RU2841915C1 - Method for integrated treatment of chronic endometritis with outcome in thin endometrium in patients with reproductive dysfunction - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention refers to medicine, namely to gynaecology. That is ensured by the integrated treatment of chronic endometritis extending into the thin endometrium in the patients with reproductive disorders. It involves anti-inflammatory therapy and irrigation of uterine cavity with ozonised cavitated solution in 1st phase of menstrual cycle. At that, irrigation of uterine cavity is carried out with ozonized cavitated saline in number of five procedures, in amount of 500-550 ml, at frequency of 25 kHz, a flow rate of 120-170 ml/min for 4-5 minutes. In addition, therapy with Superlimf preparation is administered in dose of 25 units 1 time a day rectally daily for 20 days, then after pause of 10 days, the therapy with Superlimf is repeated in dose of 25 units once a day through rectum daily for 20 days.

EFFECT: method has high clinical effectiveness and increases chances of pregnancy.

1 cl, 2 tbl, 3 ex

Description

The invention relates to medicine, namely to gynecology, and can be used to treat chronic endometritis (CE) with an outcome in a thin endometrium.

Since CE is asymptomatic, the prevalence of this disease is difficult to determine: 8-72% of patients in the reproductive period of life suffer from CE, while among infertile women its prevalence is 55.7% [Kimura F, Takebayashi A, Ishida M, Nakamura A, Kitazawa J, Morimune A, Hirata K, Takahashi A, Tsuji S, Takashima A, Amano T, Tsuji S, Ono T, Kaku S, Kasahara K, Moritani S, Kushima R, Murakami T. Review: Chronic endometritis and its effect on reproduction. J Obstet Gynaecol Res. 2019 May;45(5):951-960. doi: 10.1111/jog.13937]. It is believed that every fourth patient in gynecological departments (24.4%) can be diagnosed with chronic endometritis [Song D, Feng X, Zhang Q, Xia E, Xiao Y, Xie W, Li TC. Prevalence and confounders of chronic endometritis in premenopausal women with abnormal bleeding or reproductive failure. Reprod Biomed Online. 2018;36(1):78-83.doi: 10.1016/j.rbmo.2017.09.008]. Treatment of chronic endometritis has the potential to positively affect the reproductive function of women [Vitagliano A, Saccardi C, Litta PS, Noventa M. Chronic endometritis: Really so relevant in repeated IVF failure? Am J ReprodImmunol. 2017 Dec;78(6). doi: 10.1111/aji.12758]. The prevalence of thin endometrium syndrome is approximately 2.4% in assisted reproductive technology cycles, which in turn is associated with lower implantation rates and pregnancy rates [Mahajan N, Sharma S. The endometrium in assisted reproductive technology: How thin is thin? J Hum Reprod Sci. 2016 Jan-Mar;9(1):3-8. doi: 10.4103/0974-1208.178632].

Microbial agents act as a trigger for chronic endometritis or are the most significant modulating factor of immune, hormonal, and hemostasiological disorders that affect the normal functioning of endometrial tissues [Tapilskaya N.I., Tolibova G.Kh., A.M., Kopylova A.A., Glushakov R.I., Budilovskaya O.V., Krysanova A.A., Gorsky A.G., Gzgzyan A.M., Kogan I.Yu. Efficiency of local cytokine therapy for chronic endometritis in infertile patients. Obstetrics and Gynecology. 2022; 2: https://dx.doi.org/10.18565/aig.2022.2].

The danger of CE is that its long-term course without adequate therapy inevitably entails sclerotic damage to the extracellular matrix of the endometrium, changes in the tissue architecture and subsequent ischemia. This affects the main function of the endometrium, since the implantation of the blastocyst and the development of pregnancy are possible only if there is successful interaction between the mucous membrane and the zygote [Radzinsky V.E., Glukhov E.Yu. Cavitated solutions in reproductive medicine. Moscow: Editorial office of the journal StatusPraesens, 2017. 344 c].

The objective of this solution is the complex treatment of CE with an outcome in a thin endometrium in patients with reproductive dysfunction, including antibacterial therapy, a local cytokine therapy drug (INN: protein-peptide complex from swine blood leukocytes - Superlymph®, Altpharm LLC, Russia) and irrigation of the uterine cavity with a cavitated ozonized solution. As a result of the implementation of the invention, normalization of the thickness of the endometrium, restoration of vascularization in the endometrium according to Doppler studies, a decrease in the detection of histological signs of CE and an increase in the chances of pregnancy were observed.

Superlymph activates phagocytosis, which increases the production of IL-1, with an increase in which earlier terms of the appearance of granulation and marginal epithelialization are observed. The rate of wound contraction processes increases. Activates reparative processes in the mucous membrane and promotes the restoration of the functional activity of the mucous membrane. The drug demonstrates anti-inflammatory, antioxidant and regenerative activity, which is manifested by a decrease in the severity of inflammatory reactions and an increase in the rate of epithelialization of wound defects. After a course of therapy with Superlymph, angiogenesis processes in the tissue improve, reflected in an increase in the distribution density of the transmembrane protein CD34. [Tapilskaya N.I., Tolibova G.Kh., Obedkova K.V., Gzgzyan A.M., Kogan I.Yu. Algorithm for the diagnosis and treatment of chronic endometritis. Obstetrics and Gynecology. 2022]. Improving tissue vascularization and endometrial restoration can improve reproductive outcomes [Dobrokhotova Yu.E., Borovkova E.I., Nugumanova O.R. Improving angiogenesis processes and reproductive outcomes in patients with chronic endometritis. Obstetrics and Gynecology. 2021; 3: 145-152 https://dx.doi.org/10.18565/aig.2021.3.145-152].

The role of viral and bacterial infections in patients with CE has been revealed, which is a rationale for prescribing not only antimicrobial therapy, but also a drug with a local immunomodulatory effect. The use of Superlymph, which modulates the action of cytokines, increases the body's resistance and optimizes the treatment outcomes of patients with infertility in CE of viral and bacterial origin [Dikke G.B. Controversial issues in the treatment of chronic endometritis. Medical Council. 2023: 17 (5): 30-37].

Exogenous cytokine therapy effectively affects the restoration of the expression of innate immune factors, which leads to the relief of chronic inflammation and normalization of tissue receptivity [Dobrokhotova Yu.E., Borovkova E.I., Nugumanova O.R. Improving the processes of angiogenesis and reproductive outcomes in patients with chronic endometritis. Obstetrics and Gynecology. 2021; 3: 145-152 https://dx.doi.org/10.18565/aig.2021.3.145-152].

The use of the Superlymph drug and irrigation of the uterine cavity with a cavitated ozonized solution contributed to an increase in the chances of pregnancy. The ozonized solution has a vasodilating effect, which is accompanied by increased metabolism and restoration of receptor sensitivity. Ozone is necessary to ensure respiration and vital activity of cells. Ultrasonic cavitation irrigation of the uterine cavity helps to normalize the functional activity of immune system cells, which restores the structure of the endometrium, causes local reactions of apoptosis and proliferation, restoring the receptor field of the endometrium after a non-developing pregnancy [Burova N.A., Zabolotneva K.O., Abolotina O.V., Yarygin O.A., Shatilova Yu.A., Zharkin N.A. Restoration of endometrial receptivity in patients with chronic endometritis under the influence of physical factors of influence // Bulletin of VolSMU. 2019. No. 4 (72)].

A method for restoring reproductive function in patients with uterine infertility caused by hepatitis C (RU Patent No. 2821759) is known, characterized by the fact that patients with uterine infertility caused by hepatitis C undergo two courses of treatment.

First course: from the first day of the menstrual cycle, an antibiotic is taken orally - dispersible tablets of doxycycline monohydrate, 100 mg 2 times a day for 10 days; from the 5th to the 9th day, immunomodulatory therapy is used, which is carried out with a complex of exogenous natural antimicrobial peptides and cytokines Superlymph, suppositories of 25 U 1 time per day rectally in the evening every day for 20 days; in the same menstrual cycle, from the 5th to the 9th day, the uterine cavity is irrigated with a cavitated solution of chlorhexidine 0.05% in an amount of 200-300 ml per procedure, the duration of exposure is 3-5 minutes, 5 procedures, daily, 1 time per day.

Second course: in the next menstrual cycle, from the 5th to the 9th day, immunomodulatory therapy is used, which is carried out with a complex of exogenous natural antimicrobial peptides and cytokines Superlymph, suppositories of 25 U once a day rectally in the evening every day for 20 days; in the same menstrual cycle, from the 5th to the 9th day, the uterine cavity is irrigated with cavitated saline solution in the amount of 200-300 ml per procedure, the duration of exposure is 3-5 minutes, 5 procedures, daily, 1 time per day;

in this case, during both courses of treatment described above, the drug dydrogesterone is used at 1 tablet of 10 mg 1 time per day orally for 12 days in the second phase of the menstrual cycle from days 14 to 25 for 1-6 cycles until pregnancy occurs.

The disadvantage of this method is the use of an antibacterial drug without taking into account its sensitivity.

A method for treating endometriosis is known (RU Patent No. 2607590), which consists of a complex two-stage effect on the endometrium, in which at the first stage systemic anti-inflammatory therapy is carried out and intrauterine administration of Cathejel with lidocaine, which has an antimicrobial, adsorbent and anesthetic effect, 3-4 instillations of 12.5 g every other day per course of treatment; at the second stage, the antifibrotic drug Longidaza is administered in the form of vaginal suppositories, one suppository once every 3 days - 10 suppositories per course of treatment.

The disadvantages of the prototype include the fact that this method is intended for the treatment of patients with a morphologically verified diagnosis of CE in combination with endometrial hyperplasia and the absence of an antibacterial drug in the treatment.

The technical objective of the claimed solution is to develop a method for treating chronic endometritis with an outcome in a thin endometrium in patients with reproductive dysfunction.

The technical result of the claimed solution is: normalization of the thickness of the endometrium, restoration of vascularization in the endometrium according to Doppler studies, reduction in the detection of histological signs of chronic endometritis and an increase in the chances of pregnancy.

The said technical result is achieved by the fact that a method is proposed for the complex treatment of chronic endometritis with an outcome in a thin endometrium in patients with reproductive dysfunction, which consists in the fact that anti-inflammatory therapy and irrigation of the uterine cavity with an ozonized cavitated solution are carried out in the 1st phase of the menstrual cycle, while the irrigation of the uterine cavity is carried out with an ozonized cavitated physiological solution in the amount of five procedures, in a volume of 500-550 ml, at a frequency of 25 kHz, a flow rate of 120-170 ml/min for 4-5 minutes, while additionally therapy is carried out with the drug Superlifm in a dose of 25 U once a day rectally daily for 20 days, then after a break of 10 days, therapy is repeated with the drug Superlifm in a dose of 25 U once a day rectally daily for 20 days.

The method is carried out as follows:

Patients with CE with an outcome in a thin endometrium and a violation of reproductive function (infertility, habitual miscarriage, non-developing pregnancy in the anamnesis) at the first stage undergo antibacterial therapy with an individual choice of antibacterial drug depending on the infection.

At the same time, the uterine cavity is irrigated with an ozonized cavitated solution during the first phase of the menstrual cycle. The duration of the procedure is 4-5 minutes, the frequency of exposure is 25 kHz, the flow rate of the drug is 120-170 ml/min, with a volume of physiological solution of 500-550 ml. The ozonized physiological solution was the voiced solution.

At the same time, a peptide-protein complex of natural peptides and cytokines (Superlymph) is prescribed, 1 suppository of 25 U once a day rectally daily, which demonstrates anti-inflammatory, antioxidant and regenerative activity, which is manifested by a decrease in the severity of inflammatory reactions and an increase in the rate of epithelialization of wound defects. The course consists of 20 injections of suppositories of a peptide-protein complex of natural peptides and cytokines.

The second stage consists of a second course of peptide-protein complex of natural peptides and cytokines (Superlymph) after a 10-day break and consists of 20 suppository injections. A total of 40 suppositories for treatment.

As a result of implementing the method of the invention, an improvement in primary outcomes is observed: normalization of endometrial thickness according to ultrasound examination data, restoration of vascularization in the endometrium according to Doppler examination data, a decrease in the detection of histological signs of CE; improvement in secondary outcomes - an increase in the chances of pregnancy.

Three groups of patients matched by age and medical history were studied. In the main group, a local cytokine therapy drug (INN: protein-peptide complex from porcine blood leukocytes - Superlymph®, Altpharm LLC, Russia) was added to antibacterial therapy in combination with irrigation of the uterine cavity with a cavitated ozonized solution. In comparison group I, women received complex treatment, including antibacterial therapy in combination with irrigation of the uterine cavity with a cavitated ozonized solution. Patients in comparison group II received only antibacterial therapy.

When assessing the primary treatment outcomes, it was revealed that during the dynamic ultrasound examination of the pelvic organs in the II phase of the cycle (on the 21st-23rd day of the menstrual cycle) during the "implantation window" the endometrial thickness of 8 mm or more was determined in 84% of women in the main group, in 44% of the comparison group I and in 24% of the comparison group II. The homogeneity of the junctional uterine zone and the clarity of the echogenic line were noted in 48% of observations in the main group, in 28% of the comparison group I and in 16% of the comparison group II. Three-layer (receptive) endometrium on the days of ovulation was detected in 44% of patients in the main group, in 30% of the comparison group I and in 12% of the comparison group II. A uniform phenotypic appearance or a thin endometrium (non-receptive) was observed in 16% of observations in the main group, in 56% in comparison group I, and in 76% in comparison group II.

Reduced blood flow in the uterine vessels with predominant damage mainly at the level of the basal and spiral arteries was detected in 14% of patients in the main group, in 42% of comparison group I and in 66% of comparison group II. Increased resistance index was determined in 12% of patients in the main group, in 40% of comparison group I and in 78% of comparison group II.

Histological signs of CE after treatment were determined in 18% of observations in the main group, in 36% in comparison group I and in 74% in comparison group II. Immunohistochemical (CD138+ plasma cells) signs were detected in 20% of patients in the main group, in 38% in comparison group I and in 50% in comparison group II.

Table 1 presents the primary and secondary outcomes of chronic endometritis treatment in the main group and comparison groups I and II. When assessing the secondary treatment outcomes, it was found that pregnancy occurred in 58% of patients in the main group, in 34% in comparison group I, and in 22% in comparison group II (Table 1).

Table 1

Primary outcomes and secondary outcomes Groups Main
(AB + irrigation of the uterine cavity + Superlymph) Comparisons I
(AB + irrigation of the uterine cavity) Comparisons II
(AB) % % % Ultrasound (endometrial thickness 7-16 mm) 84.0 44.0 24.0 Decreased blood flow in the uterine vessels with a predominance at the level of the basal and spiral arteries 14.0 42.0 66.0 Histological criteria of CE 18.0 36.0 74.0 Immunohistochemical (CD138+ plasma cells) 20.0 38.0 50.0

Table 2 presents data on the pregnancy rate in the main group and comparison groups I and II. When using Superlymph in combination with antibacterial therapy and irrigation of the uterine cavity with ozonized cavitated solution, the chances of pregnancy increased by 1.7 times compared to local and antibacterial therapy and by 2.6 times compared to the group that received only the antibacterial drug (Table 2). No side effects or adverse reactions were detected during complex treatment with the inclusion of Superlymph.

Table 2

Groups Main
(AB + irrigation of the uterine cavity + Superlymph) Comparisons I
(AB + irrigation of the uterine cavity) Comparisons II
(AB) % % % Pregnancy rate 58.0 34.0 22.0

Example 1.

Patient B., 25 years old, was treated from 10.04.2023 to 19.04.2023 with the diagnosis: Chronic endometritis. Secondary infertility. History of non-viable pregnancy.

Admitted with complaints of infertility, which developed after a non-developing pregnancy, for which curettage of the uterine cavity was performed in 2021, and is concerned about periodic bloody intermenstrual discharge.

Laboratory findings on admission were as follows:

Complete blood count: hemoglobin - 129 g/l, erythrocytes - 4.4×1012/l, leukocytes - 7.9×109/l, ESR - 6 mm/hour.

Microscopic examination of a smear of vaginal discharge: Leukocytes in the urethra - 2, in the cervical canal - 6, in the vagina - 10, bacteria in small quantities, blastospores were not detected, lactobacilli were detected.

Ultrasound of the pelvic organs: thin endometrium (determinable endometrial thickness 7 mm); uneven contour, non-uniform echostructure of the endometrium. Doppler ultrasound shows decreased blood flow in the uterine vessels.

Histological examination: signs of infiltration of the endometrial stroma by lymphocytes, plasma cells; formation of lymphoid infiltrates; sclerosis of spiral arteries; focal hyperplasia of the basal layer; fibrosis, sclerosis of the stroma.

Immunohistochemical study: Plasma cells (CD138+) were detected, more than 5.

Antibacterial therapy was carried out: cefotaxime 2.0 g/day intravenously by drip for 14 days, doxycycline monohydrate 0.1, 1 tablet 2 times a day for 14 days, metrogyl 500 mg orally 2 times a day for 14 days.

At the same time, Superlymph was prescribed at 1 suppository of 25 U once a day rectally every day, a total of 20 administrations per course, a repeat course was prescribed after 10 days, 20 administrations of suppositories on an outpatient basis.

Irrigation of the uterine cavity was performed with a finely dispersed cavitated ozonized solution in the amount of five procedures during the 1st phase of the menstrual cycle. The ultrasound device AUZK-100-01 "FOTEK" was used. The duration of the procedure was 5 minutes, with a frequency of 25 kHz, a flow rate of the drug of 120 ml / min. The volume of the solution was 500 ml. The "sounded" medium was ozonized physiological solution.

Evaluation of effectiveness was carried out 1 month after the end of treatment.

Control ultrasound of the pelvic organs - endometrium without structural changes, thickness 8 mm, homogeneity of the uterine connecting zone and clarity of the echogenic line are revealed. Blood flow in the uterine vessels is not impaired.

Histological examination: no signs of inflammation were detected, no infiltration of the endometrial stroma by lymphocytes or plasma cells;

Immunohistochemical study: Plasma cells (CD138+) were not detected.

Pregnancy occurred 1 month after the end of treatment.

Example 2.

Patient G., 28 years old, was treated from 06/19/2023 to 06/29/2023 with the diagnosis: Chronic endometritis. Primary infertility.

Admitted with complaints of primary infertility, which developed after using a contraceptive in the uterine cavity for 5 years, for which the IUD was removed with curettage of the uterine cavity in 2022, she is concerned about periodic bloody intermenstrual discharge, pain during menstruation.

Laboratory findings on admission were as follows:

Complete blood count: hemoglobin - 127 g/l, erythrocytes - 4.2×1012/l, leukocytes - 9.1×109/l, ESR - 9 mm/hour.

Microscopic examination of a smear of vaginal discharge: Leukocytes in the urethra - 3, in the cervical canal - 8, in the vagina - 12, bacteria in small quantities, blastospores were not detected, lactobacilli were detected.

Ultrasound of the pelvic organs: thin endometrium (endometrial thickness 5 mm); uneven contour, non-uniform echostructure of the endometrium. Doppler ultrasound shows decreased blood flow in the uterine vessels.

Histological examination: signs of infiltration of the endometrial stroma by lymphocytes, plasma cells; sclerosis of the spiral arteries; focal hyperplasia of the basal layer; fibrosis, sclerosis of the stroma.

Immunohistochemical study: Plasma cells (CD138+) were detected, 6.

Antibacterial therapy was carried out: cefotaxime 2.0 g/day intravenously by drip for 14 days, doxycycline monohydrate 0.1, 1 tablet 2 times a day for 14 days, metrogyl 500 mg orally 2 times a day for 14 days.

At the same time, Superlymph was prescribed at 1 suppository of 25 U once a day rectally every day, a total of 20 administrations per course, a repeat course was prescribed after 10 days, 20 administrations of suppositories on an outpatient basis.

Irrigation of the uterine cavity was performed with a finely dispersed cavitated ozonized solution in the amount of five procedures during the 1st phase of the menstrual cycle. The ultrasound device AUZK-100-01 "FOTEK" was used. The duration of the procedure was 4.5 minutes, with a frequency of 25 kHz, a flow rate of the drug of 140 ml / min. The volume of the solution was 525 ml. The "sounded" medium was ozonized physiological solution.

One month after the end of treatment, the effectiveness was assessed. Control ultrasound of the pelvic organs - no structural changes in the endometrium were detected, the thickness was 9 mm, the homogeneity of the uterine connecting zone and the clarity of the echogenic line were revealed. Blood flow in the uterine vessels was not impaired.

Histological examination: no signs of inflammation were detected, no infiltration of the endometrial stroma by lymphocytes, no plasma cells.

Immunohistochemical study: Plasma cells (CD138+) were not detected.

Pregnancy occurred 2 months after the end of treatment.

Example 3.

Patient B., 30 years old, was treated from 14.08.2023 to 24.08.2023 with the diagnosis: Chronic endometritis. Secondary infertility. History of non-viable pregnancy.

Admitted with complaints of infertility that appeared after a non-developing pregnancy, for which curettage of the uterine cavity was performed in 2022, she is concerned about dysmenorrhea and periodic bloody intermenstrual discharge.

Laboratory findings on admission were as follows:

Complete blood count: hemoglobin - 130 g/l, erythrocytes - 4.3×1012/l, leukocytes - 8.5×109/l, ESR - 8 mm/hour.

Microscopic examination of a smear of vaginal discharge: Leukocytes in the urethra - 3, in the cervical canal - 9, in the vagina - 14, bacteria in small quantities, blastospores were not detected, lactobacilli were detected.

Ultrasound of the pelvic organs: thin endometrium (determinable endometrial thickness 5 mm); uneven contour, non-uniform echostructure of the endometrium. Doppler ultrasound shows decreased blood flow in the uterine vessels.

Histological examination: signs of endometrial stroma infiltration with lymphocytes and plasma cells; lymphoid infiltrates; sclerosis of spiral arteries; focal hyperplasia of the basal layer; signs of fibrosis and sclerosis of the stroma.

Immunohistochemical study: Plasma cells (CD138+) were detected, more than 5.

Antibacterial therapy was carried out: cefotaxime 2.0 g/day intravenously by drip for 14 days, doxycycline monohydrate 0.1, 1 tablet 2 times a day for 14 days, metrogyl 500 mg orally 2 times a day for 14 days.

At the same time, Superlymph was prescribed at 1 suppository of 25 U once a day rectally every day, a total of 20 administrations per course, a repeat course was prescribed after 10 days, 20 administrations of suppositories on an outpatient basis.

Irrigation of the uterine cavity was performed with a finely dispersed cavitated ozonized solution in the amount of five procedures during the 1st phase of the menstrual cycle. The ultrasound device AUZK-100-01 "FOTEK" was used. The duration of the procedure was 4 minutes, with a frequency of 25 kHz, a flow rate of the drug of 170 ml / min. The volume of the solution was 550 ml. The "sounded" medium was ozonized physiological solution.

Evaluation of effectiveness was carried out 1 month after the end of treatment.

Control ultrasound of the pelvic organs - no structural changes were found in the endometrium, the thickness is 8 mm, the homogeneity of the uterine connecting zone is revealed, the echogenic line is clear. Doppler examination showed that the blood flow in the uterine vessels is not impaired.

Histological examination: no signs of inflammation were detected, no signs of infiltration of the endometrial stroma by lymphocytes and plasma cells were found.

Immunohistochemical study: Plasma cells (CD138+) were not detected.

Pregnancy occurred 2 months after completing the full course of treatment.

Thus, treatment of CE using a complex treatment method using the drug Superlymph at a dosage of 25 U for 20 days simultaneously with antibacterial therapy and irrigation of the uterine cavity with ozonized cavitated solution has high clinical efficacy and increases the chances of pregnancy.

Claims (1)

A method for the complex treatment of chronic endometritis with an outcome in a thin endometrium in patients with reproductive dysfunction, consisting of anti-inflammatory therapy and irrigation of the uterine cavity with an ozonized cavitated solution in the 1st phase of the menstrual cycle, characterized in that the irrigation of the uterine cavity is carried out with an ozonized cavitated physiological solution in the amount of five procedures, in a volume of 500-550 ml, at a frequency of 25 kHz, a flow rate of 120-170 ml / min for 4-5 minutes, while additional therapy is carried out with the drug Superlifm at a dose of 25 U 1 time per day rectally daily for 20 days, then after a break of 10 days, therapy is repeated with the drug Superlifm at a dose of 25 U 1 time per day rectally daily for 20 days.