by Sara Gottfried, MD and Kirti Salunkhe, MD
From the President of Metagenics Institute, Sara Gottfried MD: When I practiced mainstream medicine and saw a patient on the schedule with chronic pelvic pain, I sometimes cringed. Why? Because I was so limited in what I could offer her for her severe and unrelenting pain, which typically was caused by endometriosis, gastrointestinal issues, or adhesive disease from prior surgery. Back then, most of my patients with endometriosis were on hormone suppression with a GnRH agonist. Then I had to add another drug, like a progestin (e.g., norethindrone acetate) to prevent bone loss. Next I had to follow bone density every six months to track bone loss. Chasing one prescription with another was never what I imagined I’d be doing in medical practice. Now that I practice personalized lifestyle medicine, I have many more options, and I am able to address the multifactorial nature of chronic pelvic pain—including mast cell activation or small intestinal bacterial overgrowth (SIBO) that tends to accompany endometriosis, perhaps due to mechanical issues due to a retroverted, retroflexed uterus that compresses the colon.
Endometriosis, a disorder in which tissue that normally lines the uterus grows elsewhere, is the topic of this comprehensive article. Our goal is to provide an extensive and up-to-date review for this common affliction that not only causes pain and suffering, but sometimes holds women back from achieving greatness. Fortunately, personalized lifestyle medicine provides solutions that are effective and far less likely to cause side effects.
Endometriosis (EMS) is a chronic, often estrogen-dependent inflammatory disease that is one of the most common yet underresearched, difficult to diagnose and treat health conditions affecting women around the world.1 It is estimated this condition affects nearly 6–10% reproductive-aged women globally (about 200 million) with 1 of every 10 American women (~ 5.5 million) diagnosed with endometriosis.2-4
In endometriosis, the presence of normal endometrial mucosal tissue is found abnormally planted outside the uterine cavity.3,5 Endometrial tissue can be found on the exterior of the uterus, the fallopian tubes, ovaries, peritoneum, bladder, vagina, intestines, or rectum. This abnormally located tissue, possessing the same steroid receptors as normal endometrium, is capable of responding to same monthly hormonal fluctuations of a woman’s menstrual cycle.1 This can include the bloating, pain, and swelling many women notice before and during their periods. Additionally, data have also indicated that nearly 80% of women diagnosed with dysmenorrhea and 40% of infertile women have endometriosis.5,6
At this time, there is no definitive cure for endometriosis, but the hormonal responsiveness of the extra-uterine tissue may be considered for noninvasive, medical therapy.6 Currently, the gold standard treatment for endometriosis is minimally invasive laparoscopic excision surgery. Symptom management also helps to provide some physical relief and includes use of oral contraceptives, intrauterine hormonal devices, and analgesics along with acupuncture and lifestyle modification such as dietary changes and increased physical activity.3 Natural options recommend incorporating physician-directed use of specific supplements, botanicals, vitamins, and minerals along with complete nutritional assessments.3
Due to lack of suitable animal models with which to study the natural history and anatomic relationships of endometriosis, the exact etiology and pathophysiology are still not well understood. What is known, however, is that it is a disease of menstruation and an estrogen-dependent gynecologic condition characterized by the presence and growth of endometrial tissue found outside the uterus.4,7
Another factor contributing to, and possibly affecting, endometriosis is its potential association with gut dysbiosis due to the inherent estrogen imbalance of endometriosis. This imbalance leads to dysregulation of the estrobolome with subsequent changes in the immune response.8,9
The extrauterine tissues of endometriosis respond to cyclical hormonal changes just as the intrauterine endometrium does with proliferation, secretory activity, and cyclic sloughing of menstrual material.10,3 Microscopically, the clinical consequences of this disease include inflammation, internal bleeding, neovascularization, and fibrosis leading to adhesions.2,7 Some investigators have been able to demonstrate abnormal T- and B-cell function, abnormal complement deposition, and altered interleukin (IL)-6 production in women with this disease.8,11 Clinically, symptoms are seen most often during the reproductive years and include complaints of severe and chronic pain particularly before and during menses, infertility, menorrhagia, and dyspareunia.3,4 Pain often resolves after menopause when estrogen production is reduced or stopped. However, if hormone replacement therapy (HRT) is used during menopause, symptoms may persist.6
Due to a dearth of overall preclinical and clinical research data on endometriosis, the exact cause(s) and pathogenesis for this condition remain largely unknown. However, several theories have been proposed. Primary among these are the widely recognized theories of embryologic metaplasia, retrograde menstruation, and immunologic dysfunction, but in recent times, research has also pointed toward the potential impacts of genetic and environmental influences as well as the possible association with gut dysbiosis and estrogen imbalance as contributing factors to endometriosis (Figure 1).
Figure 1. Proposed theories for etiology of endometriosis
1. Embryologic/Coelomic Metaplasia
This theory suggests an embryologic cause for endometriosis that may result from the conversion of the germinal epithelium during gonadal development. This germinal epithelium, also known as the coelomic epithelium, develops into the peritoneum, the pleura, and the surface of the ovary and has been implicated as the primary source for primary peritoneal cancer, various types of ovarian cancer, and endometriosis.8 Prior studies of pelvic peritoneal tissue from women undergoing laparotomy suggest that before endometriosis has become established in the peritoneum, there may be metaplastic changes by the peritoneal mesothelial cells into endometrial glandular cells.12 Some investigators have proposed these metaplastic changes may be linked to endocrine-disrupting chemicals (EDCs).2 The exact mechanism by which dioxin and its similes (TCDD/PCBs) act to change endometrial physiology is still to be fully understood primarily due to difficulties assessing exposure over a woman’s lifespan from intrauterine life, childhood, and adulthood with actual and reported consequences as well as the limitations to in vitro reproducibility.13
2. Retrograde menstruation
Another theory explores the concept that endometriosis is a result of transporting viable endometrial cells through retrograde menstruation, where cells flow backward through the fallopian tubes and then deposit on the pelvic organs where they continue to grow and respond to cyclical hormonal changes.2 These cells have an imbalance between pro- and antiapoptotic factors such as CD147. The microRNAs (e.g. miRNA MiR-191) have also been shown to be involved and inhibit tumor necrosis factor-α (TNF-α) apoptosis of ovarian endometriosis by targeting Death-Associated Protein Kinase (DAPK1) (Figure 2).14
3. Immunologic dysfunction
This concept in the pathogenesis of endometriosis involves interaction with the immune system (Figure 2).14 Research has indicated that women with endometriosis seem to have greater humoral immune responsiveness and increased macrophage activation with diminished cell-mediated immunity, reduced T-cell, and natural killer cell responsiveness. Humoral antibodies to endometrial tissue have also been found in the sera of women with endometriosis.15
a. Mast cell activation
An emerging field of study has focused on how activation of mast cells may contribute to endometriosis. Mast cells, the tissue cell of the immune system, mediate inflammatory responses such as hypersensitivity and allergic reactions and are found in many organs and connective tissues.16-18 These cells contain granules throughout their cytoplasm that store many different chemical mediators—including histamine, interleukins, proteoglycans (e.g., heparin), and various enzymes. When stimulated, these mediators are released (degranulation) and produce a local inflammatory response.19 Recent evidence indicates an increase in mast cell numbers in endometriosis tissues where they also appear to be activated and degranulated.20-22 These activated mast cells, and their products, could contribute to several features of endometriosis including pain and angiogenesis.23 Mast cell tryptase can activate protease activated receptors (PAR), particularly PAR-2.24 Research has shown PAR are expressed in endometrium and endometriosis, and activation of PAR-2 on cells may also participate in the pain processing and angiogenesis commonly seen in endometriosis.25,26 Mast cell tryptase has also been shown to activate myofibroblasts and contribute to fibrosis.9,10
It is also well known that histamine, released by mast cells, enhances tissue edema in addition to other—mostly untoward—effects. Activated mast cells release a number of proinflammatory cytokines, mediators, and growth factors and thus have the potential for potent, and varied, impacts on abnormally regulated tissues, such as found in endometriosis.15 Targeting mast cells with appropriate anti-inflammatory and immune-modulating therapies such as specialized pro-resolving mediators (SPMs) may be a future consideration for the management and treatment of endometriosis.27
b. Cytokines and chemokines
Cytokines and chemokines are also emerging as key players in endometriosis pathobiology. Cytokines are a broad group of secreted proteins important in cell signaling, while chemokines are a family of cytokines important in inducing chemotaxis in nearby cells.4 Research has shown these two proteins are altered in the peritoneal fluid, lesions, and serum of women with endometriosis, and increased levels of both cytokines and chemokines have been noted in fluid from chocolate cysts and endometriomas.4,28 However, large-scale controlled clinical studies or meta-analyses will have to be undertaken to fully understand the implications and interactions of cytokines and chemokines on endometriosis.
4. Other factors (genetic, environmental and gut dysbiosis)
Additional areas of emerging research into the etiology of endometriosis include genetic perspectives, possible associations with EDCs, and the impact of the gut microbiota on the estrobolome.
a. Genetic influences on endometriosis
Recently, research into the genetic and genomic aspects of endometriosis have been gaining interest, and data have revealed some insights into this condition. A review of the literature indicates research has found a familial predisposition to development of endometriosis; however, the genetics of endometriosis are intricate and remain largely unexplained, though many investigators believe it is inherited in a polygenic/multifactorial mode.29-31 This polygenic/multifactorial type of inheritance occurs when phenotype is determined by a combination of multiple genes and environmental effects.8,32 There are a number of factors that specifically make it difficult to determine the mode of inheritance of endometriosis. Primary among those is the fact that endometriosis can only be diagnosed invasively with laparoscopy or laparotomy.8 This may lead to underreporting of patients affected, as the diagnosis relies on an invasive test. Another contributing factor is that endometriosis may actually be a number of different disease processes, which can be seen by differences between in peritoneal, ovarian endometriomas, and deeply infiltrating endometriosis.
Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations that exist among individuals, differing only by a single nucleotide base pair and scattered throughout the human genome. SNPs are used as a marker to locate and delineate variations of genes associated with specific disease processes and to assess the genetic similarity between individuals.30 Genomewide association (GWA) studies have established certain SNPs associated with endometriosis disease, namely those found on chromosomes near WNT4, GREB1, VEZT, and KDR genes as seen below (Table 1):33
Prior data from GWAS had also revealed a significant association loci including rs7521902 (near WNT4), rs10859871 (near VEZT) and rs11031006 (FSHB gene) as additional endometriosis‑associated SNPs.34 Other GWAS have now identified 11 more independent SNPs for endometriosis.35 These SNPs, their location, and from which population/ethnic group are listed below (Table 2).
The association of the IL1A gene locus on 2q13 has also been recently confirmed by identifying GWA association between rs6542095 and endometriosis.35 This makes a total of 12 independent SNPs associated with endometriosis at the genomewide significance level—and all but one (rs10965235 in CDKN2BAS on 9p21.3, identified in the Japanese GWA study) are polymorphic in populations of European ancestry.28 Of the 11 European SNP risk loci, eight SNPs have been replicated and robustly implicated as susceptibility loci for endometriosis.28
Recently published findings from an Australian study identified 19 genetic variants associated with endometriosis, and many of those variants are also associated with other adverse health conditions including ovarian cancer, cardiovascular disease, and hyperlipidemia.36 In this meta-analysis of 11 GWA case control data sets, with over 17,000 participants diagnosed with endometriosis and 191,000 control patients, investigators identified five novel loci significantly associated with risk for endometriosis that implicated those genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two more at the ESR1 locus, resulting in 19 independent SNPs robustly associated with endometriosis.32
Genetic studies have demonstrated an increased frequency of the disease in close relatives with the type of inheritance that is most likely polygenic/multifactorial. Genomic studies continue to explore differences in gene expression and understanding the basic biology of the disease; future genomic studies may lead to new noninvasive diagnostic strategies as well as possible new therapies in the treatment of endometriosis.
b. Environmental impacts on endometriosis
Other potential complicating factors in the etiology of endometriosis are environmental exposures, such as dioxin and dioxin-like polychlorinated biphenyls (TCDDs and PCBs).8,37,38 Environmental factors including elevated levels of phthalate esters, persistent organochlorine pollutants, perfluorochemicals, and intrauterine exposure to cigarette smoke among others may cause endometriosis by inducing oxidative stress, altering hormonal homeostasis, or by changing immune responses (Figure 2).34,36 Exposure to chemicals from different sources in daily life is widespread, and one such source is the broad range of cosmetic products and sunscreens available to the general public.39 The main route of exposure is the skin, but the main endpoint of exposure is endocrine disruption. This is due to many substances in cosmetics and sunscreens that have endocrine-active properties that affect reproductive health but that also have other endpoints, such as cancer.37
The costs of the effects of environmental exposure are not only physical, but they can adversely affect health economics as well. Results from a study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism found that EDCs, which may contribute to reproductive health problems experienced by hundreds of thousands of women, costs the European Union an estimated $1.5 billion per year in healthcare expenditures and lost earning potential.40 The study examined rates of the two most common causes of infertility, uterine fibroids and endometriosis, as part of series of economic analyses, which included direct costs of hospital stays, physician services, and other medical costs.40 The researchers estimated that 145,000 cases of endometriosis and 56,700 cases of uterine fibroids in Europe could be attributed to exposure to endocrine-disrupting chemicals.40
Daily exposure to chemical and environmental pollutants adversely affect physiological processes. Many environmental pollutants have long half-lives and can accumulate in the environment and in living organisms; thus logically they could adversely influence the gestational process as well as health of children and adults.35
Figure 2: Proposed impacts of environmental factors and immune dysfunction on endometriosis etiology14
An analysis by the Environmental Working Group, a nonprofit organization specializing in the research and advocacy of environmental pollutants, revealed the presence of 287 different chemical agents in human umbilical cord and an important result: Although not all children have been exposed to all pollutants detected, the specific or combination effect of these numerous agents on the process or disease development in specific organs are known to be related to neoplasm development, immunological disorders, and neuropsychomotor and reproductive system changes.36 Further work through studies assessing time and degree of exposure, age group(s), and exposure to concomitant factors should be conducted to determine how all, or any, of these factors could contribute to endometriosis genesis.
c. Effects of gut dysbiosis and diet on endometriosis
One of the principal regulators of circulating estrogens is the gut microbiome. The microbiome has been shown to be influenced by estrogen; however, the microbiome also significantly impacts estrogen levels.41,42 The estrobolome is the collection of microbes capable of metabolizing estrogens; it modulates the enterohepatic circulation of estrogens and affects circulating and excreted estrogen levels.43 The estrobolome affects estrogen levels by the secretion of β-glucuronidase, which deconjugates estrogen, enabling it to bind to estrogen receptors and subsequently leading to its physiological effects downstream.44
When the gut microbiome is healthy, the estrobolome produces the appropriate amount of β-glucuronidase to maintain estrogen homeostasis. However, when gut dysbiosis is present, β-glucuronidase activity may be altered. This produces either a deficiency or an excess of free estrogen, thus promoting the development of estrogen-related pathologies.43
A healthy gut epithelial barrier is maintained by a diverse intestinal microbiome composed of four main phyla: Bacteroides, Firmicutes, Actinobacteria, and Proteobacteria.45 An imbalance of the gut microbiota is referred to as dysbiosis and has pathophysiological consequences, as it disrupts homeostasis by reducing bacterial diversity and increasing the Firmicutes/Bacteroides (F/B) ratio. This ultimately leads to an inﬂammatory response that is detrimental to gut epithelial health.39,40 Dysregulation of the intestinal microbiota, as evidenced by reduced microbial diversity, with a subsequent decrease in deconjugation may lead to reduction of circulating estrogens.39,41 This change in circulating estrogens may contribute to the development of numerous adverse health conditions including cancer, endometrial hyperplasia, and endometriosis.41
Emerging research findings, from preclinical and animal models, indicate that the estrobolome in endometriosis may have greater numbers of β-glucuronidase-producing bacteria, leading to increased levels of circulating estrogen, which in turn, drives endometriosis.9,46 Research findings that clarify the β-glucuronidase activity in the intestinal microbiota of endometriosis patients may provide additional mechanistic insights into the role the estrobolome plays in endometriosis.
Estrogens are also significant in the physiology and pathology of the gastrointestinal (GI) tract; SIBO has been considered a secondary GI condition that develops in the setting of altered intestinal anatomy, motility, and function. Several studies have shown the role estrogens play in the symptoms and pathophysiology of Irritable Bowel Syndrome (IBS) and/or SIBO, and recent data underscores that these conditions are increasingly linked to endometriosis based upon their female predominance, as well as the correlation, between symptoms of IBS and hormonal status during menstrual cycle phases, pregnancy, or menopause.47 The ratio of women to men with SIBO symptoms and diagnoses is currently understood to be 2:1.48,49 Several published studies have shown the most common symptom between all these conditions is “visceral hypersensitivity” (pain and bloating) reportedly due to the excess intestinal gas and fluid experienced by afflicted patients.46-48
In recent years, a considerable amount of research has shown that the type of diet consumed can significantly impact the intestinal microbiome; as the estrobolome is a part of the overall microbiome, it is also likely it will also be affected by the food(s) consumed. Specialized diets such as the low FODMAP (fermentable oligo-, di-, monosaccharides, and polyols) diet may be beneficial for those diagnosed with endometriosis as well as those with endometriosis and concurrent IBS.50 Results from a recent study published in the Australian and New Zealand Journal of Obstetrics and Gynaecology found in 160 women with IBS, 36% of whom had concurrent EMS, 72% reported significant improvement (> 50%) in symptoms after four weeks on a low FODMAP diet as compared to 49% improvement in those with no endometriosis.47 The researchers concluded that a low FODMAP diet appears to be most effective in those patients with concurrent gut issues and diagnosed endometriosis.46
Some studies have shown an overlap between celiac disease and endometriosis. The relationship is yet to be elucidated completely, but it has been thought the gut inflammation of celiac disease may trigger the onset (or worsen) the symptoms of endometriosis. This led to the idea that a gluten-free diet may be helpful in reducing endometriosis symptoms—whether or not there was concurrent celiac disease. In a study of 207 patients with endometriosis, 75% of participants reported significant reductions in symptom severity after 12 months on a gluten-free diet.51 They also reported improved mental health, social function, vitality, physical function, and perceived healthiness after following the diet.50
Other dietary strategies, which small studies have shown to have a beneficial effect in endometriosis patients, include assessing dietary fat consumption and ensuring intake of foods that mitigate the effects of chronic inflammation. In a recent study of nearly 71,000 women, researchers found that women who ate a diet high in trans fats were 48% more likely to endometriosis than those who ate the less trans fats.52 Other findings from this study concluded that women who consumed greater quantities of fats from animal products (particularly palmitic acid) had a 20% increased prevalence of endometriosis, and those who ate the most omega-3 fatty acids were 22% less likely to be diagnosed with endometriosis than those who ate the least.51 Even modest increases in omega-3 fat intake appear to be beneficial. The investigators noted that replacing one percent of calories from trans fats with omega-3 fats decreased risk by 50%.51 While the exact mechanism for the interaction between omega-3 fats and risk reduction of endometriosis is still unclear, it is known that these fatty acids reduce levels of cytokines and inflammatory lipid compounds such as prostaglandins.51
Common risk factors for endometriosis
Circulating estradiol and estrone, which stimulate ectopic and eutopic endometrial tissue, have been found to be elevated among women with an earlier age at menarche and in nulliparous women, particularly those diagnosed with endometriosis.2,8 A review of the literature indicates a considerable body of evidence demonstrating the estrogen dependence of endometriosis.2,53 The biosynthesis and bioavailability of estrogens depend on the balance between the production of active estrogens and their inactivation.52 This balance is determined by the activity of a large variety of enzymes involved in the conversion of androgens to estrogens, oxidative metabolism, the conjugation of estrogens, and the conversion of conjugated estrogens into nonconjugated steroid hormones.52 Most of these processes are present in the human endometrium, and some of them appear to be aberrantly regulated in the ectopic endometrium of endometriosis patients.52
The enzyme aromatase is responsible for the conversion of androstenedione to estrone and of testosterone to 17β-estradiol. Nobel and colleagues first demonstrated that aromatase mRNA and activity levels were increased in pelvic endometriosis implants, and confirmation of this early work by others supported the clinical concept of increased, localized aromatase activity with endometriosis and initiated the use of aromatase inhibitors for the treatment of endometriosis (and/or its symptoms).54-56
There are several other factors that have been linked to an increased, and decreased, risk for endometriosis. There has been considerable peer-reviewed published research demonstrating how poor dietary quality and nutritional intake, adverse environmental aspects, as well as concurrent GI issues and hormonal variations may all have a strong impact on the development of endometriosis. Additionally, data from emerging studies have implicated pain, stress, anxiety, and/or an aberrant hypothalamic-pituitary-adrenal (HPA) axis may also contribute to the adverse effects commonly seen in endometriosis.57-59
Chronic pain is considered a major cause of physical, psychosocial, and emotional impairment, and endometriosis is recognized to be source of physical and psychological stress.60,61 Research has demonstrated that emotional distress may contribute to the exacerbation of many chronic inflammatory disorders, including endometriosis.62 Women with endometriosis have consistently reported reduced quality of life, high levels of perceived stress and anxiety, and depressive symptoms, which are higher than those reported by patients with other chronic inflammatory disorders.63,64
Hypocortisolism has been reported in many chronic disorders including asthma, allergies, major depression, and a variety of chronic pain conditions.65,66 Specific to the pelvic pain associated with endometriosis and the HPA axis, studies have shown women with endometriosis have significantly lower salivary cortisol concentrations than controls despite maintaining a normal diurnal variation.52 One study further indicated that perceived levels of increased stress, along with poorer quality of life, correlated to reduced salivary cortisol levels.53
Results from a preclinical study showed that exposure to chronic stress accelerated the development of endometriosis and exacerbated the pain associated with the condition.67 This was followed up by a clinical study on 32 patients diagnosed with endometriosis. Quiñones and colleagues evaluated saliva samples from 32 patients with endometriosis and 36 healthy control women for salivary cortisol levels by colorimetric immunoassay.57 The participants also completed a series of psychological questionnaires. Findings of this small study showed significant differences in average cortisol levels between endometriosis patients and controls.57 Other results indicated a negative correlation between cortisol levels, infertility, and dyspareunia, and incapacitating pain was found to be a strong predictor of hypocortisolism. Furthermore, the participants with endometriosis reported increased levels of anxiety but showed no differences in perceived stress or in coping styles compared to the control group.57 The authors concluded that hypocortisolism may be considered a biomarker for the abnormal HPA responses commonly associated with endometriosis.57
Comorbid and chronic conditions such as asthma, allergies, autoimmune disorders, chronic fatigue syndrome, and ovarian and breast cancer have also been linked to endometriosis.11 In addition, research has also found associations between endometriosis and phthalate exposure and chemical sensitivities.68,69
Epidemiology & health economics of endometriosis
Endometriosis is a disease of adolescents and women of reproductive ages. Data have shown that this condition commonly presents with complaints of infertility and/or continued pelvic pain despite treatment with analgesics or oral contraceptive pills.70 Lifestyle factors and dietary modifications may influence risk for endometriosis by reducing inflammation and the inflammatory response, and research has shown that intake of oily fish and omega-3 fatty acids with increased physical exercise reduces inflammatory markers such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and c-reactive protein (hs-crp).71, 52
The hormonal impact on endometriosis can also been noted in the decline in the prevalence of the disease after menopause (unless HRT is begun during that life stage).72
Studies have shown the symptoms of endometriosis have, understandably, a substantial impact on the physical, social, and emotional wellbeing parameters of affected women.73,74 It has been estimated the annual total (direct and indirect) costs of this disease in the US is currently approaching $22 billion and rising steadily.1,75,76
As with most health conditions, a detailed and extensive history often helps the clinician determine the provisional diagnosis. Endometriosis is one of the most common, and chronic, conditions encountered by the gynecologist and is a leading cause of infertility.2,7 Clinicians should note that the clinical presentation of endometriosis depends on the location and extent of the disease, but the severity of symptoms does not correlate directly with the extent of disease.77
- Chronic and severe lower abdominal and/or pelvic pain—usually before and during menstruation
- Sometimes pain associated with increased sensation of intestinal upsets, bloating, gas, and pain
- Painful sexual intercourse—especially if endometriosis is present on bowel or bladder
- Pain may be reported during bowel or bladder evacuation
- Heavy and/or irregular menstrual bleeding
It should also be noted that a significant number (nearly 30%) of women with endometriosis are asymptomatic.78
Common signs & symptoms:8,7
- Tenderness and pain during physical (pelvic) examination usually at the time of menses
- Presence of tender and nodular masses along thickened uterosacral ligaments, posterior uterus, or posterior cul-de-sac
- Retroverted uterus may present with no/obliterated cul-de-sac and implies extensive disease
- Adhesions and obstruction may present with rectal and other gastrointestinal symptoms
Patients with widespread endometriosis, or in those with endometrial tissue at distant sites, may notice other focal symptoms of bleeding at the time of menstruation. For example, ectopic endometrial tissue in the lungs may produce features similar to hemothorax at time of menses.79
Staging of endometriosis
The American Society for Reproductive Medicine (ASRM) has classified endometriosis into four stages.80 These stages are based on the lesions, particularly on the number of endometrial implants and the depth that they extend into the supporting tissue.80,81 The ASRM classification includes a point system, which allows for numerical scaling of the disease and determine classification. A score of ≤ 15 indicates mild or minimal disease. A score of ≥ 16 may suggest moderate or severe disease. Clinicians should recognize that disease scoring does not necessarily reflect pain level or symptoms.8,82 Due to every numbered stage per the ASRM’s classification’s having many subjective variations, which do not specify location or patient pain perception, another organization, the Endometriosis Foundation of America (EFA), has developed more descriptive categories for endometriosis. These are classified according to anatomical location in the abdomen and pelvis. Both staging classifications are below (Table 4):3,80
Table 4. Comparison of EMS staging by ASRM and EFA standards3,80
Research shows that endometriosis is the underlying cause of 15% of all cases of pelvic pain and should be considered in those female patients of reproductive age who complain of chronic pelvic pain and do not respond to standard nonsteroidal anti-inflammatory (NSAID) pharmaceutical measures or oral contraceptives.8,2 Differential diagnoses should include:
III. Work up
At this time, though there are no specific laboratory tests that can conclusively support a diagnosis of EMS, they can help rule out some differential diagnoses. Imaging tests such as x-rays are not valuable and not recommended; pelvic ultrasonography, computerized tomography (CT) scanning, and magnetic resonance imaging (MRI) are only beneficial in cases of advanced disease, cyst formation, or in cases of severe anatomical distortion (Table 5).7,8,22
In cases with extragenital involvement (e.g. kidney, bladder, colon) it may be useful to consider intravenous pyelography or colonic studies.8 Patients should also be evaluated for concurrent chronic gut or intestinal issues such as SIBO, IBS, or Crohn’s disease as recent research has shown a strong link between symptomology and pathophysiology of these conditions.46,47
Table 5. Suggested work up for patient with endometriosis83
Potential diagnostic biomarkers for EMS listed below (Table 6) may be useful as noninvasive diagnostic tools that could be utilized early in the course of the disease and possibly delay its progression.69
Table 6: Potential diagnostic biomarkers for endometriosis70,84,85,86,87,88
IV. Management & treatment options
EMS is a progressive and chronic disease of women in their reproductive years; management and treatment options should be individualized based on patient age and desire for future fertility. At this time, there are no known methods to prevent endometriosis by conventional medical means, but some evidence suggests if the disease is caught early enough, quick and aggressive medical or surgical intervention may control its progression.8
Conventional medical management
As pain is often the primary presenting complaint, and due to the dependence of endometriosis on a woman’s cyclical menstrual hormone production, noninvasive medical management is often the first line of therapy employed by conventional medical practitioners.8 Initial management with NSAIDs is the primary treatment of choice.4,27 Continued symptoms of pain and excess bleeding during menses are considerations for physicians to utilize hormonal treatments along with ongoing analgesics. These hormonal options can include:
- Continual cyclical oral contraceptives: to induce shorter, lighter menses
- Gonadotropin-releasing hormone (Gn-RH) agonists and antagonists: to lower estrogen levels, prevent menses, and shrink endometrial tissues
- Progestin therapy: includes intrauterine devices, injections, or pills to stop menses entirely and reduce swelling of endometrial implants
- Aromatase inhibitors: to reduce serum estrogen levels and reduce pain from implants
Conventional medical physicians usually utilize 1-2 cycles of NSAIDs plus hormones to see if symptoms abate or resolve. If symptoms continue despite this, then surgery is often the next recommended step.26,25
Surgical intervention for endometriosis is selected in those patients with severe symptoms and when hormonal therapy is not providing sufficient relief. Data indicate 44% rate for recurrence of pain after surgery compared to 53% rate of pain recurrence following medical management.89,90 Diagnostic laparoscopy, usually with biopsy, is undertaken (if it has not been performed previously) to definitively determine endometriosis and also establish the extent of the disease by stage or category.8,14,27
The type of surgical intervention may be decided by age, desire for childbearing, and existing quality of life that the woman is facing:1,3,8
- Conservative surgery (laparoscopic): Aims to destroy as many endometrial implants that are visualized as well as to reduce adhesions that are sources of pain. This method helps maintain fertility.
- Semiconservative surgery: For women who have completed childbearing but are yet too young for surgical menopause. Hysterectomy plus reduction of endometrial implants is undertaken in this intervention.
- Radical surgery: Total hysterectomy with bilateral removal of ovaries (TAH-BSO), this intervention leads to surgical menopause and may involve additional surgical repairs to bowel, bladder, or ureters if endometrial implants are deep in these organs.
Options for management and treatment of endometriosis are also undertaken by the more integrated modalities of holistic medicine employed by practitioners of integrative, lifestyle, Functional, or naturopathic medicine. Central to these practitioners is the detailed assessment of their patient’s dietary intake including all supplements and exogenous nutrient consumption. Furthermore, the concept of increased physical activity and exercise is an important part of not only physical health but also improved cognitive and psychological functioning.
Lifestyle, naturopathic, Functional Medicine, and/or integrative management
Exercise, mitigating the effects of environmental toxins, reducing stress, and modifying dietary intake all form the foundation for the patient management plans utilized by the naturopathic, integrative, or Functional Medicine provider when treating chronic diseases. Many, if not all, of these practitioners recommend techniques for stress reduction, nutritional and/or botanicals supplementation, and the judicious use of pharmaceuticals (as required) for their patients with endometriosis.
Low-fat, vegetarian, or plant-based diets have been shown to increase sex hormone-binding globulins (SHBG), which, in turn, result in fewer free hormones, and the reduction in fat leads to reductions in serum estrogen levels.91,92 Increased exercise can lead to weight loss as well as providing psychological benefits. Supplemental nutrients are frequently recommended in the management of endometriosis. Certain targeted nutrients and nutritional bioactives for consideration, along with their biological mechanisms, include:93
- Flaxseed lignans and non-soy phytoestrogens: to provide healthy estrogen balance and metabolism by supporting enzymatic function in estrogen detoxification
- Calcium D-glucarate: inhibits β-glucuronidase
- Zinc: beneficially influences activity and genetic expression of metallothionein, reduces oxidative stress, and has been associated with healthy testosterone levels
- Folate, vitamin B6 and vitamin B12: improving and maintaining healthy cardiovascular health and healthy homocysteine levels to support cognitive functioning
- Magnesium: critical for proper biochemical functioning of numerous metabolic pathways
- N-Acetylcysteine (NAC): a glutathione precursor, NAC has been shown to be protective against reactive oxygen and nitrogen species and improve overall redox status by influencing signaling molecules
- Vitamin C: a powerful antioxidant
- Curcumin: may beneficially influence some Phase II detox enzymes as well as being a potent antioxidant and anti-inflammatory bioactive
- Silymarin (milk thistle seed): supports healthy hepatic functioning
Additional data regarding the significance of nutrient intake and improved outcomes in endometriosis comes from a very recently published study by Italian and Swiss researchers.94 Led by Professor Roberto Marci, MD, from University Hospital, Geneva, Switzerland, the multinational research team conducted a comprehensive review of over 390 publications on the effect of diet and nutrients on endometriosis. In this seminal publication, the authors pinpointed several common food and nutrients that have been studied as potential influences in the pathogenesis of endometriosis (Figure 3). The investigators noted that the area of research regarding diet and endometriosis remains an emerging one, and many confirmatory studies are still necessary to definitively link dietary changes and improved outcomes in endometriosis; however, the global interest and potential benefits in of food on endometriosis outcomes may be worth the effort.95
Many integrative and/or Functional Medicine physicians utilize additional labs in their patient workup that can include adrenal function tests as well as genomics and toxins testing. HPA axis dysfunction (also known as “adrenal fatigue”) refers to a combination of signs and symptoms including brain fog, fatigue, sleep disruption, low libido, and reduced stress tolerance. Adrenal fatigue is thought to be due to the effects of a modern lifestyle including poor diet, sleep deprivation, chronic stress, and inflammation.95
Traditionally, salivary testing was used to measure adrenal stress via free cortisol but cannot capture cortisol metabolites. To assess more detailed cortisol information, oftentimes the Dried Urine Test for Comprehensive Hormones (DUTCH) test—a comprehensive assessment of sex and adrenal hormones and their metabolites including daily, free cortisol, organic acids, and melatonin to name a few—is one used by these practitioners.96,97 There are several variations of this test that can include salivary measurements of cortisol (for HPA axis) as well as tests for specific metabolites.98
Figure 3: Common foods and nutrients potentially involved in development of endometriosis94
A listing of various management and treatment options, whether conventional, lifestyle, integrative, Functional, and/or natural are below (Table 7).
Table 7. Summary of recommended treatment options for endometriosis4,8,14,29,93,94
As always, it is recommended that all conventional and integrative, Functional, and natural therapies be taken, and managed, under healthcare provider (HCP) supervision. Lifestyle modifications can—and should—be added to conventional, integrative, Functional, and natural medical therapy options, but caution and monitoring by the HCP should be ensured before combining pharmaceuticals with supplements and botanicals to avoid any possible interactions or adverse events.
V. Future directions in endometriosis
Endometriosis is a common, yet enigmatic, gynecologic disease process affecting 6-10% of women during their reproductive years.1,2 It is a chronic, inflammatory condition that is characterized by pain and infertility and often accompanied by anxiety.2 As endometriosis is accompanied by an estimated annual cost in the US of $12,419 per affected woman, comprising one-third of the direct healthcare costs and two-thirds attributed to loss of productivity, research into this debilitating health condition must be undertaken to fully understand it and to develop comprehensive, effective, and safe treatment protocols.99
As endometriosis is an estrogen-dependent disease, current, conventional, and nonsurgical treatments have focused on reducing the levels and/or actions of estrogen by use of oral contraceptives, progestin analogues, gonadotropin-releasing hormone (GnRH) agonists and antagonists, levonorgestrel-releasing intrauterine devices, as well as aromatase inhibitors.4 All these noninvasive measures have been somewhat useful in some women but are still not effective or tolerated in larger numbers of affected patients.100
Future directions for management and treating endometriosis should be aimed at a personalized, targeted approach. Not all women with endometriosis present in the same manner with the same complaints or symptoms, and not all women will respond equally; treatment options in this chronic, inflammatory, and estrogen-dependent condition should be individualized based on comprehensive history, testing, and evaluation for optimal outcomes.
As more peer-reviewed publications indicate research supporting a genetic predisposition for endometriosis and data reveal more SNPs, the area of genetic and genomic research into endometriosis may help to target the condition earlier in susceptible patients and in those not responding to established therapies, which could lead to opportunities for earlier intervention and potentially improved outcomes.31,34
The impact of the microbiome on overall health is an area gaining interest among researchers and practitioners alike. The literature details the association of endometriosis with chronic GI conditions. By mitigating the symptoms of comorbid gut conditions through dietary changes and improved nutritional intake, data show a concurrent decrease in endometriosis symptoms.48,49 This area of research in the future could provide options for new, and targeted, treatments and recommendations.
An increasing body of evidence has shown that endometriosis is a chronic inflammatory condition, which supports the consideration for new possibilities and treatment options that act by blocking, or in some cases, resolving the inflammatory processes.27 Specialized pro-resolving mediators (SPMs) are a large and growing class of cell-signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes.27 Preclinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation.27 While studies have not yet determined the efficacy of SPMs in endometriosis, recent data on other chronic inflammatory conditions have suggested this area of research may be one to consider in the near future.
As greater numbers of patients seek more involvement in their healthcare and with a growing interest in managing and treating chronic conditions by less invasive measures or pharmaceuticals—often the preferred methods used by conventional practitioners, including us as we went through our medical training—future directions in managing endometriosis will be increasingly focused on an integrative, Functional, and personalized approach. Our hope is that offering patients Functional Medicine approaches such as a low-FODMAP food plan, supplements that support estrogen metabolism and detoxification including NAC, vitamin D, and others, in conjunction with conventional medical approaches, will be the wave of the future in this debilitating disease of reproductive-aged women.
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Sara Gottfried, MD
Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.
Dr. Gottfried is the President of Metagenics Institute, which is dedicated to transforming healthcare by educating, inspiring, and mobilizing practitioners and patients to learn about and adopt personalized lifestyle medicine. Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She has written three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and her latest, Younger: A Breakthrough Program to Reset Your Genes, Reverse Aging, and Turn Back the Clock 10 Years.
Kirti Salunkhe, MD
Kirti Salunkhe, MD originally trained and practiced in India as an Ob/Gyn, later joining Intermountain Healthcare in Salt Lake City, Utah, as a research physician in the Interventional Cardiology division. She was a member of University of Utah’s Selection Committee for medical students and postgraduate advisor at the College of Nursing. Dr. Salunkhe was actively involved in industry-sponsored and original clinical research activities and mentoring research assistants, and she founded a pilot program increasing awareness of heart health in women and special populations of the Intermountain region.
Dr. Salunkhe has served as Sr. Medical Director for medical marketing and communications divisions of WPP, Interpublic Group, and Publicis—the top 3 global advertising holding companies—developing academic programs, digital initiatives, and other enduring materials for peer-to-peer education, publications, and promotional strategies in Cardiology, Nutrition, and Women’s Health. Most recently, Dr. Salunkhe was Sr. Director, Medical Affairs for Metagenics and the Metagenics Institute and Director of the former Functional Medicine Research Clinic in Gig Harbor, WA. Dr. Salunkhe has published in numerous peer-reviewed journals, coauthored several book chapters, and presented original research at both national and international conferences.