RU2536829C1 - Method for patient-specific prediction of oestrogen-dependent diseases in healthy females and females with cardiovascular risk factors aged 35-45 years - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine. The method implies measuring a waist circumference (WC), height and weight for calculating the body weight index (BWI), blood pressure (PB), and measuring glucose and lipids. If WC is more than 80 cm, while BWI is more than 25 kg/m², a mild hypocaloric diet is used, which is limiting the caloric content of the dietary intake by 500-600 kcal a day with the daily dietary intake being drawn up taking into account as follows: total fat consumption of less than 30% of the total caloric content; carbohydrates - up to 50%; the protein content in the food intake - 15-20%; dietary fibre - 20-30 mg; fresh fruit and vegetables - 400-500 g; nuts, cereals and beans - 30 g; table salt - less than 5 g; calcium 1,200 mg a day; vitamin D - 800 international units, polysaturated fatty acids 0.5-1.0 g, folic acid 400 mcg, vitamin C 60 mcg, vitamin E 30 units; physical load - not less than 40 min a day and at least 5 days a week; alternating aerobic and anaerobic exercises. Additionally, if BWI falls within the range of 25 to 29.9 kg/m² with normal glucose, lipids and blood pressure, combined oral contraceptives (COC) containing natural oestrogen and dienogest, or COC containing drospiredone are used. If BWI is more than 30 kg/m², with normal glucose, blood pressure and lipid, pure progestin oral contraceptives (PPOC) are taken. If observing BWI of 25 kg/m² and more, fasting hyperglycaemia and/or impaired glucose tolerance, and normal blood pressure and lipids, the PPOC are prescribed. BWI of 25 to 29.9 kg/m², as well as dyslipidemia and normal glucose and lipids, the combined oral contraceptives (COC) containing natural oestrogen and dienogest are prescribed. If observing BWI of 30 kg/m² and more, dyslipidemia and normal glucose and lipids, the PPOC are prescribed.

EFFECT: method enables the patient-specific prevention of the oestrogen-dependent diseases.

10 cl, 2 tbl, 1 ex

Description

The invention relates to the field of medicine.

In the XXI century, it became known that women are not inferior to men in mortality from cardiovascular diseases. Coronary heart disease (CHD) is leading in female mortality (24%), which is significantly more dangerous than breast cancer, which has always been considered the “killer of women” (3%). However, this is underestimated both by the female population itself and by doctors and is due to the fact that in women, cardiovascular diseases occur 10-12 years later than in men. The risk increases with the onset of menopause due to estrogen deficiency, which leads to the development of arterial hypertension (AH), diabetes mellitus (DM), hyperlipidemia, central obesity and metabolic syndrome (MS).

Long before the onset of menopause, cardiovascular diseases (CVD) can occur in women who have both traditional (obesity, smoking, MS, AH) and specific, gender-related cardiovascular risk factors (history of preeclampsia, fetal growth retardation, diabetes of pregnant women , AH of pregnant women, polycystic ovary syndrome, miscarriage, hypoestrogenemia of hypothalamic origin, artificial termination of pregnancy.

The development of MS, AH and metabolic disorders in women with tender RF is based on a decrease in the secretion of progesterone, which is an endogenous inhibitor of receptors for mineralocorticoids, and an increase in the secretion of estradiol, a stimulant of the activity of the renin-angiotensin-aldosterone system (RAAS). The increase as a result of this activation of RAAS leads to an increase in blood pressure, an increase in visceral fat volume, impaired metabolism of carbohydrates, lipids, and the development of insulin resistance. In addition, progesterone blocks the differentiation of visceral fat adipocytes and regulates the activity of receptors responsible for insulin sensitivity. Violation of these mechanisms while reducing progesterone secretion is another mechanism for the development of MS, hypertension and their cardiovascular complications.

The secretion of estrogen in healthy women begins to gradually decline already from the age of 35, which contributes to an increased risk of diseases caused by their deficiency.

With a woman who has reached the age of 35, doctors - a cardiologist and gynecologist - should discuss the need to develop a “health program” aimed at preserving it later. It is necessary to conduct a basic survey to assess the health status, identify risk factors and needs of a particular woman in order to prepare for the future in time and to avoid or significantly reduce the risk of socially significant diseases during perimenopause, when risks increase due to estrogen deficiency.

According to the results of the examination, a woman can:

1. be healthy;

2. be healthy, but have risk factors (traditional or gender).

Basic survey methods for assessing overall health

The examination should be carried out annually and include a general clinical examination, minimal laboratory tests, gynecological examination.

The main examination methods include collecting a personal and family history, a full physical and gynecological examination, weight measurement, calculating body mass index (BMI), determining the waist circumference (OT) as an indicator of the abdominal or visceral type of obesity, basic laboratory tests, namely the determination of ESR, hemoglobin level, general blood count and lipid profile. In addition, you should get information about family life, work and social environment, evaluate lifestyle, habits and risk factors, as well as sexual activity. The need to use additional research methods is determined by history, the presence of risk factors or identified violations.

Between 35 and 45 years old, a basic mammogram should be obtained for each woman, an x-ray of the lungs should be taken, in addition, it is desirable to determine the bone mineral density (BMD) and make an electrocardiogram if indicated.

At the age of 40, additional tests include serum glucose and liver / kidney tests. The exact age after which these studies should begin to be carried out regularly, and their frequency should be determined by history and risk factors identified in each patient.

Basic gynecological examination: sexually transmitted diseases and the state of microflora, cytological examination of scrapings of the cervix and cervical canal, ultrasound examination of the pelvic organs, mammography, biochemical blood test, coagulogram, blood lipids, gynecologist consultation.

If a woman has gender risk factors (RF), an additional examination and observation by a gynecologist is necessary.

Additional gynecological examination: sex hormones (according to the days of the cycle), assessment of the follicular reserve (muller hormone), blood androgens, thyrethropic hormone (TSH), free tyrone (T4), triiodothyronine (T3), T4, seeding on mycoplasma and uroplasma of the separated vagina bacteriological culture of the discharge, densitometry, endometrial biopsy (aspiration), assessment of ovulation and luteal phase of the menstrual cycle (tests, progesterone, ultrasound (ultrasound), basal temperature), colposcopy.

If the woman visited the gynecologist as the first doctor, he should interview, examine the woman, determine weight, BMI, and OT, send him to a biochemical blood test and measure the level of blood pressure (BP). If traditional RFs such as obesity, hypertension, dyslipidemia and hyperglycemia (including women with gender-related RFs) are identified, the gynecologist should refer the woman to a general practitioner / cardiologist for examination and observation.

The woman is healthy.

Doctors therapist / cardiologist and gynecologist should recommend to the woman an annual basic examination, a healthy lifestyle (proper nutrition, sufficient physical activity), reliable contraception.

Features of nutrition for women over the age of 35: total fat intake of less than 30% of the total number of calories (20% of vegetable and up to 10% of animal origin); carbohydrates - up to 50%; especially carefully count patients with impaired carbohydrate metabolism); the protein content in the diet is 15-20%; dietary fiber - 20-30 mg; raw fruits and vegetables - 400-500 g; nuts, grains, legumes - 30 g; table salt - <5 g; 1200 mg of calcium per day; Vitamin D - 800 ME.

Polysaturated fatty acids should be present in a woman’s food after 35 years.

- The daily intake of 0.5-1.0 g of omega-3 PUFA in oily sea fish or purified fish oil reduces the risk of death from CVD in middle-aged people by 30-40%.

- In women, taking PUFA reduces the risk of coronary heart disease and thrombotic stroke.

- The source of PUFAs of the omega-6 class (linoleic acid) are vegetable oils (sunflower, corn, etc.).

- The source of omega-3-class PUFAs is oily sea fish (mackerel, sardines, Iwashi herring, halibut, etc.).

- PUFAs of the omega-3 family (α-linoleic acid) contain some vegetable oils: linseed, rapeseed, mustard, sesame, walnut, etc.).

Some vitamins, minerals (selenium) and minor components (flavonoids) contained in plant foods have powerful antioxidant properties. Vitamin C reduces the incidence of coronary heart disease and strokes, as well as cancer. Vitamin E reduces the risk of non-fatal heart attacks. Vitamin A is essential for healthy skin and mucous membranes. Vitamin D has an antiproliferative property. Vitamin D stimulates the absorption of calcium, which in turn slows the loss of bone mineral density (BMD) and reduces the risk of fractures.

The daily norm of vitamins in women after 35 years: folic acid - 400 mcg, vitamin C - 60 mcg, vitamin E - 30 units.

Physical activity in women after 35 years.

Physical activity significantly reduces the risk of coronary heart disease, hypertension, type 2 diabetes, dyslipidemia, osteoporosis, breast cancer and colon cancer, obesity and related mortality.

With age, it is necessary to adjust physical activity.

Physical activity should be coordinated with the attending physician.

Aerobic exercises (in the open air - walking and swimming) improve carbohydrate metabolism and lipid profile, reduce blood pressure and the rate of bone loss (walking only).

Anaerobic exercises (strength - lifting weights) contribute to the preservation and increase in bone mineral density due to the formation of flexibility, strength and strength.

Recommended physical exercises should be alternated and balanced, taking into account the individual characteristics of the woman, the state of the cardiovascular system and muscle strength.

Adequate calcium intake enhances the effects of exercise.

Contraception

Specific issues for women aged 35 to 45 are contraception and family planning. During this period, the number of fertile cycles may remain unchanged. With a menstrual cycle lasting from 21 to 35 days, as a rule, up to 95% of all cycles are fertile. An ideal method of preventing pregnancy should not only be reliable, but also counteract the appearance of vaginal dryness, which may first appear during this period. It is advisable that the chosen method of contraception prevent the development of osteoporosis and CVD, reduce insulin resistance, as well as the risk of developing ovarian and endometrial cancer. The choice of contraceptive method, if necessary, also depends on the individual preferences of the woman, price and availability.

In women with a regular menstrual cycle and in violation of it, oral hormones are preferred.

In the case of amenorrhea, additional studies of the state of endocrine function (follicle-stimulating hormone - FSH, prolactin) should be carried out. However, manifestations of endocrine dysfunction can appear long before the complete cessation of menstruation. The doctor should remember that symptoms such as irregular menstruation or dysfunctional uterine bleeding, hot flashes, sleep disturbances, psychological or cognitive changes, and premenstrual syndrome may be due to hormonal changes in the body. In such cases, hormone therapy is recommended, despite the presence of menstruation.

After 35 years, the secretion of estrogen gradually decreases and, thus, the risks of developing MS, AH and CVD increase. In this regard, it is necessary to choose a combined oral contraceptive (COC) containing natural estrogen that minimizes the risk of thrombosis and has a protective effect on the cardiovascular system and metabolically neutral progestin, it is also advisable to prescribe COC, which includes drospirenone, which has positive metabolic effects, ability to optimize blood pressure.

Warning: when choosing a contraceptive, it is necessary to be guided by the criteria for the acceptability of contraception, non-observance of which can lead to fatal complications and discredit a good treatment method.

When choosing a contraception, a cardiologist / therapist may recommend one or another method of contraception, taking into account the impact on risk factors and the cardiovascular system, but the final decision is made by the gynecologist after a special gynecological examination.

A woman is healthy but has risk factors

1. When RT is more than 80 cm and BMI from 25 to 29, 9 kg / m ² , the level of lipids, glucose and blood pressure, the corresponding norm:

- non-drug treatment of obesity - lifestyle recommendations for women over 35 years of age, moderately hypocaloric diet - limiting calorie intake by 500-600 kcal per day, limiting fat intake to 30%: 10% animal and 20% vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg of calcium per day, increased physical activity, at least 40 minutes per day and at least 5 times a week;

- choice of contraception - COC containing natural estrogen and dienogest, or COC containing drospirenone.

2. When RT is more than 80 cm and BMI from 30 kg / m ² and above, the level of glucose, lipids and blood pressure, corresponding to the norm:

- non-drug treatment of obesity - lifestyle recommendations for women over 35 years of age, moderately hypocaloric diet, restriction of fat intake to 30%: 10% of animal and 20% of vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg calcium per day, increased physical activity, at least 40 minutes per day and at least 5 times a week;

- drug treatment of obesity - an inhibitor of gastrointestinal lipases for the period necessary to reduce body weight;

- the choice of optimal contraception - purely progestin-based oral contraceptives (CPPO). After a decrease in body weight of less than 30 kg / m ^2, it is possible to prescribe COC with drospirenone.

According to the National Criteria for the Acceptability of Contraception, a BMI above 30 kg / m ² and abdominal obesity increases the risk of thrombosis when taking COCs. POPCs that do not contain estradiol are free from the side effects of COCs.

3. When RT is more than 80 cm and a BMI of 25 to 29.9 kg / m ² and fasting hyperglycemia (fasting plasma glucose ≥6.1 mmol / L), the level of lipids and blood pressure corresponding to the norm:

- non-drug treatment of obesity - lifestyle recommendations for women over 35 years of age, moderately hypocaloric diet, restriction of fat intake to 30%: 10% of animal and 20% of vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg of calcium per day, increased physical activity, at least 40 minutes per day and at least 5 times a week;

- biguanides to reduce fasting hyperglycemia,

- choice of contraception - ChPOK. After a 10% decrease in body weight and normalization of blood glucose values, it is possible to prescribe COCs containing natural estrogen and dienogest, or COCs containing drospirenone.

4. When RT is more than 80 cm and BMI is higher than 30 kg / m ² and fasting hyperglycemia (fasting plasma glucose ≥6.1 mmol / L), the level of lipids and blood pressure corresponding to the norm:

- lifestyle recommendations tailored to women over 35 years of age, moderately hypocaloric diet, restriction of fat intake to 30%: 10% of animal and 20% of vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg of calcium per day, increase in physical activity, at least 40 minutes per day and at least 5 times a week,

- medication for obesity - inhibitors of gastrointestinal lipases,

- treatment of fasting hyperglycemia - biguanides,

- choice of contraception - ChPOK. COCs are contraindicated. It is possible to prescribe COCs with drospirenone after reaching a BMI of less than 30 kg / m ² and normalizing glucose levels.

5. When RT is more than 80 cm and BMI from 25 to 29.9 kg / m ² and impaired glucose tolerance (NTG) (plasma glucose 2 hours after glucose loading in the range of ≥7.8 and _ <11.1 mmol / l), normal lipid and blood pressure:

- lifestyle recommendations tailored to women over 35 years of age: moderately hypocaloric diet, restriction of fat intake to 30%: 10% animal and 20% vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg of calcium per day, increase in physical activity, at least 40 minutes per day and at least 5 times a week;

- the appointment of an alpha glucosidase inhibitor;

- choice of contraception - ChPOK.

6. When RT is more than 80 cm and BMI is higher than 30 kg / m ² and NTG (plasma glucose 2 hours after glucose loading in the range of ≥7.8 and ≤11.1 mmol / l), with normal lipid and blood pressure :

- lifestyle recommendations tailored to women over 35 years of age: moderately hypocaloric diet, restriction of fat intake to 30%: 10% of animal and 20% of vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg of calcium per day, increase in physical activity, at least 40 minutes per day and at least 5 times a week;

- non-drug treatment of obesity - inhibitors of gastrointestinal lipases;

- for the treatment of NTG, an alpha glucosidase inhibitor;

- choice of contraception - ChPOK.

7. When RT is more than 80 cm and BMI from 25 to 29.9 kg / m ² and dyslipidemia (increase in triglycerides (TG) ≥1.7 mmol / l, decrease in high-density lipoprotein cholesterol (HDL cholesterol) <1.2 mmol / L in women, an increase in the level of low-density lipoprotein cholesterol (LDL cholesterol)> 3.0 mmol / L, an increase in total cholesterol (GC) ≥5.5 mmol / L), normal glucose and blood pressure:

- lifestyle recommendations tailored to women over 35 years of age: moderately hypocaloric diet, restriction of fat intake to 30%: 10% of animal and 20% of vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg of calcium per day, increase in physical activity, at least 40 minutes per day and at least 5 times a week;

- choice of contraception - COCs containing natural estradiol and dienogest;

8. When RT is more than 80 cm and BMI is higher than 30 kg / m ² and dyslipidemia (TG ≥1.7 mmol / L, HDL cholesterol <1.2 mmol / L in women, LDL cholesterol> 3.0 mmol / L, OXS ≥5.5 mmol / L) and normal glucose and blood pressure:

- lifestyle recommendations, taking into account the characteristics for women over 35 years old, moderately hypocaloric diet, restriction of fat intake to 30%: 10% of animal and 20% of vegetable origin, the proportion of carbohydrates in the daily diet should be 50%, 1200 mg of calcium per day , increased physical activity, at least 40 minutes per day and at least 5 times a week;

- medication for obesity - inhibitors of gastrointestinal lipases;

- choice of contraception - ChPOK.

9. Metabolic syndrome: OT more than 80 cm in women and 2 of the additional criteria. Additional criteria: arterial hypertension (blood pressure ≥140 / 90 mm Hg), increased triglycerides (≥1.7 mmol / L), decreased HDL cholesterol (<1.2 mmol / L in women), increased cholesterol LDL> 3.0 mmol / L, fasting hyperglycemia (fasting plasma glucose ≥6.1 mmol / L), impaired glucose tolerance (plasma glucose 2 hours after glucose loading within ≥7.8 and ≤11 , 1 mmol / l).

Additional examination methods for differential diagnosis of visceral type of obesity

The abdominal type of obesity, hypertension and metabolic disorders of carbohydrates and fats, characteristic of MS, are also observed in the disease and Itsenko-Cushing's syndrome. Even the appearance of patients with MS and Itsenko-Cushing's disease is often identical, which requires a differential diagnosis with this disease.

To conduct differential diagnosis with a particular endocrine disease occurring with symptoms similar to MS, it is necessary to use additional research methods.

Computed tomography (CT) of the adrenal gland allows you to establish or exclude the primary pathology of the adrenal glands.

CT or nuclear magnetic resonance imaging (NMR) of the pituitary gland allows you to judge its functional-structural state and establish the presence or absence of micro- or macroadenomas of the pituitary gland.

Itsenko-Cushing's disease is characterized by the presence of a pituitary tumor and bilateral adrenal hyperplasia. Itsenko-Cushing's syndrome can be caused by a unilateral lesion of the adrenal gland (corticosteroma, adenocarcinoma of the adrenal cortex).

Hormonal research methods can provide additional assistance in differential diagnosis. For this purpose, the blood levels of cortisol, aldosterone, adrenocorticotropic hormone (ACTH), prolactin, thyroid stimulating hormone (TSH), etc. are determined.

Patients with MS may also experience a slight increase in the levels of cortisol, prolactin, TSH, and ACTH, but with primary endocrine pathology, the excess of the concentration of these hormones will be tens or hundreds of times higher than normal values.

If there is a suspicion of the presence of aldosteroma, the determination of the content of aldosterone and renin will assist in the differential diagnosis.

The detection of pheochromocytoma will be promoted, along with CT of the adrenal glands and the paraaortic region, the study of catecholamines in the blood and urine and vanillyl mindic acid (IUD) in the urine, especially in the period after a hypertensive crisis.

It is not often possible to identify the organic cause of obesity, only in 1 out of 1000 patients can a disease be found that leads to an increase in body weight. However, a thorough examination of patients to identify a possible cause of obesity is necessary, as this greatly affects the treatment tactics.

- With a BMI of 25 to 27 kg / m ² , non-drug treatment of obesity is recommended (moderately hypocaloric diet, 1200 mg of calcium per day and increased physical activity);

10. With a BMI of more than 27 kg / m ² , medication for obesity (an inhibitor of gastrointestinal lipases) is indicated;

- an increase in fasting blood glucose is an indication for the appointment of biguanides;

- with NTG, an alpha-glucosidase inhibitor must be prescribed.

Hypolipidemic therapy is ineffective in women for the prevention of CVD in MS. And effective only in the presence of type 2 diabetes and severe atherosclerosis with coronary artery disease. Thus, her appointment to women with MS is ineffective.

Acetylsalicylic acid is also ineffective in women under 65 years of age for the prevention of CVD and its purpose is inappropriate for women of this age group.

11. As a prevention of CVD, it is advisable for women, in addition to the preventive measures indicated in paragraphs 1-10, to prescribe a meldonium metabolism corrector that can reduce atherogenic dyslipidemia, improve carbohydrate metabolism, both fasting and postprandial glycemia, reduce the ability to thrombus formation, and potentiate the effectiveness of antihypertensive therapy.

12. Drug treatment of hypertension - it is necessary to remember that a woman planning a pregnancy is contraindicated in the use of angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin-2 receptor antagonists (ARA), since they cause fetal malformations. For this age group of women, the drugs of choice will be imidazoline receptor agonists, non-dihydropyridine slow calcium channel blockers, highly selective beta-blockers.

For women who do not plan to have children anymore, ACEI / ARA are the drugs of choice, if necessary, a thiazide-like diuretic - indapamide can be added to the combination, if it is necessary to reduce the increased activation of the SNA, it is advisable to prescribe a highly selective beta-blocker with vasodilating properties - nebivolol.

13. Contraception - ChPOK. COC - contraindicated.

14. Women who smoke should be advised to abandon this bad habit, since smoking not only increases the risks of socially significant diseases, but also leads to premature menopause, severe menopause. In addition, smoking is a contraindication for taking COCs, due to an increased risk of vascular thrombosis.

An example of the effectiveness of biguanides in the treatment of patients with MS.

The main mechanisms of action of biguanides are the ability to reduce gluconeogenesis and reduce glucose production by the liver, inhibit the absorption of glucose in the small intestine, reduce insulin resistance (IR) and improve insulin secretion.

One of the important properties of metformin is its ability to reduce IR, which may be due to an increase in the transmission of insulin signal to the cell. Metformin causes an increase in the activity of tyrosine kinase, glycogen synthetase, stimulates the synthesis of phosphatidylinositol-3-kinase, enzymes responsible for translocation of glucose transporters. Metformin is able to increase glucose utilization. It is assumed that metformin at the postreceptor level, along with potentiation of the action of insulin, can have a direct effect on the enzyme systems involved in glucose metabolism.

Another important mechanism of action of metformin is the suppression of gluconeogenesis in the liver, which leads to a decrease in glucose production in the liver. This may be due to the suppression of the main enzymes of gluconeogenesis, an increase in the sensitivity of hepatocytes to insulin and the suppression of lipolysis in visceral adipose tissue, which leads to a decrease in the intake of free fatty acids (FFA) in the liver. A decrease in IR in hepatocytes under the influence of metformin leads to an increase in the action of insulin on glycogen metabolism enzymes - phosphorylase and glycogen synthetase, which in turn causes a decrease in glycogenolysis and an increase in glycogen synthesis in the liver. These basic mechanisms of action of metformin lead to a decrease in fasting glucose and an increase in tissue sensitivity to insulin.

The peripheral effect of metformin is manifested at the level of the small intestine, where it slows down the absorption of glucose and enhances the processes of anaerobic glycolysis, which contributes to the utilization of glucose in the intestinal wall. The peripheral mechanism of action of metformin provides a smooth hypoglycemic effect and the absence of postprandial peaks of hyperglycemia. Metformin does not affect the secretion of insulin, which is due to the absence of hypoglycemic episodes. This applies not only to patients with diabetes, but also to patients with normoglycemia.

The aim of the study was to study the effect of monotherapy with biguanide-metformin on indicators of carbohydrate, lipid metabolism, vasoactive mediators and the daily profile of blood pressure in patients with MS.

The study involved 15 middle-aged women 47.2 ± 4.69 years. The AG age was 2.3 ± 1.7 years. Clinical GARDEN and DBP equaled - 153.2 ± 1.3 mm Hg. and 94.5 ± 0.8 mm Hg respectively. The average weight was 108.08 ± 18.75 kg and BMI 38.2 ± 6.38 kg / m ² , OT - 113.5 ± 1.4 cm, OT / OB - 0.97 ± 0.04. The fasting glucose level was 5.97 ± 0.47 mmol / L and glycated hemoglobin was 5.82 ± 0.61%. Patients took metformin at a dose of 500 mg twice a day for 12 weeks. Patients did not take antihypertensive therapy throughout the study.

Before the start of the study and after 12 weeks, a complete medical history was collected from the patients, a physical examination and anthropometric examination were carried out: measuring height, body weight, waist and hips. The nature of the distribution of adipose tissue was evaluated by the OT / OB ratio. BMI was calculated using the Ketle formula. A BMI of less than 25 kg / (m) ² was considered an indicator of normal body weight, and a BMI of more than 30 kg / (m) ² was a criterion for the diagnosis of obesity, intermediate values were considered as an indicator of excess body weight. A biochemical blood test was performed (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose), an oral glucose tolerance test, blood pressure measurement using the Korotkov clinical method and 24-hour blood pressure monitoring (BPM).

results

On the background of metformin treatment, fasting plasma glucose levels decreased from 5.97 ± 0.47 mmol / L to 5.59 ± 0.58 mmol / L after 12 weeks. The postprandial glucose level decreased significantly from 8.46 ± 1.49 mmol / L to 7.87 ± 1.73 mmol / L (p <0.05). The use of metformin led to an improvement in lipid metabolism, the level of total cholesterol significantly decreased from 5.54 ± 0.59 mmol / l to 5.22 ± 0.74 mmol / l (p <0.05) and LDL cholesterol from 3.56 ± 0.69 mmol / L to 3.18 ± 0.69 mmol / L (p <0.05); HDL-C and TG cholesterol did not significantly change. Before treatment with metformin, the level of TG was 1.93 ± 0.91 mmol / L and after treatment, 2.06 ± 1.16 mmol / L. The level of HPSLP before treatment did not go beyond the normal range did not significantly change during treatment with metformin, amounting to 1.68 ± 0.86 mmol / L and 1.29 ± 0.94 mmol / L, respectively.

On the background of metformin therapy, after 12 weeks, all patients showed a decrease in body weight of an average of 6 kg. The average body weight decreased from 108.08 kg to ± 18.75 102.5 ± 17.3 kg (p <0.05) and BMI from 38.2 ± 6.38 kg / m ² to 36,35 ± 5 96 kg / m ² (p <0.05).

The results of manual office blood pressure measurement showed achievement of the target blood pressure level (less than 140/90 mmHg) in all patients taking metformin.

According to the results of SM BP against the background of metformin monotherapy as a whole, a trend was found in the group to decrease blood pressure values in the daytime. So, the GARDEN decreased from 140 ± 12 mm Hg. up to 132 ± 10 mmHg (p <0.05). DBP and mean blood pressure also decreased from 84 ± 11 mm Hg. up to 81 ± 9 mmHg and with 103 ± 11 mmHg up to 98 ± 8 mmHg accordingly, but unreliable. In addition, there was a tendency to a decrease in the pressure load parameters of SBP, DBP and average blood pressure: IV SBP decreased from 50.0 ± 20.5% to 22.3 ± 15%, PI SBP - from 161 ± 23 mm Hg . up to 51 ± 17 mm Hg; IV DBP - from 37 ± 2% to 15 ± 0.56%, IP DBP - from 58 ± 5 mm Hg up to 15 ± 4 mm Hg; IW of average blood pressure - from 40 ± 8% to 20 ± 6%, PI of average blood pressure - from 94 ± 12 mm Hg up to 18 ± 5 mm Hg

At night, the BPMS did not change significantly. The daily index indicators decreased slightly, but unreliably. So, SI SBP decreased from 9 ± 3% to 5 ± 3% (p> 0.05), SI DBP - from 14 ± 7% to 11.5 ± 6% (p> 0.05), and SI average BP - from 12.8 ± 6% to 8 ± 5% (p> 0.05).

On the background of metformin monotherapy, there was a significant decrease in the level of the thromboxane vasoconstrictor (from 352 ± 171 pg / ml to 163 ± 112 pg / ml (p> 0.01) and an increase in the level of the nitric oxide vasodilator (from 26.5 ± 22.6 μM / L up to 37.8 ± 25 μM / L (p> 0.01).

Thus, a positive effect of metformin therapy on endothelial function in MS patients was noted in the form of an increase in the level of a vasodilator - nitric oxide metabolite (NO ₃ ) and a decrease in the level of the vasoconstrictor thromboxane B ₂ .

Initially, 13 patients showed elevated leptin levels.

On the background of metformin monotherapy, there was a slight decrease in leptin levels in patients of this group. So, before treatment, the serum leptin content was 29.06 ± 21.01 ng / ml, and after treatment - 25.51 ± 19.20 ng / ml (p> 0.05).

As a result of metformin therapy, body weight in all patients significantly decreased over the course of 12 weeks by an average of 5.5%, which in itself significantly reduces the degree of cardiovascular risk, as proved by the results of large multicenter studies.

In 11 patients with metformin therapy, basal and postprandial glucose levels became consistent with normal glucose tolerance. Significantly improved overall cholesterol and LDL cholesterol.

An example of the effectiveness of an alpha glucosidase inhibitor - acarbose in the treatment of patients with MS and NTG

One of the safest drugs that affect postprandial glucose and insulin resistance (IR) is acarbose, a member of the alpha glucosidase inhibitor class.

The mechanism of action of acarbose is a reversible block of alpha-glucosidases (glucoamylase, sucrase, maltase) in the upper part of the small intestine. This leads to a violation of the enzymatic breakdown of poly- and oligosaccharides and the absorption of monosaccharides, which prevents the development of postprandial hyperglycemia and decreases insulin levels.

The aim of the study was to evaluate the efficacy of an acarbose α-glucosidase inhibitor at doses of 150 mg / day and 300 mg / day and non-pharmacological measures to change lifestyle and nutrition stereotypes during hypertension, carbohydrate and lipid metabolism and body weight in patients with impaired tolerance to glucose and arterial hypertension.

Dosage and method of use of the drug: patients randomized to the active treatment group (taking acarbose) took the drug 50 mg 1 time per day before meals (during dinner) for 2 weeks, starting from 3 weeks - 50 mg 2 times ( breakfast and dinner), 4 weeks - 50 mg 3 times a day before meals until the end of the program. For patients randomized to receive 300 mg of acarbose, its dose from the 5th week increased to 300 mg per day (100 mg 3 times a day) until the end of the study with good tolerability of treatment.

Statistical processing: in this work, we compared groups of patients (organized by different grouping criteria) using statistical nonparametric criteria that did not depend on the nature of the distribution - Fisher's exact method and chi-square criterion (the t-student test traditionally used in biomedical studies was also parallel for normally distributed variables).

Research results

The study involved only 380 people, 245 women (64%) and 135 men (36%), whose average age was 48 ± 6.8 years. The control group included 132 people, the group receiving acarbose in a dose of 150 mg - 132 people and in a dose of 300 mg - 116 people.

All patients according to inclusion criteria had overweight or obesity and mild or moderate form of hypertension. BMI averaged 33.76 ± 0.17 kg / m ² . In the vast majority of cases, abdominal type of obesity was determined in patients, the waist circumference (OT) averaged 106.9 ± 11.3 cm.

As a result of the treatment, the body weight and abdominal obesity indices significantly decreased in all three groups of patients, while in the active treatment groups these indices decreased significantly more than in the control group. The body weight of individuals taking acarbose both 150 and 300 mg per day decreased by 2 times compared with persons in the control group, to which only non-pharmacological measures were used. OT also significantly decreased.

On the background of acarbose therapy at doses of 150 and 300 mg per day, the fasting blood glucose level significantly decreased (Δ = -0.2 ± 0.01 mmol / L, Δ = -0.6 ± 0.03 mmol / L, p < 0.5, respectively) and more pronounced 2 hours after glucose loading (Δ = -1.7 ± 0.6 mmol / L, p <0.05 and Δ = -1.8 ± 0.4 mmol / L, p <0.05, respectively). There was no significant difference between these groups, as well as between them and the control group (Δ = -0.6 ± 0.03 mmol / L, p <0.5 and Δ = -2.0 ± 1.3 mmol / L, p <0.05, respectively).

The level of total cholesterol decreased significantly and equally in all studied groups (acarbose group 150 mg - Δ = -0.4 ± 0.03 mmol / l, p <0.05, acarbose group 300 mg - Δ = -0.5 ± 0 , 02 mmol / L, p <0.05 and the control group - Δ = -0.4 ± 0.05 mmol / L, p <0.05).

A significant decrease in the level of triglycerides and low-density lipoprotein cholesterol (LDL cholesterol) was observed only in the group of people who took 300 mg of acarbose per day (Δ = -0.5 ± 0.01 mmol / L, p <0.05, Δ = -0 , 5 ± 0.02 mmol / L, p <0.05, respectively), in contrast to those taking 150 mg and the control group.

A significant increase in high-density lipoprotein cholesterol (HDL cholesterol) was observed only in the group of patients taking 150 mg of acarbose per day (Δ = -0.2 ± 0.01 mmol / L, p <0.05).

In groups of patients taking acarbose 150 and 300 mg per day, the level of SBP and DBP decreased significantly lower compared with the control group: SBP (Δ = -14.2 ± 1.6 mm Hg, p <0.05, Δ = -12.3 ± 0.6 mm Hg, p <0.05, Δ = -7.3 ± 1.1 mm Hg, p <0.05, respectively, the significance of the difference between the groups is p <0.05), DBP (Δ = -8.4 ± 0.3 mm Hg, p <0.05 and Δ = -7.8 ± 0.5 mm Hg, p <0 , 05, Δ = -6 ± 1.3 mm Hg, respectively, the significance of the difference between the groups is p <0.05).

The overwhelming majority of patients taking acarbose reached the target fasting glucose and after exercise, unlike the control group. Moreover, the number of patients who reached the target glucose levels was almost equal in both groups of patients, both taking 150 mg and 300 mg of acarbose.

More than 80% of patients in each of the groups taking acarbose achieved the target level of SBP and DBP, in contrast to the control group, in which a significantly smaller number of patients reached the target level of blood pressure.

An example of the effectiveness of COCs containing natural estrogen and dienogest.

58 women aged 35-45 years for 12 months, according to the prescription of a gynecologist, took the studied COC containing estradiolvalerate and dienogest.

Against the background of one year of using COCs, the average score of symptoms of depression in women decreased from 12 ± 1.1 to 9 ± 0.7 (by 41.7%) (p <0.05), and anxiety from 7 ± 0.8 to 5 ± 0.4 (by 44.6%) (p <0.05). After a year of using COCs, the patients' answers to questions on the quality of life scale underwent certain changes that characterize the studied drug on the positive side. Thus, the physical stamina of patients increased by 11.3% (p> 0.05), psychological resistance in working and home settings by 14.8% (p> 0.05), and communication difficulties decreased by 19.1% with colleagues and relatives (p <0.05).

Table 1 The dynamics of the quality of life of women with the use of COCs (M ± m) Criterion (points) Before therapy After therapy General health (1 to 5, where 5 is the worst) 2.6 ± 0.3 2.2 ± 0.4 Restriction of physical activity (from 1 to 3, where 3 - no restrictions) 2.35 ± 0.1 2.65 ± 0.1 Heavy (running, weight lifting) 2.2 ± 0.1 2.5 ± 0.1 Moderate (home cleaning) 2.4 ± 0.1 2.6 ± 0.1 Lungs (walking, lifting bags) 2.5 ± 0.1 2.8 ± 0.1 Difficulties in work due to the physical component (from 1 to 3, where 3 - no difficulties) 2.5 ± 0.1 2.8 ± 0.1 Difficulties in work due to the emotional component (from 1 to 3, where 3 is no difficulty) 2.3 ± 0.1 2.7 ± 0.1 Disorders in family life due to the physical component (from 1 to 5, where 5 are the most severe violations) 2.4 ± 0.1 1.9 ± 0.1 Disorders in family life due to the emotional component (from 1 to 5, where 5 are the most severe disorders) 3.1 ± 0.3 2.6 ± 0.3 Difficulties in communication at work (from 1 to 5, where 5 are the strongest difficulties) 2.1 ± 0.3 * 1.7 ± 0.2 * * corresponds to p <0.05

During the year of taking COCs, the concentration of total cholesterol (CHC) decreased by 2.7% (p> 0.05), low density lipoproteins (LDL) and triglycerides (TG) - by 11.5% (p> 0.05, respectively) ) and 18.2% (p> 0.05).

During the intake of COCs, the level of glycemia decreased by 7.3% (p> 0.05). Moreover, the dynamics of the QUICKY index exacerbated insulin resistance was not observed.

The year of taking COCs slowed the growth of excess body weight. So, BMI decreased from 31.2 ± 1.3 to 29.6 ± 1.9, which amounted to 10% (p> 0.05).

As was revealed during the survey, the most common fear of women taking any hormonal COCs (58.8%) is the risk of thrombotic complications. According to our data, the use of COCs does not cause hypercoagulation, on the contrary, it contributes to an extension of the activated partial thromboplastin time by 5.9% (p> 0.05), a decrease in fibrinogen concentration by 3.9% (p> 0.05), and an increase in MHO by 9.8% (p> 0.05).

During the observation period, an average hemoglobin level increased by 5.7% (p> 0.05), ferritin concentration by 17.7% (p <0.05), and serum concentration by 14.1% (p <0.05) gland. In addition, after a year of using the studied contraceptive, the level of transferrin decreased by 6.5% (p> 0.05), which reflects the positive role of the estrogen component that is part of the studied COC in the regulation of iron metabolism.

As can be seen from the summary table.2, against the background of the use of COCs, the level of systolic and diastolic blood pressure (p> 0.05), carbohydrate (p> 0.05), lipid (p> 0.05) and water-electrolyte metabolism (p> 0.05), BMI (p> 0.05), indicators of the coagulogram (p> 0.05) and iron metabolism (p> 0.05) did not change. In addition, against the background of its use, in none of the patients pregnancy occurred.

table 2 The dynamics of clinical and laboratory parameters during therapy (M ± m) Indicator Before therapy After therapy BMI, kg / m ² 28.7 ± 1.3 25.8 ± 1.9 QUICKY Index, points 0.365 ± 0.012 0.371 ± 0.011 Systolic blood pressure, mmHg 128 ± 3 127 ± 2 Diastolic blood pressure, mmHg 78 ± 1 79 ± 2 APTT, sec 32 ± 1.8 34 ± 1.4 Fibrinogen, g / l 2.5 ± 0.2 2.4 ± 0.2 Mho 0.9 ± 0.05 1.0 ± 0.05 Hemoglobin, g / l 116.4 ± 2.7 123.3 ± 1.9 Whey, μmol / L 21.4 ± 0.8 24.9 ± 0.9 * Ferritin, mcg / l 79.9 ± 7.3 97.1 ± 5.9 * Transferrin, g / l 3.1 ± 0.4 2.9 ± 0.3 Total cholesterol, mmol / l 3.8 ± 0.3 3.7 ± 0.2 LDL, mol / L 2.6 ± 0.2 2.3 ± 0.1 Triglycerides, mol / L 1.1 ± 0.1 0.9 ± 0.1 HDL, mol / L 1.6 ± 0.1 1.7 ± 0.1 Blood glucose, mmol / l 4.1 ± 0.2 3.8 ± 0.1 Serum potassium, mmol / l 3.9 ± 0.9 4.1 ± 0.6 Serum sodium, mmol / l 137.6 ± 2.2 139.2 ± 2.4 * corresponds to p <0.05

Thus, the results obtained, reflecting the high efficiency and safety of the studied COCs, make it widely possible to use it as a hormonal contraceptive method in a wide range of women of reproductive age who do not have contraindications to the use of hormonal drugs.

1. Clinical example.

A 36-year-old woman turned to a cardiologist complaining of an increase in blood pressure about 1 time in 1-2 months before the start of the menstrual cycle, which is accompanied by headache and malaise.

From the anamnesis it is known: 1 normal birth at age 21, followed by 3 abortions, after the first abortion and subsequent abortions, she began to gain weight and the menstrual cycle was disrupted. Married. Sexual life is active, not protected.

Objectively: android type obesity. Heart sounds are rhythmic, no noise. In the lungs, vesicular breathing. The liver is not enlarged. The thyroid gland is not palpable.

Examination data: weight - 95 kg, height - 150 cm, waist circumference (OT) - 100 cm, BMI - 32 kg / m ² , fasting plasma glucose - 6.1 mmol / l, 2 hours after glucose loading inside - 7.2 mmol / L, total cholesterol (OXS) - 5.0 mmol / L, low-density lipoprotein cholesterol (HLPLP) - 2.9 mmol / L, high-density lipoprotein cholesterol (HLPVP) - 1.4 mmol / L triglycerides (TG) - 1.8 mmol / L.

Blood pressure (BP) - 138/90 mm Hg

Diagnosis: grade 1 obesity, abdominal (visceral type), fasting hyperglycemia, transient arterial hypertension (AH).

Prescribed treatment:

1. Moderately hypocaloric diet with a deficit of 600 kcal, increased physical activity, at least 40 minutes 5 times a week.

2. Orlistat 1 capsule during meals, no more than 3 times a day.

3. Metformin 850 mg 1 time in the evening.

4. The use of hormonal contraception is recommended with purely progestin-based oral contraceptives (CPPO).

Return visit after 3 months.

After 3 months, the weight dropped to 84 kg, BMI - 28.5 kg / m ² , OT - 93 cm.

HELL - 134/82 mm Hg, heart rate - 78 in 1 min.

Fasting blood glucose - 5.5 mmol / L.

It is recommended to continue treatment, cancel metformin. Change POPC to COCs with natural estradiol and dienogest as agreed with the gynecologist.

A repeated visit after 3 months: weight dropped to 79 kg, OT - 88 cm, BMI - 26.5 kg / m ² , BP - 134/74 mm Hg, heart rate - 74 in 1 min, glucose in the blood on an empty stomach - 5.0 mmol / l.

The patient notes an improvement in well-being, as well as a restoration of the regularity of the menstrual cycle.

It is recommended to continue non-pharmacological measures and contraception of COCs.

After 2.5 years, the patient appeared at the reception, consult with a cardiologist about pregnancy planning. He feels well, blood pressure does not increase, weight stabilized by 78 kg, BMI - 26.2 kg / m ² , RT - 84 cm, blood pressure - 126/78 mm Hg, fasting glucose in the blood plasma - 4.9 mmol / l, 2 hours after an oral load with glucose - 7.0 mmol / l, OXS - 4.9 mmol / l, HLPLP - 2.8 mmol / l, HLPVP - 1.5 mmol / l, triglycerides - 1.5 mmol / l. All the time the patient took the COC recommended by the gynecologist. Cardiologist's conclusion: there are no contraindications for pregnancy. Observation of a gynecologist.

The gynecologist canceled the COC and recommended mechanical protection for 1-2 months, and then stop.

After 7 months, the patient became pregnant, without complications, she endured the entire period of pregnancy and safely resolved the burden on time. The baby is healthy.

Claims (10)

1. The method of personalized prevention of estrogen-dependent diseases and reproductive disorders in women 35-45 years old with metabolic disorders, including measuring the waist circumference (OT), height and weight, to calculate body mass index (BMI), blood pressure (BP), determining the level glucose and lipids; and with RTs of more than 80 cm and a BMI of more than 25 kg / m ^{2, a} moderately hypocaloric diet is used - a calorie restriction of the diet by 500-600 kcal per day, the daily diet is based on the following: total fat intake less than 30% of the total calories; carbohydrates - up to 50%; the protein content in the diet is 15-20%; dietary fiber - 20-30 mg; raw fruits and vegetables - 400-500 g; nuts, grains, legumes - 30 g; table salt - less than 5 g; 1200 mg of calcium per day; vitamin D - 800 ME, polyunsaturated fatty acids 0.5-1.0 g, folic acid - 400 μg, vitamin C - 60 μg, vitamin E - 30 units; physical activity - at least 40 minutes per day and at least 5 times a week; alternation of aerobic and anaerobic exercises; additionally with:
a) BMI from 25 to 29.9 kg / m ² , the level of glucose, lipids and blood pressure that correspond to the norm, take combined oral contraceptives (COCs) containing natural estrogen and dienogest or COC containing drospirenone;
b) BMI from 30 kg / m ² and above, the level of glucose, blood pressure and lipids that correspond to the norm, take pure progestin oral contraceptives (POCC);
c) BMI from 25 kg / m ² and above, as well as the presence of fasting hyperglycemia and / or impaired glucose tolerance (NTG) and the level of blood pressure and lipids corresponding to the norm, take POCC;
d) BMI from 25 to 29.9 kg / m ² , as well as the presence of dyslipidemia and the level of glucose and lipids corresponding to the norm, take combined oral contraceptives (COCs) containing natural estrogen and dienogest;
d) BMI of 30 kg / m ² and above, as well as the presence of dyslipidemia and the level of glucose and lipids that are in line with the norm, take POCC. 2. The method according to claim 1, in which with a BMI of more than 30 kg / m ² and normal values of carbohydrates and lipids, an inhibitor of gastrointestinal lipases is additionally taken to reduce weight. 3. The method according to claim 1, wherein with a BMI of more than 27 kg / m ² , fasting hyperglycemia, and / or NTG, and / or hyperlipidemia, and / or arterial hypertension - blood pressure greater than 140/90 mm Hg, for weight loss additionally take an inhibitor of gastrointestinal lipases. 4. The method according to claim 1, after reducing body weight less than 30 kg / m ² take COCs containing drospirenone, or COCs containing natural estrogen and dienogest. 5. The method according to claim 1, when fasting hyperglycemia after reaching normal glucose levels take COCs containing drospirenone, or COCs containing natural estrogen and dienogest. 6. The method according to claim 1, with impaired glucose tolerance (NTG) after normalizing blood glucose, take COC containing drospirenone, or COC containing natural estrogen and dienogest. 7. The method according to claim 1, with dyslipidemia after normalization of lipid metabolism, take COC containing drospirenone, or COC containing natural estrogen and dienogest. 8. The method according to claim 1, in which with fasting hyperglycemia, biguanides are additionally taken. 9. The method according to claim 1, in which, with NTG, an alpha glucosidase inhibitor is additionally taken. 10. The method according to claim 1, in which additionally take meldonium.