RU2761982C1 - Method for personalised treatment of ovarian endometriosis in women of reproductive age based on a point diagnostic system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the field of medicine and pertains to a method for determining the risk of a reduction in the ovarian reserve of ovarian endometriosis in patients of reproductive age after surgical treatment, based on a point diagnostic system. The method is implemented as follows: the possibility of a reduction in the ovarian reserve in the patient is analysed, the clinical and anamnestic data and the results of the diagnostic examination of the patient are also analysed, the level of anti-mullerian hormone is determined, the ultrasonic and molecular biochemical markers are analysed, wherein each indicator is assigned a score: cyst size >5 cm - 2 points; bilateral symmetry - 1 point; main cyst localisation - 2 points; anti-mullerian hormone <1.5 ng/ml - 3 points; lactate dehydrogenase >107.35 units/l - 3 points; interleukin-6 >82.4 pg/ml - 2 points; interleukin-8 >94.55 pg/ml - 2 points. If the sum equals 8 points or more, a high degree of the risk of a possibility of a reduction in the ovarian reserve is identified, and if the sum is less than 7 points, a low degree of the risk of a possibility of a reduction in the ovarian reserve is identified.

EFFECT: invention provides an increase in the effectiveness of treatment of patients of reproductive age with ovarian endometriosis due to the personalised approach to the management strategy.

1 cl, 1 dwg, 3 tbl, 2 ex

Description

The invention relates to medicine, in particular to surgical gynecology and reproductive medicine, and consists in personalized treatment, based on a diagnostic point scale, of patients of reproductive age with ovarian endometriosis.

Ovarian endometriosis (endometrioid ovarian cysts) is one of the most common manifestations of external genital endometriosis in patients of reproductive age. A cyst is diagnosed in 17-44% of patients with endometriosis, while the presence of cysts is often associated with infertility. The choice of treatment should be based on the individual characteristics of the patients, such as age, clinical manifestations and severity of symptoms, degree of spread, localization of foci of endometriosis, reproductive wishes, presence of comorbidities, side effects of drug therapy and possible complications associated with surgical treatment.

A known method for the treatment of cysts and ovarian cysts (patent RU 2132656), including the removal of a neoplasm with a capsule through a minilaparotomic incision, with a preliminary laparoscopy and evacuation of the contents of the neoplasm. The disadvantage of this technique is the need for a laparotomy.

Also known is a method for the treatment of endometrioid cysts, described in the International Journal of Gynecology and Obstetrics - 59 - 1997 - P. 31-34, C.C. Chang et al. The essence of this method is that under ultrasound control, transvaginal aspiration of the cyst is carried out under high pressure, and after evacuation of its contents, a 1% solution of tetracycline hydrochloride in a volume of 1/5 of the cyst contents is injected into the cyst cavity and the solution is left in it. The disadvantages of this method are: a high percentage of relapses (46.87%).

The prototype is a method for choosing the treatment of pelvic organ prolapse after childbirth in the early stages of the disease (patent RU 2676632), according to which phenotypic, ultrasound and genetic signs of the pathological process are established. Each attribute is scored according to table 3 of the description. With a score of up to 21, a low risk of PTO progression is established and the patient is treated with conservative treatment. With a score of 21-50, a high risk of PTO progression is established and surgical treatment of the disease is performed. The method allows to determine the risk groups for PTO progression, as well as to select the optimal treatment method in the early stages of the disease by assessing the complex of the most significant indicators.

However, none of the known methods provides for predicting a decrease in ovarian reserve and possible subsequent infertility at the preoperative stage of counseling based on a comprehensive analysis of molecular biochemical markers of toxicity, ultrasound data and indicators of ovarian reserve (anti-Müllerian hormone) in women of reproductive age with endometrioid ovarian cysts, for subsequent determination of treatment tactics.

The objective of the invention is to identify patients at greatest risk of decreased ovarian reserve after surgical treatment and to select an effective treatment method, taking into account subsequent reproductive plans.

The technical result of the invention is to increase the effectiveness of treatment due to an individual approach to the treatment of patients.

The technical result consists in increasing the accuracy of the treatment of ovarian endometriosis in patients of reproductive age.

The essence of the invention lies in preliminary complex diagnostics to create a diagnostic point scale that allows predicting the risk of decreased ovarian reserve in patients of reproductive age with ovarian endometriosis after cystectomy.

When applying the claimed method to patients of reproductive age with ovarian endometriosis disease, the possibility of reducing the ovarian reserve in the patient is established. For this, the clinical and anamnestic data and the results of the diagnostic examination of the patient are analyzed. Determine the level of anti-Müllerian hormone, analyze ultrasound and molecular biochemical markers. Each sign obtained as a result of the examination is assigned a point score (see Fig. 1), with a total of less than 7 points, a low degree of risk of the possibility of a decrease in the ovarian reserve is established, in which the patient undergoes surgical treatment, and with a total of more than 8 points, a high degree of risk of a decrease is established. ovarian reserve and prescribe a personalized (individual) approach to treatment. In this case, the diagnostic examination of the patient is carried out before the surgical treatment. Personalized treatment is prescribed before surgical treatment, taking into account the patient's reproductive plans. The examination of the patient is carried out using an ultrasound diagnostic device, as well as using devices for a biochemical blood test. In the particular case of using the method, an additional examination can be carried out using devices known in the prior art, necessary to analyze the possibility of a decrease in the ovarian reserve in a patient. For the analysis of the data obtained in the course of diagnostics and research, automated devices known in the prior art, for example, operating on the basis of an electronic computer, can be used.

According to the data obtained, the most significant risk factors for a decrease in the ovarian reserve after cystectomy were identified, on the basis of which a diagnostic point scale was developed and proposed. It was found that the most significant factors are ultrasound and molecular biochemical markers of ovarian endometriosis toxicity. The maximum score was 15 points. With a total score of 8 points or more, the risk of damage to the ovarian reserve after cystectomy is predicted by 50% or more (high risk) (see Fig. 1).

The explanation to FIG. 1: OD - likelihood ratio, RR - relative risk, OR - odds ratio, LDH (C) - serum LDH, IL-6 (C) - serum IL-6, IL-8 (C) - serum IL-8 blood.

When compiling the algorithm, the factors of a point scale were used as a basis, which made it possible to distinguish a group of patients who are most likely to have a risk of a decrease in ovarian reserve after cystectomy on the basis of ultrasound and molecular biochemical markers.

Retrospectively, in the course of testing the effectiveness of the proposed algorithm, on patients with ovarian endometriosis who underwent surgery (cystectomy), it was found that 215 (92.7%) of 232 women with low ovarian reserve (serum anti-Müllerian hormone level less than 1.5 ng / ml), bilateral localization of cysts and more than 5 cm in diameter, the level of anti-Müllerian hormone decreased 1.7-2.2 times. And in 205 (97.6%) women out of 210 with normal ovarian reserve (serum anti-Müllerian hormone level more than 1.5 ng / ml), unilateral localization of the cyst and less than 5 cm in diameter, the level of anti-Müllerian hormone did not significantly change after cystectomy or decreased slightly, followed by recovery after 2-3 months to preoperative values.

The proposed algorithm for the management of patients with ovarian endometriosis, taking into account the data of ultrasound and molecular biochemical markers, makes it possible to increase the accuracy and improve long-term treatment results (pregnancy in the group of high-risk patients by 1.6 times (p <0.05)).

The study included 340 patients of reproductive age who applied to the clinic with ovarian endometriosis more than 3 cm in diameter, verified by laparoscopy and histological examination, complaints of pelvic pain of varying intensity, no history of using hormonal drugs for the last 3 months or more, regular menstrual cycle, the absence of other pathological changes in the organs of the reproductive system according to ultrasound. Patients who had previously undergone surgery on the ovaries, with endocrine diseases, and with combined gynecological diseases were excluded from the study.

The control group consisted of 30 infertile women who underwent laparoscopy without signs of external genital endometriosis. During the examination, the patients of the main group were divided depending on the state of the ovarian reserve, assessed in accordance with the ESHRE criteria (European Society of Human Reproduction and Embryology, 2011): the main group - 220 (54.2%) patients with low ovarian reserve and the comparison group - 120 (45.8%) patients with normal ovarian reserve.

For an objective assessment of the "toxicity" of endometriomas, the content of the desired molecular biochemical markers of toxicity (lactate dehydrogenase (LDH), cytokines (interleukin-6 (IL-6), interleukin-8 (IL-8)), iron ions (Fe ²⁺ )) was determined in blood serum and peritoneal fluid. The material for this study was blood serum samples obtained by centrifuging venous blood for 20 minutes at a rotation speed of 3500 rpm, as well as samples of peritoneal fluid centrifuged for 20 minutes at a rotation speed of 3500 rpm.

Echographic studies were carried out on an apparatus providing three-dimensional reconstruction, using convex multifrequency endovaginal transducers with a frequency of 3.6-8.8 MHz, with a viewing angle of 121-180 °, in real time, the volume of ovarian tissue adjacent to the formation was determined in the preoperative period. and the volume of the intact ovary. After calculating the volume of the ovary in the visualization program, an automatically calculated histogram of a three-dimensional image with blood flow indicators - vascularization index and blood flow index was displayed on the screen.

During ultrasound, special attention was paid to the localization of the cyst in the ovary relative to the great vessels. In the event that the pole of the formation was located more than 5 mm from the zone of the main vessels of the ovary, then such localization was regarded as a "marginal" location of the cyst, if the cyst was localized less than 5 mm from the zone of the great vessels of the ovary, then this localization of the cyst was classified as a "main" location cysts.

According to the task, the analysis of the content of molecular-biochemical markers of blood serum toxicity was carried out, depending on the state of the OR, the results are presented in table 2.

The results of the correlation analysis of the content of molecular-biochemical markers in the blood serum and the AMG index are presented in table No. 3.

In the blood serum, a strong negative correlation was found between the IL-6 content and the AMH index, and a moderate negative correlation between LDH and AMH.

A strong correlation was also found between serum indicators of LDH and Fe ²⁺ (r = 0.812 Pearson's test p <0.001), LDH and IL-6 (r = 0.752 Pearson's test p <0.001), LDH and IL-8 (r = 0.420 criterion Pearson p <0.001).

The results of this study confirm the presence of oxidative-inflammatory stress at the local level in patients with ovarian endometriosis. In this case, the severity of changes is inversely correlated with the content of AMG.

According to the task, an analysis of the ultrasound features of endometrioid ovarian cysts in patients was carried out, depending on the state of the ovarian reserve.

Analyzing the nature of ovarian damage, bilateral ovarian lesions by endometrioid cysts were more common (65.5%) in the group with low ovarian reserve than in the group with normal ovarian reserve (40%) (p <0.05). The results of the study indicate that patients with low ovarian reserve more often had cysts more than 5 cm in comparison with patients with normal ovarian reserve (38.3 versus 22.2%) (p <0.05), and the frequency of detection of endometriomas with a diameter up to 5 cm did not reveal significant differences in both groups (p> 0.05). Also, special attention was paid to the location of the endometriomas. Such localization of cysts as the area of the funnel-pelvic ligament, the area of the own ovarian ligament was significantly more common in patients with low ovarian reserve (32.7 and 45.5%, respectively), in comparison with the "edge" location, which was more often recorded in the group with normal ovarian reserve (in 77.8% of cases). Based on the obtained and analyzed data, a statistical analysis was carried out: a logistic regression model.

Linear regressions were determined to identify demographic (age, parity, body mass index, characteristics of the menstrual cycle and pain syndrome, presence of extragenital pathology) and ultrasound (size, location of the cyst in the ovary, Doppler characteristics of ovarian tissue) and molecular biochemical characteristics (serum LDH, IL-6, IL-8), associated with the degree of decrease in AMH levels after cystectomy.

Logistic regression was used to determine the characteristics that will best predict a decrease in ovarian reserve in patients after cystectomy. When predicting a decrease in ovarian reserve based on a decrease in AMH by more than 50%, the final logistic regression model includes such indicators as the size and location of the cyst, the baseline AMH level and serum LDH, IL-8, IL-6.

Example # 1:

Patient M., 36 years old. Diagnosis: Endometrioma of the right ovary. Ultrasound data: right ovarian endometrioma with a maximum diameter of 6.0 cm, main localization. Laboratory indicators: the level of AMG-1.35 ng / ml, LDH-385.54 U / l, IL-6 - 95.4 pg / ml, IL-8 - 115.3 pg / ml.

Points total: 2 + 0 + 2 + 3 + 3 + 2 + 2 = 14 points.

Conclusion: The patient is at high risk of decreased ovarian reserve after cystectomy.

Example # 2:

Patient N., 25 years old. Diagnosis: Left ovarian endometrioma. Ultrasound data: left ovarian endometrioma with a maximum diameter of 4.0 cm, main localization. Laboratory indicators: AMG level - 2.5 ng / ml, LDH - 87.64 U / L, IL-6 - 85.4 pg / ml, IL-8 - 95.3 pg / ml.

Points total: 0 + 0 + 2 + 0 + 0 + 2 + 2 = 6 points.

Conclusion: The patient belongs to the group of low risk of decreased ovarian reserve after cystectomy.

Claims (1)

A method for determining the risk of a decrease in the ovarian reserve of ovarian endometriosis in patients of reproductive age after surgical treatment, which consists in the analysis of the possibility of a decrease in the ovarian reserve in a patient, characterized by the analysis of clinical and anamnestic data and the results of a diagnostic examination of the patient, determination of the level of anti-Müllerian hormone, an analysis of ultrasound and molecular-biochemical markers is carried out, while each indicator is assigned a point estimate: cyst size> 5 cm - 2 points; bilaterality - 1 point; main localization of the cyst - 2 points; anti-Müllerian hormone <1.5 ng / ml - 3 points; lactate dehydrogenase> 107.35 U / L - 3 points; interleukin-6> 82.4 pg / ml - 2 points; interleukin-8> 94.55 pg / ml - 2 points; with a total of 8 points or more, a high degree of risk of the possibility of a decrease in the ovarian reserve is established, and with a total of less than 7 points, a low degree of risk of a possibility of a decrease in the ovarian reserve is established.

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