Norms on the Diagnosis and Treatment of Endometriosis Endometriosis Coordination Group, Gynecology & Obstetrics Society, Chinese Medical AssociationCommunication author:Lang Jinghe, Email: langjh@; Gynecology & Obstetrics Dept., Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (100730)Editor’s note:Endometriosis is a common and frequent disease in the young and middle-aged women. At present, its incidence rate tends to rise evidently, but its diagnosis and treatment still have many problems for solving. In order to normalize the diagnosis/treatment of endometriosis, under the leadership of Prof. Lang Jinghe, the Endometriosis Coordination Group in the Gynecology & Obstetrics Society of Chinese Medical Association prepares this norm through the repeated discussion, protocol drafting and five revisions. This norm aims to better guide the work of clinical doctors.Endometriosis means the occurrence, growth, infiltration and recurrent hemorrhage of endometrial tissues (gland and mesenchyme) at the sites other than endometrium, which can form the nodes and mass and cause the pain and infertility. Endometriosis is frequent in the women of fertility age, and its incidence rate tends to rise evidently. It possesses the following characteristics: (1) Unmatched illness severity with the symptoms and signs; (2) Extensive polymorphic lesion; (3) Extremely infiltrating to form an extensive serious adhesion; and (4) Hormone-dependent, and highly recurrent.I. Clinical Pathological Type1. Peritoneal endometriosis (PEM): It means various endometriosis foci at the pelvic/abdominal peritoneum. Mainly including: Red lesion (early one), blue lesion (typical one) and white lesion (old one).2. Ovarian endometriosis (OEM): It can form a cyst, i.e. endometriotic cyst. According to the size of cyst and the infiltration degree of endometriosis foci, it can be classified into two types. Type I: Cyst diameter of <2cm; and adhesive cyst wall of unclear anatomical layer and difficult surgical stripping. There are three sub-types of Type II. IIA: Superficial endometrial planting foci, involving the ovary cortex but not reaching the OEM cyst wall; often with concomitant functional cyst of very easy surgical stripping; IIB: Endometrial planting foci involving the OEM cyst wall, but at a clear boundary with ovary cortex, and easy surgical stripping; and IIC: Endometrial planting foci penetrating the OEM cyst wall and spreading all around, close adhesion of cyst wall to ovary cortex, with concomitant fibrillation or multiple chambers, larger adhesion of cyst to pelvic wall, difficult surgical stripping.3. Deep infiltrating endometriosis (DIEM): It means a foci infiltration depth of ≥5mm. Including: uterosacral ligament, uterorectal pouch, vaginal fornix and rectovaginal septum. There are two types of rectovaginal septum endometriosis: pseudo one (adhesion and closure of uterorectal pouch, and a foci below this adhesion); and genuine one (foci outside the peritoneum and inside the rectovaginal septum; and uterorectal pouch of no evident anatomical abnormality).4. Other endometriosis (O t EM): It can involve the digestive, urinary and respiratory system. Including: scarry endometriosis and rare distal endometriosis.II. Clinical Manifestations, Gynecological Examination and Auxiliary Examination1. Clinical manifestations: (1) Pain: 70%~80% of endometriosis patients has a pelvic pain of various degrees and incomplete matching with the lesion degree. Including: dysmenorrhea (typically secondary one of progressive aggravation), non-menstrual abdominal pain, chronic pelvic pain (CPP), dyspareunia and dysuria, and acute abdominal pain (in the case of broken OEM cyst); (2) Infertility: About 50% of endometriosis patients has a concomitant infertility. (3) Menstrual disorder. (4) Pelvic mass. In the endometriosis at special sites, there are various symptoms, often with a concomitant cyclic change and following clinical manifestations of pelvic endometriosis. For example: (1) Digestive tract endometriosis: Frequent defecation (or constipation), hemafecia and dysuria; (2) Urinary tract endometriosis: Polyuria, dysuria, hematuria, waist, and even urinary obstruction or renal dysfunction; (3) Respiratory tract endometriosis: Menstrual hemoptysis and pneumothorax; (4) Scarry endometriosis: Nodes at the incision scar of abdominal wall, prolonged menstrual period and aggravated pain after some surgeries (e.g. Caesarean birth); and nodes at the incision or incision scar, prolonged menstrual period and aggravated pain after the perineum surgery.2. Gynecological examination: Typically uterus of retro position and poor mobility; uterosacral ligament, uterorectal pouch or rear fornix tenderness/nodes; and concomitant adnexa cyst and immobile mass.3. Auxiliary examination: (1) CA125: Often mild/moderate rise of serum CA125level; (2) Radiography: Ultrasonic B examination is mainly significant for the diagnosis of OEM cyst. In the typical OEM cyst, there is a mass of no echo and strong light spot at the adnexa site under the ultrasonic B examination. MRI is significant for the diagnosis and assessment of OEM cyst, extra-pelvic endometriosis and deep infiltration foci; and (3) Others: vein/pelvis radiography, cystoscopy and colonoscopy.III. Diagnosis1. Symptoms: Pain (e.g. dysmenorrhea, CPP and dyspareunia) and infertility.2. Gynecological/auxiliary examination: There is an endometriosis foci under both pelvic examination and radiography; and mild/moderate rise of serum CA125 level.3. Laparoscopy: At present, the endometriosis is universally diagnosed through the laparoscopy mainly according to the shape of foci, which can not completely verified by the pathological examination.IV. Clinical StagingAt present, the endometriosis is staged often through the r-AFS method revised by the American Fertility Society in 1985. It is scored mainly according to the size and depth of peritoneal/ovary lesion, the range and degree of ovary-oviduct adhesion, and the closure degree of uterorectal pouch.V. TreatmentThe treatment of endometriosis mainly aims to subside/eliminate the foci, relieve/eliminate the pain, improve/promote the fertility, and reduce/avoid the recurrence. Its treatment should mainly consider the following factors: age, fertility desire, symptom severity, lesion range, past treatmentand patient demand. The treatment measures should be normative and individualized. The pelvic pain, infertility and pelvic mass should be treated separately. Its treatment methods include: surgery, pharmacotherapy, interventional treatment and fertility-assisting treatment.(I) Surgery1. Objective: To excise the foci and resume the anatomy2. Classification: According to the technique, the surgery for endometriosis is classified as follows: (1) Conservative surgery: Retain the fertility function of patients, excise the macroscopic foci and OEM cyst as far as possible, and separate the pelvic adhesion. It is applicable for young patients or those of demanding to retain the fertility function. (2) Semi-radical surgery: Excise the uterus/foci, but retain the ovary. It is mainly applicable for the patients of no fertility desire but demanding to retain the endocrine function of ovary. (3) Radical surgery: Excise the whole uterus, both adnexa and all macroscopic foci. It is applicable for the patients of older age, no fertility desire, serious symptoms or multiple ineffective treatment. (4) Auxiliary surgery: Excise the uterine nerve and anterior uterosacral nerve. It is applicable for the patients with a pain at center-line site.3. Preparation: As the most important contents before the surgery, the severity of illness should be assessed accurately, and the patients or their family members should be fully communicated to obtain their understanding and informed consent. In addition, the risk of surgery should be assessed, and the possibility should be evaluated for the surgical injury (especially the injury of urinary system and intestinal tract) and for the replacement of laparoscopic surgery with laparotomy. The intestinal tract should be fully pre-treated for the DIEM (especially that with a lesion involving the rectovaginal site). In the patients with an evident deep infiltration foci beside the uterus, the ureter and kidney should be examined for abnormality before the surgery, and the assistance should be obtained from the Urinary Surgery and General Surgery if necessary.4. Essential points: The pelvic adhesion should be first separated, so as to resume the anatomy; the PEM foci should be excised or destroyed as far as possible, so as to subside and eliminate it; the smaller and superficial foci can burnt or vaporized; and the deep infiltration foci should be excised.(1) OEM cyst: The surrounding adhesion should be first separated, the dark brown viscous liquid should be sucked out of cyst, and the inner wall of cyst should be rinsed up, the fibrous tissue ring around the cyst breach should be excised, and the inner wall of cyst should be completely stripped, and the normal ovary tissues should be protected as far as possible. In the patients with concomitant infertility, both the uteroscopy and oviduct fluid infusion can be conducted. (2) DIEM: This endometriosis is more difficult to treat. In case of no lesion involvement into the rectal/colonic wall, the foci should be excised as far as possible. In case of intestinal wall infiltration but no intestinal tract stenosis, it was generally recommended not to excise the intestinal wall or segment but to subside and eliminate the foci. If the foci is large enough to cause an intestinal stenosis and even intestinal obstruction, the intestinal segment should be excised and anastomosed according to the actual conditions. (3) Vesical endometriosis: According to the size of foci, the foci or partial vesical wall should be excised. (4) Ureteric endometriosis: According to the state of lesion and the degree of ureteric obstruction, the adhesion should be loosened or the partial ureter should be excised and anastomosed. (5) Scarry endometriosis: It should be treated mainly through the surgery, because it is usually insensitive to the pharmacotherapy. If the endometriosis foci can not be completely excised or if the important organs/tissues may be injured,the gonadotropin releasing hormone agonist (GnRH-a) can be administered for 3~6 months before the surgery. At the time of adhesion separation, uterus excision, uterus blood vessel treatment and ligament treatment, special attention should be paid to the anatomic relation around the ureter, and the ureteral catheter should be laid as the guidance before the surgery if necessary. In addition, relevant drugs can be administered to prevent the adhesion after the surgery.(II) PharmacotherapyThe pharmacotherapy aims to inhibit the function of ovary, retard the progress of endometriosis, decrease the activity of endometriosis foci and reduce the formation of adhesion. Principles of pharmacotherapy: (1) Applicable for the patients of basically-definite diagnosis, and not recommended for long-term tentative treatment; (2) Of yet no standard protocol; (3) Basically same effectiveness but different adverse reactions of various protocols; (4) According to the demand and economic strength. The endometriosis can be treated with four categories of drugs with the following protocol, action mechanism and adverse reactions.1. Oral contraceptive: Administer continuously or cyclically for 6 months. It can inhibit the ovulation. Less adverse reactions: Digestive tract symptoms or liver dysfunction.2. High-performance progestin: Medroxyprogesterone Acetate, 20~30mg/d po, bid or tid, for 6 months. It can cause the decidual change of endometrium tissues and finally cause the atrophy of endometrium; and inhibit the hypothalamus-pituitary-ovary axis in negative feedback. Main adverse reactions: bloated pain rupture hemorrhage, breast swelling pain, body weight gain, digestive tract symptoms and liver dysfunction.3. Androgen derivatives: (1) Danazol: 600~800mg/d po, bid or tid, for 6 months. It can inhibit the peak of luteotropic hormone (LH) at middle menstrual period for ovulation inhibition, inhibit various enzymes participating in the synthesis of steroids, and improve the free testosterone level in blood. Main adverse reactions: Masculine signs (e.g. hypenrichosis, emotional change and voice coarseness), lipoprotein dysbolism, liver functional injury and body weight gain. (2) Ethylnorgestrienone: 2.5mg po, 2~3 times a week, for 6 months. It can antagonize the progestin and estrogen, decrease the level of sex hormone binding globulin, and improve the free testosterone level in blood. Main adverse reactions: Basically same but milder antagonism of estrogen and androgen to that of Danazol.4. GnRH-a: Inject subcutaneously or intramuscularly (according to the medicinal form), monthly administration for 3~6 months. It can down-regulate the function of pituitary to cause a transient medicinal desexuality and a low estrogen level in body. Main adverse reactions: Climacteric symptoms caused by the hypoestrinemia (e.g. hectic fever, vaginal dryness, hyposexuality, insomnia and bone substance loss (at long-term administration).The combined protocol of GnRH-a + Add-back is based on the theory of “Window dose of estrogen”. The sensitivity of estrogen varies with tissues. The estrogen level in body is maintained at 110~146pmol/L estradiol to not stimulate the growth of ectopic endometrium or cause the climacteric symptoms (or bone substance loss) and not affect the effectiveness but relieve the adverse reactions, so as to prolong the treatment time. Add-back protocol: (1) Combined estrogen-progestin protocol: Estrogen (trade name: Premarin) (0.3~0.625mg/d) + Medroxyprogesterone Acetate (2~4mg/d). (2) Tibolone (synonym: Livial): 1.25mg/d.The Add-back protocol at an individualized dose is recommended generally after the administration of GnRH-a for more than 3 months, or begins from the Month 2 of GnRH-aadministration according to the severity of symptoms. The estrogen level should be monitored if possible.(III) Auxiliary treatment of dysmenorrhea and infertility1. Treatment of dysmenorrhea: In the patients with concomitant pelvic nodes or adnexa mass, the surgery is preferred; and otherwise, the pharmacotherapy is preferred. In the patients ineffective to the pharmacotherapy, the surgery can be adopted.Common therapeutic drugs for dysmenorrhea: (1) First-line drugs: Non-steroid anti-inflammatory drugs or oral contraceptives. The oral contraceptives can be administered cyclically or continuously, continue in effective case, but is replaced with the second-line drugs in ineffective case. (2) Second-line drugs: Progestin, androgen derivatives and GnRH-a; preferably the combined protocol of GnRH-a + Add-back to effectively control the adverse reactions at long-term administration; and the surgery can be adopted in ineffective case. (3) Pre-surgical drugs: In the patients with a serious illness, unable complete excision or possible important organ injury, relevant drugs can be temporarily administered for 3 months to reduce the surgical difficulty. (4) Post-surgical drugs: In the patients with milder illness or complete excision, relevant drugs can temporarily not be administered according to the actual conditions. In the patients with serious pelvic lesion or unable complete foci excision, relevant drugs can be administered for 3~6 months according to the existence of pain or not.2. Treatment of infertility: In the infertile endometriosis patients without other infertility factors and ineffective to pure pharmacotherapy as shown by complete examination, the laparoscopy can be conducted to assess the type and stage of endometriosis. In the young patients with mild/moderate endometriosis, the natural pregnancy can be expected half a year after the surgery, and fertility guidance should be offered. In the high-risk patients (aged ≥35 years old, oviduct adhesion and low functional score, infertility duration ≥3 years; and especially primary infertility, moderate/serious endometriosis with concomitant pelvic adhesion, and incomplete foci excision), the fertility-assisting technique should be actively adopted. For infertility treatment, the conservative laparoscopic surgery should excise the foci as completely as possible, separate the adhesion, and resume the anatomy. While excising the OEM cyst, the normal ovary tissues should be protected, the oviduct fluid infusion test should be conducted to know the smoothness of oviduct, and the uteroscopy should be made to grasp the conditions of uterine cavity. The following fertility-assisting technique should be selected according to the actual conditions of patients. (1) controlled ovarian hyperstimulation and/or artificial fertilization: Mainly applicable for the infertility patients with mild/moderate endometriosis, masculine factor (mild oligospermia and asthenospermia), cervical factor and unknown cause. The artificial fertilization has a single-cycle pregnancy rate of about 15%. If the pregnancy fails after 3~4 treatment courses, the fertility-assisting technique should be adjusted. (2) In vitro fertilization-embryo transplantation (IVF-ET): Mainly applicable for the infertility patients with serious endometriosis, long illness duration, old age or ineffective to other therapeutic methods (e.g. natural pregnancy, induced ovulation, artificial fertilization and surgery). Before the IVF-ET, GnRH-a is preferably administered for 2~3 months, so as to better improve the success rate of fertility assistance. The duration pharmacotherapy should be adjusted according to the severity of endometriosis and the storage conditions of ovary.Fig.1: Diagnosis and treatment of endometriosisVI. Problems of Hormone TreatmentAfter the menopause or radical surgery, the endometriosis patients can receive the hormone treatment, so as to improve their quality of life. The hormone treatment should be individualized according to the symptoms. Even after the hysterectomy, the combined estrogen with progestin had better be administered in case of residual endometriosis foci. Without the residual endometriosis foci, the single estrogen can also be administered. When possible, the estradiol level should be monitored, so that the estrogen level is high enough to not cause the symptoms or recurrence of endometriosis and is low enough not to cause the loss of bone substance.VII. RecurrenceThe recurrence of endometriosis means the re-appearance of clinical symptoms and their restoration to the degree before the treatment (or their aggravation) or the re-appearance of endometriosis foci after the subsidence/disappearance of foci and the relief of symptoms throughthe surgery or normative pharmacotherapy. It should be treated basically through the original treatment measures of endometriosis, and in the following individualized ways. OEM cyst: surgery or ultrasonic puncture, with subsequent pharmacotherapy. Dysmenorrheal: surgery for its recurrence after the pharmacotherapy; first pharmacotherapy and then surgery at ineffective pharmacotherapy for its recurrence after the surgery; and radical surgery for the patients of old age, serious symptoms but no fertility desire. Infertility patients with concomitant OEM cyst: surgery or ultrasonic puncture, with subsequent first GnRH-a administration for 3 months and then IVF-ET. Infertility patient without concomitant OEM cyst: first GnRH-a administration for 3 months and then IVF-ET.VIII. CancerationThe canceration of endometriosis has an incidence rate of about 1%. Under the following conditions, the canceration should be alerted: (1) Cyst diameter >10cm, or evident cyst enlargement within a short time; (2) Recurrence after the menopause; (3) Change of pain pace or continuation of dysmenorrhea; (4) Solid or papillary structure of cyst (radiography); and abundant blood flow and low resistance index at the foci (color Doppler ultrasonic examination); (5) Evident rise of serum CA125 level (>200kU/L).Diagnostic criteria for atypical endometriosis: (1) Cancer tissues and endometriosis tissues coexist at the same foci; (2) Both above tissues are histologically correlated just as the endometrial mesenchyme and gland; or there is a remote hemorrhage; (3) Other primary tumors are excluded; or the cancer tissues appear at the endometriosis foci, but do not metastasize from other sites; (4) There is a morphological evidence for the transformation of endometriosis lesion to malignant lesion; or the benign endometriosis lesion is mutually infiltrated with the malignant tumor tissues. The atypical endometriosis is a histopathologically-diagnosed atypic or nucleus atypia change of ectopic endometrium glandular epithelium, which does not break through the basal membrane. It has the following histopathological signs: deep/light staining of ectopic endometrium glandular epithelium, with concomitant moderate/serious nucleus atypia, increase of nuclear/cytoplasm proportion, and dense cells of multiple layers or clustery protrusion. The atypical endometriosis is regarded as a precancerous lesion or boundary tumor state.The canceration of endometriosis occurs mainly at the ovary, but less at other sites (e.g. rectovaginal septum and belly/perineum incision). It is treated according to the treatment principles for oophoroma.IX. AdenomyosisIn the myometrium, there are endometrium gland and mesenchyme. Under the action of hormones, there will be a hemorrhage and hyperplasia of muscular fibers and connective tissues, to cause a diffuse/local lesion or endometrioma.1. Etiology: At present, there is yet unknown cause for adenomyosis, including: invasion of endometrium (primary cause), diffusion of blood/lymph vessel, metaplasia of epithelium, and influence of hormone.2. Clinical manifestations: (1) Dysmenorrhea: More than half of patients have a secondary dysmenorrhea and its progressive aggravation; (2) Menstrual disorder: Hypermenorrhea, prolonged menstrual period and irregular hemorrhage; (3) Infertility; (4) Uterus enlargement:Generally uniform spherical enlargement, and sometimes uneven protrusion and hard texture.3. Diagnosis: The preliminary diagnosis can be obtained according to the symptoms, pelvic examination and following auxiliary examinations: (1) Ultrasonic scanning: uterus enlargement, myometrium thickening, more evident posterior uterus wall, and forward shifting of endometrium equal or enhanced echo at the foci, intermittent punctual low echo between the foci, and no evident boundary between the foci and its periphery. (2) MRI: foci of unclear boundary and low signal intensity. T2 enhanced scanning: foci of high signal intensity, and widening bonding area between endometrium and myometrium (>12mm). (3) Serum CA125level: generally rise. (4) Pathological examination: golden diagnostic criteria.4. Treatment: (1) Temporization: Regularly observe the patients of no symptoms or no fertility desire. (2) Surgery: Main treatment method (including the radical surgery of uterus excision). In the young patients requiring to retain the fertility function, the foci can be excised and the uterus is wedge uterectomy; or the auxiliary surgery should be conducted (i.e. uterus nerve excision, anterior uterosacral nerve excision or uterus artery blockage). In the patients with concomitant hypermenorrhea and of no fertility desire, the endometrium can be excised. (3) Pharmacotherapy: Same as endometriosis. (4) Intervention treatment. (5) Fertility-assisting treatment: after the GnRH-a administration for 3~6 months in the infertility patients; and after the combined protocol of surgery + GnRH-a in the patients with a local lesion or adenomyosis.Members of Endometriosis Coordination Group:Peking Union Medical College Hospital, Medical University, Chinese Academy of Medical Sciences (Lang Jinghe, Y u Qi, Leng Jinhua, Zhu Lan); People’s Hospital of Peking University (Wei Lihi, Cui Heng); First Hospital of Peking University (Zhou Yingfang); Affiliated Beijing Chaoyang Hospital of Capital Medical University (Zhang Zhenyu); China-Japan Friendship Hospital (Bian Meilu); Affiliated Gynecology & Obstetrics Hospital of Medical College of Fudan University (Cao Binrong); Second Affiliated Hospital of Sun Yat-Sen University (Yang Dongzi); Affiliated Union Hospital of Huazhong University of Science and Technology (Gu Meijiao); First Affiliated Hospital of Medical College of Zhejiang University (Zhang Xinmei); Second Xiangya Hospital of Central South University (Xiao Hongmei); First Affiliated Hospital of Jinan University (Luo Xin); Maternity and Child Health Hospital for women & children of Fujian Province (Chen Jie)。
