CHAPTER 8 Maria Victoria Vargas1 and Kathy Huang2 Department of Obstetrics and Gynecology, George Washington University Medical Center, USA Department of Obstetrics and Gynecology, NYU Langone Medical Center, New York, NY, USA Endometriosis is a common disease, estimated to affect 10% of reproductive aged women. It is defined as the presence of ectopic endometrial glands and stroma outside of the uterine cavity [1]. The most common anatomical locations affected by endometriosis are the pelvic peritoneum and the ovaries, but endometriosis can involve almost any organ including the pericardium, pleura, and the brain [2]. Symptoms of endometriosis can be debilitating, affecting work productivity and quality of life (QoF) [3, 4]. Common manifestations include painful menses, chronic pelvic pain, pain with intercourse, and infertility. In subgroups of women manifesting symptoms of endometriosis, prevalence rates are markedly increased. For example, women with chronic pelvic pain have an estimated prevalence of up to 87%, and women with infertility have an estimated prevalence of up to 50% [5]. An estimated 1/3 of women with endometriosis do not have symptoms of the disease [6]. Similar to eutopic endometrium, implants of endometriosis are hormone responsive, expressing both estrogen and progesterone receptors. In addition, implants of endometriosis produce estrogen locally through aromatase activity. Another key component of the pathology of endometriosis implants is the creation of a proinflammatory milieu secondary to the production of cytokines, prostaglandins, and metalloproteinases. Inflammation present in endometriosis lesions leads to an abnormal peritoneal environment that may impact fertility and lead to adhesions between pelvic organs. In addition, endometriotic implants release angiogenic and neurogenic growth factors leading to the expression of nerve fibers, lymphatic vessels, and blood vessels [7]. Disease severity has been historically described using the American Society of Reproductive Medicine (ASRM) endometriosis staging system [8]. Points are assigned based on factors such as lesion appearance, size, depth of invasion, and location. Endometriosis is classified as stage I (mild), stage II (minimal), stage III (moderate), and stage IV (severe). Several limitations exist with the ASRM staging system, including lack of reproducibility [9] and poor correlation of symptoms with stage of disease [10, 11]. In 2005, the Enzian system was proposed as an adjunct to the ASRM staging of endometriosis to describe deeply infiltrative disease in further detail [12]. More recently, the Endometriosis Fertility Index (EFI) was developed and validated for the prediction of spontaneous pregnancy in women with endometriosis [13, 14]. Both the ENZIAN and EFI systems have recognized clinical utility, but neither has been adopted for the staging of endometriosis in the United States. From a clinical perspective, endometriosis is distinguished by three distinct manifestations: (i) superficial endometriosis, (ii) ovarian endometriomas, and (iii) DIE [15, 16]. Though they can present simultaneously, these three types of endometriosis vary in severity, symptoms, and management. Endometriosis involving the superficial pelvic peritoneal surfaces is the most common form of the disease. Women who only have peritoneal endometriosis are classified as having minimal to moderate disease. However, symptom severity (pain and infertility) does not correlate with severity of disease and patients with superficial endometriosis may manifest severe symptoms. Endometriomas are pseudocysts that form from the invagination of ectopic endometrium implanted on the ovarian cortex. They are present in 17–44% of women with endometriosis. Women with endometriomas commonly experience dysmenorrhea, chronic pelvic pain, and infertility and often also have superficial disease [17]. DIE is relatively rare and is estimated to affect 1–% of all reproductive age women [18]. It is the most advanced form of endometriosis and is associated with significant distortion of pelvic anatomy. The lesions of DIE invade at least 5 mm beyond the superficial peritoneum and most commonly involve the uterosacral ligaments, the rectosigmoid colon, the vagina, and the bladder. Three to thirty‐seven percent of women with DIE have intestinal involvement and many require extensive surgical intervention [19]. There is some association of depth of infiltration of lesions and symptom severity. The most predictable symptoms of DIE are menstrual dyschezia and severe dyspareunia [20]. The presence of endometrial tissue glands and stroma located within the myometrium is termed adenomyosis, or endometriosis in situ. The endometrial tissue may invade throughout the entire myometrium – diffuse adenomyosis, or may form a circumscribed collection – focal adenomyosis. The pathophysiology of adenomyosis is thought to be distinct from that of endometriosis. The most widely held theory regarding the development of adenomyosis is that the endometrial basalis layer invaginates into the myometrium when the boundary between endometrial basal layer and myometrium is disrupted. This process is thought to be facilitated by the lack of intervening submucosa between the endometrial‐myometrial interface. As such, even in normal uteri, it is common that endometrium superficially invades normal myometrium [1]. Myometrial weakness caused by prior pregnancy or surgery may incite invasion by endometrial tissue [21]. In addition, impaired immunologic control of cell division at the endometrial‐myometrial interface may be present [22]. Estrogen and progesterone are suspected to contribute to the development and maintenance of adenomyosis. This is suggested by the development of adenomyosis in the reproductive years and regression after menopause. In addition, adenomyosis is associated with other hormonally driven pathologies such as leiomyomas, endometriosis, and endometrial cancer [23]. The most significant risk factors of adenomyosis are parity and age. Nearly 90% of women with adenomyosis are parous, and nearly 80% of cases develop in women in their 1940s and 1950s [1]. Other risk factors include chronic endometritis, abortion, uterine trauma from childbirth, elevated BMI, early menarche, and use of the selective estrogen receptor modulator, tamoxifen. Use of combined oral contraceptives (COCs) has been associated with adenomyosis, but it is unclear whether this is because of a causal relationship or because symptoms of adenomyosis are often managed with COCs [24, 25]. About 2/3 of women with adenomyosis are symptomatic and symptom severity correlates with increasing number of ectopic foci and extent of invasion. The most common symptoms are menorrhagia (40–50%) and dysmenorrhea (15–30%) [21]. About 10% of women with adenomyosis report dyspareunia [25]. The association of infertility and adenomyosis is not completely clear, but findings suggestive of adenomyosis are being more frequently noted on imaging for women with otherwise unexplained infertility [26]. In addition, women with adenomyosis and infertility undergoing in‐vitro fertilization with intracytoplasmic sperm injection have lower clinical and ongoing pregnancy rates as well as higher miscarriage rates [27]. The exact prevalence of adenomyosis is not known given that the diagnosis is usually based on histologic findings in surgical specimens. Reported incidences in hysterectomy specimens range from 20% to 60% [21, 28]. The following search strategy was used to identify potential studies to answer the clinical questions. A search of the MEDLINE, Embase, and the Cochrane Database of Systematic Reviews database was made from inception until January 2016. The following search terms were used: endometriosis, endometrioma, deeply infiltrating endometriosis (DIE), adenomyosis, infertility, surgery, systematic review, and meta‐analysis. In addition, consensus guidelines were reviewed. The formal diagnosis of endometriosis involving the abdominal cavity is through laparoscopy or laparotomy, with or without biopsy for histologic confirmation [2]. However, endometriosis can be suggested clinically with the assistance of a good history, exam, and appropriate imaging. Questions should focus on menstrual history as well as a detailed history of any pain or infertility symptoms. Severe dysmenorrhea and chronic pelvic pain are the most common symptoms of women diagnosed with endometriosis. In a study of 1000 women with endometriosis, 79% reported having dysmenorrhea and 69% reported chronic pelvic pain [29]. Women with dysmenorrhea will often report pain before the onset of their menses and sometimes lasting for days after their menses is over. Dyspareunia is reported in 45% of women with endometriosis and is associated with rectovaginal and uterosacral involvement [29, 30]. Dysuria, dyschezia, constipation, and diarrhea may also be present and can be suggestive of DIE involving the bladder and bowel respectively [31, 32]. However, these symptoms may also be present without deeply infiltrative disease [33, 34]. In cases of DIE of the rectosigmoid, cyclic hematochezia may be reported [31], and in rare cases of transmural infiltration of lesions, stenosis and even occlusion of the intestinal lumen can occur [35, 36]. Up to 50% of women with endometriosis suffer from infertility and even higher rates can be seen with worsened disease severity. In some cases, infertility is the only symptom suggesting the presence of endometriosis [5]. Thus, questions about pregnancy and prior attempts at conception should be included in the history to guide evaluation and management. Other symptoms commonly seen with endometriosis include depression, and anxiety as well as central sensitivity syndromes such as myofascial pain syndrome, painful bladder syndrome, and irritable bowel syndrome [33, 34, 37]. Inquiry about these symptoms should also be made during the collection of the history as management for these related disorders should be simultaneously pursued in parallel to any specific therapy for endometriosis. Depending on the severity of disease, the physical examination may vary. In the case of superficial endometriosis, lesions cannot be palpated on bimanual exam. Endometriomas may be palpable on bimanual or abdominal examination depending on the size. Adnexal tenderness may also be present. Deeply infiltrating nodules of endometriosis are often palpable on bimanual and recto‐vaginal examination as uterosacral nodularity, retroflexion of the uterus, and fixation of the posterior cul‐de‐sac. When concomitant myofascial or painful bladder syndrome symptoms are present, levator ani pain and bladder pain may also be present. Transvaginal ultrasonography is the initial imaging study of choice and when possible, should be performed in the late secretory phase of the menstrual cycle given that this is when the disease is most active. Superficial lesions are often not visible on transvaginal ultrasonography but endometriomas can be reliably diagnosed by ultrasound [38]. For cases of DIE, transvaginal, and transrectal ultrasonography can be useful for the identification of lesions involving the rectovaginal septum, parametrium, and utero sacral ligaments [39]. However, ultrasonography is highly operator dependent and in can lack sensitivity for smaller nodules of DIE [38]. In addition, many facilities are not able to offer transrectal sonographic imaging due to a lack of trained ultrasonographers. T1 and T2‐weighted magnetic resonance imaging (MRI) with and without fat suppression can reliably diagnose small nodules when DIE is suspected but transvaginal ultrasound is equivocal. MRI should be performed with and without gadolinium. When bladder involvement is suspected, ensuring a full bladder during MRI may enhance the ability to recognize nodules. When rectal involvement is suspected, a bowel prep followed by an antispasmodic agent to reduce artifact from peristalsis may also enhance the sensitivity of MRI [40]. In cases where bladder and/or ureteric endometriosis are suspected, cystoscopy, renal ultrasonography, and intravenous urography can assist with diagnosis. In addition, rectosigmoidoscopy should be performed, ideally during menses, if rectal infiltration is suspected [41]. Similar to endometriosis, the diagnosis of adenomyosis is formally made using histologic findings in surgical specimens. However, adenomyosis can also be suspected clinically with the assistance of history, exam, and imaging [26]. During the collection of the history, questions should focus on menstrual history including amount of bleeding, intermenstrual bleeding, and painful menses. Severe dysmenorrhea and menorrhagia are the most common symptoms of women diagnosed with adenomyosis. Other common symptoms include intermenstrual spotting and dyspareunia. Adenomyosis does not typically cause uterine enlargement beyond 12 weeks, but in women with significant enlargement from very severe adenomyosis, large adenomyomas, and/or concomitant leiomyomas (up to 50%), pressure type symptoms may be present [21]. An estimated 12% of women with adenomyosis may report infertility and an estimated 11% of women with adenomyosis will have concomitant endometriosis. As such, associated symptoms and conditions should be addressed during the collection of the history. The physical exam may be notable for enlargement of the uterus and uterine tenderness. In addition, exam findings may suggest co‐existing leiomyomas or endometriosis [25]. Transvaginal ultrasonography can be utilized to elucidate subtle myometrial findings that suggest the presence of adenomyosis. A systematic review of 14 studies found that transvaginal ultrasound had a pooled sensitivity of 79% and specificity of 85% of identifying adenomyosis using histologic diagnosis as the gold standard. Findings used to diagnose diffuse adenomyosis on ultrasound included: [1] myometrial texture heterogeneity, [2] globular asymmetric uterus, [3] small myometrial hypoechoic cysts, [4] striated projections extending from the endometrium into the myometrium, [5] ill‐defined endometrial echo [6] anterior or posterior myometrial wall appearing thicker than its counterpart, [7] thickening of anterior and posterior myometrial walls with associated hypo‐ or hyper‐echogenecity [26]. Focal adenomyosis, also known as adenomyomas, was identified by the following criteria: discrete hypoechoic nodules with poorly defined margins, elliptical shape, minimal mass effect on surrounding tissues, lack of calcifications, and presence of anechoic cysts of varying diameter [1, 26]. Similar to endometriosis, operator experience influences diagnostic accuracy and the common presence of concurrent uterine disease such as leiomyomas can limit the accuracy of transvaginal ultrasound. In these settings, MRI imaging may be complementary. The aforementioned systematic review assessing transvaginal ultrasound also assessed MRI for the diagnosis of adenomyosis. A pooled analysis of six studies showed a sensitivity of 74% and specificity of 92% for the identification of adenomyosis using histopathology for confirmatory diagnosis. Findings on MRI used to diagnose adenomyosis included (i) a myometrial mass with indistinct margins of primarily low intensity, (ii) diffuse or local widening of junctional zones on T2 weighted images, (iii) junctional zone thickness of >15 mm, (iv) subjective thickening of junctional zone, localized or diffuse, (v) ill‐defined low intensity lesion, (vi) junctional zone wider than 12 mm, (vii) uterine enlargement or (viii) small hypointense myometrial spots [26]. Treatment algorithms are dependent on patient symptomatology, location of lesions, desire to conserve the option for future childbearing, and plans for immediate child bearing. In patients presenting with mild to moderate pain and without the desire for immediate conception, medical therapy is appropriate. This is true even if endometriosis is suspected but not yet confirmed. First line regimens include COCs and progestins. COCs inactivate implants of endometriosis through a process of decidualization. Abundant observational data supports the use of COCs for the relief of endometriosis related pain. [42]. In addition, one large randomized control trial (RCT) showed significant improvement in endometriosis related pain with COCs when compared to placebo [43]. Regimens for oral contraceptives may be cyclic but extended cycle and continuous regimens are often used for women with severe dysmenorrhea. COCs have a good side effect profile and are generally well tolerated by patients. For women on extended cycle and continuous regimens, break through bleeding is the most common side effect [43]. For women who are not candidates for estrogen containing therapy, progestins alone are utilized. These agents inactivate endometrial implants by antagonizing the effects of estrogen. Two randomized trials showed equivalence in pain reduction of depot medroxyprogesterone (DMPA) acetate against gonadotropin releasing hormone (GnRH) agonists for pain symptoms related to endometriosis [44, 45]. In addition, women who received DMPA had less loss of bone mineral density. Other progestins have also been shown to improve symptoms related to endometriosis, such as norethindrone acetate and the levonorgestrel intrauterine device [46, 47]. One small prospective cohort study showed significant improvement in pain symptoms with the levonorgestrel intrauterine device during a three year follow‐up period [48] and another RCT showed equivalence in pain reduction of the levonorgestrel intrauterine device with GnRH agonist [49] Side effects of progestins can include weight gain, edema, acne, and irregular bleeding which may limit their acceptability by patients. For women with symptoms refractory to COCs and progestins, second line agents include GnRH agonists, such as leuprolide acetate. There is strong evidence supporting the efficacy of GnRH agonists to reduce pain related to endometriosis. However, GnRH agonists lead to a hypoestrogenic state that simulates menopause and side effects can be poorly tolerated. These include significant loss of bone mineral density and vasomotor symptoms (hot flashes) [50]. Combining GnRH agonists with low dose “add‐back” hormone therapy (e.g. norethindrone acetate 5 mg daily) significantly reduces the hypoestrogenic effects and makes the regimen more tolerable for patients. In addition, with use of “add‐back” therapy, bone mineral density loss is significantly reduced if not eliminated [51]. Notably, a Cochrane Review comparing GnRH agonists with other medical therapies for pain related to endometriosis found little or no difference in pain relief. GnRH agonists also have a higher cost compared to other medical therapies and as such are not typically recommended as first line medical therapy [52]. Aromatase inhibitors have been more recently introduced as a potential treatment for endometriosis‐related pain. Several studies have shown that these agents reduce pain symptoms in women with endometriosis. When used alone, they share a similar side effect profile to GNRH agonists that make them difficult to tolerate. However, recent study of aromatase inhibitors with a COC showed significant pain relief with an improved acceptability [53]. This option remains promising for otherwise refractory cases but is not yet widely utilized. Androgens, such as danazol, have also been shown to significantly reduce the size endometriotic lesions and improve pain symptoms, but have significant androgenic effects making them generally not well accepted by patients [7]. There is limited data available about antiprogestins that suggest these agents could reduce pain related to endometriosis. However, a Cochrane Review found no benefit in pain reduction when compared to danazol and leuprorelin [54]. The biggest limitation of medical options for the treatment of pain related to endometriosis is the recurrence of pain after discontinuation. This is most notable is with GnRH agonists since the Food and Drug Administration (FDA) has only approved a 12‐month course of GnRH therapy for the treatment of endometriosis related pain. The pain recurrence rate at five‐year follow‐up after discontinuing GnRH agonist therapy ranges from 53% to 73% in women with advanced disease [20]. A number of alternative therapies for pain related to endometriosis have also been studied. One randomized trial comparing acupuncture to traditional Chinese medicine met criteria for a systematic review of alternative therapies for endometriosis. This trial showed an overall reduction in pain with auricular acupuncture with the greatest benefit in cases of severe dysmenorrhea [55]. Another systematic review assessing alternative therapies for the treatment of dysmenorrhea (rather than endometriosis) identified a single trial of acupuncture vs. placebo acupuncture or no treatment and showed reduction of symptoms in the acupuncture group [56]. The same systematic review for the treatment of dysmenorrhea assessed seven trials of high frequency transcutaneous electrical nerve stimulation (TENS) therapy. High frequency TENS was found to reduce reported pain when compared to placebo TENS [56]. Though a number of imaging characteristics have been identified as being associated with a diagnosis of adenomyosis, no formal ultrasonographic or MRI criteria have been established as diagnostic. As a result, monitoring treatment effect and comparing findings among studies is challenging. In addition, there is a lack of randomized trials assessing the medical management of adenomyosis. The main objective of medical treatment is relief from pain and bleeding symptoms. Conservative therapy for symptomatic adenomyosis is similar to that for endometriosis. Combination oral contraceptives and progestin‐only regimens can be used to induce endometrial atrophy and decrease endometrial prostaglandin production to improve dysmenorrhea and menorrhagia. However, no randomized controlled trials have assessed these regimens for the management of symptoms of adenomyosis [57]. Limited data suggests that the levonorgestrel‐releasing intrauterine device is effective for treatment of adenomyosis‐related bleeding and dysmenorrhea [58–60
Endometriosis and adenomyosis
Background
Endometriosis
Adenomyosis
Search strategy
Clinical questions
Endometriosis
Adenomyosis
Endometriosis
Adenomyosis
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