Note to the reader: This literature review was written in 2015 for a course at UMaine Orono (BIO 208), from the perspective I had at that time. An updated review is in order, as these references are now beyond the 5-year mark. The paper was written using APA formatting rather than my current standard AMA formatting, I actually prefer seeing the authors' names and dates of publication as I read, as it helps me to assess the source material.
Endometriosis is a chronic pelvic inflammatory condition that currently affects 5 million (womenshealth.gov, 2015) to 6.5 million American women (Endometriosis Association, 2015). It was first described in 1927 (Nothnick et at., 2001). Each month during a menstrual cycle, the uterine lining, called the endometrial lining, sheds. For some women, endometrial cells implant outside the uterus, an event called retrograde menstruation. This tissue attaches to other organs and tissues, such as ovaries, fallopian tubes, ligaments, and other parts of the abdominopelvic cavity (Endometriosis Association, 2015). It can cause a great deal of pain during monthly cycles, intercourse, excretion, as well as fatigue, irregular menstruation, and infertility (Endometriosis Association, 2015). It can also cause pain during daily movement and impede normal physical activity.
I chose to investigate this topic because it is personal for me. I had surgery for endometriosis in 2012, and had many of these symptoms prior to surgery. I also experienced the aftermath of treatment with suppressive hormone therapy (lupron). In addition, throughout the past ten years I have been diagnosed with many food intolerances that challenged my immune system, and I dealt with chronic bronchitis and chronic fatigue. I became interested in the link between endometriosis and autoimmune reactions to food when a fertility specialist mentioned a possible link between the two, and as the scientific community has become more aware of the systemic problems that chronic inflammation can cause. This paper comprises a literature review of five research papers regarding endometriosis as an autoimmune disorder.
Sinaii and colleagues (2002) reported high rates of autoimmune and endocrine conditions in women with endometriosis in a large (over 3,600 participants) survey conducted by The Endometriosis Association. These women, a largely white population of childbearing age, had significantly (statistically) higher rates of hypothyroidism (low thyroid hormone production, affecting body metabolism), fibromyalgia, chronic fatigue syndrome, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, multiple sclerosis, allergies, and asthma (Sinai et al., 2002). These women also had higher rates of infertility, which is known to accompany endometriosis. Particularly, women 35-44 years of age with both endometriosis and autoimmune inflammatory diseases had the highest infertility rates (Sinai et al., 2002). Debilitating pain was reported in a statistically significant number of endometriosis cases as compared with the general population, and the researchers found that it took on average 10 years from symptom onset until a diagnosis was made (Sinai et al., 2002). The authors (Sinai and
colleagues, 2002) suggest that there could be a genetic basis (based on familial tendencies) for endometriosis and hope that further study enables earlier diagnosis and treatment.
Another study focused on the inflammatory irregularities of endometriosis, a common factor between this disease and many of the autoimmune conditions with which it is associated. Maybin and colleagues (2011) studied inflammatory pathways in endometrial disorders and compare these with the normal inflammation that occurs in a monthly cycle. Normal monthly menstrual cycles involve cyclic, predictable inflammation, but during endometriosis the inflammatory cycle exhibits irregularities. There is a window of time during a normal menstrual cycle when the endometrium is receptive to implantation by a blastocyst, and during that time it undergoes extensive remodeling, characterized by preceding estrogen exposure followed by high progesterone levels (Maybin et al., 2011). Immune cells, cytokines, and growth factors, as well as hormones, play a role in endometrial remodeling and blastocyst implantation. If pregnancy does not occur, the endometrium is shed, a process that also involves both hormonal and immune factors. These events are particularly characterized by a drop in progesterone, which is the catalyst for inflammatory mediators and matrix metalloproteinases (MMPs) that break down the endometrial lining (Maybin et al., 2011). Leukocyte, neutrophil, and macrophage levels rise during this time, and are responsible for the inflammatory response, but also help to repair the endometrium. The authors (Maybin et al, 2011) suggested that progesterone withdrawal may indirectly regulate these immune cells. Research has shown that progesterone withdrawal, rather
than an estrogen-rich environment, may be responsible for endometrial repair after normal
menses. Maybin and colleagues (2011) hypothesized that decreased fertility in women with endometriosis could be related to increased inflammation that affects ovulation and implantation. This research linked compromised endometrial remodeling and an incomplete transition from proliferative (ovarian follicle maturation) to secretory (corpus luteum secretes progesterone after ovulation) phases within the endometrium to a hyper-inflammatory environment (Maybin et al., 2011). Increased macrophages and cytokine expression (interleukin-6), as well as down-regulation of MUC-1 and osteopontin (implantation factors) have also helped researchers to understand the infertility associated with endometriosis (Maybin et al, 2011).
Barrier (2010) performed a literature review of research covering endometriosis and autoimmunity, focusing on clinical associations between the two conditions, antibody autoreactivity, and inflammation and autoreactivity. He found that associations have been made between endometriosis and patients with the following conditions: headaches, joint and muscular pain, allergies, eczema, hypothyroidism, fibromyalgia, chronic fatigue, and a tendency to develop candidiasis. Barrier (2010) reported that patients with systemic lupus erythematosus and endometriosis have similar symptoms. In population studies of women with endometriosis, higher rates of hypothyroidism, rheumatoid arthritis, Sjogren syndrome, multiple sclerosis, asthma, and allergies have also been found. Barrier (2010) noted that a small study involving a Spanish population detected no connection between women with lupus, Sjorgren syndrome, and endometriosis. Studies have found antinuclear antibodies and autoantibodies in the fluids of women with endometriosis, but Barrier (2010) cautioned that “their presence is not exclusive of these conditions,” and “their role in the development of autoimmunity is still unclear.” Barrier (2010) also related that endometriosis has been associated with activated immune cells and local inflammation. A normal immune response occurs during the luteal phase when progesterone levels are low, and endometrial tissue has been associated with the same cytokines, but in an abnormal fashion (Barrier, 2010). Barrier (2010) also reported studies that found an abnormal lack of progesterone receptor expression in endometrial tissue, which he postulates could stimulate a chronic inflammatory environment. Progesterone is well known to be anti-inflammatory in nature (Aisemberg et al., 2013). Barrier (2010) concluded by saying that although there are similarities between autoimmune conditions and endometriosis, he believes that there is not a strong association.
Nothnick and colleagues (2001) performed a literature review on autoimmunity as a possible factor in the development of endometriosis, comparing pathological similarities between endometriosis and autoimmunity. This paper's authors sought to better understand the local biochemical environment in females with retrograde tissue implantation in an attempt to decipher what factors cause endometriosis symptoms to develop in some women with retrograde menstruation, but not others. Altered immunity and autoimmunity have been considered possible factors. Autoimmunity as a mechanism for endometriosis was a theory first postulated by Gleicher and colleagues (1987). At the time of this review (Nothnick, 2001) no studies had been done to confirm the disease as autoimmune, but evidence suggested many similarities between endometriosis and autoimmune disorders, including increased inflammation, tissue-remodeling biochemicals, cytokine levels (such as tumor necrosis factor-alpha), as well as altered apoptosis, which is programmed cell death (Nothnick, 2001). Women with endometriosis have demonstrated alterations in cell-mediated immunity (T cells), but studies have been inconsistent in their results regarding this immunity. Women with endometriosis have the following: reduced peripheral plasma lymphocytes in the presence of endometrial antigens, decreased cytotoxicity of these lymphocytes to endometrial cells, and increased ratio of T-helper to T-suppressor cells in peripheral blood and peritoneal fluid (although some studies show no differences here). Nothnick and colleagues (2001) hypothesized
that differences in results may have arisen from variable methodology and variability within participant populations. Peripheral and peritoneal natural killer cells showed less cytotoxicity in women with endometriosis, but levels of these cells were increased, decreased, or unaltered. Peritoneal fluid and sera from women with endometriosis reduced natural killer cell activity in laboratory experiments (Nothnick et al., 2001). Peripheral monocytes and peritoneal macrophages were also altered in women with endometriosis, with some studies showing increased activation of monocytes, and others showing increased number, concentration, and activation of macrophages (Nothnick et al., 2001). Increased levels of macrophages were associated with the release of growth factors and cytokines, which were thought to stimulate growth, implantation, remodeling, and angiogenesis of endometrial tissue. Humoral-mediated immunity (B cells) is also altered in women with endometriosis, with some studies showing altered antigen-antibody reactions, decreased B-cell activity, and autoantibodies for immunoglobulins G and A.
Matarese and colleagues (2003) joined the debate about whether endometriosis can be better described as an autoimmune dysfunction or a product of natural immunity irregularity. This paper presented two hypotheses: implantation and metaplasia theories. The implantation theory suggested that retrograde menstruation and implantation outside the uterus was the main stimulus for endometriosis development; the metaplasia theory postulated that hormonal transformation of peritoneal cells was the main stimulus. The authors (Matarese et al., 2003) indicated that the body of evidence supported the implantation theory, and that the local biochemical environment (production of TNF-alpha, IL-1, IL-6, and IL-8) could promote the implantation and growth of endometrial cells. Peripheral and peritoneal macrophages appeared to be involved with regulation of the pathogenic microenvironment, and were in an activated state during endometriosis. Researchers, at the time of this review, were not sure whether the presence of retrograde endometrial tissue caused a greater immune response, or had greater success implanting because the microenvironment was already altered (Matarese et al., 2003). It appeared that the physical qualities of women with endometriosis (genetic and acquired) also increased the chances for retrograde endometrial tissue implantation, growth, and survival. These authors cited several studies that demonstrated reduced cytotoxicity in peripheral and peritoneal NK lymphocytes. Researchers postulated whether lower NK activity was either constitutive (the genetic basis of a person’s constitution) or occurred as part of the altered inflammatory response during endometriosis. Nevertheless, they found that treatment with gonadotropin-releasing hormone (GnRH) restored NK activity in patients with endometriosis, suggesting hormonal interplay (Matarese et al., 2003).
According to Matarese and colleagues (2003) endometriosis has displayed many characteristics of autoimmune dysfunctions: tissue damage, autoantibody production, association with other autoimmune disorders, and repeated immune-mediated abortion. Although autoimmune disorders have been grouped together and poorly understood, they have displayed the common characteristics of altered T- and B-lymphocyte activation, and antigen-presenting cells such as macrophages and dendritic cells that presented to autoreactive T-cells produced by the host body. These researchers (Matarese et al., 2003) noted that increased T- and B-lymphocyte activity contrasted sharply with decreased NK cell activity. However, they explained that there are two branches of the immune system: natural (innate) immunity mediated by granulocytes, monocytes, and macrophages, that do not require activation to fight invaders, and adaptive immunity which is antigen-specific T- and B-cell production of cytokines and antibodies following activation, and offer lifelong protection against specific pathogens (Matarese et al., 2003). NK cells acted as a bridge between these two domains, sharing characteristics of both. Matarese and colleagues (2003) explained that NK cells might have been less effective at killing endometrial cells with self-antigens, but increased the presentation of these cells to autoreactive T-cells. These authors (Matarese et al., 2003) concluded that endometriosis can be considered an autoimmune disorder with immune and hormonal dysfunction based on the evidence supporting this view. They suggested that endometriosis provides an ideal model for studying the interface between natural and adaptive immunity, since so many of the immune factors involved with the pathogenesis of endometriosis hover along the overlap between these two systems; they also suggested that studying the immune aspects of the endometriosis could lead to new and more effective treatments for this pathogenesis, in addition to the already-effective hormonal and invasive surgical methods (Matarese et al., 2003).
In summary, Sinaii and colleagues (2002) found that women with endometriosis also have higher rates of autoimmune conditions. Maybin et al., (2011) presented the normal inflammation and immune reaction that occurs in the body during menses and progesterone withdrawal, and showed that endometriosis is associated with the same biochemical mediators, but in an abnormal, altered fashion. Nothnick and colleagues (2001) presented a review of research that demonstrated altered inflammatory and immune activity in women with endometriosis, including decreased NK cells and increased presence of autoantibodies and T-cells. Matarese and colleagues (2003) explained their support for the implantation theory, but pondered whether the endometriosis had greater success implanting due to an already altered biochemical environment, or whether the implanted tissue created that altered local environment. They suggested that endometriosis has a genetic, familial basis, and can be observed in the physical traits of women with endometriosis (Matarese et al., 2003).
In conclusion, researchers have found many links between endometriosis and autoimmune
conditions, but the scenario is complex, and much more knowledge is needed before new treatments are available. Endometriosis has many of the same characteristics of autoimmune dysfunction, with inflammation being the primary hallmark of the two. Local inflammatory environments triggered by increased monocyte and macrophage levels, increased pro-inflammatory cytokines such as tumor necrosis factor-alpha (and others), greater number of T- and B-lymphocytes, and decreased NK cells are characteristics of endometriosis, as well as many autoimmune conditions. Scientists continue to attempt to better understand the relationship between the complex genetic and biochemical factors involved with the etiology and pathogenesis of endometriosis, but cannot agree whether endometriosis should be considered an autoimmune disorder. There are marked similarities, but are these initiated by underlying factors that cause and sustain both conditions, or does one of the conditions create the ideal local environment for the other to develop? Regardless, it is extremely important to note that women with endometriosis have higher rates of autoimmune conditions, and that there is some association between the two. As researchers learn more about endometriosis and autoimmune conditions, scientists get closer to developing more effective treatments to allay the painful physical and emotional ramifications of endometriosis. For people like me, this accumulation of knowledge, small but sure, is very personal. And it may take years before the knowledge gathered by science in this very specific area of study yields any results beneficial to patients, but it will be gratifying nonetheless to know that others’ future suffering might be lessened by advances made today.
References
Aisemberg, J., Vercelli, C.A., Bariani, M.V., Billi, S.C., Wolfson, M.L., and Franchi, A.M.
(2013). Progesterone Is Essential for Protecting against LPS-Induced Pregnancy Loss. LIF as a Potential Mediator of the Anti-inflammatory Effect of Progesterone. PLoS One, 8(2):e56161. Retrieved on April 25, 2015, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567061/
Barrier, B.F., (2010). Immunology of Endometriosis. Clin Obstet Gynecol, 53(2):397-402.
Matarese G., De Placido, G., Nikas Y., Alviggi C. (2003). Pathogenesis of endometriosis: natural
immunity dysfunction or autoimmune disease? Trends Mol Med, 9(5): 223-228.
Maybin, J.A., Critchley, H.O.D., and Jabbour, H.N. (2011). Inflammatory pathways in
endometrial disorders. Mol Cell Endocrinol, 335: 42-51.
Nothnick, W.B., (2001). Treating endometriosis as an autoimmune disease. Fertil Steril, 76(2):223-231.
The Endometriosis Association. What is endometriosis? Retrieved on April 9, 2015, from
http://www.endometriosisassn.org/endo.html
Women’s Health. Endometriosis. Retrieved on April 9, 2015, from
http://www.womenshealth.gov/publications/our-publications/fact-sheet/endometriosis.html
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