Endometriosis (endometrioid disease)

Endometriosis is a benign condition in which functioning endometrial tissue is implanted outside the uterine cavity. Symptoms of endometriosis depend on the location of the endometriotic lesions and may include dysmenorrhea, dyspareunia, infertility, dysuric disorders, and pain during defecation.

The diagnosis of endometriosis is established on the basis of a biopsy obtained by laparoscopy. Treatment includes the prescription of anti-inflammatory drugs, drugs to suppress ovarian function and suppress endometrial growth. In severe cases of the disease, if the birth of a child is not planned, a hysterectomy with removal of the ovaries is performed.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ]

Epidemiology

In the structure of gynecological diseases, endometriosis ranks third after inflammatory diseases of the genital organs and uterine fibroids. It is diagnosed in 2-10% of women who first consult a gynecologist and in 30% of patients who need gynecological surgeries. When using laparoscopy, foci of endometriosis are detected in 20-50% of women suffering from infertility of unclear genesis.

[ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ], [ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ]

Causes endometriosis

At present, there is no clearly formulated theory of the origin of endometrioid heterotopias. The main concepts of the origin of endometriosis (endometrioid disease):

• Embryonic ("congenital" form).
• Metaplastic.
• Endometrial (translocation).

Most researchers believe that endometriosis develops as a result of the transplantation of viable endometrial cells, thrown through the fallopian tubes during menstruation, into the abdominal cavity. Their engraftment and growth of endometriosis foci occur when the body's immunological status changes.

The development of endometriosis (endometrioid disease) is determined by a number of pathogenetic factors.

Leading pathogenetic factors:

• Hormonal disorders.
• Dysfunction of the immune system and perverted biological response of endometrial cells to sex hormones.
• Constitutional-hereditary (genetic) predisposition.
• Deficiency of the body's antioxidant system.
• Long-term stress of protective-adaptive reactions and a decrease in the body's non-specific resistance.

Additional pathogenetic factors:

• Menstrual dysfunction (from the onset of menarche).
• Inflammatory diseases of the internal genitalia leading to anovulation or insufficiency of the corpus luteum function.
• Disorders of the liver and pancreas.
• Retrograde wave of uterine contraction from the cervix to the fundus during menstruation.
• Surgical interventions, including cesarean sections and frequent abortions, operations on the uterus and uterine appendages, diagnostic curettage of the uterus.
• Long-term use of intrauterine contraceptives.
• Stressful situations.
• Deterioration of the environmental situation.

As the disease progresses and during treatment, the significance of pathogenetic factors may change.

[ 16 ], [ 17 ]

Pathogenesis

The most widely accepted hypothesis is that endometrial cells are transported from the uterine cavity and implanted in other organs. Retrograde flow of menstrual tissue through the fallopian tubes may facilitate intra-abdominal transport of endometrial cells; the lymphatic and circulatory systems may also facilitate transport of the endometrium to distant sites (e.g., the pleural cavity).

There is a hypothesis of coelomic metaplasia: the transformation of the coelomic epithelium into glands resembling the endometrium.

Microscopically, endometriosis consists of glands and stroma identical to the endometrium. These tissues contain estrogens and progesterone receptors and thus grow, differentiate, and bleed in response to hormonal changes during the menstrual cycle.

Endometriosis is more common in first-degree relatives of patients with endometriosis. Heredity is thought to be a risk factor for developing the disease. An increased incidence of endometriosis is observed in women who have had nulliparity, few children, shortened menstrual cycles (<27 days), prolonged periods (>8 days), and Müllerian duct anomalies.

Endometriosis occurs in approximately 10-15% of women aged 25-44 with active menstruation. The average age of patients with endometriosis is 27 years, but the disease can also occur in teenagers.

Approximately 25-50% of infertile women have endometriosis. Patients with severe forms of the disease, with pelvic adhesions and abnormal pelvic anatomy, are more likely to be infertile because the mechanisms of egg capture and tubal transport are impaired. Some patients with minimal manifestations of endometriosis and normal pelvic anatomy also suffer from infertility. These patients may have decreased fertility due to abnormal luteal phase of the cycle or the presence of luteinization syndrome of an unovulated follicle; increased production of peritoneal prostaglandins or increased peritoneal macrophage activity (leading to phagocytosis), or the endometrium is non-receptive.

Potential protective factors include multiple pregnancies, the use of micro-dose oral contraceptives (continuous or cyclic), and regular exercise (especially if started before the age of 15 and for 7 hours per week).

Endometriosis is usually limited to the peritoneal or serous surfaces of abdominal organs, most often the ovaries, broad ligaments, uterorectal space and uterosacral ligaments. Less common is endometriosis on the serous surface of the small and large intestine, ureters, bladder, vagina, cervix, in the area of postoperative scars, pleura and pericardium. Bleeding from peritoneal endometrioid foci contributes to the development of an inflammatory process, accompanied by fibrin deposition, adhesion formation. All this leads to anatomical disorders of the pelvic organs and abdominal cavity.

[ 18 ], [ 19 ], [ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ]

Symptoms endometriosis

Correctly assessed complaints, a detailed anamnesis and analysis of objective examination data in patients with endometriosis (endometrioid disease) allow the doctor to make a preliminary diagnosis and develop the correct algorithm for differential diagnostic search.

Features of endometriosis symptoms

Complaints. Among the large number of complaints, the leading ones in patients with endometriosis are:

Pain. The severity of pain syndrome depends on:

• localization and prevalence of the process;
• the degree of endometriosis affecting the pelvic peritoneum, intestines, and urinary system;
• duration of the disease.

In the initial period, the pain is cyclical. As endometriosis progresses, the cyclical nature of the pain is disrupted, it becomes constant and debilitating, and its intensity increases. Then pelvic pain becomes chronic; asthenia increases, and the ability to work is impaired or lost. In such cases, it should be considered that the patient has developed persistent pain syndrome. The pain may be constant, radiating to the lumbar region, sacrum, coccyx, anus, and perineum. The relationship between the intensity of the pain syndrome and the severity of endometriosis has not been established.

[ 25 ]

Menstrual dysfunction

The nature of menstrual dysfunction largely depends on the location of endometriosis foci, the degree of damage to the genitals and pelvic organs. The most common are:

• Progressive algomenorrhea (with intrauterine endometriosis with damage to the isthmus, endometriosis of the ovaries, pelvic peritoneum, sacrouterine ligaments, retrocervical endometriosis with damage to the pararectal tissue and the wall of the rectum).
• Menometrorrhagia (with intrauterine endometriosis and adenomyosis in combination with uterine fibroids).
• Bleeding before and after menstruation, contact bloody discharge (with endometriosis of the vagina, cervix, cervical canal, endometriosis of the ovaries and adenomyosis of the uterus).
• Irregular menstruation (with a combination of ovarian endometriosis and sclerocystic disease).

Pelvic organ dysfunction

Dysfunction of the bladder or rectum (hematuria, bloating, constipation, blood in the stool) when these organs are affected by endometriosis (endometrioid disease).

Reproductive dysfunction

Infertility: primary, secondary, miscarriage. It has been established that 30-40% of women with endometriosis suffer from infertility.

History of the disease. In the history of the disease, it is necessary to find out when the patient first visited the doctor, what it was associated with (pain, menstrual dysfunction, infertility, dysfunction of adjacent organs), what changes were detected.

Results of instrumental examination and treatment. Particular attention should be paid to the use of hormonal drugs (name, duration of use, tolerance), their effect on the nature of changes in menstrual function (cyclicity, duration, painfulness). The use of immunomodulators, physiobalneotherapy (type, duration of treatment, effect) and other treatment methods.

Family history and heredity. Menstrual and reproductive dysfunction in close relatives, as well as the presence of endometriosis in them, suggest a genetic basis for these diseases.

Past illnesses. First of all, it is necessary to find out about past gynecological diseases (acute and chronic adnexitis), obstetric and gynecological surgeries, during which the uterine cavity was opened (conservative myomectomy, reconstructive and plastic surgeries for uterine malformations, cesarean section, suturing of perforations on the uterus, ectopic pregnancy, etc.). Particular attention should be paid to surgeries on the cervix (diathermosurgical, cryosurgical manipulations). If the anamnesis indicates a past operation on the ovaries, then the scope of the intervention and the result of the histological examination of the removed specimen should be clarified.

Of the extragenital diseases, liver diseases, acute and chronic infectious diseases (their frequent exacerbations, indicating the failure of the immune system) deserve attention.

Menstrual function. Age of menarche, regularity, duration and painfulness (time of onset, localization, duration, irradiation) of menstruation. It is necessary to determine the nature of discharge from the genital tract before and after menstruation. Heavy and prolonged menstruation, having the character of meno- and metrorrhagia, is characteristic of adenomyosis or uterine fibroids.

Reproductive function. If there are pregnancies, it is necessary to find out their course and outcome, complications during pregnancy and childbirth (weakness of labor, bleeding in the afterbirth and early postpartum periods, etc.). If the patient suffers from infertility, then it is necessary to find out its duration, the results of the conducted examination (HSG, laparoscopy, etc.).

Symptoms of endometriosis with different localization of implants

Localization	Symptoms
Genitals	Dysmenorrhea Pain in the lower abdomen and pelvic area Infertility Irregularity of menstruation Pain in the lumbosacral region
Gastrointestinal tract	Tenesmus and rectal bleeding associated with the menstrual cycle Diarrhea, colon obstruction
Urinary system	Hematuria and pain associated with the menstrual cycle Ureteral obstruction
Surgical scars, navel	Pain and bleeding associated with the menstrual cycle
Lungs	Hemoptysis associated with the menstrual cycle

Stages

Staging the disease helps doctors formulate a treatment plan and assess response to therapy. According to the American Society for Reproductive Medicine, endometriosis can be classified into stages: I - minimal, II - mild, III - moderate, IV - severe. The classification is based on the number, location, and depth of penetration and the presence of loose or dense adhesions.

Another classification system is based on the presence of pelvic pain. The degree of pain threshold assessment varies, so existing classification systems require revision.

Symptoms of endometriosis (endometrioid disease) depend largely on the localization of endometrioid heterotopia.

Classification of staging of endometriosis (endometrioid disease) [Zemm K]

• Stage I - Endometriosis foci in the pelvis and on the vaginal part of the cervix measuring less than 5 mm. Both fallopian tubes are mobile and passable.
• Stage II - Foci of endometriosis in the pelvis more than 5 mm, blood in the Douglas pouch, foci of endometriosis in the bladder area, peritubal and periovarian adhesions, severe ampullary stenosis or phimosis.
• Stage III - Foci of endometriosis in the uterus, fallopian tubes, “chocolate” cysts in the ovaries, infiltration in the area of the uterosacral ligaments and broad ligaments.
• Stage IV - Extragenital endometrioid lesions in the abdominal cavity and in the bladder (cystoscopy), in the lungs and on the skin

Depending on the localization of endometrioid heterotopia, the following are distinguished:

• genital endometriosis (lesions of the genital organs: uterus, vagina, ovaries, peritoneum of the recto-uterine and vesico-uterine space, perineum);
• extragenital endometriosis (development of the pathological process in other organs and systems: rectum, appendix, small and large intestine, hernial sac, lungs, pleural cavity, skin, navel, limbs, eyes, lymph nodes, central nervous system, etc.).

American Fertility Society Classification of Endometriosis (R-AFS, 1985).

• Minor forms: stage I (1–5 points).
• Mild forms: stage II (6–15 points).
• Moderate forms: stage III (16–40 points). Multiple implants, endometrioid cysts less than 2 cm in diameter, a small number of adhesions.
• Severe forms: stage IV (more than 40 points). Endometrioid cysts with a diameter of more than 2 cm, pronounced adhesions of the fallopian tubes and ovaries, obstruction of the fallopian tubes, damage to the intestines and/or urinary tract.

Adenomyosis can be diffuse and focal (nodular).

Classification of adenomyosis (internal endometriosis) of the diffuse form (Kulakov V.I., Adamyan L.V., 1998):

• Stage I - the pathological process is limited to the submucosal membrane of the body of the uterus.
• Stage II - the pathological process moves to the muscle layers.
• Stage III - the spread of the pathological process throughout the entire thickness of the muscular wall of the uterus to its serous cover.
• Stage IV - involvement in the pathological process, in addition to the uterus, of the parietal peritoneum of the small pelvis and adjacent organs.

Classification of endometrioid ovarian cysts

• Stage I - small, pinpoint endometrioid formations on the surface of the ovaries, the peritoneum of the rectal-uterine space without the formation of cystic cavities.
• Stage II - endometrioid cyst of one of the ovaries no more than 5-6 cm in size with small endometrioid inclusions on the peritoneum of the small pelvis. Minor adhesions in the area of the uterine appendages without involvement of the intestine.
• Stage III - endometrioid cysts of both ovaries. Small endometrioid heterotopias on the serous layer of the uterus, fallopian tubes and on the parietal peritoneum of the small pelvis. Expressed adhesions in the area of the uterine appendages with partial involvement of the intestine.
• Stage IV - large bilateral endometrioid ovarian cysts (more than 6 cm) with the pathological process spreading to adjacent organs - the bladder, rectum and sigmoid colon. Widespread adhesions.

Classification of endometriosis of the rectovaginal septum.

• Stage I - endometrioid lesions are located within the rectovaginal tissue.
• Stage II - the growth of endometrioid tissue into the cervix and vaginal wall with the formation of small cysts.
• Stage III - the spread of the pathological process to the uterosacral ligaments and the serous membrane of the rectum.
• Stage IV - involvement of the rectal mucosa in the pathological process, spread of the process to the peritoneum of the rectal-uterine space with the formation of an adhesion process in the area of the uterine appendages.

[ 26 ], [ 27 ], [ 28 ], [ 29 ], [ 30 ]

Diagnostics endometriosis

The diagnosis is based on typical symptoms of the disease. The diagnosis must be confirmed by biopsy, which is performed during laparoscopy, sometimes by laparotomy, vaginal examination, sigmoidoscopy or cystoscopy. When diagnosing endometriosis, the biopsy material must identify the intrauterine glands and stroma. Endometriosis has the following macroscopic signs: the presence of transparent, red, brown, black implants, the size of which changes during the menstrual cycle; the most typical area of endometriosis is the pelvic peritoneum, where punctuation of red, blue or purple-brown grains larger than 5 mm is determined.

Endometriotic tracts can be detected by ultrasonography, barium passage through the intestine, intravenous urography, CT, MRI, but the data obtained are not specific and adequate for diagnosis. At the current level, serological studies of endometriosis markers are carried out (for example, serological cancer antigen 125 [> 35 units / ml], anti-endometrioid antibodies), which can help in diagnosis, but these data require further processing. Women who have endometriosis must be examined for infertility.

Objective examination of patients

Considering the cyclical changes in the condition of patients, the increase in manifestations of endometriosis (endometrioid disease) in the second phase of the menstrual cycle, it is advisable to conduct an objective examination of patients during this period.

Inspection. Height, body weight, body type and constitution. Skin color. Presence and condition of scars on the anterior abdominal wall, condition of the umbilical ring. Shape and degree of development of the mammary glands.

It is advisable to conduct a gynecological examination to detect endometrioid heterotopias in the second phase of the menstrual cycle, 3–5 days before the expected period. The examination begins with an examination of the perineum (scars, infiltrates, ulcers, etc.).

When examining the vagina, attention should be paid to the area of the posterior fornix (polypous growths, infiltration). When examining the cervix, areas suspicious of endometriosis may be detected (nodular or small cystic growths, clearly visible on the eve of or during menstruation). When palpating the uterus, its shape, size, mobility, and soreness are determined; the condition of the isthmus (infiltration, soreness when affected by endometrioid disease) and the posterior fornix of the vagina (infiltration in endometriosis) should be assessed. When palpating the area of the uterine appendages, their size, mobility, soreness, and consistency are determined. The condition of the uterosacral ligaments is assessed (thickened, tense, painful when affected by endometrioid heterotopia).

Gynecological examination is one of the most important methods for diagnosing endometriosis.

• It is necessary to carefully examine the vulva, vagina and cervix to detect any signs of endometriosis. When examining the vaginal part of the cervix, endometrioid lesions of various sizes and shapes (from small dots to cystic cavities with a diameter of 0.7-0.8 cm, of various colors) are visible.
• In the isthmus of the uterus, compaction, expansion, and soreness are detected; in the posterior fornix of the vagina, tissue infiltration and adhesion changes are detected. Palpation reveals thickening, tension, and soreness of the sacrouterine ligaments.
• In nodular adenomyosis, the uterus is of normal size or slightly enlarged with dense painful nodes in the fundus, body or corners. Before and during menstruation, the size of the nodes increases slightly, the uterus softens, and the pain increases sharply. In diffuse adenomyosis, the size of the uterus reaches 5-8 weeks of pregnancy and more. A clear dependence of the size of the uterus on the phases of the menstrual cycle is noted.
• In ovarian endometriosis, painful, immobile, dense, enlarged ovaries or a conglomerate of uterine appendages are palpated on one or both sides. The size and soreness of the conglomerate of uterine appendages change depending on the phases of the cycle. Endometrioid cysts are defined as painful tumor-like formations of an ovoid shape, of varying size (on average 6-8 cm), of a hard-elastic consistency, limited mobility, located on the side and behind the uterus.
• Endometriosis of the rectovaginal septum is diagnosed during vaginal (or vaginal-rectal) examination when a dense painful formation with an uneven surface, 0.8–1 cm or more (up to 4–5 cm) in size, is detected on the posterior surface of the isthmus of the uterus. The node is surrounded by dense painful infiltration extending to the anterior wall of the rectum and the posterior fornix of the vagina.

Colposcopy. This is performed on all patients. This examination can reveal foci of ectopia on the cervix.

[ 31 ], [ 32 ], [ 33 ], [ 34 ], [ 35 ], [ 36 ]

Functional diagnostic tests

Endometrioid disease is characterized by a monophasic curve (absence of ovulation) of rectal temperature or a slow rise in temperature in phase II, which indicates insufficiency of the corpus luteum function. It is also possible to have a biphasic curve indicating ovulation.

Radiation research methods

X-ray methods. It is advisable to conduct hysterosalpingography in the first phase of the menstrual cycle. The presence of contour tissues is characteristic of adenomyosis, but this symptom is not constant. Excretory urography allows us to identify the involvement of the urinary tract (ureters, bladder) in the process.

Irrigoscopy is performed when there is a suspicion of endometriosis spreading to the lower parts of the colon. In this case, a narrowing of the intestinal lumen or its deformation is determined. Filling defects have smooth and clear contours.

X-ray examination of the chest organs is performed if thoracic forms of endometriosis (lungs, pleura, diaphragm) are suspected. X-ray examination of the lumbar spine is performed during differential diagnostics.

Ultrasound examination. The method allows to establish the presence of endometrioid ovarian cysts. The uneven consistency of the cyst contents and close connection with the uterus are characteristic. Retrocervical endometriosis appears as a homogeneous dense infiltrate, on the eve of or during menstruation – a cellular structure. Adenomyosis is characterized by sparseness of the myometrium structure, however, this sign is inconstant.

Computer tomography and magnetic resonance imaging. The methods help to determine not only obvious localizations of heterotopias, but also smaller lesions of the genital area. MRI is one of the most accurate methods for establishing the localization of endometriosis foci (endometrioid disease) by the difference in the density of the tissues being examined.

Invasive methods of diagnostics of endometriosis (endometrioid disease)

Laparoscopy. This method is the most informative for diagnosing genital endometriosis. "Small forms" of endometriosis are defined as eyes 1-5 mm in diameter, rising above the surface of the peritoneum, bright red, dark brown in color. The most common localization of endometrioid heterotopia is the peritoneum covering the sacrouterine ligaments and the rectouterine pouch. Endometrioid cysts are defined as rounded formations with a thick capsule, dark brown contents, with extensive adhesions. The patency of the tubes is determined by introducing a dye through the uterus.

Hysteroscopy. If endometriosis of the uterus (adenomyosis) is suspected, hysteroscopy is performed in the first phase of the cycle. In this case, against the background of a thin mucous membrane, the mouths of endometrioid passages of a round, oval and slit-shaped form, dark red or bluish in color, from which blood flows, can be seen.

Histomorphological studies

Any part of the removed organ is subject to examination in order to verify and detect pathomorphological studies characteristic of endometriosis.

Differential diagnosis

Differential diagnosis of genital endometriosis is carried out with:

• uterine fibroids;
• chronic endometritis;
• hyperplastic processes of the endometrium;
• ovarian tumors;
• metrophlebitis;
• malignant neoplasms of the genitals;
• tubo-ovarian formations of inflammatory etiology.

Treatment endometriosis

The goal of endometriosis treatment is to remove endometriosis foci, relieve clinical symptoms, and restore reproductive function.

Indications for hospitalization

• Severe pain syndrome that cannot be relieved by the administration of medications.
• Rupture of endometrioid cyst.
• Metrorrhagia associated with adenomyosis.
• Planned surgical treatment.

In widespread forms of the disease and high risk of recurrence, the modern approach to treating patients with endometriosis is a combination of surgery and hormonal therapy.

When choosing a treatment method for endometriosis, the following factors must be taken into account:

• age;
• attitude towards reproductive function;
• general somatic condition and past illnesses;
• personality traits, psychosomatic status (profile);
• localization, prevalence and severity of the course (anatomical and morphological changes, such as: inflammatory, cicatricial-adhesive processes, endometrial hyperplasia, destructive changes in the ovaries and uterus, etc.).

The main methods of treating endometriosis are:

1. Surgical treatment.
2. Conservative treatment, including hormonal and adjuvant (syndromic) therapy.
3. Combined treatment (surgical and conservative).

Surgical treatment

The scope of surgical treatment for endometriosis is determined by its clinical form and the stage of spread of the pathological process.

Indications for surgery:

• Endometrioid cysts (endometriomas).
• Internal endometriosis (adenomyosis of the uterus), accompanied by profuse bleeding and anemia.
• Ineffectiveness of hormonal treatment, intolerance to hormonal drugs.
• Endometriosis of postoperative scars, navel, perineum.
• Continued stenosis of the intestinal lumen or ureters, despite the elimination or reduction of pain under the influence of conservative treatment.
• Combination of endometriosis with genital anomalies (endometriosis of the accessory horn).
• A combination of uterine fibroids, subject to surgical treatment, with some localizations of endometriosis (isthmus of the uterus, retrocervical, etc.).
• Endometriosis (endometrioid disease) in patients who have had cancer for which surgery, radiation therapy and/or chemotherapy were performed (ovarian cancer, thyroid cancer, stomach cancer, colon cancer, etc.); the situation is somewhat different with breast carcinoma. In this localization, Zoladex can be used to treat endometriosis.
• Combination of endometrioid disease and infertility, when pregnancy does not occur within 2 years. The operation is performed in a sparing volume.
• The presence of somatic pathology that excludes the possibility of long-term hormonal therapy (cholelithiasis, urolithiasis, thyrotoxicosis, hypertension with crisis course).
• Combination of endometriosis with nephroptosis requiring surgical correction, or Allen-Masters syndrome.

Moderate and severe endometriosis is treated most effectively with ablation or excision of as many areas of endometriosis as possible, while preserving reproductive potential. Indications for surgical treatment are the presence of limited growths of endometriosis, significant adhesions in the pelvic area, obstruction of the fallopian tubes, the presence of debilitating pain in the pelvis, and the patient's desire to preserve reproductive function.

Endometriosis is also treated with microsurgery to prevent adhesions. Laparoscopy is used to remove lesions; peritoneal or ovarian endometriotic heterotopias can be removed by electrocautery or vaporization and laser excision. After this treatment, fertility is restored in 40-70% and is inversely proportional to the severity of endometriosis. If resection is incomplete, oral contraceptives or GnRH agonists may increase the fertility rate. Laparoscopic resection of the uterosacral ligaments with electrocautery or laser excision may reduce pelvic pain. Some patients require presacral neurectomy.

Hysterectomy is performed in patients who have endometriosis and pelvic pain of a debilitating nature and in patients who have fulfilled the function of childbearing. After removal of the uterus and both ovaries, estrogens may be administered postoperatively or, if a significant amount of endometriotic tissue remains, estrogens may be delayed for 46 months; suppressive drugs are necessary during this interval. A prolonged progestin (eg, medroxyprogesterone acetate 2.5 mg orally once a day) may be administered with estrogens because pure estrogen can lead to proliferation and hyperplasia of residual endometrial tissue and to endometrial cancer.

Conservative (hormonal and adjuvant) treatment

The goal of hormonal therapy is the development of atrophic changes in the tissue of endometrioid heterotopias. However, hormonal therapy does not eliminate the morphological substrate of endometriosis, but has an indirect effect on it; this explains the symptomatic and clinical effect of therapy.

The choice of drugs and the method of their use depend on the age of the patient, the location and extent of endometriosis, drug tolerance, and the presence of concomitant gynecological and somatic pathology.

Gonadotropin-releasing hormone agonists:

• buserelin in the form of depot forms intramuscularly at 3.75 mg once every 28 days or buserelin in the form of a spray at a dose of 150 mcg in each nostril 3 times a day from the 2nd day of the menstrual cycle;
• goserelin subcutaneously 3.6 mg once every 28 days;
• triptorelin (as depot forms) intramuscularly at 3.75 mg once every 28 days; Gonadotropin-releasing hormone agonists are the drugs of choice in the treatment of endometriosis. The duration of therapy is 3–6 months.

If severe side effects associated with the development of a hypoestrogenic effect (hot flashes, increased sweating, palpitations, nervousness, urogenital disorders, etc.) occur, return therapy with hormone replacement therapy drugs is indicated (for example, tibolone, 1 tablet per day continuously for 3–6 months).

• Dalteperin sodium is prescribed orally, 1 capsule (100 or 200 mg) 3 or 4 times a day (daily dose 400–800 mg) for 3–6 months, less often 12 months.
• Gestrinone is prescribed orally at 2.5 mg 2 times a week for 6 months.
• COCs are prescribed from the 1st to the 21st day of the menstrual cycle or continuously, for a course of 6–12 months.

Progestogens:

• medroxyprogesterone acetate orally 30 mg/day or intramuscularly 150 mg of the depot substance once every 2 weeks for 6–9 months;
• dydrogesterone orally 10–20–30 mg/day for 6–9 months.

The following groups of drugs are currently used for hormonal treatment of endometriosis:

• combined estrogen-gestagen drugs (silest marvelon, etc.);
• progestins (Duphaston, Depo-Provera, 17-OPK);
• antigestagens (gestrion);
• antigonadotropins (danazol, danogen);
• GnRH agonists (zoladex, buserelin, decapeptyl);
• antiestrogens (tamoxifen, zitosonium);
• anabolic steroids (nerabol, retabolil).

When choosing a drug and method of hormonal therapy, it is necessary to consider:

• Age of the patient. In active reproductive age (up to 35 years), preference should be given to progestins, then combined estrogen-progestin drugs, anabolic steroids; the use of androgens should be minimal. At the age of over 35, in the absence of contraindications, it is permissible to use a variety of drugs.
• Associated symptoms and syndromes: hyperpolymenorrhea, virilism syndrome, excess body weight.
• Reproductive system condition: concomitant diseases (e.g. mammary glands), which may contraindicate the use of drugs.
• Profession. The gestagen properties of progestins can cause voice changes (announcers, singers, actresses, teachers, etc.).
• Background hormonal profile: levels of gonadotropins and sex steroids in the blood serum or their metabolites in the urine.
• Period of therapy: before the surgical stage and in the postoperative period.
• Activity of manifestation of clinical forms of endometriosis.
• The required regimen of administration (continuous or cyclic) of drugs (for hormonal contraceptives and gestagens).

The presence or absence of contraindications to the use of hormonal drugs in conservative therapy, which are:

• Polyvalent allergy.
• Hypersensitivity to specific drugs.
• Thrombosis, thromboembolic processes, chronic thrombophlebitis, hypercoagulation syndrome.
• Pregnancy, lactation.
• Combination of endometriosis with uterine fibroids*.
• Diseases of the mammary glands**.
• Porphyria.
• Liver diseases (cirrhosis, acute and chronic hepatitis, Rotor syndrome, Dubin-Johnson syndrome, cholestatic jaundice).
• Blood diseases (leukopenia, thrombocytopenia, hypercalcemia).
• Bleeding of unknown etiology from the genital tract.

*Exception for monophasic estrogen-progestogen preparations.

** Exception for gestagens.

• Herpes, history of jaundice during pregnancy, otosclerosis, severe itching.
• Dysplasia of the epithelium of the cervix and cervical canal.
• Tumors of the uterine appendages.
• Kidney diseases in the stage of decompensation of their function (including urolithiasis).
• Diabetes mellitus.
• Hypertension (stages II – B).
• Diseases of the visual organs (glaucoma).
• Organic diseases of the central nervous system and manic-depressive states (severe depression).
• Malignant tumors of any localization.

Conducting hormonal therapy is aimed at creating the effect of "imaginary pregnancy" or "therapeutic amenorrhea". The onset of pregnancy during the treatment of endometriosis is an indication for the cancellation of hormonal drugs and the implementation of measures aimed at its preservation. During hormonal therapy, prevention of liver, gastrointestinal tract, and kidney damage should be carried out. Control examinations at least once every 3 months.

The criteria for the effectiveness of the therapy are:

• dynamics of clinical manifestations of endometriosis;
• results of histological examination.

Endometriosis treatment begins with the prescription of nonsteroidal anti-inflammatory drugs. Differentiated treatment should be carried out individually, taking into account the patient's age, symptoms of the disease, and the desire to preserve reproductive function. The drugs of choice are agents for suppressing ovarian function, growth, and activity of endometriosis. Conservative surgical resection of as many endometrioid growths as possible is effective; gentle operations are performed and drugs are prescribed. In severe cases, oral contraceptives used in continuous mode, GnRH agonists, and danazol are drugs for suppressing ovarian function and suppressing endometrial tissue growth. GnRH agonists temporarily suppress estrogen production, but treatment should not last more than 6 months, because longer use can lead to bone loss. If treatment lasts more than 4-6 months, daily use of low-dose oral contraceptives is added to this therapy. Danazol is a synthetic androgen and antigonadotropin that inhibits ovulation. However, the drug's androgenic adverse effects limit its use. Oral contraceptives are given cyclically or continuously after danazol or GnRH agonists; they may also slow disease progression and provide contraceptive protection for women who do not wish to become pregnant in the future. Fertility rates in women with endometriosis recover in 40-60% after drug therapy. Whether fertility improves with treatment of minimal or mild endometriosis is unclear.

[ 37 ], [ 38 ]

Adjuvant (syndromic) treatment

Conducting syndromic treatment of endometrioid disease is aimed at reducing pain, blood loss, etc. and includes the use of the following:

• nonsteroidal anti-inflammatory drugs (prostaglandin inhibitors);
• immunocorrection (levomisole, thymogen, cycloferon);
• antioxidant therapy (HBO, tocopherol acetate, etc.);
• desensitizing therapy (sodium thiosulfate);
• correction of psychosomatic and neurotic disorders (radon, iodine-bromine baths);
• treatment of concomitant diseases.

[ 39 ], [ 40 ], [ 41 ]

Combination treatment

The idea that patients with endometriosis are subject to predominantly radical surgical treatment, which has existed for decades, has been replaced by a trend towards combined therapy for this group of patients. This tactic involves surgical treatment (as indicated) based on the principles of minimizing surgical trauma in combination with hormonal correction and various types of adjuvant therapy.

The leading role in the combined therapy of genital endometriosis belongs to surgical treatment. At the first stage, endosurgical interventions are performed, and laparoscopy allows for an objective selection of patients for laparotomy at earlier stages of damage to adjacent organs, removal of the most affected areas, cryodestruction of the bed of the removed infiltrate and small foci of endometriosis.

After performing surgeries for endometriosis (especially organ-preserving, non-radical, as well as in the case of a widespread process and combined form), adjuvant hormone-modulating therapy is indicated for 6-12 months. The choice of hormonal drugs and the duration of treatment after surgery should be differentiated for each patient, taking into account the degree of prevalence of the disease, concomitant somatic pathology, and the state of the immune system.

[ 42 ], [ 43 ], [ 44 ]

Rehabilitation

• Conducting general strengthening therapy (physical therapy, multivitamins, calcium supplements).
• The vast majority of patients require 6-12 months of anti-relapse therapy after surgery, especially when performed in a sparing volume. Treatment is carried out with the obligatory inclusion of hormonal drugs and immunomodulators. The latter are especially necessary after extensive surgeries for widespread genital and extragenital endometriosis, when the secondary deficiency of the immune system is expressed significantly. Hormonal therapy is also indicated after bilateral oophorectomy, if it was not possible to perform radical removal of extragenital endometriosis. It has been established that hormonal treatment prescribed immediately after surgery significantly improves treatment results and reduces the frequency of relapses of the disease. Clinical recovery occurs 8 times more often in the case of hormonal therapy immediately after surgical removal of endometriosis.
• Prescribing and conducting an anti-relapse course of treatment with progestins (Duphaston, Norcolut, Non-Ovlon, etc.) is recommended after exposure to factors that contribute to an exacerbation of the disease (abortions, diathermosurgical manipulations on the cervix, exacerbation of inflammatory diseases, etc.).
• Physical factors without a significant thermal component (drug electrophoresis, ultrasound, magnetophores, diadynamic currents, etc.) are prescribed for the purpose of carrying out resorption and anti-inflammatory therapy, and preventing “adhesive disease”.
• After surgical removal of endometriosis foci or suppression of their activity with hormonal drugs, it is advisable to use resort factors (radon and iodine-bromine waters) to eliminate psychoneurological manifestations, cicatricial-adhesive and infiltrative tissue changes, as well as to normalize the function of the gastrointestinal tract.
• Treatment of pronounced neurological manifestations in patients with endometrioid disease allows not only to eliminate lesions of the peripheral nervous system, but also to prevent the development of neurosis-like conditions. Therapy should be targeted, taking into account the identified neurological syndromes. The use of physical and resort factors, tranquilizers, analgesics, psychotherapy, acupuncture allows for faster elimination of neurological disorders.

Forecast

The success of surgical intervention to restore reproductive function depends on the prevalence of endometriosis: the effectiveness of treatment at stage I of the disease is 60%, with widespread endometriosis - 30%. Relapses of the disease within 5 years after surgical treatment develop in 19% of patients.

When using hormonal therapy, 70–90% of women report relief of pain and a decrease in the intensity of menstrual-like bleeding. The recurrence rate of endometriosis one year after a course of therapy is 15–60%, the pregnancy rate is 20–70% depending on the group of drugs.