002) and excess concentrations of sex hormones. Chronically elevated estrogen receptor levels and aromatase activity in ectopic endometrial tissue have also been reported (Bulun et al., 2012). While the uterine lining normally contains sex hormone receptors, the number increases and decreases with each menstrual cycle. When endometrial tissue resides outside the uterus, however, receptor levels may remain chronically high and thereby susceptible to hormonal influence on a continual basis. Newer studies also suggest progesterone resistance among ectopic endometrial cells as a contributing factor (Wu, Shi, & Guo, 2008).
Additional mechanisms for endometriosis include genetic Single Nucleotide Polymorphisms (SNP’s) (Augoulea, Alexandrou, Creatsa, Vrachnis, & Lambrinoudaki, 2012), immune system activation or inhibition (Bulun et al., 2000) and metaplastic transformation of healthy uterine cells (Buletti et al., 2002). Decreased endometrial blood flow has also been associated with dysregulated uterine contractions (Sales & Jabbour, 2003). It’s likely then that a number of factors combine synergistically to create conditions which favor onset.
Symptomology and Treatment
Symptoms associated with endometriosis involve irregularity or cessation of menstruation, pelvic pain, dysmenorrhea, difficulty with both urination/elimination and infertility (Vercellini et al., 2014). Adhesion formation, inflammation and the release of various chemical messengers arises from pathogenesis and often results in altered physiology. Reproduction is commonly impacted as are other functions associated with nearby structures.
Conventional treatments focus on pain management, surgery or ablation of the endometrial tissue. While such interventions have reportedly reduced pain, restoration of fertility has proved to be more elusive (Bulletti et al., 2010). Aromatase inhibitors have been used clinically to reduce the presence of excess sex hormones and their subsequent stimulation of ectopic endometrial tissue (Bulun et al., 2000). Some research has actually established a positive relationship between rising estrogen levels and PGE2 production, suggesting a potential link between sex hormones and uterine dyskinesia (Bulun et al., 2000; Jabbour et al., 2006).
Whole Food Intervention
Darling, Chavarro, Malspeis, Harris, and Missmer (2013) examined the association between vitamin intake and endometriosis among women who completed the second Nurses’ Health Study between 1991 and 2005 (n=1,383). Their findings revealed an inverse relationship between endometriosis and the consumption of certain vitamins found in whole foods. Thiamine (RR=.84), folate (RR=.79), Vitamin C (RR=.81) and Vitamin E (RR=.70) were all associated with risk reductions with Vitamin E demonstrating the greatest benefit. Surprisingly, synthetic forms of these same vitamins contained in supplements did not demonstrate any improvement in incident rate ratios.
Other studies examining the relationship between endometriosis and whole foods found similar results. Parazzini et al. (2004) conducted two case control studies that compared vegetable and fruit intake with onset. Risk for disease development dropped 70% among those whose consumption of green vegetables was in the highest quintile (OR=.30). Those with the greatest amount of fresh fruits in their diets saw a 40% reduction in risk (OR=.60). The authors connected their findings with estrogen related cancer studies that reported benefits for those with diets high in Vitamin C, carotenoids and folic acid.
It is worth noting that despite the significant reductions in risk recorded in their study, the researchers were cautious about overgeneralizing results. Fruit and vegetable intake may have been associated with other healthy habits among subjects and could have influenced recorded outcomes.
There are a few mechanisms which potentially shed light on the findings of Parazzini et al. (2004). Vitamins C and E are thought to attenuate inflammation by counteracting oxidative stress (Darling et al., 2013). B vitamins, especially B6, catalyze the conversion of estrogen into an inactive form and may thereby reduce excess hormone levels (Darling et al., 2013). Pyridoxine also supports the conversion of linoleic acid into gamma linoleic acid (GLA), which is an upstream precursor to the anti-inflammatory series 1 prostaglandins (PGE1).
As indicated previously, endometriosis may be related to increased levels of pro-inflammatory PGE2 (Bulun et al., 2000), so raising levels of anti-inflammatory prostaglandins could be beneficial. In a similar analysis of the Darling et al. (2013) cohort, Missmer et al. (2010) found that intake of omega 3 fatty acids was associated with a 22% decreased rate of endometriosis. Omega 3 fatty acids from fish oil provide upstream precursors to series 3 prostaglandins (PGE3), which also promote anti-inflammatory effects.
USDA (2019) Food Composition Database:
Foods high in Vitamin E: wheat germ oil, sunflower seeds and almonds
Foods high in Folate: duck/goose liver, turkey, mung beans, lentils and dried rosemary
Foods high in Vitamin C: red peppers, acerola cherries, green chili peppers, yellow peppers and black currants
Foods high in Thiamine (B1): spirulina, wheat germ, sesame butter, sunflower seeds
Foods high in Pyridoxine (B6): red cayenne pepper, pistachio nuts, shallots and garlic powder
Supplemental Intervention
Some supplements may be helpful for providing relief. Schwertner et al. (2013) found that 10mg of supplemental melatonin reduced pain scores by nearly 40% among endometriosis sufferers [CI-95%, 12.88-43.01%]. Their research consisted of a randomized placebo-controlled trial of 40 women over an 8-week period. At the end of the experiment, subjects reported a drop in pain scores as well as a 38% reduction in dysmenorrhea [CI-95%, 15.96-49.15].
Schwertner et al. (2013) were following up an earlier study which found that administration of melatonin reduced endometrial lesions in animals (Güney, Oral, Karahan, & Mungan, 2008). Researchers for the human trial believe that melatonin exerts inhibitory effects on Brain Derived Neurotrophic Factor (BDNF), which is involved in pain signals originating from nerves irritated by endometrial tissue. Others have suggested that melatonin inhibits cytokines and chemokines associated with inflammation (Pandit, Begum, Chatterjee, & Swarnakar, 2018).
Conclusion
Interventions featuring antioxidants or anti-inflammatory properties may benefit sufferers of endometriosis. Studies have also established a critical role for the detoxification and elimination of excess estrogens. While restoration of structure and function has proved difficult, symptomatic relief and attenuation of inflammatory processes is still an important aim for therapy. If dysbiosis does play a role in etiology, restoration of normal flora and arresting the ensuing immune response would also serve as key strategies. There is still much research to be done, but existing findings suggest a number of therapeutic options for immediate clinical application.
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