RU2143892C1 - Method of treatment of patient with ovary hyperstimulation syndrome - Google Patents

Abstract

FIELD: medicine, gynecology. SUBSTANCE: invention proposes the use of cytostatic preparation colchicine at the dose 3 mg per 24 h for 3-7 days. Method ensures to effect on pathophysiological mechanism of development of increased permeability of histohematic barrier by inhibition of hormones and enzymes activity. EFFECT: decreased period of patients recovery. 3 ex

Description

 Ovarian hyperstimulation syndrome (OHS) is a complex of pathological symptoms that occur during treatment with ovulation inducers / B.I. Bodyazhkina et al. Guidelines for non-operative gynecology. - M. 1990 /. Code 620 - non-inflammatory ovarian diseases / ICD-10, Geneva: WHO, 1995 /.

 It occurs with a frequency of 22% among all patients receiving treatment to stimulate ovulation, according to the embryogenesis laboratory of the Russian Center for Obstetrics, Gynecology and Perinatology, Russian Academy of Medical Sciences. Severe and moderate course of the syndrome develops in 11 - 11.8% / Obstetrics and gynecology. - 1993 - N 6 /.

 Being iatrogenic, the syndrome can be fatal against the background of timely conducted conventional therapy. The risk group is young patients with low body weight, with polycystic ovary syndrome, with a high initial level of blood estradiol, and after pituitary desensitization by gonadotropin releasing hormone agonists. The pathogenesis of OHSS has not been fully elucidated; it is believed that prostaglandins / B.I. play an important role in its occurrence. Bodyazhkina et al. Guidelines for non-operative gynecology. - M., 1990 /, estrogens / Am. J.Physiol. - 1960 .-- N 199 /, C.A. Gemzell. Induction of ovulation with human gonadotropins. Resent Prog Horm Res 1965; 21: 179 /, vascular endothelial growth factor / Lancet. - 1994. - N 8917 /, aldosterone, histamine, renin-angiotensin system / Obstetrics and gynecology. - 1993 - N 6 /.

 The clinical picture of OHSS consists of anasarca and enlarged cystically altered ovaries.

 There are two methods of treatment - conservative and surgical. The conservative method is used for moderate and severe clinic syndrome, and the surgical method in the presence of specific complications is hemorrhagic shock due to bleeding from rupture of ovarian cysts, or torsion of ovarian cysts. The surgical method is always carried out against the background of conservative treatment / B. I. Bodyazhkina et al. Guidelines for non-operative gynecology. - M., 1990 /. The conservative treatment method is applied without regard to the presence or absence of pregnancy. In severe cases, embryo replanting is not performed.

 The prototype of the invention chose a conservative method for the treatment of moderate and severe ovarian hyperstimulation syndrome. The essence of the method is that the patient is prescribed an extensive range of pharmacological drugs: donor plasma, protein, albumin, reopoliglyukin, hemodesis, polydes, glucocorticoids, antihistamines, ascorutin, calcium preparations, heparin, antiplatelet agents, estrogen-progestogen drugs, danazole, indomethacin, and they conduct thorough reusable clinical and laboratory monitoring of the following parameters: the volemic and rheological properties of blood, the state of kidney perfusion, the degree of restoration of the central and peripheral heme dynamics, the state of water and electrolyte balance, the state of coagulation and anticoagulation systems of blood, the degree of heart and lung function, the state of carbohydrate metabolism and /V.I.Bodyazhkina al. Guidelines for non-operational gynecology. - M., 1990 /. The duration of treatment for OHSS is from 2 to 6 weeks.

 The disadvantages of the prototype include the fact that due to the lack of accurate data on the pathogenesis of OHSS, therapy is carried out as symptomatic, but not pathogenetic, this can lead to a protracted course or death in severe form of the syndrome. It is also necessary to note the large drug load of various drugs, which can lead to the development of a variety of life-threatening side effects / M.D. Mashkovsky. Medicines In two parts. - 12th ed. - M .: Medicine, 1993 /, the probability of development of which cannot be predicted in each specific case. In addition, the drugs and laboratory methods used in the treatment of OHSS are expensive, which leads to high material costs. The complexity of the diagnosis, treatment and monitoring requires the availability of expensive medical equipment and highly qualified specialists in the hospital, which makes it difficult to use the prototype in a city or district gynecological hospital, where patients with an OSS clinic are first and foremost. This leads to a delay in the start of treatment and the development of complications leading to death. The presence or absence of pregnancy on the background of OHSS, to select the most effective drugs, is not taken into account in the prototype.

 The objective of the invention is the reduction of treatment time, the reduction of drug load. The problem is solved in that for the treatment of severe OHSS, a cytostatic drug is prescribed, for 3 to 7 days, which disrupts the biophysical synthesis of nucleotides (DNA, RNA) and hormones in hyperstimulated ovarian cells, interrupts the pathophysiological mechanism of development of anasarca.

 Under normal conditions, theca cells and theca-lutein ovarian cyst cells under the influence of luteotropic hormone produce the polypeptide hormone relaxin. The main effects of relaxin are: 1) relaxation of the smooth muscles of the uterus / J. Tepperman, X. Tepperman. Physiology of metabolism and endocrine system. - M., 1989 /; 2) stimulation of the synthesis of enzymes depolymerizing collagen and proteoglycans, and / or their activators - proteoglycanases and procollagenases, in target cells of relaxin - ovarian stroma fibroblasts, histogenetic barrier fibroblasts and chondrocytes / J.Tepperman, X. Tepperman. Physiology of metabolism and endocrine system. - M., 1989 /; 3) a dose-dependent effect on prostaglandin synthesis - suppression of the synthesis of prostaglandins of the E1 group at low concentrations and an increase in the synthesis of prostaglandins of the E1 group at high concentrations of relaxin greater than 4-5 μg / ml / N. N. Kevorkov et al. Hormones of reproduction in the regulation of immunity processes. - Ekaterinburg, 1993 /, / Brit. J. Obstet. Gynaecol. 1987. V. 94, N 11 /; 4) a change in water balance - a decrease in plasma osmolarity / J. Endocrinol., - 1993. - 137, N 3 /; 5) increased levels of oxytocin and vasopressin in plasma / J. Endocrinol. - 1994. - 141, N 1 /.

 In ovarian hyperstimulation syndrome, the mechanism of hypersecretion of relaxin by the cells of theca-luteal cysts and theca cells in an amount significantly exceeding the physiological level is activated. This leads to cAMP dependent increase in the synthesis and secretion of collagenase and proteoglycanase or their activators in the fibroblasts of the histohematological barrier. The accumulation of enzymes depolymerizing collagen and proteoglycans in the vascular bed and in the intercellular spaces leads to the destruction of the main molecular bonds of the histohematological barrier and the development of a systemic reaction of increased permeability of the walls of blood vessels and basement membranes, which is manifested by the transudation of fluid from capillaries into all serous cavities of the body, up to the development anasarca, and a significant increase in the level of excretion of degradation products of connective tissue - glucosaminoglycans in daily urine, which is confirmed etsya our data / cm. examples N 1, 2, 3 /.

 For treatment, we suggest using a cytostatic agent, for example, the preparation "Kolchicin HOUDE" containing colchicine alkaloid. Colchicin (Colchicinum) is one of the alkaloids isolated from the corms of the magnificent Colchicum (Colchicum Speciosum Stev.), Fam. Liliaceae (Liliaceae). In terms of chemical structure, colchicine is (S) N- (5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo [α] heptalen-7-yl) acetamide. Synonyms for colchicine: Artrichine, Colchiquim, Colchisol, Colcin, Colgout, Coluric, Novolchine. Colchicine has antimitotic activity due to impaired formation of the microtubule system in the cytoplasm of various secretory cells / J. Tepperman, H. Teperman. Physiology of metabolism and endocrine system. - M., 1989 /. Because of this property, the drug is proposed for the treatment of recurrent illness and gout. Dosages not exceeding 6.0 mg per day for several days and not more than 3 mg per day with prolonged use (up to 5 years or more) are allowed for use. The drug is contraindicated in renal and liver failure, purulent diseases, pregnancy. Release form: tablets, coated with a white color, 0.001 g (1 mg) / M.D. Mashkovsky. Medicines In two parts. Part II.- 12th ed. - M.: Medicine, 1993 /.

 Our studies have shown that in the treatment of colchicine, due to the destruction of the microtubule system in the cytoplasm of the secreting cells of the ovaries and fibroblasts, the synthesis and secretion of relaxin, collagenase, proteoglucanase ceases, which leads to the elimination of the increased permeability of the histohematological barrier and the reverse development of anasarca.

A detailed description of the method and examples of its specific implementation
The proposed method of treatment is used in the diagnosis of a patient with moderate or severe ovarian hyperstimulation syndrome. Upon admission, the patient undergoes a differential diagnostic study to exclude diseases of the peritoneum, portal hypertension, nephrotic syndrome, heart and pericardial diseases, gastrointestinal diseases, myxedema, Meigs syndrome, pancreatitis, and ovarian carcinoma. At the same time, a clinical and laboratory study is carried out to eliminate contraindications to the use of colchicine or colchamine preparations: "Kolchicin HOUDE", Artrichine, Colchiquim, Colchisol, Colcin, Colgout, Coluric, Novolchine, Colcemid, Demecolcin, Omain - exclude the presence of pregnancy, purulent diseases, and kidney and liver failure, pronounced inhibition of bone marrow hematopoiesis (leukocyte count below 4 • 10 ⁹ / l, platelet count below 100 • 10 ⁹ / l) and anemia / M.D. Mashkovsky, Medicines. In two parts. Part II.- 12th ed. - M.: Medicine, 1993 /.

 With confirmation of the OHSS and the exclusion of contraindications to the use of cytostatics, treatment with Kolchicin HOUDE is started, 1 mg x 3 times a day for 3-7 days. Against the background of the application of which careful clinical and laboratory monitoring of the patient is carried out to monitor the dynamics of anasarca involution, reduce ovarian size and early detection of known side effects of colchicine / M.D. Mashkovsky, Medicines. In two parts. Part II.- 12th ed. - M.: Medicine, 1993 /.

 From laboratory methods that reflect the effectiveness of cytostatic therapy, glucoseaminoglycan excretion in daily urine, ultrasound scanning of the pericardium, pleural cavities, and abdominal cavity are used. Recovery is diagnosed in the absence of fluid in the pleural cavities, pericardial cavity, abdominal cavity, a decrease in ovarian size and a decrease in the excretion of glucosaminoglycans in daily urine to normal levels.

 Example No. 1: Case history No. 936. Patient I., 32 years old, was admitted to the gynecological department of RNIIAiP with a diagnosis of: Condition after in vitro fertilization. Ovarian hyperstimulation syndrome.

 2 weeks after embryo transfer, the patient turned to the gynecological department of the central hospital with complaints of constant weakness, shortness of breath at rest and when walking, a significant increase in the abdomen. An inpatient examination revealed ascites and enlarged cystically altered ovaries. Several medical diagnostic punctures were performed, and a total of about 9 liters of fluid was removed. Due to the rapid recurrence of ascites after punctures (within 8-12 hours), the appearance of effusion in the pleural cavities, and the general condition worsening, the patient with sanitation was delivered to the RNIIAiP.

 Clinical examination and ultrasound revealed ascites, hydrothorax and hydropericardium, cardiopulmonary insufficiency syndrome, enlarged, with multiple cysts, ovaries, total size 13x14x10 cm, low level of HGG β-subunit in several blood serum samples, indicating embryo rejection, increased the level of excretion of glucosaminoglycans of daily urine in two samples is 112 and 109 mg / day (normal up to 10 mg / day) / N.U. Tits. Clinical evaluation of laboratory tests - M .: Medicine, 1986 /. A differential diagnostic study was conducted to exclude diseases of the peritoneum, portal hypertension, nephrotic syndrome, heart and pericardial diseases, gastrointestinal diseases, myxedema, Meigs syndrome, pancreatitis, and ovarian carcinoma. As a result of clinical and laboratory examination, the diagnosis was made: Condition after the program - IVF. Severe ovarian hyperstimulation syndrome. Complications: Cardiopulmonary insufficiency of the II degree. Anasarca.

 The absence of indications for surgical treatment (rupture of ovarian cysts with bleeding; clinic of cystic torsion) determined the tactics of generally accepted conservative therapy aimed at improving the rheological properties of blood, normalizing water-electrolyte balance, improving central and peripheral hemodynamics, reducing capillary permeability, and preventing coagulopathy. In order to inhibit prostaglandin synthesis, dexamethasone was used.

 Against the background of treatment carried out for 7 days, the patient's condition remained unchanged. There remained a risk of developing acute cardiopulmonary failure. Due to the lack of effect from the generally accepted treatment methodology, the drug Kolchicin HOUDE was prescribed at 1 mg x 3 times a day. As a result of treatment, effusion in the pericardial and pleural cavities disappeared on the third day, and effusion in the abdominal cavity on the fifth. Colchicine therapy was carried out for seven days. With careful clinical and hematological monitoring of the patient, within 30 days from the start of therapy, side effects characteristic of colchicine and relapse of anasarca were not detected.

 Example No. 2: Case history N 1916. Patient M., 30 years old, was admitted to the Department of IVF RNIIAiP with a diagnosis of: Condition after in vitro fertilization. Ovarian hyperstimulation syndrome.

 10 days after embryo transfer, the patient turned to the department complaining of weakness, shortness of breath when walking, and an increase in the abdomen.

 Clinical examination and ultrasound revealed ascites, pleurisy, enlarged, with multiple cysts, ovaries, with a total size of 15x12x10 cm, a low level of HGG β-subunit in several blood serum samples, indicating embryo rejection, an increased level of excretion of glucose aminoglycans of daily urine - 72 mg / day (normal to 10 mg / day) / N.U. Tits. Clinical evaluation of laboratory tests - M .: Medicine, 1986 /.

 As a result of clinical and laboratory examination, the diagnosis was made: Condition after the program - IVF. Severe ovarian hyperstimulation syndrome. Complications: Ascites. Pleurisy.

 The patient was prescribed the drug "Kolchicin HOUDE" at 1 mg x 3 times a day. As a result of treatment, transudate in the abdominal and pleural cavities disappeared on the fifth day. Colchicine therapy was carried out for five days. With careful clinical and hematological monitoring of the patient, within 30 days from the start of therapy, side effects characteristic of colchicine, as well as relapse of ascites, pleurisy, were not detected.

 Example No. 3: Case history No. 206. Patient K., 30 years old, was admitted to the IVF department of RNIIAiP with a diagnosis of Condition after in vitro fertilization. Ovarian hyperstimulation syndrome of moderate severity.

 12 days after embryo transfer, the patient turned to the IVF department with complaints of weakness, an increase in the abdomen.

 Clinical examination and ultrasound revealed ascites, enlarged, with multiple cysts, ovaries, with a total size of 12x8x6 cm, a negative immunological pregnancy test in several samples of blood serum, indicating embryo rejection, an increased level of excretion of glucosaminoglycans of daily urine - 60 mg / day and 40 mg / day (normal up to 10 mg / day) / N.U. Tits. Clinical evaluation of laboratory tests - M .: Medicine, 1986 /.

 As a result of clinical and laboratory examination, the diagnosis was made: Condition after the program - IVF. Ovarian hyperstimulation syndrome, moderate. Complications: Ascites.

 The patient was prescribed the drug "Kolchicin HOUDE" at 1 mg x 3 times a day. As a result of treatment, ascites disappeared on the third day. Colchicine therapy was carried out for three days. With careful clinical and hematological monitoring of the patient within 30 days from the start of therapy, side effects characteristic of colchicine, as well as relapse of ascites, were not detected.

Thus, as a result of clinical studies of the proposed method, the following advantages were revealed in comparison with the prototype:
- the proposed method for the treatment of OHSS is pathogenetic, interrupting the action of one of the main mechanisms for the development of ovarian hyperstimulation syndrome - synthesis and secretion of the hormone relaxin and enzymes that destroy the basic molecular structures of the histohematological barrier;
- the proposed method reduces the healing time to 3-7 days, instead of 2-6 weeks;
- the proposed method is economically more profitable, as it reduces the number of necessary medications, the number of necessary expensive laboratory tests and the length of hospital stay of patients;
- the proposed method eliminates the possibility of fatal complications developing with a prolonged course of ovarian hyperstimulation syndrome due to a reduction in the duration of treatment;
- the proposed method allows to reduce the drug load on the body and prevent possible side effects of therapy due to the use of a small number of drugs with well-studied properties and can be widely used in obstetric and gynecological practice, as it requires standard laboratory equipment available in the city (district) gynecological hospital, minimal medication, easy to use.

 Clinical testing of the method was carried out at the Rostov Research Institute of Obstetrics and Pediatrics of the Ministry of Health and the Ministry of Health of the Russian Federation.

Claims (1)

 A method of treating ovarian hyperstimulation syndrome by prescribing pharmacological preparations, characterized in that a colchicine preparation of 3 mg per day is prescribed for 3 to 7 days.