RU2655538C1 - Method of endometrial dysfunction treatment - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to gynecology and physiotherapy, and can be used to treat endometrial dysfunction. To do this, intrauterine instillation of the solution of placental hydrolyzate in a dose of 112 mg/2 ml once in 2 days, for a course of 3–5 intrauterine procedures. Between intrauterine procedures, intravenous placental hydrolyzate is administered at 4–6 ml after dilution with 200 ml of 0.9 % saline in a course of 7–10 injections. At the same time, daily physiotherapy is carried out using an infrared laser with a wavelength of 0.59–0.89 mcm, a pulse power of 5 W and a pulse repetition rate of 50–1,500 Hz daily on the abdomen with an exposure of 3–5 minutes for each projection zone of the uterus and appendages, course of 10 procedures.

EFFECT: method provides adequate growth of endometrium, improvement of its echostructure and blood flow parameters in the uterine artery basin, increased thickness and receptor sensitivity of the endometrium, stimulation of angiogenesis and a decrease in the likelihood of developing fibrosis, which leads to the restoration of reproductive function in the absence of adverse reactions and complications of treatment.

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Description

The invention relates to medicine, namely to drug therapy and radiation therapy, and can be used in gynecology for the treatment of patients with endometriopathy and reproductive disorders associated with it.

Among other significant reasons in considering disorders of childbearing function in recent years, increasing attention has been paid to pathological processes in non-tumor tissue of the endometrium, in connection with which the term "endometriopathy" has become quite popular. The most recognized point of view is that endometriopathy implies the formation of a failed, morphofunctional endometrium, where there may be signs of a residual inflammatory reaction, microcirculatory disorders, endothelial dysfunction and oxidative stress. Clinical and morphological signs of the presence of endometriopathy are as follows:

- decreased secretory activity of epithelial cells;

- a decrease in the expression of receptors for estrogens and progesterone with a loss or a sharp decrease in their sensitivity;

- allo-and autoimmune reactions;

- “thin endometrium” (leptometrium, less than 7 mm in the luteal phase, which is registered in at least two consecutive cycles).

Endometriopathy can result in dystrophic changes in the uterine cavity as a result of invasive interventions, a chronic inflammatory process of the endometrium, ovarian failure, vascular disorders in the uterine artery pool and rheological blood disorders. In this case, multiple morphological and functional disorders occur, manifested by a change in receptivity and cyclic transformation of endometrial tissue. An imbalance between two different processes - proliferation and apoptosis of endometrial cells - leads to defective tissue regeneration and fibrosis. A so-called “thin endometrium” is formed, the thickness of which, according to ultrasound data in the periovulatory phase of the menstrual cycle, does not exceed 7 mm (1, 2, 3, 4, 5, 6, 7, 8).

The above changes in the future become the cause of menstrual dysfunction, impaired embryo implantation processes, resulting in infertility, miscarriage, failure of ART methods, burdened pregnancy and childbirth. The attrition of clinical symptoms, the absence of clear diagnostic criteria often lead to delayed, long, expensive and ineffective treatment, which worsens the prognosis of the restoration of menstrual and reproductive functions.

The following methods are known for treating endometrial dysfunction, including “thin endometrium”: empirical antimicrobial chemotherapy to suppress pathogenic microflora, synthetic analogues of sex steroids to stimulate the receptor sensitivity of the endometrium, various types of physiotherapy.

Literature data indicate that endometriopathy is most often the result of an autoimmune process in endometrial tissue with possible post-inflammatory changes; while the frequency of detection of microflora in the uterine cavity is negligible. In this regard, the appointment of antimicrobial therapy in the vast majority of cases is not justified.

The need for adequate preparation of the endometrium for the full implantation of the embryo is not in doubt, however, routine hormonal therapy by prescribing estrogen drugs may be ineffective and even exacerbate inflammation, taking into account their well-known pro-inflammatory effects. In addition, during the pathological process, the susceptibility of the endometrium to the exogenous effects of estrogens and progestogens is impaired, and therefore the expected effect of the therapy is not observed in this group of patients. In addition, the systemic use of hormones can cause the progression of endocrinopathy and the development of hyperplastic processes in the female genital area.

For the prototype of the present invention, a well-known method for the treatment of endometrial dysfunction was selected, including intravenous administration of a placental hydrolyzate (“Experience with the use of a human placental hydrolyzate in the treatment of endometrial dysfunction.” Kuznetsova IV, Uspenskaya Yu.B., Kovalenko MA // Obstetrics archive and Gynecology named after VF Snegirev, vol. 1, No. 1, 2014, pp. 22-24, M., “Medicine”).

The known method is as follows. Patients with insufficiency of proliferative function of the endometrium are injected intravenously with 6 ml of human placenta hydrolyzate (Laennec®) in 250 ml of saline 2 times a week. The course of treatment of 10 droppers for 5 weeks.

The drug Laennec - a new unique drug that helps rejuvenate the body and restore health, is an immunomodulator, hepatoprotector, and helps increase immunity. Laennec is a Japanese drug - a human placenta hydrolyzate that contains growth factors: cytokines (interleukins 1, 6, 8, 10, 12), erythropoietin, interferon, amino acids (18), aminoglycosides (hyaluronic acid), vitamins B1, B2, B6, S, D, PP. When introduced into the bloodstream, into the muscles, under the skin, into the scalp or acupuncture points, a fluid composed of the most useful and most effective components for a person effectively eliminates the foci of pathology, restoring immunity, mobilizing internal resources, vitality and psychological resistance person. The Laennec preparation preserves the natural structure and biological activity of the components of the placenta - growth factors (36), cytokines, amino acids, and vitamins. The reparative activity of the drug was determined by the presence of HGF hepatocyte growth factors, insulin-like IGF, FGF fibroblast growth factors, EGF epidermocytes, NGF nerves, and CSF colonies. The effectiveness and hypoallergenicity of the Laennec drug has been proven by 55 years of use in clinics in Japan in the treatment of more than 80 diseases.

The authors of the known method consider this technique effective in women with infertility and miscarriage due to the "uterine" factor. The maximum increase in the endometrium with a gradual increase in the clinical effect during the described method of treatment, the authors noted by the 6th month of treatment. The method helps to restore the regenerative abilities of the endometrium, normalize ovarian function and improve pregnancy outcomes in women with infertility and miscarriage.

However, the main disadvantage of this method should be recognized as insufficient or significantly delayed clinical effect, since the placental preparation does not have strict selectivity for the endometrium, and when it enters the systemic circulation, its concentration in the uterine blood flow is negligible. The created concentrations of the placenta hydrolyzate directly in the uterine cavity are insufficient and are not able to ensure the implementation of an adequate etiopathogenetic effect on the endometrium.

The task of the invention is to provide a method of treatment that is devoid of the disadvantages of the prototype.

The technical result of the proposed method is to increase the effectiveness of the treatment of endometrial dysfunction due to the direct effect on the failed endometrium with the elimination of its post-inflammatory changes, increase the thickness and receptor sensitivity of the endometrium, stimulate angiogenesis and reduce the likelihood of developing fibrosis, which together becomes the key to the restoration of reproductive function.

The technical result is achieved by the fact that in the known method of treating endometrial dysfunction, including intravenous administration of a placenta hydrolyzate solution, an intrauterine instillation of a placenta hydrolyzate solution is performed at a dose of 112 mg / 2 ml, every other day, for a course of 3-5 uterine procedures, intravenous procedures are carried out between intrauterine procedures the introduction of a placental hydrolyzate in 4-6 ml after dilution in 200 ml of 0.9% physiological solution of sodium chloride in the course of 7-10 injections, at the same time daily physiotherapy is carried out using using an infrared laser with a wavelength of 0.59-0.89 μm, a pulse power of 5 W and a pulse repetition rate of 50-1500 Hz daily to the lower abdomen with an exposure of 3-5 minutes for each zone of the projection of the uterus and appendages, a course of 10 procedures.

The proposed method meets the criteria of the invention of “novelty” and “industrial applicability”, since the analysis of scientific, technical and patent documentation did not reveal sources of information discrediting the novelty of the proposed method, as well as technical solutions with essential features of the proposed invention.

The technical result of the proposed method is to increase the effectiveness of the treatment of endometriopathy, which, in particular, contributes to the absorption and exposure of the placenta hydrolyzate directly to the uterine cavity. The combination of drug effects of placental therapy and infrared laser radiation eliminates post-inflammatory changes in endometrial tissue, optimizes local immunity factors, realizes a local metabolic effect, stimulates the proliferative activity of epithelial cells, as well as reduces the overall drug load on the patient’s body and the duration of treatment. Treatment can be carried out in a day hospital or on an outpatient basis. With the simultaneous use of intravenous and intrauterine administration of the drug against the background of the use of radiation from a therapeutic laser, there is an increase in the therapeutic effect on the endometrium at both the biological and physico-chemical levels, which contributes to the impact on all levels and links of the etiopathogenesis of endometriopathy. reduction of the treatment time for endometriopathy due to potentiation and acceleration of the onset of the clinical effect by combining intrauterine and injection placental and laser therapy. Contraindications to the use of "Laennec": individual intolerance to the components of the drug, children's age, pregnancy, lactation.

Contraindications to the use of a therapeutic laser: individual intolerance to laser radiation, uterine fibroids, adenomyosis, cancer, decompensated vascular diseases, pulmonary and heart failure, blood system diseases, nervous system diseases, systemic skin diseases, fever of unknown origin.

The proposed method is as follows. After preliminary treatment of the vagina and cervix with antiseptic preparations (chlorhexidine, povidone iodine, octenidine dihydrochloride and phenoxyethanol, etc.) in the first phase of the menstrual cycle, for 5-7 days (after menstruation), after the bladder is empty, the patient is placed on gynecological chair. Under aseptic conditions, an intrauterine instillation of a placenta hydrolyzate solution (Laennec drug No. 3-5) at a dose of 112 mg / 2 ml is performed through a thin flexible catheter without expansion of the cervical canal. After that, a tampon is inserted into the posterior vaginal fornix to prevent leakage of the drug. The procedures are carried out every other day, for a total of 3-5 intrauterine procedures. Between intrauterine procedures, a placental hydrolyzate is administered 2-3 times a week, intravenously, in a drop-by-drop manner, 4-6 ml after dilution of a 0.9% physiological solution of sodium chloride in 200 ml per course of 7-10 injections. In parallel, the patient is daily given a physiotherapy course with an infrared laser with a radiation wavelength of 0.56-0.89 microns, a pulse power of 5 W and a pulse repetition rate of 50-1500 Hz, daily to the lower abdomen with an exposure of 3-5 minutes for each area of the projection of the uterus and appendages, in the course of 10 procedures. Thus, the total duration of treatment is 2.5 weeks.

Examples of specific performance.

Example 1

Patient A. 32 years. Complaints about the absence of pregnancy for 2 years. A history of 1 birth, 5 abortions. Hysterosalpingography - fallopian tubes are passable. Hormonal status - without features. The husband is healthy. In the process of further examination according to the data of hysteroscopy and morphological examination of endometrial scraping - chronic non-specific endometritis, a hypodystrophic variant, without exacerbation, immunohistochemical study - a decrease in the expression of estrogen receptors and a violation of the ratio of steroid receptors. In menstrual blood, a slight increase in IL-6 to 3800 pg / ml was noted. Endometrial culture is sterile. According to ultrasound and dopplerometry in the 2nd phase of the menstrual cycle M-echo 6.5 mm, blood flow is disturbed in the spiral arteries. The treatment was carried out according to the proposed method - intrauterine instillation with a placenta hydrolyzate solution (Laennec drug No. 3-5) in a dose of 112 mg / 2 ml. The procedures were performed every other day, for a total of 3 intrauterine procedures. Between the intrauterine procedures, the placenta hydrolyzate was injected intravenously slowly 4-6 ml after diluting in 200 ml of 0.9% physiological solution of sodium chloride, for a course of 7 injections. In parallel, the patient was daily given a physiotherapy course with an infrared laser with a radiation wavelength of 0.56-0.89 μm, a pulse power of 5 W and a pulse repetition rate of 50-1500 Hz, daily to the lower abdomen with an exposure of 3-5 minutes for each area of the uterus projection and appendages, in the course of 10 procedures. Next, the appointment of micronized progesterone for 2 months in the 2nd phase of the cycle. After a course of treatment, the content of IL-6 in menstrual blood for a month and a half decreased to normal values and amounted to 1000 pg / ml, according to the result of femoflor-screen and inoculation from the cervical canal and vagina - normocenosis. There are no sonographic signs of chronic endometritis, the blood flow at the level of the spiral arteries is partially restored, the M-echo is 8.5 mm. 3 months after completion of treatment, pregnancy occurred, which progresses without signs of a threat of interruption.

Example 2

Patient M. 36 years. Complaints about the absence of pregnancy in marriage for 7 years, scanty menstruation. History 1 spontaneous miscarriage with curettage of the uterine cavity. A comprehensive survey of the couple was conducted. STIs by routine methods were not detected; spouse spermogram - the norm. Reproductive hormones - a decrease in AMH to 0.67 ng / ml. According to hysterosalpingography, the fallopian tubes are passable, the uterine cavity is not deformed. According to the results of hysteroscopy and morphology, the endometrium is thin, dysfunctional, does not correspond to the day of the menstrual cycle, according to the IHC, the expression of steroid receptors is moderate. By the method of PCR in the endometrium, ureaplasma ureality in a diagnostically significant titer was detected - treated with antibiotics, control was performed. In cervical mucus, an increase in IL-6 to 58 pg / ml was noted. According to ultrasound in the 2nd phase of the M-echo cycle of 6.4 mm. Spiral arteries are not located. The treatment according to the proposed method. The procedures were performed every other day, for a total of 4 intrauterine procedures. Between the intrauterine procedures, intravenous administration of the placenta hydrolyzate was carried out in a dropwise droplet of 6 ml each after diluting in 200 ml of 0.9% physiological sodium chloride solution for a course of 8 injections. In parallel, the patient was daily given a physiotherapy course with an infrared laser with a radiation wavelength of 0.56-0.89 μm, a pulse power of 5 W and a pulse repetition rate of 50-1500 Hz, daily to the lower abdomen with an exposure of 3-5 minutes for each area of the uterus projection and appendages, in the course of 10 procedures. The appointment of progesterone for 3 months. After the course of treatment, the content of IL-6 in cervical mucus decreased to normal. There are no sonographic signs of chronic endometritis; blood flow at the level of the spiral arteries has been restored. M-echo 8.6 mm. Menstruation has become more plentiful. 4.5 months after the completion of treatment after IVF and PE, a single pregnancy has progressed and progresses without signs of interruption.

Example 3

Patient D. 28 years. Complains of the inability to endure pregnancy. A history of preterm labor at 28 and 32 weeks of gestation followed by curettage of the uterine cavity. Then antibiotic therapy and COC for 6 months. Hysteroscopically - without features. In endometrial scraping, a picture of hypoplastic endometrium with the phenomena of stromal sclerosis. A routine examination was carried out. According to the tests of functional diagnostics, there are ovulatory cycles. The husband is healthy. STIs are excluded, the endometrium is sterile. The level of IL-6 in the menstrual blood is within normal limits. According to ultrasound and dopplerometry in the 2nd phase of the menstrual cycle - hyperechoic inclusions in the basal layer of the endometrium, M-echo 6.5 mm, spiral arteries are not located. Carriage of high-risk genetic thrombophilia has been identified. The treatment according to the proposed method. Intrauterine administration was performed every other day, for a total of 5 intrauterine procedures. Between the intrauterine procedures, the placental hydrolyzate was injected intravenously slowly in a dose of 6 ml after diluting in 200 ml of a 0.9% physiological solution of sodium chloride, for a course of 10 injections. In parallel, the patient was daily given a physiotherapy course with an infrared laser with a radiation wavelength of 0.56-0.89 μm, a pulse power of 5 W and a pulse repetition rate of 50-1500 Hz, daily to the lower abdomen with an exposure of 3-5 minutes for each area of the uterus projection and appendages, in the course of 10 procedures. After the therapy according to the proposed method, pregravid preparation was carried out with progestogens in the 2nd phase of the cycle for 3 months M-echo 8.5 mm, in the spiral arteries single blood flow loci were visualized. Pregnancy has come and is progressing with micronized progesterone 200 mg vaginally and enoxaparin 0.4 ml subcutaneously daily.

The proposed method provides an increase in efficiency and a reduction in the treatment time for endometrial dysfunction, which is manifested by the normalization of menstrual function, the leveling of residual phenomena of inflammation, an adequate increase in the endometrium, and an improvement in its echo structure and blood flow parameters in the uterine artery pool. There is an increase in the receptivity of the endometrium according to the results of an immunohistochemical study. At the same time, there are no significant adverse reactions and complications, during the treatment and before the onset of pregnancy, the appearance of fibrous adhesions in the uterine cavity is not observed. This method is effective, simple, affordable, well tolerated by patients and can replace long-term costly and ineffective traditional courses of treatment. Provides restoration of reproductive function.

Sources of literature

1. Endometriopathy, or regenerative-plastic insufficiency syndrome, is the realization of tissue stress, which is based on the depletion of the regenerative potential of endometrial tissue. Non-developing pregnancy. Guidelines for MARS (Interdisciplinary Association of Reproductive Medicine Specialists). / [Aut. - comp. V.E. Radzinsky et al.]. - M .: Editorial office of the journal StatusPraesens, 2015 .-- 48 p. ITEM 5.3.2.

Marinkin I.O., Kuleshov V.M., Ilizarova N.A., Aydagulova S.V. A new interpretation of the decrease in endometrial receptivity with habitual miscarriage // StatusPraesens, 2013. No. 6 (23). S. 74-80.

2. Melkozerova OA, Bashmakova N.V., Esareva A.V. Communication problems of the embryo and endometrium: markers of disorders and mechanisms of influence // Russian Bulletin of the Obstetrician-Gynecologist. 2016; 16 (5): 29-36.

3. Kuznetsova I.V., Uspenskaya Yu.B., Kovalenko M.A. // Archive of Obstetrics and Gynecology. V.F. Snegireva, t. 1, No. 1, 2014, p. 22-24, M., "Medicine".

4. Kuznetsova IV, Sheveleva TV, Pobedinskaya O.S. et al. Use of a human placenta hydrolyzate in the treatment of insufficient endometrial proliferation // Gynecology. 2013. No3. S. 29-33.

5. Kuznetsova I.V., Zemlina N.S., Rashidov T.N., Kovalenko M.A. The problem of thin endometrium and possible ways to solve it // Effective pharmacotherapy. 2015. No5. S. 42-49.

6. Vartanyan E.V., Tsaturova K.A., Devyatova E.A. Modern possibilities of non-invasive diagnosis of endometriopathy // Reproductive technologies today and tomorrow. Materials of the XXV Anniversary international conference of the Russian Association of Human Reproduction September 9-12, 2015, Sochi. - S. 45-47.

7. Zuev V.M., Kalinina E.A., Alexandrov M.T., Pimancheva Yu.I. Failure of the endometrium in IVF programs: pathogenesis, diagnosis and rehabilitation // Reproductive technologies today and tomorrow. Materials of the XXV Anniversary international conference of the Russian Association of Human Reproduction September 9-12, 2015, Sochi. - S. 47-49.

Volkova E.Yu., Silantyeva E.S., Korneeva I.E. The role of physiotherapy in the correction of uterine hemodynamics in women with impaired reproductive function and “thin” endometrium // Health of a girl, girl, woman: materials of the All-Russian Scientific and Practical Conference (Tomsk, December 4-5, 2012). - Tomsk: NIIAGiP SB RAMS, 2012 .-- S. 8-10.

8. Gleicher N., Kim A., Michaeli T., Lee H.J., Shohat-Tal A., Lazzaroni E., Barad D.H. A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies. Hum Reprod. - 2013 Jan .; 28 (1): 172-7.

9. Kasius A., Smit J.G., Torrance H.L. et al. Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis. Hum. Reprod. Update 2014. Vol. 20. No. 4. P. 530-541.

Claims (1)

A method of treating endometrial dysfunction, including intravenous administration of a placenta hydrolyzate solution, characterized in that the intrauterine instillation of the placenta hydrolyzate solution is performed at a dose of 112 mg / 2 ml, every other day, for a course of 3-5 intrauterine procedures, intravenous administration of the placenta hydrolyzate is carried out between 4-6 ml after dilution in 200 ml of 0.9% physiological solution of sodium chloride in the course of 7-10 injections, at the same time physiotherapy is carried out daily using an infrared laser with a wavelength of 0.59-0.89 microns, a pulse power of 5 W and a pulse repetition rate of 50-1500 Hz daily to the lower abdomen with an exposure of 3-5 minutes for each zone of the projection of the uterus and appendages, a course of 10 procedures.