Endometriosis Part 1: Complex Etiology and Diagnosis

Dr. Bethany Mattson, ND

Endometriosis is a common and complex inflammatory gynecological condition that many women suffer with and do not often receive a timely or correct diagnosis. Endometriosis occurs when endometrial glands and stroma are found outside of the uterine cavity. Ectopic tissue can be found in many locations including the ovaries, fallopian tubes, broad ligaments, bowel, and pleural cavity. Endometriosis mainly affects reproductive aged women 25-35 years old and effects 15-20% of the general population. 

The hallmark symptom that occurs with endometriosis is chronic pelvic pain. Additional symptoms can include:

• Dysmenorrhea
• Bladder pain
• Abnormal uterine bleeding
• Low back pain 
• Fatigue 
• Ovarian mass 
• Infertility 
• Diarrhea, constipation, and abdominal bloating

There are many factors that increase the prevalence of endometriosis including early menarche, nulliparity, family history, menstrual cycles less than 28 days, low body mass, and consumption of a high fat diet.

Etiology:

Pelvic adhesions and scaring are common in moderate to severe endometriosis. Adhesions are bands of scar tissue that can fuse two structures together. The bands found in endometriosis patients contain scar tissue, endometrium glands, and inflammation. The most common locations for endometriosis adhesions are between the ovaries and fallopian tubes, uterus, between the bowel, and between the recto-vaginal septum. The mechanism of formation may include inflammation produced by the estrogen-dependent ectopic tissue and resulting proliferation and neovascularization.

Endometriosis is typically categorized as an estrogen-dependent condition, but there are much wider etiology theories that are reflected in the literature involving the immune system, the gut/vaginal microbiome, and the complex interplay between genetic and epigenetic factors. 

There are several current proposed theories for the pathophysiology of the condition including metaplasia of endometrial tissue, metaplasia of ovarian mesothelium, and immunologic defects. The most widely recognized theory of etiology is Sampson’s theory of reflux menstruation. This theory proposes that endometrial tissue travels backwards through the fallopian tubes and into the peritoneal cavity during menstruation. 

However, the theory of reflux menstruation isn’t the full picture, because many women without endometriosis can experience reflux menstruation and the body is able to clear the tissue. A deeper dive into the etiology of endometriosis offers clues such as a core underlying immune dysfunction. 

The Immune System and Endometriosis:

Chronic inflammation and changes in immune response are common in endometriosis. An increased immune response can cause a build-up of inflammatory cytokines, prostaglandins, and decreased macrophage activity, which in turn increase growth and proliferation of ectopic tissue. There is documented immune dysfunction present in patients with endometriosis including polyclonal B-cell activity, decreased T-cell reactivity, reduced natural killer cell activity, and increased immunoglobulin antibody production, which may allow endometrial tissue to adhere and proliferate. 

There is a known correlation between endometriosis and other autoimmune conditions, but a causal association has not been established yet in the literature. Several anti-endometrial antibodies including anti-SLP2, anti-PDIK1L, anti-TMOD3 are currently being studied as potential laboratory markers for enhanced endometriosis diagnosis. There is also a strong association between endometriosis and other autoimmune conditions such as Hashimoto’s thyroiditis, Sjogren’s syndrome, and multiple sclerosis. 

Gut Health and the Microbiome:

Gut health greatly impacts immune function and is another key area of research for endometriosis etiology. The gut and immune system are closely interconnected through the gastrointestinal-associated lymphoid tissue and can activate adaptive immune function. Although endometriosis is not yet formally classified as an autoimmune condition, there is a known link between gut dysbiosis and immune dysfunction, and women with endometriosis often experience both. 

There is also a bidirectional link between endometriosis and the microbiome. The microbiome can be altered in patients with endometriosis, with overgrowth of many bacteria including Proteobacteria, Enterobacteriaceae, Streptococcus, and Escherichia coli species. In addition to gut microbiome disruptions, there are also known disruptions in the vaginal microbiome in patients with endometriosis. Elevated Gardnerella and decreased Lactobacillus species were associated with subfertility in patients with endometriosis. These bacteria produce inflammation and an endotoxin lipopolysaccharide (LPS), which is involved in the “bacterial contamination hypothesis” that has been getting more attention in the literature.  

There are also associations between endometriosis and other gut disorders such as irritable bowel syndrome (IBS), small intestinal bacterial overgrowth (SIBO), and inflammatory bowel disease. 

*A 2020 meta-analysis found that IBS occurred at a doubled rate in patients with endometriosis!

Environmental Exposures (in utero and beyond):

The role of environmental toxins and endocrine disrupting chemicals also have a place in the endometriosis etiology discussion. Environmental toxins not only affect hormonal health and can promote excess estrogen exposure, but these toxins affect the immune system and increase inflammation as well, which in turn further damages the gut lining… which then further causes an increased immune and inflammation response! It’s all connected and all important when moving towards diagnosis and management of endometriosis. 

Diagnosis: 

Endometriosis can be difficult to diagnose because laparoscopy is needed for a formal diagnosis. Additionally, a clinical diagnose can be challenging when a patient may not present with classic endometriosis symptoms or may even be asymptomatic. When symptoms are present, diagnosis is easier but still complex. Endometriosis has been diagnosed in 70% of women with pelvic pain, 50% of women with infertility, and 40% of women with genital tract abnormalities. 

Pain that worsens during menstruation is a key component of the history that needs to be identified. Lab markers that can help rule in (but not rule out) endometriosis include CA-125, inflammatory markers such as c-reactive protein, and vitamin D levels. 

It is also important to note that the degree of severity of lesions does not often correlate with the degree of pain a patient may be feeling. Many women are under-diagnosed with endometriosis because they are either accustomed to chronic severe pain, or because they have been dismissed by the healthcare system. If a patient presents with cyclic pelvic pain, compassionate and comprehensive care can go a long way for a chronically underserved population. 

Management Approach: 

Focusing on the key proposed areas of etiology can help guide best treatment options. The natural approach to endometriosis treatment includes:

• Reducing environmental exposures
• Reducing inflammation
• Optimizing gut health
• Immune support
• Dietary intervention 
• Chronic pain management

In general, natural treatment options for endometriosis focus mainly on lifestyle modifications and restoring foundations of health. Exercise, stress reduction, and detoxification are often recommended. Because of the increased inflammation and immunological response seen in endometriosis, an anti-inflammatory diet that is high in antioxidants is recommended. Diets high in antioxidants such as selenium, vitamin E, and vitamin C can help limit the formation of reactive oxygen species and repair cellular damage. Supplementation with antioxidants may also be beneficial in reducing the reactive oxygen species and inflammation. 

Diving deep into hormonal balance and gut health can help expand the treatment plan and uncover root imbalances for patients. Functional testing including a DUTCH hormone panel and stool microbiome testing can provide a deeper evaluation and better guide treatment choices. For example, if excess estrogen is a consideration for a patient, the DUTCH test can provide estrogen metabolite information including which detoxification pathways are being utilized. 

Conclusion:

The etiology of endometriosis is likely multifaceted and involves a complex interplay between hormones, the immune system, gut health, and underlying genetic predisposition. Timely and accurate diagnosis can help guide treatment options and provide patients with a roadmap forward to achieve goals including reducing pain and inflammation and achieving healthy pregnancies. There are many lifestyle and nutritional factors that can help minimize symptoms and help patients suffering from endometriosis lead more balanced lives.