Endometriosis affects 5 to 10% of women of childbearing age and affects an estimated 176 million women worldwide, according to The Lancet 2021.In the United States alone, the economic burden of ecds exceeds $22 billion a year；

     A benign disease caused such a big economic burden however, what kind of characteristic does internal disorder have?What are the problems in its diagnosis and treatment?

     At present, there are three problems in the diagnosis of endodynia：

Problem 1. Delayed diagnosis -- ubiquitous：

     The time to diagnose endopathy varies from four to 11 years, and 65 percent of women are initially misdiagnosed；

Problem two, it is difficult to diagnose by clinical symptoms：

    1. Patients with endopathy often find it difficult to identify their symptoms, or become accustomed to pain and other discomfort because of long-term endurance;

    2. Endodynia lacks specific symptoms, and its symptoms are similar to dysmenorrhea, pelvic inflammatory disease, ovarian cysts, pelvic adhesions, intestinal and bladder dysfunction, fibromyalgia and musculoskeletal diseases;

     3. Adenomyosis and leiomyoma of uterus may be combined with endometriosis;

Problem three, the defective "gold standard" -- surgical diagnosis：

     There are also missed diagnoses in laparoscopic surgery, and all ectopic endometrial lesions may not be found during surgery.Endometriosis as a chronic systemic disease: Clinical challenges and new innovations, published in The Lancet, systematically explores The mechanisms, clinical diagnosis and treatment of endometriosis；

【I】，The pathogenesis of endometriosis：

     1, the widely accepted classic menstrual blood reflux theory:

     In 1921, Sampson's theory of countercurrent implantation of menstrual blood became the leading theory in the pathogenesis of endometriosis.The theory is that the blocked flow of menstrual blood leads to the reversal of menstrual blood flow, and the reversal of menstrual blood flow is associated with the occurrence of endotropic diseases；

     2. The current "stem cell" theory:

     1) Stem cell transport to the pelvic cavity is thought to be highly associated with the development of endopyrosis；

     2) Women with endopecia have more basal-like cells during menstruation, which play a critical role in the formation of ectopic endometrial lesions；

      3) Stem cells from bone marrow or their origin are closely related to the occurrence of endometriosis diseases；

【II】，Progesterone resistance is a key disease mechanism of endopathy

     Endopecia is a hormone-dependent disease in which the growth of ectopic endometrium is dependent on estrogen. Progesterone usually inhibits estrogen-dependent endometrium hyperplasia, causes endometrium decidualization, and plays an anti-inflammatory role.Overexpression of estrogen receptor β (ER-β) in ectopic endometrial tissue leads to estrogen receptor α (ER-α) inhibition, which in turn leads to ER-α -mediated progesterone receptor inhibition, and ultimately ER-β allows ectopic endometrial tissue to survive and maintain an inflammatory environment；

     Reduced ratio of progesterone receptor subtype B (PR-B) to progesterone receptor subtype A (PR-A) in patients with endopyrosis suggests that progesterone resistance is mediated in part by reduced PR-B；

     Progesterone resistance is an important clinical feature of endopathy, promoting endometrial hyperplasia and possibly limiting the local effects of progesterone therapy.Abnormal responses to progesterone in endopausal lesions lead to an estrogen-rich pro-inflammatory environment that further mediates the systemic effects of the disease；

     Based on this, some scholars predicted the response of patients to progesterone therapy based on the expression of progesterone receptors in ectopic endometrial lesions. However, the study results showed that only 6% of women with low progesterone receptor expression were effective in progesterone therapy；

【III】，Redefine endodynia from mechanism: systemic, inflammatory disease：

     Antibodies to endometrial and ovarian antigens were also detected in the serum of women affected by endopyrosis, and these results suggest that endopyrosis has characteristics similar to those of autoimmune diseases.Changes in pro-inflammatory cytokines and circulating immune cells create an inflammatory environment that is not confined to the pelvic cavity.Because this can have certain effect to the systemic respect such as cardiovascular, nerve and metabolic system；

    1. Effects of endovascular diseases on cardiovascular diseases:

The study showed that patients with a surgically diagnosed endopathy had a significantly increased risk of cardiovascular disease compared to women without endopathy.This high risk may result from high levels of oxidative free radicals and cytokines；

    2. Effects of endotropia on nervous system:

    1) Neurological manifestations are common in patients with endopathy, including anxiety and depression, and fatigue occurs in 50-87% of patients；

    2) Patients with endodynia have central pain sensitivity；

    3) The neuropsychological effect of endosis is a real and often overlooked extra-pelvic effect.Existing evidence suggests a close link between endopathy and brain remodeling；

    3. Influence of endodynia on metabolic system:

     1) Patients with endopathy have a lower BMI, and BMI has always been considered as a risk factor for endopathy；

     2) It has been reported that in animal experiments, mouse models induced by endopecia have lower BMI and altered liver gene expression, which is known to play an anorexia role. Subsequent studies have also confirmed altered metabolic gene expression in adipocytes of endopecia patients；

     There is growing evidence that endopathy is more than just a localized pelvic disease.Endopathy affects the metabolism of the liver and fat tissue, causes systemic inflammation and changes in the brain, leading to increased pain sensation and mood and anxiety disorders, which are more common in people with endopathy than in the general population；

     For the clinical diagnosis of endodynia, the Lancet 2021 provides more specific reference suggestions from three aspects: the corresponding mechanism of clinical symptoms and history, imaging examination and serological examination indicators；

【IV】，The seven major clinical symptoms and their corresponding mechanisms are not limited to pelvic systemic effects：

    1. Periodic pelvic pain, periodic difficulty defecating, and dysuria caused by prostaglandin and cytokine production;

    2. Deep sexual pain and progressive dysmenorrhea: affected by the depth and location of lesion infiltration;

    3. Chronic pelvic pain and aperiodic pelvic pain: associated with pain sensitization and immune-mediated nerve injury;

    4. Infertility: the effect of inflammation on oocytes, abnormal gene expression in endometrium, abnormal stem cell transport, adhesion of ectopic endometrial lesions that alter normal anatomical structure and prevent ovulation;

    5. Low BMI and metabolic changes: anorexia gene expression in liver, miRNAs mediated lipid cell metabolic changes;

    6. Systemic inflammation: estradiol mediated increase of prostaglandin E2, abnormal immune cell function, abnormal miRNAs expression, production of inflammatory cytokines;

    7. Mood disorders (anxiety, depression) : abnormal gene expression of brain regions, reduced volume of brain regions related to emotions and feelings;

【V】，Different imaging tests have different characteristics for different subtypes of endodynia：

    1. Ultrasound: Transvaginal ultrasound, as the most commonly used examination method, has 93% sensitivity and 95% specificity for ectopic cysts, and has a high diagnostic ability for deep invasion of the disease (DIE), but its ability to display peritoneal lesions is limited；

    2. MRI: can assess the depth of endometrium invasion in DIE patients, with 91% sensitivity and 96% specificity for lesions involving the colorectal, and can confirm the diagnosis of ovarian endometrium cyst.Although MRI can diagnose peritoneal lesions, it is not very good for superficial lesions；

    3. CT: For chest abnormalities, chest CT can effectively display the lesions, and MRI can provide soft tissue comparison；

【VI】，Different serological indicators are in urgent need of accurate biomarkers：

    1. Muc-16 (CA 125) is thought to be associated with the severity of endopyrosis, but it lacks sufficient sensitivity and specificity.

    2. There is insufficient evidence to prove the diagnostic effectiveness of il-6, IL-8, CCL5, CCL2, VEGF, CA19-9 and other biomarkers, whether used alone or in combination；

    3. Circulating miRNAs are considered as promising next-generation markers that maintain a stable and highly specific expression profile in the blood circulation.It has been reported that the combination of miRNAs with LET-7b, LEt-7D, LEt-7F, Mir-3613, Mir-451, and Mir-125b-5p can effectively distinguish patients with ectopia from the control group.A prospective study showed that Mir-125b-5p, Mir-150-5p, Mir-61, Mir-342-3p, Mir-451A, Mir-3613-5p, and LET-7b can be used to accurately identify patients with endodynia；

【VII】，Surgical treatment：

    Laparoscopic surgery remains the "gold standard", improving fertility in mild and moderate patients, and robotic surgery offers similar outcomes.However, surgical treatment cannot cure endodynia radically. 40-50% of patients have recurrence after surgery, 15-20% of patients need to be operated again within 2 years, and 50% of patients need to be operated again within 5-7 years；

    Postoperative medication can reduce the risk of recurrence and reduce the systemic effects of endodynia；

【VIII】，Drug treatment：

    1、Non-steroidal anti-inflammatory drugs (NSAIDs) :

    First-line therapy, which effectively inhibits the function of cycx, thereby reducing prostaglandin concentration and inflammation, is often used in combination with progesterone therapy；

    2、Medications containing progesterone:

Modern compound oral contraceptive is mainly progesterone, which mainly causes decidualization and pathological atrophy. Continuous application has good therapeutic effect；

    Progesterone alone, including medroxyprogesterone, noregestrel and denorgestrel, inhibits inflammation and apoptosis of endometriosis cells and has similar therapeutic effects to GNRH-A in the treatment of endometriosis related pain.The major adverse reactions are irregular uterine bleeding, breast tenderness, mood changes, and weight gain, and up to one-third of patients cannot tolerate treatment due to progesterone resistance or side effects；

    3、Gnrh-a combined with reverse addition therapy：

    A large number of clinical trials have shown that approximately 85% of women treated with GNRH-A for endoparasis-related pain experience pain relief;

    It is theorized that an estradiol concentration of 30-40 pg/mL will lead to regression of endotropy without the low estrogen side effects (i.e., vasomotor symptoms and bone loss)；

    Based on this theory, reverse supplementation (progesterone or estrogen combination) can eliminate symptoms caused by low estrogen without affecting pain control in patients with endodynia；

    Endodynia is a systemic and heterogeneous disease.At present, its clinical diagnosis is still very dependent on surgical diagnosis, and early treatment cannot be provided to avoid further progression of the disease, which also leads to greater changes in our understanding of the mechanisms related to the disease and clinical diagnosis methods.Although pelvic pain is the most direct and major symptom of endopathy, it does not mean that endopathy is a disease limited to the pelvic cavity；

     Main purpose of surgery and hormone therapy is to suppress pelvic lesions, but they have their own limitations and cannot completely manage the systemic effects of endotropia.In the future, with the in-depth study of this disease, more diagnostic markers and treatment plans will appear, which will help us better manage the whole body and long-term；