RU2749783C1 - Method for treatment of polycystic ovary syndrome associated with metabolic syndrome - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine and concerns a method for the treatment of polycystic ovary syndrome associated with metabolic syndrome. The essence of the method is that the following drugs are prescribed orally: myo-inositol at a dose of 2000-3000 mg, as well as D-chiro-inositol at a dose of 400-600 mg per day in combination with oral administration of sulodexide at a dose of 500-750 lipoprotein lipase units per day for at least 6 months.

EFFECT: use of the method makes it possible to effectively treat PCOS associated with metabolic syndrome.

1 cl, 2 ex

Description

The invention relates to medicine, namely to gynecology, can be used in gynecological practice for the treatment of polycystic ovary syndrome (PCOS) associated with metabolic syndrome, prevention of endothelial dysfunction and cardiometabolic complications in this group of patients.

PCOS is a common disease in women of reproductive age with an incidence of up to 11%. Depending on the clinical picture and taking into account the metabolic characteristics, there are two pathogenetic variants of PCOS: the first - the classic reproductive and the second, associated with metabolic syndrome - with a high risk of cardiometabolic disorders and endothelial dysfunction [Genazzani A.D. Inositol as putative integrative treatment for PCOS. Reprod Biomed online. 2016; 33 (6): 770-780. DOI: 10.1016 / j.rbmo.2016.08.024].

The latter type should be considered as an interdisciplinary problem with the involvement in the pathogenesis of not only reproductive system disorders, but also metabolic, hemostasiological disorders of varying severity [Jamwal S., Sharma S. Vascular endothelium dysfunction: a conservative target in metabolic disorders. Inflammation research: official journal of the European Histamine Research Society. 2018; 67: 391-405].

At the moment, the first line of treatment for women with PCOS of any pathogenetic variant is the appointment of estrogen-gestagenic combined oral contraceptives (COCs) in a long-term mode [Rotterdam ESHRE / ASRM Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004; 19 (1): 41-47. Doi: 10.1093 / humrep / deh098] (prototype).

However, this therapeutic strategy does not affect metabolic disorders, which are more pronounced in patients with the second pathogenetic variant of PCOS, which leads to a lack of prevention of these disorders and an increased risk of cardiometabolic complications.

In addition, the negative effect of hormonal treatment on the hemostatic system in women with PCOS is known. In large clinical studies, there has been an increase in the risk of venous thromboembolic complications when using COCs [Lidegaard O., Nielsen L., Skovlund C. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and estrogen doses: Danish cohort study, 2001-9. BMJ 2011; 343: d6423].

When analyzing the effect of estrogen-progestogen drugs on the hemostatic system, there is an increase in protein C activity and a decrease in protein S, an increase in procoagulant activity, as well as a decrease in antifibrinolytic parameters, which aggravates the already pronounced metabolic disorders in patients with PCOS and metabolic syndrome [Jick S., Hernandez R. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: Casecontrol study using United States claims data.BMJ 2011; 342: d2151].

Taking COCs leads to shifts in the hemostasis system, while there are adverse effects manifested by a decrease in the concentration of anticoagulant proteins and an increase in the concentration of procoagulant proteins, with a simultaneous compensatory increase in fibrinolysis.

Known positive effect of glycosaminoglycans, namely sulodexide, on the hemostasis system in patients with PCOS, including those associated with metabolic syndrome [Lapina I.A., Ozolinya L.A., Dobrokhotova Yu.E., Gavrilov M.V., Taranov V.V., Koltinova T.G. Comprehensive assessment of the effect of glycosaminoglycans on the hemostatic system in patients with polycystic ovary syndrome (PCOS). Issues of gynecology, obstetrics and perinatology 2019. - N 5. - S. 35-41].

However, the use of this drug in the proposed treatment regimen does not exclude the use of hormonal therapeutic agents in the treatment of PCOS associated with metabolic syndrome, a pathology that has a complex pathogenesis, polyetiological nature of development.

It is known to use inositol as a drug for the treatment of menstrual irregularities, premenstrual syndrome and PCOS without metabolic syndrome.

It exists in two isoforms: myo-inositol, which regulates glucose consumption and the transmission of impulses of follicle-stimulating hormone, and D-chiro-inositol, which controls glycogen synthesis, is involved in the synthesis of androgens

It is known that the use of myo-inositol significantly improves the hormonal profile in patients with PCOS and reduces insulin resistance [Genazzani A.D., Lanzoni C., Ricchieri F., Jasonni V.M. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecological Endocrinology. 2008; 24 (3): 139-144. doi: 10.1080 / 09513590801893232].

It is also known that D-chiro-inositol enhances the action of insulin in patients with polycystic ovary syndrome, thereby improving ovulatory function and reducing serum androgen concentration, blood pressure and plasma triglyceride concentration [Nestler J.E., Unfer V. Reflections on inositol (s) for PCOS therapy: steps toward success. Gynecological Endocrinology. 2015; 31 (7): 501-505. doi: 10.3109 / 09513590.2015.1054802; [Costantino D., Minozzi G., Minozzi F., Guaraldi C. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. European Review for Medical and Pharmacological Sciences. 2009; 13 (2): 105-110].

However, in the proposed dosages and treatment regimens, isolated forms of inositol do not allow it to be considered the drug of choice in the treatment of complex PCOS pathology associated with metabolic syndrome, which precludes the appointment of hormonal drugs. This position is confirmed by the fact that PCOS associated with metabolic syndrome is accompanied by serious disorders in the homeostasis system, such as an increase in glycated hemoglobin, cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), the atherogenic coefficient, for which the effect of inositol is not known

We have set the task: to develop an affordable method for the treatment of PCOS associated with metabolic syndrome, allowing to exclude the appointment of hormonal drugs and associated complications.

The technical result achieved with the implementation of the invention consists in the prevention of complications caused by the appointment of hormonal drugs in the conservative treatment of PCOS associated with metabolic syndrome, by simultaneous restoration of the function of the ovarian vascular endothelium, correction of metabolic disorders, lipid profile and hemostasiological parameters, as well as prevention of the development of cardiovascular complications due to the use of the proposed treatment regimen, which presupposes the appointment of a complex of pathogenetic therapeutic agents in original dosages and duration of treatment.

We have found that two forms of inositol (myo-inositol and D-chiro-inositol) potentiate the effect of sulodexide on the hemostatic system and endothelial dysfunction, enhancing its therapeutic effect in patients with PCOS associated with metabolic syndrome.

According to the results of our study, when using a combination of sulodexide and inositol, there is a significant improvement in both the parameters of the hemostasis system and the parameters of lipid and carbohydrate metabolism in patients with PCOS and metabolic syndrome.

Moreover, as it turned out, when using inositol, the presence of metabolic disorders does not prevent the implementation of the therapeutic efficacy of sulodexide, but, on the contrary, contributes to a greater manifestation of the beneficial effect of this drug on the dynamics of hemostatic and metabolic parameters.

It was previously believed that the presence of obesity and overweight as components of the metabolic syndrome is a serious limitation in the implementation of the therapeutic effects of sulodexide on the hemostatic system due to the weakening of the energy supply of sanogenetic reactions.

At the same time, against the background of a more pronounced therapeutic effect and normalization of the metabolic profile, in the overwhelming majority of cases, spontaneous restoration of ovulatory function occurs.

Taking into account the close relationship of the etiopathogenesis of PCOS, metabolic disorders and the state of the microvasculature system, we proposed a variant of drug treatment of PCOS associated with metabolic syndrome using two non-hormonal drugs.

One of them - sulodexide (glucurono-2-amino-2-deoxyglucoglucan sulfate) has a high affinity for the endothelium, which helps to prevent the development of endothelial dysfunction and complications associated with it.

As the second drug, which potentiates the action of sulodexide and has its own therapeutic effect, we used two forms of inositol in the original dosage.

The proposed method reduces the risk of endothelial dysfunction and unfavorable cardiometabolic outcomes in patients with PCOS in the presence of metabolic syndrome, insulin resistance due to endothelial restoration, antithrombotic and angioprotective effects. The presence of glycosaminoglycans, heparinoids and dermatan sulfate in the composition also causes the implementation of antiadhesive, hypolipidemic, anticoagulant effects, which prevents the progression or occurrence of violations of the metabolic profile and the hemostatic system.

Thus, the use of this combination helps to reduce the risk of thrombus formation and endothelial dysfunction due to a positive effect on the parameters of the hemostasis system, the absence of a damaging effect on the vascular endothelium, restoration of a favorable metabolic background and restoration of ovulatory function.

As it turned out, the proposed treatment regimen reliably arrests various manifestations of metabolic syndrome, as a result, ensures the normalization of ovarian function - it is effective in PCOS, and, contributing to the "reverse development" of combined pathology, allows you to refuse additional prescription of hormonal drugs in PCOS in combination with metabolic syndrome.

The essence of the invention is as follows.

For the treatment of polycystic ovary syndrome associated with metabolic syndrome, the following drugs are prescribed orally: myo-inositol at a dose of 2000-3000 mg, D-chiro-inositol at a dose of 400-600 mg per day in combination with oral administration of sulodexide at a dose of 500-750 lipoprotein lipase units per day for at least 6 months.

The method is carried out as follows.

In order to confirm the diagnosis of PCOS, a thorough collection of anamnestic data and a full examination were carried out. The diagnosis was based on the presence of at least 2 of the 3 following signs according to the 2003 ESHRE / ASRM clinical protocols:

1) chronic oligo / anovulation (menstrual irregularities - cycle duration <21 or> 35 days or presence of <8 cycles per year), in the presence of a normal menstrual cycle, the presence of ovulatory dysfunction was assessed by the results of determining the level of progesterone in serum 7 days before the expected menses. A decrease in progesterone levels below 3-4 ng / ml confirmed anovulation;

2) hyperandrogenism (clinical and / or biochemical signs);

3) polycystic ovarian morphology according to transvaginal ultrasound (the presence of 12 or more follicles with a diameter of 2-9 mm and / or an increase in ovarian volume of more than 10 ml).

The diagnosis of metabolic syndrome was confirmed based on the presence of at least 3 of 5 of the following IDF criteria, 2009:

1) waist circumference more than 80 cm;

2) triglycerides (TG) ≥1.7 mmol / L (≥150 mg / dL) or taking lipid-lowering drugs;

3) high density lipoproteins (HDL) <1.3 mmol / L (<50 mg / dL);

4) blood pressure (BP): systolic BP (SBP) ≥130 mm Hg. or diastolic blood pressure (DBP) ≥85 mm Hg or treatment of previously diagnosed hypertension;

5) fasting plasma glucose ≥5.6 mmol / L (≥100 mg / dL).

For treatment, myo-inositol is prescribed at a dose of 2000-3000 mg and D-chiro-inositol at a dose of 400-600 mg per day in combination with sulodexide at a dose of 500-750 lipoprotein lipase units per day. As a preparation that combines the required doses of myo-inositol and D-chiro-inositol, for example, Dikirogen in a sachet form or preparations of myo-inositol and D-chiro-inositol with the same name in capsules (manufactured by Fairhaven Health "And" Klaire Labs "), and as a drug with the active substance sulodexide, you can use Wessel DUE F or Angioflux in capsule form.

The application is carried out with the help of oral administration of drugs for a course of treatment of at least 6 months.

In the course of treatment, a dynamic assessment of the parameters of the hemostasis system, metabolism of carbohydrates, lipids should be carried out, as well as the state of the relationship between coagulation, anticoagulant blood components and the level of markers of cytotoxic damage should be analyzed by measuring the concentrations of fibrinogen, homocysteine and coagulogram.

To prove the possibility of realizing the stated purpose and achieving the indicated medical and technical result, we present the following data.

Clinical example 1.

Patient B., 29 years old, when referring to the obstetrician-gynecologist of the polyclinic, notes complaints of an irregular menstrual cycle for three years, the absence of menstruation for 42 days. She is not physically burdened, and does not take medications all the time. The patient is planning a pregnancy.

According to an objective examination, there are signs of hyperandrogenism in the form of acne, when measuring BMI - 29 kg / m ² . According to ultrasound of the pelvic organs (17th day of the cycle), there is an increase in the ovaries on both sides up to 12 cm ³ , in the right ovary there are 8 follicles up to 7 mm in size, in the left ovary there are 6 follicles up to 8 mm in size. A blood test for B-chorionic gonadotropin is negative. Taking into account irregular menstruation, the presence of clinical signs of hyperandrogenism and ultrasound criteria for PCOS (ovarian volume more than 10 cm ³ ), the patient is recommended a comprehensive examination: 1) a detailed study of the indicators of the hemostasis system in order to assess the state of the hemostasis system and the presence of markers of endothelial dysfunction: platelets, fibrinogen, thrombin time , fibrinolytic activity, activated partial thromboplastin time, antithrombin III, protein C, protein S, prothrombin, homocysteine, PAI-1 (plasminogen activator inhibitor -1); 2) analysis of the presence of metabolic syndrome components: waist circumference more than 80 cm, triglyceride level ≥1.7 mmol / l (≥150 mg / dl) or taking lipid-lowering drugs, high-density lipoprotein level <1.3 mmol / l (<50 mg / dl), blood pressure: SBP ≥130 mm Hg. or (DBP) ≥85 mmHg, fasting plasma glucose ≥5.6 mmol / L (≥100 mg / dL); 3) analysis of the main predictors of metabolic syndrome: insulin resistance index, lipid profile and atherogenic coefficient.

When analyzing survey following pathologic characteristics were observed: increased insulin resistance index up to 2.9, a BMI of 29 kg / m ^2, 83 cm waist circumference, triglycerides 2 mmol / l, high density lipoproteins (HDL) - 0.83 mmol / l, LDL density (LDL) - 3.89 mmol / L, very low density lipoproteins (VLDL) - 1.98 mmol / L, cholesterol - 6.1 mmol / L, atherogenic coefficient - 4.02, glycated hemoglobin 6.0%, increase the level of prothrombin by 10.1% against the background of a decrease in the concentration of antithrombin III and protein C compared to the reference values, an increase in the level of homocysteine - 21 μmol / l, fasting glucose 5.5 mmol / l, blood pressure: SBP 135 mm Hg. Art., DBP 85 mm Hg,

Diagnosis: PCOS. Metabolic syndrome.

Given the presence of PCOS in combination with metabolic syndrome, the patient was prescribed treatment according to the following scheme: inositol (myo-inositol 2000 mg and D-chiro-inositol 400 mg) 1 r / day, 2 sachets (total dose 2400 mg per day) for 6 months + sulodexide, 500 lipoprotein lipase units (2 capsules) per day for 6 months, followed by metabolic profile assessment.

After 6 months in the course of the treatment, it was noted: a decrease in the concentration of fibrinogen by 29.0%, an increase in thrombin time by 3 seconds, a decrease in the concentration of prothrombin by 10.1%, an increase in the level of natural anticoagulants - protein C + 5.8% and S +9 , 5%, a decrease in homocysteine levels to 10 μmol / L and a decrease in PAI-1 (plasminogen activator inhibitor -1), which indicates a beneficial effect on hemostatic parameters and a decrease in the concentration of markers of endothelial dysfunction. There was also a normalization of the insulin resistance index - 2.0, the atherogenic coefficient - 3.2, HDL - 1.07 mmol / L, LDL - 2.76 mmol / L, VLDL - 1.02 mmol / L, cholesterol - 4.9 mmol / l, glycated hemoglobin 5.6%, and a decrease in BMI to 26.2 kg / m ² , which characterizes the corrective effect on the metabolic profile. After 6 months, against the background of treatment, significant efficacy was noted in the form of a decrease in the severity of acne, restoration of the menstrual cycle, as well as a decrease in the volume of the ovaries to 5-6 cm3 according to ultrasound of the pelvic organs.

Clinical example 2.

Patient M., 32 years old, when contacting the obstetrician-gynecologist of the polyclinic, notes complaints of an irregular menstrual cycle for five years. She is not physically burdened, and does not take medications all the time. The patient is planning a pregnancy.

According to an objective examination, there are signs of hyperandrogenism in the form of hirsutism, when measuring BMI - 31.9 kg / m2. According to ultrasound of the pelvic organs (8 day of the cycle), there is an increase in the ovaries on both sides up to 12 cm ³ , in the right ovary there are 10 follicles up to 7 mm in size, in the left ovary there are 12 follicles up to 8 mm in size.

When analyzing survey following pathologic characteristics were observed: increased insulin resistance index up to 4.8, a BMI of 31.9 kg / m ^2, 95 cm waist circumference, triglycerides 2.5 mmol / l, high density lipoproteins (HDL) - 0.78 mmol / L, low density lipoproteins (LDL) - 3.77 mmol / L, very low density lipoproteins (VLDL) - 1.9 mmol / L, cholesterol - 7.3 mmol / L, atherogenic coefficient - 8.3, glycated hemoglobin 6, 0%, an increase in the level of prothrombin by 18.4% against the background of a decrease in the concentration of antithrombin III and protein C compared to the reference values, an increase in the level of homocysteine - 28 μmol / L, fasting glucose level 5.7 mmol / L, blood pressure level: SBP 135 mm Hg, DBP 85 mm Hg

Diagnosis: PCOS. Metabolic syndrome.

Given the presence of PCOS in combination with metabolic syndrome, the patient was prescribed treatment according to the following scheme: inositol (myo-inositol 3000 mg and D-chiro-inositol 600 mg) 1 r / day, 3 sachets (total dose 3600 mg per day) for 7 months + sulodexide, 750 lipoprotein lipase units (3 capsules) per day for 7 months, followed by metabolic profile assessment.

After 7 months, in the course of the treatment, there was a decrease in the concentration of fibrinogen by 21.0%, an increase in thrombin time by 2 seconds, a decrease in the concentration of prothrombin by 9.6%, an increase in the level of natural anticoagulants - protein C + 7.9% and S +10, 7%, a decrease in the level of homocysteine to 16 μmol / L, which indicates a favorable effect on hemostatic parameters and a decrease in the concentration of markers of endothelial dysfunction. There was also an improvement in indicators: insulin resistance index - 2.9, atherogenic coefficient - 3.69, HDL -1.07 mmol / L, LDL - 2.56 mmol / L, VLDL - 1.05 mmol / L, cholesterol -5, 1 mmol / L, glycated hemoglobin 5.6%, and a decrease in BMI to 28.2 kg / m ² , which characterizes the corrective effect on the metabolic profile. After 7 months, against the background of treatment, significant effectiveness was noted in the form of a decrease in the severity of acne, restoration of the menstrual cycle, as well as a decrease in the volume of the ovaries to 6-7 cm ³ according to ultrasound of the pelvic organs.

According to this scheme, we treated 25 patients aged 25 to 34 years with PCOS associated with metabolic syndrome. During treatment, normalization of the insulin resistance index, the atherogenic coefficient, the level of glycated hemoglobin and lipid profile indicators, a decrease in BMI, and restoration of the menstrual cycle were noted. In addition, a positive effect on the parameters of the hemostasis system and other markers of endothelial dysfunction was noted. There were no cardiovascular complications.

Thus, the proposed treatment algorithm is highly effective in treating PCOS of the second pathogenetic variant, reduces the risk of endothelial dysfunction, normalizes lipid and carbohydrate profiles, and prevents cardiometabolic complications in patients with PCOS and metabolic syndrome without the use of hormonal drugs.

The claimed invention will optimize treatment and prophylactic tactics in the practice of an obstetrician-gynecologist and improve the state of the hemostasis system and metabolic parameters in patients with PCOS.

Claims (1)

A method for the treatment of polycystic ovary syndrome associated with metabolic syndrome, including oral administration of myo-inositol at a dose of 2000-3000 mg and D-chiro-inositol at a dose of 400-600 mg per day in combination with oral administration of sulodexide at a dose of 500-750 lipoprotein lipase units a day for at least 6 months.