Endometriosis: Clinical Guidelines

List of Abbreviations

GnRH-a – gonadotropin-releasing hormone agonists (ATC: Gonadotropin-releasing hormone analogues);

AUB – abnormal uterine bleeding;

LNG-IUS – levonorgestrel-releasing intrauterine system;

ART – assisted reproductive technologies;

COC – combined oral contraceptives (ATC: Progestogens and estrogens, fixed combinations);

MHT – menopausal hormone therapy;

MPA – medroxyprogesterone**;

BMD – bone mineral density;

MRI – magnetic resonance imaging;

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs;

RCTs – randomized controlled trials;

ultrasound – ultrasound examination;

CPD – chronic pelvic pain.

Terms and Definitions

Endometriosis is a pathological process characterized by the presence of tissue with morphological and functional properties similar to the endometrium outside the uterine cavity [1], [2].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Endometriosis is a pathological process characterized by the presence of tissue with morphological and functional properties similar to the endometrium outside the uterine cavity [1], [3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Endometriosis is traditionally subdivided into genital and extragenital. Genital endometriosis, in turn, is divided into internal (adenomyosis, or endometriosis of the uterine body) and external (endometriosis of the cervix, vagina, perineum, rectovaginal septum, ovaries, fallopian tubes, peritoneum, rectouterine pouch, etc.).

Endometriosis is a multifactorial disease, and despite being studied for a long time, its etiology remains unclear [4]. Numerous theories of the pathogenesis of endometriosis have been proposed: implantation theory (retrograde menstruation theory by J. A. Sampson, 1921), metaplastic, embryonic, dyshormonal theory, and immune imbalance theory, among others. Along with hyperestrogenism, progesterone resistance, inflammatory changes, and induction of neoangiogenesis—which underlie infiltrative growth, invasion into surrounding tissues with subsequent destruction, and disease spread [5]—the role of stem cells [6], genetic mutations, and epigenetic factors (such as environmental factors) in the development of endometriosis has been discussed over the past decade.

Despite its infiltrative growth, recurrence tendency, and invasive potential, endometriosis is classified as a benign proliferative disorder [1].

1.3 Epidemiology of the Disease or Condition

Endometriosis affects approximately 10% of women worldwide, predominantly of reproductive age. Because endometriosis can be asymptomatic, its true prevalence is difficult to estimate. Given its diverse clinical symptoms—cyclic and chronic pain, infertility, abnormal uterine bleeding, impaired function of adjacent organs, and other complaints that reduce quality of life and negatively affect the psycho-emotional status of women primarily of reproductive age—endometriosis remains one of the most socially and demographically significant diseases requiring a multidisciplinary approach [7], [8], [9], [10].

1.4 Features of Coding the Disease or Condition

Endometriosis (N80):

N80.0 – Endometriosis of the uterus;

N80.1 – Endometriosis of the ovary;

N80.2 – Endometriosis of the fallopian tubes;

N80.3 – Endometriosis of the pelvic peritoneum;

N80.4 – Endometriosis of the rectovaginal septum and vagina;

N80.5 – Endometriosis of the intestine;

N80.6 – Endometriosis of cutaneous scar;

N80.8 – Other endometriosis;

N80.9 – Endometriosis, unspecified.

1.5 Classification of the disease or condition

1.5.1 Clinical classifications of endometriosis:

• by origin; [D. Redwine, 1987]

• by depth of lesion; [D. Martin, 1989]

• by localization of extragenital endometriosis. [J. Rock et al., 1989]

• by anatomical manifestations [Huffman et al., 1951; Riva et al., 1962, Beecham et al., 1966; R. Kistner, 1977]

• by localization and area of the lesion, and associated adhesions [rASRM, 1996]

• by morphofunctional features and etiopathogenesis [Wicks, Larson et al., 1949; Ph. Koninckx, 1994; M. Nisolle et al., 1997; I. Brosens et al., 2000];

• by anatomical characteristics and required extent of intervention, i.e., clinical classification of endometriosis [L.V. Adamyan et al., 1993; A. Acosta, 1973; Buttram et al., 1978].

C. Chapron (2003) proposed a classification of deep infiltrating endometriosis with involvement of adjacent organs based on anatomical manifestations and the required extent of intervention.

1.5.2 Classification of internal endometriosis:

• Stage I – the pathological process is limited to the submucosa of the uterine body;

• stage II – the pathological process extends to the muscle layers;

• stage III – spread of the pathological process through the entire thickness of the myometrium to its serosal covering;

• stage IV – involvement of the parietal peritoneum of the minor pelvis and adjacent organs in the pathological process, in addition to the uterus [11].

Adenomyosis can be diffuse, focal, or nodular and cystic. A characteristic difference from uterine myoma is the absence of a capsule and clear margins.

1.5.3 Classification of ovarian endometriomas:

• stage I – small punctate endometriotic lesions on the surface of the ovaries and the peritoneum of the rectouterine pouch without the formation of cystic cavities;

• stage II – an endometrioid cyst of one ovary measuring no more than 5–6 cm with small endometriotic inclusions on the pelvic peritoneum. Minor adhesions in the uterine adnexa area without bowel involvement;

• stage III – endometrioid cysts of both ovaries (diameter of the cyst in one ovary greater than 5–6 cm and a small endometrioma of the other). Small-sized endometrioid heterotopias on the parietal pelvic peritoneum. Pronounced adhesions in the uterine adnexa area with partial bowel involvement;

• stage IV – large bilateral endometrioid cysts of the ovaries (greater than 6 cm) with extension of the pathological process to adjacent organs – the urinary bladder, rectum, and sigmoid colon. Widespread adhesions [5].

1.5.4 Classification of rectovaginal endometriosis:

For rectovaginal endometriosis, a universally recognized clinical classification determines the scope of intervention and treatment tactics [1].

• stage I – endometrioid lesions are located within the rectovaginal septum;

• stage II – invasion of endometrioid tissue into the cervix and vaginal wall with the formation of small cysts and into the serosa of the rectosigmoid and rectum;

• stage III – spread of the pathological process to the uterosacral ligaments, and the serous and muscular layers of the rectum;

• stage IV – involvement of the rectal mucosa in the pathological process with spread to the peritoneum of the rectouterine pouch, formation of adhesions in the uterine adnexa area, as well as spread toward the parametrium, involving the distal urinary system (ureters and bladder) [1], [5], [8], [12].

One of the most widely used classifications in global practice is the one proposed in 1979 by the American Fertility Society (since 1995, the American Society for Reproductive Medicine) and revised in 1996, based on scoring the total lesion area:

Stage I - minimal endometriosis (1-5 points);

Stage II - mild endometriosis (6-15 points);

Stage III - moderate endometriosis (16-40 points);

Stage IV- severe endometriosis (more than 40 points).

However, this classification does not account for the presence and spread of infiltrative forms.

The Enzian classification (2021) is based on describing the location of endometrioid lesions, the depth of their invasion into pelvic organs and tissues, as well as the presence of infiltration into adjacent organs and impairment of their functions. This classification provides continuity between preoperative imaging and surgical assessment of endometriosis severity [13].

The 2021 AAGL endometriosis classification allows the identification of objective intraoperative findings and can be used to assess the complexity of surgical intervention [14].

1.6 Clinical presentation of the disease or condition

The most significant clinical manifestations of endometriosis are pelvic pain (dysmenorrhea, dyspareunia, dyschezia, and chronic pelvic pain (CPP)) [15], [16], infertility, menstrual irregularities, abnormal uterine bleeding, and the presence of pelvic mass lesions (endometrioid cysts).

Endometriosis should be suspected in the presence of the following symptoms, including in young women under 17 years of age [17]:

• Chronic pelvic pain [18], [19];

• Dysmenorrhea negatively affecting quality of life and daily activities;

• Pain occurring during and/or after intercourse – dyspareunia;

• Gastrointestinal symptoms associated with menstruation – bowel pain, constipation or diarrhea, tenesmus;

• Urinary symptoms associated with menstruation, e.g., dysuria, blood in the urine;

• Infertility combined with 1 or more symptoms.

Endometriosis may be suspected in the presence of the following factors [20]:

• Heavy menstrual bleeding, postcoital bleeding;

• Dysmenorrhea and/or dyspareunia whose symptoms do not resolve or are poorly relieved by combined oral contraceptives (COCs) (ATC code: progestogens and estrogens, fixed combinations) and nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs);

• Dysmenorrhea and/or dyspareunia that may cause absenteeism from school or work;

• Repeated emergency visits for dysmenorrhea;

• Presence of endometriosis in the patient's mother or sister;

• Subfertility with regular ovulation, patent fallopian tubes, and normal partner's spermogram;

• Diarrhea, constipation, nausea, pain with defecation, intestinal cramps, bloating, and early satiety;

• Presence of premenstrual and postmenstrual light spotting for ≥ 2 days [21];

• Presence of grass pollen allergy, allergic rhinitis, and food hypersensitivity - relative risk (RR) 4.28 (95% CI: 2.93–6.27) compared to women without endometriosis [22];

• Depression, anxiety, chronic fatigue syndrome - endometriosis was significantly more frequent (adjusted odds ratio 3.67; 95% CI, 1.53–8.84) [23];

• Presence of migraine - the prevalence of migraine among endometriosis patients in the perimenstrual period is 30.1–47.2%, whereas among healthy women it is 15% (p < 0.001) [24];

• Frequent, urgent urination with or without pain - patients with endometriosis are significantly more likely to suffer from interstitial cystitis (RR: 10.6; 95% CI: 1.9–56.5) [25].

Extrapelvic localization of endometriosis [26]: lungs, eye, diaphragm, pericardium, nerve endings and plexuses, postoperative scars, etc.; lesions of these structures are accompanied by the following symptoms: spontaneous pneumothorax, dyspnea, chest pain, hemolacria – "bloody tears" [27], etc. Symptoms of extrapelvic endometriosis are cyclic in character, worsening during menstruation, and respond to therapeutic agents effective against endometriosis that suppress its activity.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is established based on patient complaints and medical history, physical examination, and instrumental diagnostic methods (pelvic ultrasound, pelvic MRI, diagnostic laparoscopy).

2.1 Complaints and Anamnesis

See the "Clinical Presentation" section.

2.2 Physical Examination

Comments: Gynecological examination is not always informative. The following changes may be detected [20], [29]:

• lateral displacement of the cervix;

• fixed and markedly displaced uterus;

• adnexal mass lesions;

• presence of nodules in the uterosacral region, thickening, tension, and/or masses in the uterosacral ligament;

• shortening and tension of the vaginal fornices;

• marked cervical stenosis;

• presence of a micronodular mass in the rectovaginal region;

• tenderness and restricted mobility of the intestinal mucosa (upon rectoabdominal examination).

During a gynecological examination, it is necessary to note local (myofascial trigger points) and generalized hyperalgesia and increased pain sensitivity (allodynia) as evidence of central sensitization.

2.3 Laboratory Diagnostics

Specific laboratory diagnostics for endometriosis have not been developed [30].

Comment: An elevated CA-125 level may be associated with endometriosis [28]. However, endometriosis can be present despite a normal CA-125 level (less than 35 IU/mL) [32].

2.4 Instrumental Diagnostics

Comments: Ultrasound is necessary to diagnose suspected endometriosis [9] even if the gynecological examination reveals no pathology, in order to diagnose endometrioma and deep infiltrative endometriosis involving the bowel, urinary bladder, or ureter.

If performing a transvaginal ultrasound of the uterus and appendages is difficult, a transabdominal ultrasound and/or transrectal ultrasound of the uterus and appendages may be performed [32].

The sensitivity of transvaginal ultrasound of the uterus and appendages in diagnosing endometriosis averages 91%; for deep infiltrative forms, it is 79%, meeting the criteria for lesions of the uterosacral ligaments, rectovaginal septum, vaginal wall, pouch of Douglas, and rectosigmoid colon. Transrectal ultrasound of the uterus and appendages is most informative for diagnosing rectosigmoid endometriosis.

Comments: Pelvic MRI should be considered to assess the extent of deep infiltrative endometriosis involving the bowel, urinary bladder, or ureter [32], [40], [41]. MRI should be performed (if available) in patients of reproductive age with comorbid conditions – adenomyosis (nodular or cystic form) – to choose the surgical access and scope of reconstructive plastic surgery. Pelvic MRI interpretation should preferably be performed by a specialist in gynecological imaging [32].

Magnetic resonance imaging (MRI) with a sensitivity of 95% meets the criteria for vaginal and rectosigmoid endometriosis [42].

Comments: Laparoscopy is the "gold standard" for diagnosing endometriosis [17], [32], [43].

Comments: In cases of infertility in patients with endometriosis and a history of 2 or more failed IVF attempts, hysteroscopy is a method to rule out intrauterine synechiae, endometritis, and genital malformations while simultaneously removing these pathologies or correcting the uterine malformation, as well as assessing fallopian tube patency [17].

Comments: Laparoscopy for suspected endometriosis should be offered in the following situations [17]: when achieving pregnancy is a priority for the patient; in the presence of pain syndrome and lack of response to conservative treatment.

Comments: A positive morphological result confirms the diagnosis of endometriosis; a negative result does not rule it out [32].

In all cases of ovarian endometriosis and deep infiltrative endometriosis, an ovarian biopsy is necessary to rule out malignancy [32].

Comments: The evaluation of least function (LF) upon completion of surgery in patients with endometriosis and the Endometriosis Fertility Index (EFI) are presented in the tables (Appendix G2) [45], [46].

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Medical treatment

Comments: Nonsteroidal anti-inflammatory and antirheumatic drugs can be prescribed for a short term of up to 3 months in the absence of contraindications, either alone or in combination with first-line therapy. If pain relief is insufficient, another treatment should be prescribed.

Comments: Progestogen therapy can be administered in a continuous regimen to induce glandular epithelium atrophy and decidualization of the stromal component; progestogens can also be used in a cyclic regimen in patients with endometriosis planning a pregnancy [57].

Comments: The use of GnRH agonists for more than 6 months requires the administration of add-back therapy [3].

Comments: The duration of LNG-IUS use (ATC: Plastic progestogen-only intrauterine devices) in adult patients is 5 years, after which treatment can be continued by inserting a new system. Side effects are similar to those seen with the continuous use of other progestogens [58].

Comments: Used extremely rarely due to pronounced side effects. The course of treatment with danazol is usually 6 months, with amenorrhea typically developing after the first 2 months. The menstrual cycle restores approximately 4 weeks after treatment cessation. The clinical efficacy of danazol depends on the dose: for stage I–II disease, a dose of 400 mg/day is sufficient; for stage III–IV disease, the dose may be increased to 600–800 mg/day.

Comments: Aromatase inhibitors may be prescribed in combination with combined hormonal contraceptives (progestogens and estrogens, fixed combinations per ATC), progestogens (progestogens per ATC), gonadotropin-releasing hormone agonists (GnRH agonists per ATC) [26].

Comments: Preoperative hormonal treatment causes shrinkage ("masking") of lesions, thereby contributing to their non-radical removal.

3.2 Surgical treatment

Comments: Surgical and medical treatment methods should not be contrasted with one another. The advantages and disadvantages of each method must be carefully weighed before starting treatment, taking into account the individual characteristics of the case. This will minimize negative outcomes and maximize positive ones [70].

Intraoperatively, the possibility of using anti-adhesion measures, such as oxidized cellulose or hyaluronic acid-based products, should be considered to reduce the formation of postoperative adhesions [26].

In case of involvement of adjacent organs, the surgical team must include profile specialists (urologist, general surgeon, etc.) or an obstetrician-gynecologist with appropriate certification. Surgical treatment in patients with stage III–IV endometriosis involving adjacent organs and extensive adhesions should be performed in level 3 hospitals (hospitals providing specialized, including high-tech, medical care to women and developing new methods for the diagnosis and treatment of gynecological pathology).

Robotic surgery has become more frequently used for the surgical treatment of endometriosis [71].

Comments: Enucleation of the cyst capsule minimizes the risk of endometriosis recurrence, helps preserve ovarian reserve, and consequently increases the likelihood of spontaneous pregnancy in patients with endometriosis-associated infertility [75]. Evacuation of endometriotic tissue within a containment bag reduces the risk of disease dissemination and recurrence [75].

When performing surgery in women with an ovarian endometrioma, vaporization of the cyst capsule with a CO2 laser may be considered [26].

In cases of extensive endometriosis (endometriotic cysts, rectovaginal endometriosis involving pelvic structures), the risks of reduced ovarian reserve—caused by both the endometriotic cyst itself and the surgical intervention—should be discussed prior to surgery, and the possibility of fertility preservation should be considered.

Comments: The pregnancy rate in patients with stage 3–4 adenomyosis does not exceed 10–15%, as none of the treatment modalities can create favorable conditions for embryo implantation. The only effective treatment for adenomyosis is total hysterectomy. In the presence of infertility in patients with the nodular form of adenomyosis accompanied by AUB, reconstructive plastic surgery with maximum removal of the affected tissue may be performed to reduce uterine bleeding and increase the chances of realizing reproductive function.

• In adult patients with advanced forms of stage 4 endometriosis (deep infiltrating endometriosis, endometriotic cysts) who have completed their reproductive function, in the absence of an effect from conservative therapy and in the presence of severe pain syndrome or abnormal uterine bleeding, it is recommended to perform a total hysterectomy [26].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: Subtotal hysterectomy (uterine amputation) should not be performed. If the ovaries are preserved, the risk of disease progression persists.

Comments: Pregnancy in patients suffering from endometriosis, adenomyosis, or deep infiltrating endometriosis should be regarded as a high-risk pregnancy due to potential maternal and fetal obstetric complications (preterm birth, spontaneous abortion, cyst rupture, etc.).

3.3 Other Treatment

3.4 Endometriosis in adolescents (under 18 years of age)

In adolescents, a thorough medical history must be taken to identify potential risk factors for the development of endometriosis, such as a positive family history, obstructive anomalies of the reproductive tract, early menarche, or a short menstrual cycle [26].

Symptoms of the disease quite often begin at a very early age. About two-thirds of adult women with endometriosis report symptoms starting from adolescence [90], [91]. An increasing body of research indicates that severe forms of endometriosis and deep infiltrating endometriosis are quite common among adolescents. Nearly 50% of adolescents diagnosed with endometriosis during laparoscopy have the severe form of the disease [92], [93].

The most common localizations of endometriosis in adolescents are the ovaries, the pouch of Douglas, the posterior leaves of the broad ligaments, and the uterosacral ligaments [94]. On average, 7 to 10 years pass from the onset of the first symptoms to the establishment of the diagnosis, with adolescents waiting for help 2 to 3 times longer than adult women [26].

Adolescents diagnosed with endometriosis predominantly complain of symptoms such as pain syndrome (including chronic pelvic pain, acyclic pain), dysmenorrhea, dyspareunia, gastrointestinal symptoms (dyschezia, nausea, abdominal bloating), and dysuria [26], [95].

Surgical (laparoscopic) diagnosis of endometriosis in adolescents acquires special significance.

Treatment goals for endometriosis in adolescents [86]:

• treatment of symptoms,

• prevention of further disease progression,

• preservation of reproductive function.

• The prescription of GnRH agonists (ATC: Gonadotropin-releasing hormone analogues) is not recommended under the age of 18 [99].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: When prescribing this group of drugs, it is necessary to use «add-back» therapy, monitor serum calcium levels and vitamin D metabolites, as well as bone mineral density due to the potential for bone loss in adolescents receiving GnRH agonists.

Comments: Acute pain in endometriosis can be the cause of emergency hospitalization in surgical hospitals and mistaken surgery for suspected acute appendicitis, intestinal obstruction, or intraperitoneal hemorrhage.

3.5 Postmenopausal endometriosis

The detection rate of endometriosis in postmenopausal women is 2–5%. The most critical issues facing the physician in the management of postmenopausal patients are: the risk of malignancy [102] (especially in infiltrative forms and the presence of endometriomas) and the feasibility of MHT when indicated [103], [104], [105]. Intestinal lesions and ovarian endometrioid cysts are more frequently diagnosed in postmenopausal women (usually as a recurrence of endometriosis or a previously undiagnosed condition). According to R.Koninckx et al., endometriosis in menopause can also develop independently (de novo) [106].

Estrogen-only treatment regimens for vasomotor symptoms should be avoided in postmenopausal women with a history of endometriosis, as these regimens may be associated with a higher risk of malignant transformation [26].

Comments: Numerous cases of disease recurrence in the postmenopausal period have been described, both with and without the use of menopausal hormone therapy (MHT), as well as instances of newly diagnosed endometriosis [106]. When endometrioid ovarian cysts and extragenital forms of the disease are detected, oncological alertness should be maintained. It should be remembered that the persistence of endometriosis in the postmenopause increases the risk of malignancy, which requires prompt surgical treatment.

Comments: This therapy reduces the risk of disease recurrence and malignancy of remaining endometriosis foci.

3.6 Endometriosis and cancer

Comments: Despite the low prevalence of ovarian cancer in the population, as well as the low frequency of its detection in endometriosis (less than 1%), the relationship between endometriosis and ovarian cancer is of high clinical significance, especially for clear cell and endometrioid carcinomas. When performing surgical treatment for endometriosis, a pathomorphological examination of the endometrioid tissue biopsy (per NMS: Pathological examination of biopsy (surgical) material) must be performed to clarify the diagnosis and rule out a concomitant malignant process.

It is advisable to inform women with endometriosis requesting information about cancer risk that endometriosis is not associated with a significantly higher overall risk of cancer. Although endometriosis is associated with a higher risk of ovarian, breast, and thyroid cancer in particular, the increase in absolute risk compared to women in the general population is small [26].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Endometriosis may be accompanied by increased anxiety and/or depression [26].

For rehabilitation, in the presence of appropriate complaints, the use of psychotherapy, relaxation techniques, art therapy, pelvic floor muscle exercises (imbilding), water gymnastics, balneotherapy, medical massage, electrotherapy, behavioral therapy, social and sex counseling, and acupuncture is possible [45].

5. Prevention and Dispensary Observation

When establishing a diagnosis, it is necessary to determine health groups and follow-up medical observation in accordance with Order 1130n [1].

Comments: It is advisable to recommend that a patient with endometriosis lead a healthy lifestyle, eat properly, reduce alcohol consumption, and engage in regular physical activity [26].

[1] Order of the Ministry of Health of the Russian Federation dated October 20, 2020, No. 1130n «On Approval of the Procedure for Providing Medical Care in the Profile «Obstetrics and Gynecology (Excluding Assisted Reproductive Technologies)» (with amendments and additions)

6. Organization of Medical Care

Comments: Before laparoscopy, the following issues should be discussed with the patient [32]:

- What laparoscopy involves;

- How the surgery will affect endometriosis symptoms;

- Benefits and risks;

- Potential effect on ovarian reserve and fertility;

- Possibility of subsequent surgeries (if bowel and bladder are involved).

- Possibility of medical treatment after surgery.

Indications for planned hospitalization in a medical organization:

1) Chronic pelvic pain;

2) Infertility;

3) Tumors and tumor-like formations of the lesser pelvis (endometrioid cysts);

4) AUB.

2. Indications for emergency hospitalization in a medical organization:

1) AUB;

2) Rupture of an endometrioid cyst or torsion of a cyst pedicle;

3) Pain syndrome in the presence of pelvic masses;

4) Symptoms of acute abdomen.

Considering the need to provide highly specialized medical care to patients with widespread and infiltrative endometriosis, hospitalization in a level 3 medical organization is recommended.

If adjacent organs are involved, consultation with relevant specialists is required.

7. Additional Information

7.1 Endometriosis and infertility

Endometriosis affects 25–50% of infertile women, and 30–50% of women with endometriosis experience infertility [45], [2]. Endometriosis is detected in 58% of women undergoing laparoscopy as the final stage of infertility work-up [83]. The proportion of endometriosis-associated infertility appears to have racial and geographical characteristics [75].

• Patients with endometriosis-associated infertility are not recommended to receive hormonal treatment prior to surgery to improve spontaneous pregnancy rates, as there is no evidence of a positive effect of hormonal therapy on fertility [32].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: The use of NSAIDs and aromatase inhibitors in patients with endometriosis-associated infertility is inappropriate.

Comment: Removal of small endometriomas prior to IVF (according to local nomenclature - In vitro fertilization, embryo culture and transfer) is not recommended, especially in cases of repeated surgeries with a confirmed diagnosis of endometriosis. Nevertheless, surgery remains mandatory in the presence of suspicious ultrasound findings and in women with pelvic pain syndrome. Both expectant and surgical management for ovarian endometriomas in women planning ART have potential benefits and risks, which must be carefully weighed before making a decision. Assessment of ovarian reserve (AMH monitoring and antral follicle count) is required before planning surgical treatment in patients with ovarian endometriomas [17], [84], [85] and post-operative follow-up at 3–6 months.

Comments: Operative laparoscopy in patients with endometriosis suffering from infertility helps to broaden the search for causes of infertility, identify concomitant disorders or diseases (inflammation, adhesions, tubal patency disorders) and correct them.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Leyla V. Adamyan – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Honored Worker of Science of Russia, Head of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine, Chief Freelance Gynecologist of the Russian Ministry of Health, member of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecological Endoscopists, the Russian Endometriosis Association, and the Russian Society of Obstetricians and Gynecologists.

Elena N. Andreeva – Doctor of Medical Sciences, Professor, Deputy Director – Director of the Institute of Reproductive Medicine, Head of the Department of Endocrine Gynecology, Professor at the Department of Endocrinology of the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine, President of the International Association of Obstetricians, Gynecologists and Endocrinologists, member of the Russian Association of Gynecological Endoscopists, the Russian Endometriosis Association, the Russian Society of Obstetricians and Gynecologists, and ROSGEM.

Yulia S. Absatarova – Candidate of Medical Sciences, Researcher at the Department of Endocrine Gynecology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, member of the International Association of Obstetricians, Gynecologists and Endocrinologists.

Natalia V. Artymuk – Doctor of Medical Sciences, Professor, Head of the Professor G.A. Ushakov Department of Obstetrics and Gynecology at Kemerovo State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Siberian Federal District (Kemerovo).

Vitaly F. Bezhenar – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Neonatology at Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology for the Healthcare Committee of Saint Petersburg, member of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecological Endoscopists, and the Russian Society of Obstetricians and Gynecologists.

Tatiana E. Belokrinitskaya – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology at the Faculty of Additional Professional Education, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Far Eastern Federal District (Chita), member of the Russian Society of Obstetricians and Gynecologists, President of the Transbaikal Society of Obstetricians and Gynecologists.

Aleksandr I. Gus – Doctor of Medical Sciences, Professor, Head of the Department of Functional Diagnostics at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, member of the Russian Society of Obstetricians and Gynecologists.

Yulia E. Dobrohotova – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology at the Faculty of Medicine, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Honored Doctor of the RF, Honored Worker of Science of the RF, recipient of the RF Government Prize, member of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecological Endoscopists, and the Russian Society of Obstetricians and Gynecologists.

Natalia V. Dolgushina – Doctor of Medical Sciences, Professor, Deputy Director for Research at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Chief Freelance Specialist in Women's Reproductive Health of the Russian Ministry of Health, member of the Presidium of the Board of the Russian Society of Obstetricians and Gynecologists.

Elena A. Kalinina – Doctor of Medical Sciences, Head of the Department of Assisted Technologies in Infertility Treatment at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, member of the Russian Society of Obstetricians and Gynecologists.

Sergey A. Levakov – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology at Sechenov First Moscow State Medical University of the Russian Ministry of Health, member of the Russian Society of Obstetricians and Gynecologists

Anna I. Malyshkina – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology, Medical Genetics at Ivanovo State Medical Academy of the Russian Ministry of Health, member of the Society for Reproductive Medicine and Surgery, the Russian Endometriosis Association, and the Russian Society of Obstetricians and Gynecologists.

Tatiana A. Nazarenko – Doctor of Medical Sciences, Professor, Director of the Institute of Reproductive Medicine at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

Laura G. Pivazyan – Obstetrician-gynecologist at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

Larisa V. Suturina – Doctor of Medical Sciences, Professor, Head of the Department of Reproductive Health Protection at the Scientific Centre for Family Health and Human Reproduction Problems (Irkutsk).

Elena V. Uvarova – Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Honored Worker of Science of the RF, Head of the 2nd Gynecological Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Obstetrics, Gynecology and Reproductology of the Institute of Professional Education at Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Chief Freelance Pediatric and Adolescent Gynecologist of the Russian Ministry of Health, President of the Association of Pediatric and Adolescent Gynecologists of Russia, member of the Russian Society of Obstetricians and Gynecologists.

Ildar F. Faizullin – MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology named after Prof. V.S. Gruzdev, Kazan State Medical University of the Russian Ministry of Health; Chairman of the Society of Obstetricians and Gynecologists of the Republic of Tatarstan; Honored Scientist of the Republic of Tatarstan; Honored Physician of the Republic of Tatarstan; Member of the Russian Society of Obstetricians and Gynecologists.

Oleg S. Filippov – MD, PhD, Professor, Honored Physician of the Russian Federation, Chief Freelance Obstetrician-Gynecologist of the FMBA of Russia, Deputy Director of the Federal Scientific and Clinical Center for Children and Adolescents of the FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine.

Narine M. Tonoyan – PhD, Obstetrician-Gynecologist at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

Assiyat Z. Khashukova – MD, PhD, Professor at the Department of Obstetrics and Gynecology, Faculty of General Medicine, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecological Endoscopists, and the Russian Endometriosis Association.

Elena P. Khashchenko – PhD, Leading Researcher at the 2nd Gynecological Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

Galina E. Chernukha – MD, PhD, Professor, Chief Researcher at the Department of Gynecological Endocrinology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; President of the Interregional Public Organization "Association of Gynecologic Endocrinologists".

Maria I. Yarmolinskaya – Professor of the RAS, MD, PhD, Professor, Head of the Department of Gynecology and Reproductive Endocrinology, Ott Research Institute of Obstetrics and Gynecology; Professor at the Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health; Member of the Russian Society of Obstetricians and Gynecologists.

Ekaterina L. Yarotskaya – MD, PhD, Professor at the Department of Reproductive Medicine and Surgery, Yevdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health; National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Member of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecological Endoscopists, the Russian Endometriosis Association, and the Russian Society of Obstetricians and Gynecologists.

Conflict of interest:

All members of the working group declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Obstetricians-gynecologists,

2. Endocrinologists,

3. Surgeons,

4. Urologists,

5. Oncologists,

6. Family medicine physicians,

7. Students, residents, PhD candidates, and faculty of medical universities.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Order of the Ministry of Health of the Russian Federation No. 1130n dated October 20, 2020, "On approval of the Procedure for providing medical care in the field of 'obstetrics and gynecology (excluding the use of assisted reproductive technologies)'" (as amended);

2. Order of the Ministry of Health of the Russian Federation No. 803n dated July 31, 2020, "On the procedure for using assisted reproductive technologies, contraindications, and restrictions on their use."

3. Savelieva G. M. et al. National Guidelines // Obstetrics. – M.: Geotar-Media. – 2015.

4. NICE Guideline “Endometriosis: diagnosis and management”. September 2017. Last updated: 16 April 2024 date of access 22.07.24 https://www.nice.org.uk/guidance/ng73/chapter/Context

5. ACOG. Dysmenorrhea and Endometriosis in the Adolescent. 2018.  date of access 22.07.24 https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2018/12/dysmenorrhea-and-endometriosis-in-the-adolescent

6. Leyland N., Casper R., Laberge Ph. et al. Endometriosis: Diagnosis and Management // Clinical Practice Guideline // JOGC. – 2010. – Vol. 32. – № 7. – P. 1–27.

7. ACOG Committee Opinion No. 760 Summary: Dysmenorrhea and Endometriosis in the Adolescent. Obstet Gynecol. 2018;132(6):1517-1518.

8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Ovarian Cancer Including Fallopian Tube Cancer & Primary Peritoneal Cancer. Version 2. – 2011.

9. Hwang H, Chung YJ, Lee SR, Park HT, Song JY, Kim H, Lee DY, Lee EJ, Kim MR, Oh ST. Clinical evaluation and management of endometriosis: guideline for Korean patients from Korean Society of Endometriosis. Obstet Gynecol Sci. 2018 Sep;61(5):553-564.

10. Endometriosis and infertility: a committee opinion. ASRM. 2012

11. Endometriosis: Diagnosis and Management. SOGC CLINICAL PRACTICE GUIDELINE. No. 244, July 2010

12. Serov V. N., Sukhikh G. T. Clinical Guidelines. Obstetrics and Gynecology // M: GEOTAR-Media. – 4th ed. – 2017. Moscow: Problemy Reproduktsii.

13. Abrao M. S. et al. AAGL 2021 endometriosis classification: an anatomy-based surgical complexity score // Journal of minimally invasive gynecology. – 2021. – Vol. 28. – No. 11. – P. 1941-1950

14. Hirsch M. et al. Diagnosis and management of endometriosis: a systematic review of international and national guidelines //BJOG: An International Journal of Obstetrics & Gynaecology. – 2018

15. Burghaus S. et al. Diagnosis and treatment of endometriosis. Guideline of the DGGG, SGGG and OEGGG (S2k Level, AWMF registry number 015/045, August 2020) // Geburtshilfe und Frauenheilkunde. – 2021. – Vol. 81. – No. 04. – P. 422-446

16. Singh S. S. et al. Guideline No. 449: Diagnosis and Impact of Endometriosis–A Canadian Guideline //Journal of Obstetrics and Gynaecology Canada. – 2024

17. ESHRE guideline: endometriosis. Hum Reprod Open. 2022 

Classifications of endometriosis

Appendix B. Physician Action Algorithms

Algorithm of physician actions in suspected endometriosis [8]

Physician management strategy after surgical treatment of endometriosis [120]

Appendix C. Patient Information

• Endometriosis is a condition in which tissue similar in structure to the inner lining of the uterus (the endometrium) is found in other locations, usually in the pelvic area, around the uterus, and in the ovaries.

• Endometriosis can sometimes be difficult to diagnose. Comprehensive pelvic ultrasound is typically used to diagnose this condition, supplemented by MRI and CT when necessary. Laparoscopy is the most accurate diagnostic method.

• Endometriosis is a chronic disease that can affect your physical, sexual, psychological, and social well-being. The most common symptoms of endometriosis include pelvic pain, painful and sometimes irregular or heavy periods. Pain during or after sexual intercourse and impaired fertility may also occur.

• Treatment options include nonsteroidal anti-inflammatory and antirheumatic analgesics (according to ATC – non-steroidal anti-inflammatory and anti-rheumatic products), hormones, and/or surgery.

• Surgery is most commonly performed via a laparoscopic approach. However, in severe cases of the disease, open laparotomic surgery may be performed.

• Medical treatment is not effective for restoring fertility; surgical treatment is required.

• Despite limited evidence of efficacy, certain interventions may reduce pain and improve quality of life for some women: reflexology, transcutaneous electrical nerve stimulation (TENS – according to the Russian NOM – Transcutaneous electrical neurostimulation for peripheral nervous system disorders), acupuncture, vitamin B1 (according to ATC – thiamine**) and magnesium supplements, traditional Chinese medicine, herbal medicine, and homeopathy.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1 Visual Analogue Scale (VAS) for pain

Russian title: Visual Analogue Scale for pain

Original title: Visual analogue scale.

Source (official developer website, validation publication): visualanalogscaleVAS. Clark, W. Crawford

Chokhavatia, Sita S.Kashani, Abbas. Pain Management Secrets. 2009.

Clark, Susanne Bennett

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Content (template):

Key: The VAS is a straight line 10 cm in length. The patient is asked to make a mark on the line corresponding to the intensity of pain experienced. The starting point of the line indicates no pain (0), followed by mild, moderate, severe, and ending with unbearable pain (10). The distance between the left end of the line and the made mark is measured in millimeters.

Notes: We recommend performing the assessment when enrolling the patient in the study prior to intervention (treatment, surgery). Since filling out the VAS questionnaire does not take much time, the assessment can be performed daily throughout the entire course of treatment. Data obtained in this manner can serve as a valuable reflection of the analgesic effect of the treatment administered. The volume of analgesic therapy should also be recorded whenever possible and included in the reporting data when assessing pain syndrome.

Appendix G2. Determination of the endometriosis fertility index

Russian title: Determination of the endometriosis fertility index.

Original title: Endometriosis fertility index.

Source (official developer website, validation publication): The Endometriosis Fertility Index, EFI.

 G. David Adamson, M.D. and David J. Pasta, M.S. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010;94(5):1609-15

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Content (template):

Figure 1. Calculation of the Endometriosis Fertility Index. (Adapted from Adamson and Pasta, Fertil Steril 2010;94(5):1609-15) It is important to note that to calculate the least function score (LF-score), you must select the lowest score in each of the columns (left and right) and add them together. If one ovary is absent, to calculate the LF-score, you must double the selected lowest score from the other column.

Note: Calculation of this indicator incorporates surgical findings from laparoscopy, medical history, and other evaluation parameters according to the AFS classification [American Fertility Society. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 1985;43:351–2.] (Fig. 1). A prerequisite for calculating the fertility index is laparoscopically confirmed endometriosis with a surgeon's report that includes an assessment of the function of the main anatomical structures involved in reproduction. Special tables have been developed for intraoperative determination of the degree of pelvic organ dysfunction [1,3].

Key (interpretation): The fertility index ranges from 0 to 10 (10 being the best prognosis). There is a recommended nomogram associated with the fertility index assessment, which helps navigate the prognosis and pregnancy rate in cases of endometriosis (Fig. 2).

Figure 2.Clinical evaluation of the endometriosis fertility index (after Adamson and Pasta, Fertil Steril 2010;94(5):1609-15)