RU2727299C1 - Method of treating external genital endometriosis - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely to treating external genital endometriosis, involving surgical treatment and drug-induced exposure by administering metformin orally. After the surgical treatment, prior to prescribing metformin, the body weight index of the patient is pre-determined and the carbohydrate metabolism is evaluated by performing an oral glucose tolerance test with determining the level of basal and stimulated insulin to confirm the safety of hypoglycemic agents, then, with the consent of the patient to oral glucose tolerance test and body weight index of more than 18.5 kg/mmetformin is used in dose of 1,500 mg in monotherapy or in combination with dienogest 2 mg daily for at least 6 months, and if the body weight index is less than 18.5 kg/mor if the patient refuses to perform the oral glucose tolerance test, metformin is orally administered in combination with dienogast 2 mg daily 750 mg a day for at least 6 months.EFFECT: invention provides a wider range of agents for treating EGE, higher safety of taking metformin, as well as provides a differentiated approach to prescribing metformin and selecting its dose, reduces pain syndrome, prevents recurrences, enables pregnancy planning with metformin monotherapy.1 cl, 3 ex

Description

The invention relates to medicine, namely to obstetrics and gynecology, and can be used to treat external genital endometriosis (EGE).

The current approach to the long-term management of patients with EGE includes surgical treatment and drug therapy (Federal Clinical Guidelines for Patient Management, 2013). In most cases, the first stage is therapeutic and diagnostic laparoscopy, which allows you to establish the extent of the process and remove visible foci of the disease. However, even with radical excision of the foci of endometriosis, there is a fairly high frequency of relapses and persistence of the disease. In this regard, in most cases, the treatment of endometriosis is complex and is carried out using various medications.

Routine drug therapy for EGE can reduce pain, improve the quality of life of women and, in some cases, implement reproductive plans. Treatment consists in suppressing ovulation with hormonal drugs, as well as in the induction of a hypoestrogenic state. The foci of endometriosis first undergo deciadualization, and then, as a result of prolonged therapy, and atrophy.

Currently, hormonal therapy for endometriosis includes a diverse range of drugs related to different lines of therapy: progestins, combined oral contraceptives, gonadoliberin agonists (GnRH), an intrauterine device with levonorgestrel, antigonadotropins, aromatase inhibitors, nonsteroidal anti-inflammatory drugs, RF Clinical Protocols and approved by the Minutes of the meeting of the Expert Commission on Health Development Issues No. 23 dated December 12, 2013).

The aforementioned methods have some disadvantages: GnRH ages cause vasomotor disorders, in some cases seriously impairing the quality of life of patients. Progestogen therapy (dienogest, medroxyprogesterone acetate) can lead to irregular uterine bleeding and weight gain. Long-term use of GnRH ages, like other progestogens listed above, is accompanied by a decrease in bone mineral density. In addition, these drugs belong to category X according to the FDA classification and are incompatible with pregnancy planning, which, together with the above side effects, makes it impossible to use them for a long time if the patient with EGE is interested in the implementation of reproductive function.

There is a known method for the treatment of EGE, in which, in addition to surgical treatment, metformin is administered orally at a dose of 1500 mg once a day for at least 6 months (application for invention No. 2018133550 dated 09.21.2018).

The disadvantage of the claimed method is the lack of a preliminary assessment of the patient's carbohydrate metabolism to identify diseases requiring observation by an endocrinologist (diabetes mellitus types I and II, impaired glucose tolerance, impaired fasting glycemia). In addition, the use of metformin at a dose of 1500 mg may not be justified in patients with low body weight, as well as in patients who refrain from performing an oral glucose tolerance test with insulin.

The technical result of the invention is to expand the arsenal of means for treating EGE, increase the safety of taking metformin, a differentiated approach to prescribing metformin and the choice of its dose, reducing pain, preventing recurrence of the disease, the possibility of planning pregnancy against the background of monotherapy.

The specified technical result is achieved in a method for the treatment of EGE, including surgical treatment and drug exposure by introducing metformin orally at a dose of 1500 mg once a day for at least 6 months, characterized in that after surgical treatment before prescribing metformin, body mass index is preliminarily determined patients and assess carbohydrate metabolism by performing an oral glucose tolerance test to determine the level of basal and stimulated insulin to confirm the safety of the use of hypoglycemic drugs, after which metformin is used at a dosage of 1500 mg in monotherapy or in combination with dienogest 2 mg daily for at least 6 months ... If the body mass index is less than 18.5 kg / m ² or if the patient refuses to perform the oral glucose tolerance test, metformin is administered orally in combination with dienogest 2 mg daily at a dose of 750 mg per day for at least 6 months.

Normally, when performing an oral glucose tolerance test, the level of fasting glycemia is less than 6.1 mmol / L, two hours after the test, less than 7.8 mmol / L, the level of fasting insulin is less than 24.9 μU / ml (Diagnostic criteria for diabetes mellitus and other disorders glycemia, WHO, 2013).

The method is based on a study of 146 women with EGE of varying degrees of prevalence and persisting pain syndrome against the background of standard therapy. In all patients, the diagnosis was confirmed by the data of laparoscopy and histological examination. 102 (69.8%) of 146 women had stage III-IV EGE according to the R-AFS classification, in 44.1% of cases - with the presence of endometrioid infiltrates (deep infiltrative endometriosis), 32 (21.9%) women had the disease recurrent nature.

When assessing weight and height indicators, it was found that in most patients (91%) BMI was within normal values, 4% had excess body weight, 5% had body weight deficit, the average BMI level in the group was 22.49 ± 3.26 kg / m ²

In patients with EGE, carbohydrate metabolism in 62% of cases is characterized by a threefold increase in the level of stimulated insulin compared to the level in the group of healthy women (65.3 ± 20.3 μU / ml and 20.9 ± 9.3 μU / ml, respectively, p < 0.05), however, the revealed changes do not correlate with BMI or age of patients. In patients with EGE, there was a positive correlation between the level of stimulated insulin and the prevalence and recurrent nature of the disease.

In 32.7% of patients, lipid metabolism was found to be impaired, mainly due to an increase in the fraction of low density lipoproteins (22.6%). In patients with grade I and II EGE according to the R-AFS classification, more pronounced changes in the lipid profile were noted. A positive correlation was found between BMI in patients with EGE and the level of total cholesterol in blood serum.

The study was divided into four groups: the first group (32 patients, 21.9%) received standard therapy with dienogest at a dosage of 2 mg / day, the second group (61 patients, 41.7%) received combination therapy according to the scheme metformin 1500 mg and dienogest 2 mg, daily, the third group (29 patients, 19.8%), had a body weight deficiency and received therapy with metformin 750 mg and dienogest 2 mg daily, in 16.4% of cases (24 patients) metformin at a dose of 1500 mg daily was prescribed in monotherapy regimen.

For all patients, the duration of treatment was 6 months or more.

The leading complaint of patients was algodismenorrhea, which occurred in 84% of patients, 56% of patients complained of dyspareunia, 42% of chronic pelvic pain. In order to assess the severity of pain, the McGill Visual Analogue Scale of Pain (VAS) was used. The severity of algomenorrhea, pain outside of menstruation, and dyspareunia were evaluated separately. The most pronounced pain of the patient was noted during menstruation - 5.7 ± 3.07 points, during sexual activity the average level of pain was 3.64 ± 1.9 points, the average level of pain in the pelvic region, not associated with menstruation, was 3, 32 ± 3.03 points.

Before the start of therapy, algodismenorrhea (VAS 6.5 ± 2.4) was observed in 52 women with EGE, 34 patients complained of chronic pelvic pain (VAS 4.8 ± 2.2), 28 patients noted the presence of dyspareunia (VAS 5.1 ± 2.9).

In patients who received standard therapy with dienogest 2 mg, a decrease in pain syndrome was noted in 79% of cases: the severity of dysmenorrhea decreased 2.2 times, chronic pelvic pain - 1.7 times, dyspareunia - 1.5 times.

When using a combination of 1500 mg of metformin with dienogest, 85% of patients showed a significant decrease in pain syndrome: the severity of dysmenorrhea decreased 2.6 times, chronic pelvic pain - 2.5 times, dyspareunia - 1.3 times.

The use of a combination of metformin 750 mg and dienogest 2 mg in patients with EGE was also accompanied by a significant decrease in pain syndrome in 71% (the severity of dysmenorrhea decreased 2 times, chronic pelvic pain - 1.6 times, dyspareunia - 2.9 times).

In all cases, the decrease in the severity of symptoms is significant (p <0.05).

In the case of metformin monotherapy, a significant decrease in the severity of pain was noted by 62% of patients with EGE: the level of dysmenorrhea decreased 1.8 times, chronic pelvic pain - 1.9 times, dyspareunia - 2.2 times.

It should be noted that during therapy with metformin 1500 mg per day, most patients (71%) noted a decrease in body weight, on average by 1.9 kg over 6 months, the maximum weight loss was 9 kg over 15 months of using the drug in combination with a hypocaloric diet ... Tolerance to metformin was assessed as good in 87.2% of women; nausea (6.9%), diarrhea (3.5%) and metallic taste in the mouth (2.3%) prevailed among the side effects.

Both with metformin monotherapy and with the combined use of metformin at a dosage of 750 mg and 1500 mg per day and dienogest 2 mg per day, there were no clinical and laboratory signs of a relapse of the disease. Against the background of the use of monotherapy with dienogest 2 mg - in one case (3.1%), a relapse of the disease was recorded, which entailed repeated surgery.

The results obtained suggest that the addition of metformin to the standard therapy for endometriosis leads to a more pronounced reduction in pain. Dosage of metformin 1500 mg per day leads to a more pronounced reduction in pain syndrome than with 750 mg of metformin per day. However, a dosage of 750 mg per day may be recommended for patients with low body weight or abstaining from a glucose tolerance test. Metformin monotherapy can also be considered as a method of treating endometriosis-associated pain, but it is inferior in effectiveness to dienogest. It is possible to prescribe metformin as monotherapy in women with contraindications to hormonal treatment, as well as in patients with EGE planning pregnancy.

The effectiveness of the method is confirmed by the results of the use of metformin in an experimental model of surgically-induced endometriosis in 20 Wistar rats. At the first stage of the experiment, a model of the disease was formed by autotransplantation of fragments of the uterine wall onto the inner surface of the anterior abdominal wall. Laparoscopy was performed two weeks later to confirm model formation and to assess the starting dimensions of the endometrioid implants. After randomization, daily oral administration of the drug to rats of the main group was started at a dose of 300 mg / kg / day. The use of metformin for 3 weeks resulted in implant resorption in 39% of cases, in other cases the average implant area decreased 2.4 times. In the control group (without treatment), the size of the implants increased by 26 ± 7%. The average area of endometrioid implants in the main group after treatment was significantly (p <0.05) less than in the control group (9.1 ± 2.9 mm ² and 18.3 ± 5.2 mm ² , respectively). (Yarmolinskaya MI et al. Comparative assessment of the effectiveness of promising drugs for targeted therapy of endometriosis based on an experimental model of the disease // Gynecology. - 2018. - T. 20. - No. 5.)

The method is carried out, for example, as follows.

After confirming the diagnosis of EGE and the surgical stage of treatment, before prescribing metformin, the patient's body mass index is preliminarily determined and carbohydrate metabolism is assessed by performing an oral glucose tolerance test with determining the level of basal and stimulated insulin to confirm the safety of the use of hypoglycemic drugs, after which metformin is used at a dosage of 1500 mg in the regimen monotherapy or in combination with dienogest 2 mg daily for at least 6 months. When ≤18,5 BMI kg / m ^2, or failure of the patient from oral glucose tolerance test metformin is administered orally in combination with dienogest 2 mg daily dose of 750 mg per day for at least 6 months.

The method is confirmed by the following clinical examples.

Example 1. Patient Ch., 37 years old, complained of painful menstruation, pulling pains in the lower abdomen (according to VAS 8 and 7 points, respectively). Gynecological history: menstruation from 13 years old, 3-4 days, 25-26 days later, regular, moderate, painful.

Obstetric and gynecological history: 2 pregnancies: 2000 - urgent childbirth, girl 3800/56, the postpartum period was uneventful, 2001 - early medical abortion without complications. In 2014, in connection with severe syndrome of chronic pelvic pain, dysmenorrhea and dyspareunia, a cyst of the left ovary, laparoscopy was performed. Separation of adhesions and seams. Dissection of the rectovaginal septum. Left adnexectomy.

Postoperative diagnosis: grade IV EGE. Ovarian endometriosis. Deep infiltrative endometriosis - endometriosis of the rectovaginal septum with involvement of the sacro-uterine ligaments. Adhesion process in the small pelvis.

The results of histological examination: endometrioid cyst of the left ovary; fibrosis of the left fallopian tube; fibrous and adipose tissue with endometrial glands (endometrioid infiltrate).

Results of hormonal examination in 2018 (on the 3rd day of the menstrual cycle): FSH -15.3 MV / l; LH -7.1 IU / L, AMH -0.62 ng / ml.

Concomitant diseases: hereditary thrombophilia, high risk of complications. Heterozygous mutation of the V gene (Leiden factor). Taking into account the results of genetic examination of the blood coagulation system, hormonal therapy for endometriosis is contraindicated.

The patient was overweight (BMI 28 kg / m ² ).

When conducting an oral glucose tolerance test: fasting glucose 5.1 mmol / l, 2 hours after exercise 5.43 mmol / l, fasting insulin 5.9 μU / ml, after exercise - 84.9 μU / ml.

Treatment: Received therapy with metformin 1500 mg for 8 months. Based on the results of the examination of the blood coagulation system in dynamics (extended coagulogram, D-dimer, intravascular platelet activation), there were no deviations from the reference values.

Result: against the background of metformin therapy, clinical improvement, a decrease in the pain of menstruation (VAS-3), there is no pain in the lower abdomen (VAS-0). Within 8 months - decrease in body weight by 3 kg. There are no clinical and instrumental data indicating a relapse of the disease.

Example 2. Patient B., 42 years old, BMI 24.5 kg / m ² , complained of pulling pains in the lower abdomen radiating to the lower back (up to 8 points on the VAS), dyspareunia (5 points on the VAS).

Gynecological history: menstruation from 13 years old, for 6-7 days, after 24-25 days, regular, moderate, painful.

Obstetric and gynecological history: 1 pregnancy: 2014 - complete spontaneous miscarriage during early pregnancy, without abrasio cavi uteri.

Laparoscopy was performed in 2013. Excision and coagulation of endometriosis foci. Hysteroresectoscopy. Polypectomy.

Postoperative diagnosis: IGE grade III. Endometrial polyp.

Histological examination: fibrous tissue with endometrial glands; endometrial glandular polyp.

Results of hormonal examination (4th day of the menstrual cycle): FSH - 2.28 IU / l; estradiol - 1642 pmol / l, AMG - 0.33 ng / ml.

When conducting an oral glucose tolerance test: fasting glucose - 4.5 mmol / l, 2 hours after exercise - 7.4 mmol / l, fasting insulin - 2.81 μU / ml, after exercise - 40.25 μU / ml.

Treatment: she received therapy with dienogest 2 mg / day for 11 months, with a partial effect, a decrease in pain syndrome from 8 points on the VAS to 5 points, noted marked emotional lability. Then she received combination therapy with dienogest 2 mg in combination with metformin 1500 mg for 4 months, after which she independently canceled dienogest due to her reluctance to continue taking hormonal therapy.

She continued monotherapy with metformin 1500 mg for 2 months, the tolerance was good; during therapy, she noted the disappearance of pain syndrome (0 points on the VAS), stabilization of the emotional state. BMI before the start of therapy is 24.5 kg / m ² , during therapy - weight loss by 2 kg. She is planning a pregnancy in the ART cycle.

Example 3. Patient R., 32 years old, complained of painful menstruation (7 points on the VAS), dyspareunia (6 points), recurrent pulling pains in the lower abdomen not associated with menstruation (6 points), recurrent miscarriage.

Gynecological history: menstruation from 14 years old, for 6-7 days, after 31-35 days, regular, moderate, painful.

Obstetric and gynecological history: 3 pregnancies: 2016 - complete spontaneous miscarriage during early pregnancy, without abrasio cavi uteri, 2017 - non-developing pregnancy at 7/8 weeks, medical abortion, 2018 - non-developing pregnancy at the same 7/8 Bedel, medical abortion.

In January 2019, laparoscopy was performed. Excision of the endometrioid infiltrate of the sacro-uterine ligament on the left. Hysteroscopy. Endometrial biopsy (for histological examination and bacteriological examination - Femoflor 16).

Postoperative diagnosis: IGE grade II, infiltrative form. Chronic endometritis.

Histological examination: fibrous tissue with endometrial glands; chronic endometritis. Femoflora 16 results from the uterine cavity - growth of Ureaplasma urealyticum 10 ⁴ .

The results of hormonal examination (4th day of the menstrual cycle): FSH - 5.78 IU / l; LH - 5.46 IU / l; AMG - 3.43 ng / ml, estradiol - 536 pmol / l.

The patient's height is 170 cm, weight is 53 kg, BMI is 18.4 kg / m ² (body weight deficit), the patient refrains from performing an oral glucose tolerance test.

Treatment: after surgery, she received a course of antibacterial therapy (doxycycline) in connection with chronic endometritis, as well as therapy with dienogest 2 mg / day for 1.5 months. During the therapy, the pain syndrome decreased, but the patient noted pain 3 points on the VAS during the onset of bleeding), dyspareunia persisted (3-4 points), recurrent pulling pains in the lower abdomen not associated with menstruation (2 points). Metformin 750 mg / day was added to the therapy for 6 months, with a positive effect, good tolerance. During therapy, weight loss was not observed, pain was absent. She is planning a pregnancy after the end of therapy.

EFFECT: method allows expanding the arsenal of EGE treatment agents, increasing the safety of metformin administration, provides a differentiated approach to metformin prescribing and the choice of its dose, reduces pain syndrome, prevents disease recurrence, makes it possible to plan pregnancy against the background of monotherapy.

Claims (1)

A method of treating external genital endometriosis, including surgical treatment and drug exposure by introducing metformin orally, characterized in that after surgical treatment, before prescribing metformin, the patient's body mass index is preliminarily determined and carbohydrate metabolism is assessed by performing an oral glucose tolerance test with determining the level of basal and stimulated insulin to confirm the safety of hypoglycemic agents, after which the consent of the patient to hold an oral glucose tolerance test and a body mass index of 18.5 kg / m ² is used in a dosage of metformin 1500 mg monotherapy or in combination with 2 mg of dienogest daily for at least 6 months, and with a body mass index of less than 18.5 kg / m ² or if the patient refuses to perform an oral glucose tolerance test, metformin is administered orally in combination with dienogest 2 mg daily at a dose of 750 mg per day b for at least 6 months.