More than 10 years following the publication of “The General Rules for Clinical Management of Endometriosis: The second edition” in January 2010, the long-awaited third edition has arrived. The second edition represents the bible for endometriosis treatment and has become the go-to reference in clinical practice in Japan; it was published after the introduction of low-dose estrogen–progestin (LEP) therapy and the novel progestin dienogest on the market. Looking back, this was the turning point from the era when laparoscopic surgery + GnRH agonist therapy was the predominant treatment and introduced an era of novel treatments. With the development of lightweight, high-resolution endoscopes that allow for more delicate and precise surgical operations, endometriosis surgery has transitioned from laparotomy to laparoscopy. Conversely, despite their potency in alleviating the symptoms of endometriosis, GnRH agonists could only be used for up to 6 months due to adverse effects associated with estrogen deficiency. Thus, the predominant treatment was centered on laparoscopic surgery, with GnRH agonists used as an adjunct. Following the publication of the second edition, the use of LEP and dienogest became widespread. With both agents have been shown to be effective and safe, long-term medical therapy has become possible. Owing to technical advancements in laparoscopic surgery, surgery is now also performed for deep endometriosis or less common and rare site endometriosis. However, for ovarian endometriotic cysts, ova, and normal ovarian tissues should be resected along with the endometrial tissue, thus, diminishing the ovarian reserve. Therefore, surgery must be performed carefully for young women and women wishing to have children in the future. We are now in an era in which we take advantage of long-term medical therapy and laparoscopic surgery, as we consider treatment tailored to the life stages of individual women while attempting to preserve ovarian functions. In this revised edition, we refer to the second edition for fundamental knowledge in clearly elaborating current perspectives on the review of the diagnosis and treatment, in addition to the advance over the last 10 years. Therapeutic strategies are explained with detailed flow charts. The clinical questions (CQs) in the latter half of this edition are intended as a useful guide for decision-making in clinical practice. The authors are all physicians working tirelessly at the frontiers of endometriosis research in Japan, and this edition has undergone multiple generous revisions amid their busy schedules. Integration of the overall structure, revision of inconsistencies and duplication among CQs, and other onerous editing tasks were undertaken with tremendous dedication by the secretaries on the Japan Society of Endometriosis, Drs. Fuminori Taniguchi, Michio Kitajima, Kaori Koga, Taisuke Mori, and Ken Yamaguchi. Once again, I would like to offer them my deepest gratitude. I hope that this revised edition would be helpful in the treatment of women with endometriosis not only in Japan but worldwide. Tasuku Harada Table of Contents Introduction Chapter 3 Treatment guidelines (Clinical questions) CQ 1 How should adolescents with suspected endometriosis be treated? CQ 2 How should ovarian endometriotic cysts be managed in view of their potential for malignant transformation? CQ 3 Do endometriosis and adenomyosis increase the risk of obstetric complications? CQ 4 How should adenomyosis-associated pain be managed? CQ 5 How should adenomyosis-associated infertility be managed? CQ 6 Is endometriosis a risk factor for cardiovascular events? CQ 7 Does endometriosis affect quality of life? CQ 8 What to be aware of when performing conservative surgery for ovarian endometriotic cyst? CQ 9 Is surgery for ovarian endometriotic cysts effective in improving fertility? CQ 10 Is surgery for deep rectovaginal endometriosis effective in improving fertility? CQ 11 Is surgery effective in improving fertility in women with peritoneal lesions? CQ 12 Is assisted reproductive technology (ART) effective for endometriosis-associated infertility? CQ 13 Are hormone therapies effective for endometriosis-associated infertility? CQ 14 Is surgery effective for endometriosis-associated pain (excluding deep lesions)? CQ 15 Is surgery effective for deep rectovaginal endometriosis-associated pain? CQ 16 Are oral contraceptive/low dose estrogen-progestin (OCs/LEPs) effective for endometriosis-associated pain? CQ 17 Are GnRH agonists effective for endometriosis-associated pain? CQ 18 Are oral progestins effective for endometriosis-associated pain? CQ 19 Is the levonorgestrel intrauterine system (LNG-IUS) effective for endometriosis-associated pain? CQ 20 Is there evidence of a superior efficacy between oral contraceptive/low dose estrogen-progestin (OCs/LEPs), GnRH agonists, and progestins for endometriosis-associated pain? CQ 21 Is medical therapy effective for deep endometriosis-associated pain? CQ 22 Are complementary and alternative therapies effective for endometriosis-associated pain? CQ 23 Are pre-operative or post-operative medical therapies effective at surgery for endometriosis- associated pain? CQ 24 Is medical therapy following conservative surgery effective in preventing the recurrence of ovarian endometriotic cysts? Diagnosis Overview of Diagnosis Clinical significance of endometriosis diagnosis A pathologically benign disease, endometriosis is unlike other malignancies that are diagnosed by the detection of lesions. In the absence of symptoms, the diagnosis of microlesions has almost no clinical value, as they often disappear naturally and do not necessarily enlarge. In contrast, when symptoms are present, the lesions can be identified to establish a diagnosis that then becomes the basis for treatment. However, even in asymptomatic cases, lesions of a certain size can cause various symptoms and require therapeutic intervention. Diagnostic therapy is considered in endometriosis. When symptoms such as dysmenorrhea strongly indicate endometriosis, the patient's response to hormone therapy is considered. However, endometriosis can be difficult to distinguish from functional disorders, such as functional dysmenorrhea; this line of thinking is acceptable in certain circumstances. The relationship between lesions and symptoms in endometriosis patients remains largely unknown, while some aspects of the etiology of the lesions are vague. Consequently, the clinical significance of the diagnosis may change in the future. Methods for diagnosing endometriosis Endometriosis is characterized by the presence and growth of endometrial tissue in locations other than the uterine cavity. While a definitive diagnosis should be made histologically, alternative diagnostic methods, such as laparoscopy are performed. The American Society of Reproductive Medicine (ASRM) staging system has become the most common and international system, and diagnosis based on laparoscopic findings has been recognized as the standard. However, laparoscopic findings have various limitations and flaws and therefore cannot necessarily serve as a perfect alternative to histological diagnoses. Ultrasonography and magnetic resonance imaging (MRI) have later been incorporated into the diagnosis of endometriosis. As diagnostic imaging has improved in quality, invasive laparoscopic diagnosis has somewhat diminished in relative value, and the exclusive use of laparoscopy for diagnosis has become much less common. Subjective and objective findings and biochemical tests are all useful only when combined with the results of diagnostic imaging and laparoscopy; none are used separately for diagnosis. Procedure for diagnosing endometriosis The first steps in diagnosing endometriosis are an interview and a pelvic examination, as with a typical gynecological examination. Patients are asked in detail about the information related to endometriosis, such as family history, history of illness, menstrual history, and pregnancy/delivery history. If the history of the present illness includes pain, the chronological changes, properties, and sites of the pain are important. In vaginoscopy, observation of the posterior vaginal fornix is particularly important. If endometrial lesions are present, other methods can be used in addition to vaginoscopy to determine whether the lesions extend only to the vaginal wall or if they are continuous with deep endometriosis in the rectovaginal pouch. Subsequently, in the pelvic examination, important findings consist not only of the size, properties, and motility of the uterus and ovaries but also pain during examination and induration surrounding the rectouterine pouch. In a typical vaginal ultrasound during pelvic examination, asking the patient during observation whether the ultrasound probe cause any pain can be useful in the identification of lesions. If rectal endometriosis is suspected, a rectal examination may also be proactively performed to confirm the status of the bowel wall. However, when pelvic and rectal examinations are difficult, such as in the cases of young women and women who have not had sexual intercourse, a diagnosis should be established according to the results of other tests such as MRI, which yields even more detailed information regarding lesions. The finding of a serum CA 125 test can be used in combination with other tests as necessary, for differentiation with malignancy and to assess lesion activity. Details of diagnosis Subjective findings Commonly cited symptoms of endometriosis include menstrual pain (abdominal pain and low back pain) and infertility. In a survey of patients definitively diagnosed with endometriosis by the Japan Endometriosis Association, 88% of the patients experienced menstrual pain, and nonmenstrual abdominal pain, low back pain, dyspareunia, and dyschezia. Approximately half of the patients who responded reported infertility. Although uncommon, when lesions spread beyond the pelvic organs, symptoms may manifest elsewhere, such as in the gastrointestinal tract, urinary tract, or respiratory system (Table 1). Findings of the pelvic examination and rectal examination Adhesions secondary to endometrial lesions often develop in the rectovaginal pouch and around the adnexa and are a characteristic finding of endometriosis in pelvic examinations. The findings indicative of endometriosis include limited uterine motility, uterine retroflexion, tenderness, and induration of the rectouterine pouch. Rectal examination is crucial in the diagnosis of rectouterine endometriosis. Rectovaginal pouch lesions that have formed small masses may become fibrotic and be palpable as indurations with tenderness. However, these lesions are evidently palpable on rectal examination. Biochemical tests Although there are no definitive biomarkers to diagnose endometriosis, CA125 and CA19-9 levels are often mildly elevated in patients with endometriosis.1 Although these biomarkers do not have high diagnostic accuracy individually, they are useful for diagnosis when combined with other findings. Sometimes, the levels of these biomarkers increase abruptly in the rupture and acute phase of hemorrhage of ovarian endometriotic cysts. CA125 and CA19-9 levels seldom indicate positivity for early endometriosis and are useful only in advanced cases.2, 3 Serum HE4, in combination with serum CA125, is useful for differentiating between epithelial ovarian cancer and ovarian endometriotic cysts.4 Diagnostic imaging Ultrasound findings in endometriosis Ultrasonography is emphasized as a means of diagnosing endometriosis and determining its course. Vaginal ultrasonography is generally superior to abdominal ultrasonography for visualizing pelvic lesions and is therefore preferred. However, for women who have not had sexual intercourse, either abdominal ultrasonography is performed or ultrasonography is performed rectally with a vaginal probe. If endometriosis is suspected, ultrasonography is performed in which the entire pelvis is observed first according to a set procedure and then the details. For example, briefly scan the uterus and ovaries to check for endometriosis and ovarian endometriotic cysts. Next, determine any adhesion associated with endometriosis but not with the endometrial lesions themselves. Check for site-specific pain, ovarian mobility, and sliding between the uterus and surrounding organs. Lastly, evaluate the deep endometriosis in the region of the uterus, as necessary. Sites of cysts Ultrasound findings for ovarian endometriotic cysts present as nearly circular or elliptical unilocular or multilocular cysts that adhere to the uterus and are often located in the posterior aspect of the uterus or the rectovaginal pouch (Figure 1). Ultrasound findings of cysts Cyst wall The wall is seldom uniformly thin and often appears to be thickened. However, the images show blood clots and fibrin clots, not neoplastic thickening; papillary projections are also not observed in epithelial tumors. Internal echoes The inside of an ovarian endometriotic cyst is formed by accumulated blood and therefore presents with low, medium, or high intensity based on the density of free-floating blood. Uniform−diffuse echoes or low-intensity punctate−spotty echoes are often observed throughout the mass or in the inferior portion of the mass. When fibrin deposits are present, various hyperechoic regions and solid echoes are also observed. Fibrin clots demonstrate fluidity due to postural changes and present with a rippling motion when the cysts are vibrated from the abdominal wall manually or with a vaginal probe. Color Doppler can confirm the absence of blood flow in fibrin clots. The insides of the cysts occasionally present with relatively low-intensity solid echoes. As cysts can be localized near the wall, it is important to differentiate ovarian mature teratomas with ovarian cancer (Figure 2). Hair shafts and sebum in ovarian mature teratomas and papillary projections in cancer are often hyperechoic. Although cysts are often unilocular, they sporadically have a few loculi, in which case septa are depicted. The surfaces of these septa are relatively smooth, and the septa do not present with dendritic or papillary projections. In the case of thick, irregular septa, ovarian cancer must be considered. In rare cases, mixed tumors comprising serous cysts or ovarian mature teratomas may develop in the ipsilateral ovary. When several various echo patterns are present, mixed tumors must be considered. Ultrasound findings in deep endometriosis.5, 6 Although deep endometriosis has conventionally been defined as endometriosis involving deep infiltration (5 mm) from the peritoneal surface, this view is now considered as outdated. Recently, lesions that arise with fibrous or myogenic tissue from adenomyosis-like tissue (adenomyosis externa) have often been clinically addressed as deep endometriosis. Deep endometriosis most likely occurs in the vesicouterine pouch, the rectovaginal pouch, or the uterosacral ligaments. On ultrasonography, deep endometriosis is typically visualized as a hypoechoic area. To observe the vesicouterine pouch, a probe is inserted into the anterior vaginal fornix. To observe the bladder wall, storing urine in the bladder creates contrast, to visualize endometriosis; multiple small cystic echoes are often detected on the surface of the bladder. To observe the rectovaginal pouch or the uterosacral ligaments, a probe is inserted into the posterior vaginal fornix. Deep endometriosis generally involves rectovaginal pouch obliteration. The status of rectovaginal pouch obliteration can be determined based on the height of intraperitoneal effusion. In deep endometriosis of the bowel wall, the rectal serous membrane and mucosal surface are visualized as hyperechoic areas surrounding the hypoechoic deep endometriosis area, thus, confirming the diagnosis. While normal uterosacral ligaments are difficult to distinguish from the surrounding tissue in an ultrasound, deep endometriosis results in hypoechoic thickening, facilitating confirmation of the ligaments. The role of MRI diagnosis MRI can play a major role in diagnosing endometriosis because MRI “can specifically diagnose the blood flow based on signals.” Hematomas present with characteristic signals from bleeding that change over time, facilitating the deduction of timing and composition (Table 2, Figure 3).7 The values of sensitivity and specificity of MRI for differentiating between ovarian endometriotic cysts and adnexal masses are extremely high, 95% and 91%, respectively, making MRI a reliable cornerstone for deciding on a therapeutic strategy.8 In contrast, small implants in the peritoneal surface and membranous adhesion are difficult to diagnose. Thus, although MRI is inferior to laparoscopy in terms of the exclusion and staging of endometriosis, it is worthwhile as a non-invasive method that can potentially reliably diagnose ovarian endometriotic cysts. Thus, the two types of tests are considered to complement each other. Due to the absence of other reliable methods for diagnosing deep/bladder/rectal endometriosis, MRI diagnosis contributes greatly to clinical practice. Imaging methods T1-weighted images and T2-weighted images must be taken in the same plane. Fat suppression is useful for differentiating between fat and blood. In addition, contrast media are sometimes necessary to differentiate between clots in ovarian endometriotic cysts and solid tissue indicative of ovarian cancer. The images are taken in the transverse plane in principle, although sagittal T2-weighted images are also often taken to observe adhesion between the uterus and ovaries as well as adhesion between the rectum and uterus. In addition, infusing water-soluble gel into the vagina and rectum to create contrast improves the diagnosis of deep endometriosis adjacent to the rectovaginal pouch.9 Diffusion-weighted imaging and apparent diffusion coefficient are useful for differentiating endometriosis from malignancy.10 Susceptibility-weighted imaging is reported to be useful for detecting microbleeding in endometriosis.11 Imaging findings Malignant ovarian tumors must not be misdiagnosed as ovarian endometriotic cysts. Ovarian endometriotic cysts can be confirmed in one of two ways: presentation of high signal intensity similar to that of subcutaneous fat on T1-weighted images and the presence of two or more cysts with signals not suppressed in fat-suppressed imaging, or similar cysts presenting with heterogenous low signal intensity on T2-weighted images (shading). The former demonstrates that the cysts are multiple cysts with blood, while the latter demonstrates that the cyst fluid is old blood that has become viscous, thereby, enabling differentiation with other hemorrhagic masses. In the images, only the pronounced adhesive changes, not the slight ones, can be identified, but not the slight adhesive changes. Adhesion must be suspected when the bilateral ovaries are in contact with each other, when the ovary is in contact with the uterus or pelvic wall over a wide area, or when the intestine appears to be pulled in a beak shape toward the uterine serosal surface or the ovary. Abdominal wall/deep/bladder/rectal endometriosis is depicted as fibrosis in MRI. Endometriosis is identified in the umbilical region, the groin, or scarring from gynecological operations, such as cesarean section or hysterectomy in T2-weighted images as hypoechoic nodules and as hypertrophy limited to the bladder wall and bowel wall. However, in several cases, these findings are slight and easy to miss. The diagnosis is definitive if a 2–3-mm section of tissue presenting with high signal intensity on T1- and T2-weighted images is observed in the center of the endometriosis. Differential diagnosis Blood and fat can present with markedly high signal intensity on T1-weighted images. Therefore, although differentiating ovarian endometriotic cysts from ovarian mature teratomas is sometimes difficult, they are easily differentiated with fat saturation. Fat presents with low signal intensity due to signal suppression, whereas blood continues to present with high signal intensity (Figure 4). The presence of chemical shift artifacts and morphological characteristics also help with differentiation; however, fat suppression is the most reliable method. It is important not to make a diagnosis of ovarian endometriotic cysts based solely on a cyst presenting with high signal intensity in T1-weighted images (i.e., signals indicating hematomas). This finding alone is not enough to differentiate an ovarian endometriotic cyst from a corpus luteum hemorrhage or ovarian tumoral hemorrhage. The corpus luteum is often 1–2 cm in size and disappears when observed during a menstrual cycle. Images of deposition of high-signal intensity tissue only in the base of a cyst show the hematocrit effect and indicate functional intracystic hemorrhage, such as in the corpus luteum. With ovarian tumoral hemorrhage, due to the mixture of blood and other fluids in cysts, the fluid often does not present with a signal intensity as high as that of blood or fat. Carcinomas such as clear cell carcinoma and endometrioid carcinoma rarely develop from ovarian endometriotic cysts. Even when all findings suggest ovarian endometriotic cysts, ovarian carcinoma should be suspected when the mass has a solid portion inside it. Differentiation between small mural nodules and clots adhering to walls based on contrast-enhanced MRI can also aid diagnosis. Clots have no blood flow and do not show contrast, whereas solid mural nodules show strong contrast. Although contrasted solid areas also appear in ovarian endometriotic cysts decidualization, such as that observed during pregnancy, diffusion-weighted imaging is useful for differentiation.10 Hydrosalpinx also presents with a variety of signals and can be difficult to differentiate from ovarian endometriotic cysts. However, a close examination of the hydrosalpinx often reveals it to have a tubular structure. Laparoscopic examinations Laparoscopic examination is highly useful for endometriosis and is necessary for a definitive diagnosis. The r-ASRM classification of endometriosis is widely used as a clinical staging system.12 This classification is used as an objective indicator to demonstrate the status of foci in laparoscopic visual examination and to determine severity according to a point-summing scoring system. However, this classification system is not necessarily correlated with symptoms, such as pain or with pregnancy rates after treatment.13 The r-ASRM classification system is superior to others in that, unlike other systems, it incorporates the recording of the colors of peritoneal lesions. Although the colors of peritoneal lesions have been reported to be associated with disease activity, red, black, and white lesions have also been indicated to potentially reflect an aging process.14 Table 3 shows the r-ASRM classification. Photos from actual cases corresponding to each classification of peritoneal lesion are also presented (Figure 5). 2. Treatment Overview of treatment The first step in the treatment of endometriosis is to design a regimen that targets the most important and urgent symptom in the patient based on an accurate diagnosis of clinical endometriosis. In most cases, the treatment factors are often broadly divided into infertility, pain, and ovarian endometriotic cysts, and patients sometimes have two or all three of the above. In light of these factors, based on a thorough discussion with the patient, the most suitable of the following therapeutic strategies is selected: medical therapy, surgical therapy, fertility treatment, or follow-up without treatment. These symptoms markedly decrease the quality of life (QOL) for endometriosis patients at all stages of life from the onset of symptoms in adolescence or later until menopause. In adolescence, dysmenorrhea is a risk factor for endometriosis later in life1; therefore, possible interventions are performed as necessary, and mild endometriosis should be monitored to avoid becoming severe. Once sexual maturity is reached, ovarian endometriotic cysts should be sufficiently removed in terms of the possibility of recurrence after treatment and the risk of malignant transformation. However, conservative therapy intended to preserve the ovarian reserve to maintain fertility conflicts with the removal of ovarian endometriotic cysts. Therefore, a therapeutic strategy must be decided with sufficient consideration of these factors. Furthermore, as recent studies have demonstrated, endometriosis itself is a risk factor for obstetric complications, such as preterm birth and hemorrhage.2, 3 These risks must also be considered. Other recent studies have determined endometriosis to be a risk factor for heart disease.4, 5 Endometriosis must no longer be considered as a disease limited to the pelvis but rather as a systemic chronic inflammatory disease that must be managed until middle and old age. Instead of only focusing on symptoms during a specific period, a three-dimensional therapeutic strategy that also considers age should be considered for endometriosis patients. Medical therapy Medical therapy for endometriosis is broadly divided into symptomatic treatment and hormone therapy. Symptomatic treatment consists mainly of analgesics and Chinese herbal medicine used to relieve pain associated with endometriosis. Currently, the only treatment that works on endometriotic foci is hormone preparations. Hormone therapy in Japan began in 1965, when the progestin dydrogesterone was introduced as treatment in the market, and pseudopregnancy therapy with medium-dose oral contraceptives (OCs) was performed. In 1983, danazol was released on the market as a therapeutic drug for endometriosis and hormone therapy began to develop. In 1988, buserelin, the first GnRH agonist, was commercially released, followed by a succession of other GnRH agonists, which are still used today as potent therapeutics. In 1999, long-awaited low-dose OCs were introduced to treat endometriosis-associated pain due to their side benefit. After approximately 9 years without the introduction of novel drugs, the fourth-generation progestin dienogest was released in January 2008. The launch of the ethinylestradiol/norethisterone combination, the first LEP formulation, was in July 2008. Although these are the same components as in OC, OCs are used for birth control and are not covered by insurance, while LEPs have been covered by insurance for the treatment of dysmenorrhea since they were released. Other LEPs have since been released on the market. Currently, LEPs and dienogest are the most widely used therapies for endometriosis. Furthermore, the levonorgestrel-releasing intrauterine system (LNG-IUS), which was initially not covered by medical insurance as an intrauterine contraceptive device, is now covered by it for the treatment of dysmenorrhea and hypermenorrhea and is consequently now also used for patients with endometriosis. Recently, oral GnRH antagonist is covered by medical insurance for treating pelvic pain associated with endometriosis (Table 4). Although a definitive diagnosis of endometriosis requires both laparoscopic surgery and laparotomy, performing both in all cases is difficult. In daily clinical practice, clinical endometriosis is diagnosed according to clinical symptoms and various other methods, such as pelvic/rectal examination, diagnostic imaging (ultrasonography and MRI), and biochemical testing (CA 125 levels), with medical therapy selected after a diagnosis is established. Symptomatic treatment Non-steroidal anti-inflammatory drugs The primary mechanism of action of NSAIDs is inhibition of prostaglandin synthesis. They are the first-line treatment for severe menstrual pain in unmarried women from adolescence, when women first complain of pain, to their twenties. Chinese herbal medicine In Chinese herbal medicine treatment, dysmenorrhea is interpreted as “congestion” or “water poisoning” and is widely treated with formulations such as shakuyakukanzoto (peony and licorice decoction), tokishakuyakusan (angelica and peony powder), keishibukuryogan (cassia twig and tuckahoe pill), and tokakujokito (peach kernel purgative decoction). The reasons for selecting Chinese herbal medicine include relief of menstrual pain in unmarried and adolescent adult women and the reduction of adverse effects associated with other drugs. Hormone therapy GnRH agonists have become widely used as a first-line option in hormone therapy since they first emerged. However, since the launch of dienogest and OCs/LEPs, GnRH agonists have ceded their first-line status and are chosen only when OCs/LEPs are not sufficiently effective.7 LNG-IUS, which specifically releases hormones into the uterine cavity, is sometimes also used. Danazol is known to be effective; however, due to the risks of adverse effects, namely virilization and thrombosis, its use has declined in the recent years. When medical therapy fails to sufficiently inhibit pain, surgical therapy is considered. Ovarian endometriotic cysts recur frequently after conservative surgery, and postoperative hormone therapy is considered a means of preventing decreased ovarian reserve resulting from repeated surgeries.8 OCs/LEPs9 and dienogest are effective for preventing the postoperative recurrence of ovarian endometriotic cysts. Six months of GnRH agonist administration followed by continuous administration of OC/LEP or dienogest is effective in preventing postoperative recurrence.10 Oral contraceptive/low-dose estrogen/progestin (OC/LEP) OC/LEP, which are administered to suppress ovulation, contain estrogen and progestin. The long-term use of OC/LEP combinations inhibits follicle maturation, ovulation, and luteinizatio
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