Endometriosis Overview

*This is a scholastic paper on endometriosis shared with us.

Endometriosis 

by Heidi Hill 

Endometriosis is an inflammatory disorder defined by the presence of glandular endometrial and stromal cells outside the uterine cavity (Becker, 2015). An estimated 11% of women have endometriosis with varying degrees of severity of symptoms and infertility; the severity of symptoms does not necessarily correlate with extent of lesions (McCance & Huether, 2014).  Despite the high incidence of endometriosis, diagnosis is often delayed by 10 years due to symptoms being misdiagnosed or dismissed as normal menstrual cramps, by the lack of satisfactory biomarkers to diagnose, and by the definitive diagnostic standard being surgical visualization with histological confirmation (Ahn, Singh, & Tayade, 2017; Schliep, 2015). While endometriosis is a benign condition, it is related to higher incidence of ovarian carcinomas, autoimmune disorders, and cardiovascular disease (Kvaskoff, Mu, Terry, Harris, Poole, Farland, & Missmer, 2015).  

Precipitating Factors 

The cause of endometriosis is unknown, but it is likely to be multi-factorial, including environmental and genetic factors (Ashrafi, Sadatmahalleh, Akhoond, & Talebi, 2016). Being female is a significant risk factor as endometriosis is mainly seen in females; however, it has been in seen in men, usually those undergoing chemotherapy for prostate cancer (Jabr & Mani, 2014; Martin & Hauck, 1985). Several risk factors have been associated to be relational to endometriosis but not causative. Patient gravidity has been negatively associated with endometriosis with the thought that pregnancy provided suppression due to anovulation and amenorrhea as well as metabolic, hormonal, immune and angiogenesis changes (Maggiore et al., 2015). However, this lack of pregnancy can also be considered as a symptom as endometriosis is highly related to infertility with up to 50% of infertility cases being related to endometriosis (Dunselman et al., 2014).  

A family history of endometriosis is also a risk factor, with one study reporting a rate of 56% of patients studied with endometriosis having a family history (Dun, Kho, Morozov, Kearney, Zurawin, & Nezhat, 2014).  Some studies have reported the proportion of endometriosis cases due to genetic factors to be in the range of 52% (Rahmioglu, Nyholt, Morris, Missmer, Montgomery, & Zondervan, 2014; Chettier, Albertsen, & Ward, 2014).  However, while multiple genetic aberrations have been identified, none have been proven conclusive enough to be a biomarker for endometriosis (Rahmioglu, Nyholt, Morris, Missmer, Montgomery, & Zondervan, 2014). One theory of the origin of endometriosis is Mullerian rests that allows for endometriosis to be laid down during fetal development and is associated with other Mullerian disorders (Acién & Velasco, 2013).  

There is an increased risk of endometrial polyps with endometriosis (Wang, Zhang, & Liu, 2016; Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015). Evidence of similar pathologies, such as estrogen driven proliferation of tissue, between endometriosis and endometrial polyps are noted (Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015). This association with endometriosis and endometrial polyps is important in infertility (Galal, 2016). Other risk factors include early age of menarche, short menstrual cycles, long duration of menstrual flow, and defects in the uterus or fallopian tubes (Ashrafi, Sadatmahalleh, Akhoond, & Talebi, 2016).  

Cellular Analysis 

Endometriotic lesions on a cellular level are not the same as the endometrium as endometriotic lesions are capable of high estrogen production, high prostaglandin production, and have a resistance to progesterone (Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). This is important in the symptoms seen. The endometriotic lesions respond to estrogen which signals to increase lesion size, fluid volume, increased epithelial cell height, and epithelial cell proliferation (Burns, Rodriguez, Hewitt, Janardhan, Young, & Korach, 2012). However, the endometriosis lesions are capable of estrogen production, have decreased responsiveness to progesterone, can produce cytokines and prostaglandins, and are capable of angiogenesis and neurogenesis (Hey-Cunningham, Peters, Zevallos, Berbic, Markham, & Fraser, 2013; Reis, Petraglia, & Taylor, 2013; Bulun et al., 2012; Chaban, 2012). These capabilities of the endometriotic lesions are thought to be responsible for the symptoms noted with endometriosis. 

The location of the lesions and the presence of adhesions can also affect the symptomology seen (Lu, Zhang, Jiang, Zou, & Li, 2014). Most symptoms arise from a chronic inflammatory state, noxious chemical release such as prostaglandins, musculoskeletal sequelae, and/or adhesions. An estimated 30-50% of patients with endometriosis are infertile due to the inflammatory environment and physical abnormalities such as adhesions (Koga, Yoshino, Hirota, Hirata, Harada, & Osuga, 2014). 

 Pain:  

• Chronic pelvic pain:  

          Chronic pelvic pain is strongly associated with endometriosis (Donnelly & Yeung, 2015). Pain with endometriosis is related to increased inflammation, nociceptors, and noxious stimuli (Alvarez, Bogen, & Levine, 2014; McKinnon, Bertschi, Bersinger, & Mueller, 2015). Morotti, Vincent, Brawn, Zondervan, and Becker (2014) note higher nerve fiber production and density, increased neurotrophins, and the location of lesions in proximity to areas such as the bowel to be contributory to pain in endometriosis. These nerve fibers are found within and near the endometriotic lesions as well as in the peritoneum and endometrium of those with endometriosis (Fraser & Berkley, 2013). In patients with endometriosis, increased pro-inflammatory estrogen unchecked by antiinflammatory progesterone (due to progesterone resistance) has also been hypothesized to be problematic in endometriosis pain (Bruner-Tran, Herington, Duleba, Taylor, & Osteen, 2013; Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). The peritoneal fluid of endometriosis patients has been noted to have higher amounts of tumor necrosis factor-α, several interleukins, RANTES, monocytes, and prostaglandins (Aredo, Heyrana, Karp, Shah, & Stratton, 2017). Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, and Pop (2013) describe an “overproduction of estrogen in endometriotic stromal cells with high local production of prostaglandins” (p. 95) as well as overproduction of prostaglandins PGE2 and PGF2-alpha not only in the endometriotic lesions but also in the uterus. Pain can be either cyclical or acyclical.  Pelvic floor muscle dysfunction has been shown to be pathologic in pain with endometriosis patients (Raimondo et al., 2016). Most often hypertonicity of the pelvic floor is implicated in the musculoskeletal pain experienced (Aredo, Heyrana, Karp, Shah, & Stratton, 2017).  

• Dysmenorrhea: 

         Dysmenorrhea is a classic signal for endometriosis. Erasmo and Ferrero (2015) state that “in patients suffering from dysmenorrhea, the incidence of endometriosis ranges from 40% to 60% and the 70% of adolescents who experience dysmenorrhea are diagnosed with endometriosis” (p. 63). Erasmo and Ferrero (2015) note the pain to be visceral and somatic. They also indicate that inflammation, prostaglandins, nerve growth factors, deep infiltrating lesions, and increased uterine contractility to be causes of dysmenorrhea in endometriosis (Erasmo & Ferrero, 2015).  

• Intermenstrual pain 

           Pain between menstruations can be caused by the factors already mentioned of inflammation, nociceptors, noxious stimuli, and musculoskeletal dysfunctions. 

• Pain during exercise 

         The location of the lesions, the presence of adhesions, and other factors such as pelvic floor dysfunction, trigger points, and muscles spasms can all factor into pain with exercise (Hartmann & Sarton, 2014; Aredo, Heyrana, Karp, Shah, & Stratton, 2017).  High impact exercises can affect the tonicity of the pelvic floor. Adhesions can cause pulling sensations as well as musculoskeletal imbalances.  

• Fatigue: 

            Pain is one factor leading to fatigue (Morotti, Vincent, Brawn, Zondervan, & Becker, 2014).  Luisi et al. (2015) also noted hormonal alterations, chronic inflammation and impaired immune function as causes of fatigue in endometriosis. 

• Menstrual: 
  • Premenstrual spotting: 

Spotting for greater than two days prior to menstruation has been associated as a strong indicator for endometriosis (Heitmann, Langan, Huang, Chow, & Burney, 2014). Although hormonal and inflammatory alterations could play a part in spotting, in this case, the presence of an endometrial polyp is the most likely cause of spotting in this patient (Thubert, Demoulin, Lamazou, Rivain, Trichot, Faivre, & Deffieux, 2014). 

• Menorrhagia 

While dysmenorrhea is defined as a classic sign of endometriosis, menorrhagia is more often associated with conditions that frequently coexist with endometriosis. Adenomyosis, leiomyomas, and endometrial polyps are often comorbidities of endometriosis and have the primary symptom of menorrhagia (Habiba & Benagiano, 2016; Nezhat et al, 2016; Thubert, Demoulin, Lamazou, Rivain, Trichot, Faivre, & Deffieux, 2014).  It may also be noted that polycystic ovarian syndrome is also frequently seen in endometriosis patients which can contradict this symptom (Likes & Lessey, 2014).  

• Gastrointestinal: 
  • Dyschezia 

Elevated prostaglandin levels within the peritoneal fluid are seen in patients with endometriosis, and these prostaglandins affect gastrointestinal motility (McAllister, Giourgas, Faircloth, Leishman, Bradshaw, & Gross, 2016). The irritation of the gastrointestinal tract from the cytokines released can also contribute to dyschezia, particularly seen if lesions are located within the posterior cul de sac (Avila, Filogônio, Costa, & Carneiro, 2016). Hypertonic pelvic floor muscles can contribute to the pain and spasms felt upon defecation (Preil, Belkin, & Goldstein, 2016).  

• Bloating 

The exact cause of the bloating experienced with endometriosis is unknown. Some contribute it to the inflammatory process while others cite the coexistence of irritable bowel syndrome; however, many patients experience gastrointestinal symptoms cyclically which might indicate the inflammatory and/or hormonal impact (Ek, Roth, Ekström, Valentin, Bengtsson, & Ohlsson, 2015). Ek, Roth, Ekström, Valentin, Bengtsson, and Ohlsson (2015) identify mast cells as possible contributors from the inflammatory spectrum, but they also point out that hormonal receptors in the gastrointestinal tract could also explain the symptoms.  

• Alternating constipation/diarrhea 

Again, prostaglandins and inflammatory markers are contributory to altered bowel function as is pelvic floor muscular dysfunction. Endometriosis on or near the bowel has been seen as contributory to bowel symptoms, even to the extent of bowel obstruction due to lesion growth (Ruffo et al., 2014).  

• Urinary: 
  • Pain on micturition  

While endometriosis of the urinary tract is rare, the most common site is the bladder (Knabben, Imboden, Fellmann, Nirgianakis, Kuhn, & Mueller, 2015). Estay et al. (2015) describes bladder symptoms as cyclical dysuria, dyspareunia, or resembling recurrent cystitis, and more rarely hematuria. Estay et al. (2015) described ureteral obstruction from endometriosis lesions presenting more as the loss of kidney function including anuria and hydronephrosis. Knabben, Imboden, Fellmann, Nirgianakis, Kuhn, and Mueller (2015) point out that bladder symptoms are usually symptomatic whereas ureteral are often not symptomatic. Again, irritation of the urinary tissue from the inflammatory markers described above can cause symptoms, particularly of the bladder. Endometriosis of the ureters would present more from obstruction due to lesion growth versus inflammation. In this case, endometriosis of the bladder would be suspected, however interstitial cystitis would need to be ruled out as it is frequently seen in endometriosis patients as well (Chen, Lee, & Wu, 2016).  

• Examination: 
  • Tenderness with palpation 

Tenderness can be due to pelvic floor muscular dysfunction and/or to lesion location (Yamamoto, Carillo, & Howard, 2014). Particularly tenderness is noted in the rectovaginal area, bladder, and close to the uterosacral ligaments in many patients with endometriosis (Nourmoussavi, Bodmer‐Roy, Mui, Mawji, Williams, Allaire, & Yong, 2014; Yamamoto, Carillo, & Howard, 2014; Williams et al., 2016). If a patient had been sexually active, the symptom of dyspareunia might also have been described.  In addition to the contributory causes of inflammation, muscular dysfunction, and adhesions, Williams et al. (2016) also describe increased nerve bundle density noted in endometriosis patients with dyspareunia. This could also cause pain upon pelvic examination.  

• Diagnostic laparoscopic findings: 
  • Glands and stroma in the pelvic cavity 

Endometriosis is diagnosed by the visualization and preferably the histological confirmation of endometrial glands and/or stroma outside of the uterus (Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). Visually, endometriosis can vary from the clear, white, red, tan, and black colorations that may be very small to blister like formations to polypoid masses (Kondi-Pafitis, 2012). Kondi-Pafitis (2012) describes the histological presentation as “one or more endometrioid glands surrounded by stromal cells, resembling the endometrial stromal cells of the proliferative phase…. consistent with inactive or irregular proliferative endometrium, although typical proliferative or secretory changes may be observed” (p. 106). Kondi-Pafitis (2012) also notes that inflammatory cells and fibrosis may be present. An older study, but worth noting, performed by Demco (2000) utilized patients under conscious sedation to perform pain mapping of the lesions. The study found that the different colored lesions produced different amounts of pain, that the pain extended beyond the visible border of the lesion, and that palpation of the endometriotic lesions produced “cramps” (Demco, 2000). This information is important in understanding the symptomology and in treating the disease.  

o Endometrial polyp 

As noted previously, endometrial polyps are frequently seen with endometriosis (Wang, Zhang, & Liu, 2016; Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015). Estrogen driven proliferation of tissue is seen in endometrial polyps as well as endometriosis (Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015). 

Medical Management 

Pharmalogical 

 Hormonal: Balancing hormones is reasoned to be beneficial in alleviating symptoms; however, it does not rid the patient of the disease. Most efforts are concentrated on lowering estrogen in order to alleviate symptoms, particularly pain. Birth control pills, progestins, gonadotropin-releasing hormone antagonists, aromatase inhibitors, selective estrogen receptor modulators, and oral and intravaginal danazol are different hormonal therapies trialed to decrease symptoms and slow progression of the disease. However, some of these therapies have limited evidence and many have untoward side effects, so much so that some are only recommended if all other medical and surgical options fail (Tosti, Biscione, Morgante, Bifulco, Luisi, & Petraglia, 2016; Dunselman, et al., 2014; Brown & Farquhar, 2015).  Also note that the resistance to progesterone seen in endometriosis lesions can cause some patients to be refractive to the effect of progestins (Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). In the following order, depending on patient tolerance, hormonal therapy could be trialed:  

• Oral contraceptives: Oral contraceptives are useful for dysmenorrhea, reduction of pelvic pain, and reduction in the recurrence rate for endometriomas (ovarian cyst endometriosis) (Zorbas, Economopoulos, & Vlahos, 2015).  
• Progestins (oral, intrauterine, injections): These can be useful for pain reduction (Gezer & Oral, 2015).

• Gonadotropin-releasing hormone analogs: These are as effective as other hormonal methods for endometriosis pain, but associated with a significant reduction in bone mineral density (Jeng, Chuang, & Shen, 2014). The most commonly prescribed is sold under the brand name Lupron, who recommends a lifetime maximum of 12 months of treatment (Lupron, n.d.).  
• Danazol: Danazol is useful for decreasing pain and lowering inflammation (shown via a lowered CA-125) (Szubert, Suzin, Duechler, Szuławska, Czyż, & KowalczykAmico, 2014). However, danazol can have strong androgenic side effects (deepening of voice, facial hair growth) (Godin & Marcoux, 2015). Vaginally administered danazol might help decrease the pain and the nodule size in rectovaginal endometriosis (Godin & Marcoux, 2015). 
• Aromatase inhibitors: These are only used if other hormonal methods and surgical therapies have failed but can be useful for pain (Hashim, 2014). 
• Selective estrogen receptor modulators: Their effectiveness and safety are not established and have shown an increased risk for thromboembolism, vaginal dryness, rash and abdominal cramps (Chen, Zheng, & Wan, 2014). 

Surgical 

As discussed, surgical visualization is the definitive method for diagnosing endometriosis. Surgical intervention within the diagnostic surgery is preferable and is aimed at removing the endometriotic lesions. Surgical treatment can help prevent the reoccurrence of endometriosis without the use of hormones afterwards (Jovanovic, Dikic, Janković-Raznatovic, Savija, & Radaković, 2015). While ablation of endometriosis has been utilized extensively, newer data suggests excising the lesions may lead to a better long term outcome for patients. Ablation may or may not destroy the full thickness of the lesion while excision allows for better margins and provides samples for histological study.  

A randomized, double-blind, five year follow up study concluded that surgical intervention was effective for at least up to five years and demonstrated that in some areas excision was more effective than ablation (Healey, Cheng, & Kaur, 2014). Excision is preferred in order for all tissue to be sent for histological review and confirmation (Dunselman et al., 2014; Donnelly & Yeung, 2015). Complete excision of deep infiltrating endometriosis has shown better outcomes versus incomplete surgical removal coupled with postoperative hormonal therapy (Angioni, Pontis, Dessole, Surico, Nardone, & Melis, 2015). Mackenzie (2015) suggests that excision be the standard of care for bowel endometriosis. Several other studies also suggest that excision is the preferable treatment method (Laganà, 2016; Alvarez, Giudice, & Levine, 2015; Koninckx, Donnez, & Brosens, 2016; Gingold & Falcone, 2016).  

Other 

• Dietary: Several dietary changes are suggested to alleviate symptoms. A diet rich in vegetables, fruit, and omega-3 fatty acids is recommended due to the oxidative stress created by the chronic inflammatory state (Gupta, Harlev, Agarwal, Al Safaar, Gupta, & Hack, 2015; Halpern, Schor, & Kopelman, 2015). Celiac disease has been connected with endometriosis through inflammatory markers and genetics and a gluten free diet has been shown to decrease painful symptoms (Santoro et al., 2014; Mormile & Vittori, 2013; Marziali, 2012). A study cites the role of inflammation and oxidative stress from endometriosis as factors leading to an increase in the risk of coronary heart disease in endometriosis patients, therefore a heart healthy diet would be beneficial as well (Mu, Rich-Edwards, Rimm, Spiegelman, & Missmer, 2016). A low fat diet is suggested as high fat consumption has been associated with increased inflammatory markers (Heard, Melnyk, Simmen, Yang, Pabona, & Simmen, 2016).  Due to the frequent diagnosis of irritable bowel syndrome in endometriosis patients, a low FODMAPs diet is suggested (Moore, Gibson, & Burgell, 2014).
• Physical Activity: As noted, endometriosis patients can be susceptible to pelvic musculoskeletal disorders, so physical therapy with a women’s health qualified physical therapist would be beneficial (DeBevoise, Dobinsky, McCurdy-Robinson, McGee, McNeely, Sauder, & Sullivan, 2015). This might include retraining of the pelvic floor muscles to prevent spasms, reestablishing musculoskeletal balance, trigger point therapy, and other pain relieving modalities (dos Bispo et al., 2016). Yoga therapy has been shown to decrease menstrual pain and increase quality of life (Yonglitthipagon et al., 2017; Gonçalves, Barros, & Bahamondes, 2016). 

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