RU2527357C1 - Method for individual prevention of oestrogen-dependent diseases in healthy females and females suffering cardiovascular risk factors at age of 45-60 years old - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: waist circumference (WC), height and weight are measured to calculate a body weight index (BWI), to determine glucose and lipids. The WC more than 80 cm requires prescribing a moderately hypocaloric diet that implies limiting an energy value of food ration by 500-600 kkal a day with the daily food ration composed taking into account as follows: total fat consumption less than 30% of total energy consumption; carbohydrates - up to 50%; protein content in the food ration - 15-20%; dietary fibre - 20-30 mg; fresh fruit and vegetables - 400-500 g; nuts, cereals, beans - 30 g; table salt - less than 5 g; 1000 mg of calcium a day for females taking hormonal contraception or replacement hormonal therapy (RHT), and 1500-2000 mg in females taking no hormonal contraception or RHT, vitamin D - 800 IU, polysaturated fatty acids 0.5-1.0 g, folic acid - 400 mcg, vitamin C - 60 mcg, vitamin E - 30 Units; physical exercises - not less than 40 min a day and not less than 5 times a week; alternating aerobic and anaerobic exercises. If BWI falls within the range of 25 to 29.9 kg/m, a normal glucose and lipid level, combined oral contraceptives (COC) with natural oeastrogen and dienogest, or the COC with drosperinone are taken. The BWI within the range of 30 kg/mand more, the normal glucose and lipid level, pure progestin oral contraceptives (PPOC) are administered. If the BWI exceeds 25 kg/m, and fasting hyperglycemia, impaired glucose tolerance (IGT) and/or dyslipidemia are observed, pure progestin oral contraceptives (PPOC) are administered. If a postmenopausal female has the BWI less than 30 kg/mand suffers climacteric syndrome, a combined replacement hormonal therapy (RHT) containing drospirenone is prescribed. The BWI more than 30 kg/mrequires administering meldonium into postmenopausal females.EFFECT: method enables individual prevention of oestrogen-dependent diseases.6 cl, 14 tbl, 2 ex

Description

The invention relates to the field of medicine.

According to the results of modern research, it is known that women are not inferior to men in mortality from cardiovascular disease (CVD). 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 CVD occurs in women 10-12 years later than in men. The risk increases with the onset of menopause, partly due to a deficiency of hormones produced by the ovaries, which leads to the development of arterial hypertension (AH), diabetes mellitus (DM), hyperlipidemia, central obesity and metabolic syndrome (MS). Long before menopause, CVD can occur in women who have specific, gender-related cardiovascular risk factors, such as a history of preeclampsia, fetal growth retardation, pregnancy diabetes, pregnant hypertension, polycystic ovary syndrome, miscarriage, hypoestrogenemia (infertility, amenorrhea hypothalamic) origin, artificial termination of pregnancy (after 10-20 years, the risk of hypertension, MS, acute myocardial infarction (AMI), acute cerebrovascular accident (stroke) increases by 2-4 times). Risks later its age period of women’s life is premature surgical menopause (up to 45 years), timely menopause, menopause syndrome, which increase the risk of developing diabetes by 3 times, CVD (IHD, stroke) by 2 times, hypertension by 3-4 times. In cases of timely and competently selected hormone replacement therapy can preserve health, ability to work, youth and femininity.

The significance of many of the traditional cardiovascular risk factors differs in women and in men. For example, the effects of smoking, increased triglycerides (TG), or low cholesterol high density lipoprotein (HPSLP) on the risk of CVD are much higher in women than in men. On the other hand, drugs commonly used to increase cholesterol, such as statins, are not effective as the primary prophylaxis of coronary events in women with low or moderate cardiovascular risk, compared with men in whom they effectively reduce the cardiovascular rate events even in people at low risk. Acetylsalicylic acid is also ineffective in women for the prevention of AMI up to 65 years, and in men it has been effective since 45 years.

As you move to the next age group, it is necessary to take into account not only these general needs, but also the state of health of each specific woman, since she can:

1. be healthy;

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

This allows the doctor to concentrate on the main issues related to the patient’s health, and plan measures to preserve and maintain overall well-being in the future. Along with the traditional division into menopause phases: premenopause, perimenopause or postmenopause, this provides the doctor with additional options.

The women's management system should be flexible and adapted to a modern understanding of the pathophysiology of menopause / postmenopausal periods with the use of new technologies and therapeutic techniques.

In most women, the menopausal transition covers a period of time between 46 and 55 years, on average, menopause occurs in 50-51 years. For many women, this age period is associated with the appearance of significant health problems in the present and potential adverse events in the future.

Risk factors in women 35-60 years old

Menopausal syndrome

Menopausal syndrome plays a particular danger to women's health and prognosis. During this period, vasomotor instability can lead to hot flashes, excessive sweating, which sometimes occur against the background of preserved menstrual function, which is an indicator of impending menopause. Manifestations of estrogen deficiency can also be urogenital symptoms. The most common vaginal symptoms include dryness, irritation, itching, and dyspareunia. Specific manifestations resulting from atrophic processes in the vagina include petechiae, which are often accompanied by the development of infection. Symptoms from the lower urinary tract include dysuria, rapid urination (without dysuria), urination and nocturia, recurrent infection and urinary incontinence. Data from cross-sectional studies indicate a decrease in orgasm ability, frequency of sexual intercourse, and sexual interest.

In addition, the onset of menopause is associated with the appearance of psychological disorders, deterioration in cognitive function and overall quality of life. Psychological changes include poor mood, low self-esteem, increased susceptibility to stress and inability to adequately communicate with others. Some women may notice changes in cognitive function: forgetfulness, decreased concentration, distraction, difficulties in solving life problems. Such an indicator as the quality of life significantly decreases with the appearance of the above symptoms, but it is also affected by changes in the socio-economic status of women, dietary features, medication, level of physical activity and adverse life circumstances.

Smoking

Numerous studies have proven the relationship of smoking at the moment or earlier, with the duration and number of cigarettes smoked per day (or packs of cigarettes per year) with the presence and severity of menopausal symptoms in peri- and postmenopausal women. Non-smoking women exposed to “passive” smoking at home are also more likely to experience vasomotor symptoms.

Visceral obesity and menopausal metabolic syndrome

In premenopause (from the age of 45), there is a significant decrease in the secretion of estrogens, first progesterone with a normal level of estradiol. It is known that estradiol increases the activation of the renin-angiotensin-aldosterone system (RAAS), and progesterone blocks it. With a decrease in progesterone secretion, its inhibitory effect on RAAS is lost, which in turn causes an increase in blood pressure and the development of visceral obesity. Elevated levels of angiotensin 2, which interacts with adipocytes of visceral fat, cause an increase in its volume. In addition, progesterone blocks the differentiation of visceral fat adipocytes and regulates insulin sensitivity by acting on PPRy receptors. A decrease in progesterone secretion leads to the development of visceral obesity, a decrease in the formation of adiponectin in adipocytes and, as a result, to insulin resistance.

With the onset of menopause, there is a rapid decrease in estradiol secretion, while androgen secretion decreases more slowly and smoothly. Thus, there is a relative, sharp decrease in estrogen, hyperandrogenism. This, in turn, causes the development of android obesity with the redistribution of subcutaneous fat in the upper half of the body and an increase in visceral fat mass. The progression of visceral obesity is also facilitated by a decrease in the level of growth hormone (STH), which is a consequence of estrogen deficiency. STH deficiency causes impaired insulin secretion and insulin resistance (IR). The development of obesity exacerbates the increase in glucocorticoids, which is observed with increasing age. In this case, the feedback mechanism is violated and, in response to any, even insignificant, stressful situation, the restoration of the initial level of stress hormones, in particular glucocorticoids, whose concentration has been kept at high values for a long time, slows down. With age, there is a change in the ratio of mineralcorticoids to glucocorticoids in the hippocampus and hypothalamus in favor of an increase in glucorticoids. Estrogens are also involved in the regulation of appetite. It was found that in the reproductive period, women in the ovulation phase, when there is a maximum release of estrogen, eat less high-calorie foods and to a lesser extent than in the luteal phase, when the secretion of sex steroids decreases. In postmenopausal women, there is a change in eating behavior towards an increase in appetite, which contributes to an increase in body weight and the progression of MS.

Arterial hypertension

Before menopause, hypertension is much less common in the female population than in men, which is to some extent explained by the multidirectional effects of testosterone and estrogen on the cardiovascular system. An increase in blood pressure has long been considered more characteristic of men, but to date, convincing data have been obtained that postmenopausal hypertension is more common among women. After eliminating the influence of other risk factors (age, impaired fat and carbohydrate metabolism, overweight), the onset of menopause increases the risk of hypertension almost twice. The prevalence of hypertension in postmenopausal women is approximately 50%.

AH is not only more common in postmenopausal women compared with male peers, but also has certain sexual characteristics. Women have higher average daily and maximum levels of systolic blood pressure (SBP), greater variability during the day, especially at night, and the frequency of disturbance of the circadian rhythm of this indicator. Many of the identified disorders play an important role in the defeat of target organs, as they contribute to cardiovascular remodeling and the development of left ventricular hypertrophy (LVH). It has been shown that after 50 years, the level of SBP in women continues to increase, while the level of diastolic blood pressure (DBP) is maintained at the previous values or even decreases, so the pulse pressure increases.

Estrogen deficiency, in addition to affecting the smooth muscle structures of the vascular wall and endothelial function in postmenopausal women, has indirect effects on the mechanisms of AH development, including an increase in the tone of the sympathetic nervous system (SNS), RAAS activity, changes in body weight and proportions, and an increase in IR.

During this period, the formation of catecholamines increases and there is a clear shift in the activity of the autonomic nervous system in the direction of increasing sympathetic tone. An increase in sympathetic tone promotes not only functional, but also structural changes that facilitate the development of hypertension, and also causes activation of RAAS, an increase in plasma levels of angiotensin II and aldosterone. The increased activity of RAAS, apparently, plays a key role in the mechanisms of increasing blood pressure in women in peri- and postmenopausal women. Aldosterone enhances sodium reabsorption in the kidneys, which contributes to an increase in circulating blood volume (BCC) and blood pressure, and stimulation of proliferation of endothelial and smooth muscle cells in the vessel wall and in the myocardium leads to the development of irreversible structural changes in them. RAAS plays a major role in controlling blood pressure and fluid volume in the body, not only in a direct way, but also by stimulating proendothelin synthesis and oxidative stress. Although plasma renin activity decreases with age both in humans and in animals, it is known that in postmenopausal women, its plasma level and subsequent formation of angiotensin II are significantly higher than in premenopause. In this regard, drugs that affect RAAS are referred to as first-choice drugs for the treatment of hypertension in perimenopausal women. The neutral effect of drugs of this series on carbohydrate and lipid metabolism, as well as the proven organoprotective effect makes them especially attractive for the treatment of hypertension in women with menopausal metabolic syndrome.

The main survey methods for determining health status

Examination of women aged 46 to 60 years should include a thorough history taking and a full physical examination, while maximum attention should be paid to identifying neuroendocrine and urogenital changes that are closely associated with the menopausal transition. Using special techniques can help with this examination. These questionnaires allow you to identify the extent to which a woman experiences symptoms such as hot flashes, sleep disturbance, mood and memory, changes in skin and hair conditions, rapid urination or urinary incontinence, dyspareunia, sexual dysfunction, etc. In addition, much attention should be paid to nutrition, especially excessive consumption of fatty foods and lack of calcium-containing foods.

Key studies should include weight, height, waist-to-hip ratio (RT / V), body mass index (BMI), and blood pressure. In addition, it is necessary to conduct an examination of the skin, to examine the state of the thyroid gland, mammary glands, and cardiovascular system (ECHOCG, ECG test with exercise, BPM, waste ECG monitoring, ultrasound of the carotid arteries, stiffness of the vascular wall), abdominal organs, and small pelvis , rectum, central nervous system, as well as vision and hearing. It is possible to determine the state of the muscles of the pelvic floor.

The choice of certain laboratory tests is determined by the history and physical examination. Tests that must be performed in women of this age group include:

basic gynecological examination: sexually transmitted diseases and the state of microflora, cytological examination of scrapings of the w / uterus and cervical canal, ultrasound examination of the pelvic organs, mammography, coagulation, consultation of a gynecologist;

additional: sex hormones (on the days of the cycle), assessment of the follicular reserve (muller hormone), blood androgens, culture on the mycoplasma and uroplasm of the vaginal discharge, bacteriological culture of the discharge, densitometry, endometrial biopsy (aspiration), assessment of ovulation and luteal phase of the menstrual cycle ( , progesterone, ultrasound, basal temperature), colposcopy. Sigmoidoscopy should be performed every 3-5 years and colonoscopy every 10 years or as indicated.

From the list above, the necessary tests must be selected individually. For example, a mammogram can be performed once every 3-5 years in women with low risk, in the absence of fibrotic mastopathy, or annually in women with high risk in whom the sisters have had breast cancer.

Based on the survey, each woman assesses her general health and determines a risk profile, which should be reviewed at each visit.

The woman is healthy.

Doctors a cardiologist / therapist and gynecologist should give the woman recommendations for a healthy lifestyle, including proper nutrition and physical activity for a given age, the need for an annual examination by a cardiologist and gynecologist and, if necessary, hormonal contraception or hormone replacement therapy (HRT).

The basics of healthy nutrition for women 46-60: total fat intake <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), proteins - 15-20%, dietary fiber - 20-30 mg; raw fruits and vegetables - 400-500 g; nuts, legumes - 30 g; table salt - <5 g; consumption of 1500 - 2000 mg of calcium per day without hormonal contraception and HRT and 1000 mg for women taking hormonal contraception or HRT; Vitamin D - 800 ME.

Polysaturated Fatty Acids (PUFAs)

- The daily intake of 0.5-1.0 g of omega-3 PUFAs 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.)

The role of vitamins and minerals.

- 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 BMD and reduces the risk of fractures.

The daily need for vitamins

Folic acid - 400 mcg.

Vitamin C - 60 mcg.

Vitamin E - 30 units.

Products containing phytoestrogens:

legumes (peas); flax seeds; bran; whole grains; vegetables; fruits.

Physical activity

It has been proven that adequate physical activity reproduces many of the positive effects of hormone replacement therapy.

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.

If a woman under 45 was not engaged in physical activity, then you can not start with powerful physical exertion.

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 balanced and take 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

The probability of pregnancy persists in women before menopause. In this connection, it is recommended to take COCs containing natural estrogen with a metabolically neutral dienogest, or COCs with drosperinone for 1 year after the last menstruation, with a transition in the future if there are indications for HRT.

Hormone replacement therapy.

Indications for HRT: menopause, early or premature menopause, urogenital disorders, and prevention of osteoporosis.

The advantage is a combined preparation for HRT, which includes natural estrogen with drospirenone.

The fixed combination contains a combination of 1 mg of 17β-estradiol and 2 mg of drospirenone - a drug for the combined regimen of hormone replacement therapy - provides a new alternative approach to postmenopausal women and, thanks to additional therapeutic benefits, surpasses the capabilities of other drugs used for the traditional purpose of “hormone replacement”.

Drospirenone (DRSP) is a new progestogen, the pharmacological profile of which is closest to endogenous progesterone compared to other synthetic progestogens currently in use. In addition, DRSP is a progestogen with the properties of an aldosterone receptor antagonist, i.e. possesses unique properties not characteristic of other synthetic progestogens. Due to the antialdosterone activity, DRSP causes a moderate increase in the excretion of sodium and water. While during the first year of taking other oral drugs for hormonal therapy, there is a slight increase in the level of systolic blood pressure and this trend persists with continued treatment, the antimineralocorticoid properties of HRT with DRSP contribute to a decrease in blood pressure in postmenopausal women with hypertension as against monotherapy, and when combining its use with various antihypertensive agents.

Smoking and HRT in postmenopausal women

When HRT is prescribed, estrogen levels in smokers reach ≈50% of their level in non-smokers. A decrease in the level of bioactive estrogen fractions contributes to the insufficient / inadequate effects of HRT in smokers. Smoking disrupts the beneficial effects of HRT. Forgetting the anti-estrogenic effects of smoking, doctors can discredit HRT as an effective prophylactic against osteoporotic fractures and coronary heart disease with timely appointment.

The initial appointment of HRT is permissible only up to the age of the woman - 60 years. Older than 60 years - contraindicated.

Woman with risk factors

1. Metabolic syndrome: waist circumference (OT) of more than 80 cm in women and 2 of the additional criteria. Additional criteria: AH (blood pressure ≥ 140/90 mm Hg), an increase in TG (≥1.7 mmol / L), a decrease in HDL cholesterol (<1.2 mmol / L in women), an increase in lipoprotein cholesterol low density (LDL cholesterol)> 3.0 mmol / L, fasting hyperglycemia (fasting plasma glucose ≥ 6.1 mmol / L), impaired glucose tolerance (NTG) (plasma glucose 2 hours after glucose loading in limits ≥7.8 and ≤11.1 mmol / l).

2. With a BMI of 25 to 27 kg / m ² , non-drug treatment of obesity is recommended (moderately hypocaloric diet with a deficit of 500-600 kcal, 1200 mg of calcium per day and increased physical activity).

3. With a BMI of more than 27 kg / m ² , medication for obesity is shown as an inhibitor of gastrointestinal lipases.

4. An increase in fasting blood glucose is an indication for the administration of biguanides.

5. With NTG, an alpha-glucosidase inhibitor must be prescribed.

6. Treatment of hypertension:

In this age period, women choose drugs for the treatment of hypertension are drugs that affect RAAS - angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin 2 receptor blockers (ARBs). If it is necessary to use combined antihypertensive therapy, it is advisable to prescribe drugs that reduce the increased activation of the SNA - imidazoline receptor agonists or beta-blockers and diuretics - thiazide-like diuretics.

Of the group of drugs that affect RAAS, losartan is an advantage for women of this age period, as the only drug, along with the main effects inherent in these classes, which reduces uric acid levels. It is known that in women in perimenopause, the level of uric acid rises. From the group of beta-blockers, priority must be given to highly selective, with vasodilating properties, nebivolol, not only metabolically neutral, but also with positive metabolic effects. And the drug of choice from the class of diuretics should be indpapamide, as the only metabolically neutral drug.

7. As a prevention of CVD, it is advisable for women 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.

8. The choice of contraception for premenopausal women with MS and hypertension is pure progestin contraceptives (POCC). COCs are contraindicated.

9. Postmenopausal women with MS and AH, if indicated, are recommended to use a fixed combination of 1 mg of 17β-estradiol and 2 mg of drospirenone, which along with therapeutic effects has an additional prophylactic effect, reducing the severity of visceral obesity, atherogenic dyslipidemia, and reducing elevated blood pressure , improving vascular endothelial function and reducing the rigidity of the vascular wall.

10. In the absence of indications for HRT or a woman's unwillingness to take it, the appointment of meldonium as an alternative to HRT is indicated.

Thus, according to the developed methodology:

for RTs over 80 cm, 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; 1000 mg of calcium per day for women taking hormonal contraception or hormone replacement therapy (HRT), and 1500-2000 mg not taking hormonal contraception or HRT; vitamin D - 800 ME, polyunsaturated fatty acids 0.5-1.0 g, folic acid - 400 μg, vitamin C - 60 μg, vitamin E - 30 DB; 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 and lipids corresponding to the norm, take combined oral contraceptives (COCs) with natural estrogen and dienogest or COC with drosperinone;

b) BMI from 30 kg / m ² and higher, glucose and lipid levels that correspond to the norm, take pure progestin 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 / or dyslipidemia; take pure progestin contraceptives (PSC);

d) a BMI of not more than 30 kg / m ² and menopausal syndrome in postmenopausal women take combined hormone replacement therapy (HRT) containing drospirenone;

e) A BMI of more than 30 kg / m ² postmenopausal women take meldonium.

In addition, with a BMI of more than 30 kg / m ² and normal carbohydrates and lipids, an inhibitor of gastrointestinal lipases is additionally taken to reduce weight. With a BMI of more than 25 kg / m ² , fasting hyperglycemia and / or NTG and / or hyperlipidemia and / or arterial hypertension - blood pressure greater than 140/90 mm Hg, an inhibitor of gastrointestinal lipases is additionally taken to reduce weight. With fasting hyperglycemia, biguanides are additionally taken. With NTG, an alpha glucosidase inhibitor is additionally taken. After a decrease in body weight of less than 30 kg / m ² , postmenopausal women with menopause take HRT with drospirenone.

An example of the use of COCs with drosperinone in premenopausal women.

The study involved 54 premenopausal women who turned to a gynecologist for the selection of contraception. The average age of the patients was 43.0 ± 5.9 years. All of them had menopause syndrome (CS) of varying severity. After the gynecologist determined the indications and contraindications for contraception, 23 patients (group 1) were prescribed a low-dose COC containing 20 μg ethinyl estradiol and 3 mg DRSP. The regimen is 1 tablet 1 time per day, the regimen includes 24 days of hormonal treatment, followed by a shortened 4-day period without hormones (24/4). The control group (1a) of menopausal women who did not take hormonal contraception was 31 patients.

Research methods

All patients underwent a standard general clinical examination with the determination of anthropometric parameters, a gynecological examination (including a smear for oncocytology). Laboratory studies included the study of the lipid spectrum, glucose, uric acid, aspartic and alanine hepatic transaminases, creatine phosphokinases, an oral glucose tolerance test, a general blood count, a hormonal blood count, and a hemostasiogram was studied.

Also, during the examination, an office measurement of blood pressure and ECG was performed. All women were questioned using the Beck test to assess the severity of depressive disorders, the Spielberger test, a questionnaire to identify signs of autonomic changes, and a study of the modified menopausal index.

Statistical data processing was performed using the software package "StatSoftIns." (USA) Statistica 6.0 for Microsoft Windows. All indicators were checked for compliance with the normal distribution. Used Student's t-test. The results are presented as the arithmetic mean and its standard deviation (M ± σ), as the median, or as a percentage of the analyzed group. Comparison of groups by quantitative and ordinal signs was carried out by a nonparametric method using the Mann-Whitney criterion. Comparison of the results of treatment within groups was carried out using the Wilcoxon test. Differences were considered significant at a significance level of p≤0.05.

results

Assessment of changes in the severity of CS in the studied groups 1 and 1a of women in the menopausal transition was carried out initially and after 12 months of observation. At the beginning of the study, according to the questionnaire survey, the MMIs of groups 1 and 1a were comparable in terms of severity of CS, the neurovegetative and psychoemotional symptoms prevailed in the structure of menopausal disorders in both groups (Table 1).

Table 1. Distribution of CS symptom complexes in the studied groups 1 and 1a among women in the menopausal transition (average score for MMI) (M ± sd) Symptoms Points R Group 1 (n = 23) Group 1a (n = 31) Neurovegetative 15.2 ± 0.7 16.4 ± 0.5 = 0.06 Metabolic endocrine 4.3 ± 0.2 3.8 ± 0.5 = 0.41 Psycho-emotional 10.0 ± 0.7 11.6 ± 0.4 = 0.11

After 12 months, the severity of neuro-vegetative, metabolic-endocrine and psychoemotional symptoms in patients with COC in group 1 decreased significantly. In the control group of women in the menopausal transition, no positive dynamics were detected (Table 2).

Table 2. The percentage of changes in the severity of symptomatic complexes of CS in women in the menopausal transition,% Group 1 Group 1a Originally After 12 months Originally After 12 months Neurovegetative symptoms Mild 65 5* 60 65 Medium grade 34 5* 25 23 Severe degree one 0 * eleven 12 Exchange-endocrine symptoms Mild 76 90 * 80 79 i degree 24 10* 21 21 Psychoemotional symptoms Mild 40 10* 38 40 Medium grade 46 12* fifty 49 Severe degree 13 2 * 12 12 Note: p values are marked in the table (* p <0.001)

Thus, after 12 months of using COCs in the menopausal transition, there was a significant decrease in the severity of all symptom complexes of CS with a transition from severe and moderate severity to mild and / or absence of symptoms. In control group 1a, who did not take hormonal contraception, there were no significant changes in the complaints of women.

Initially, 13 (24%) women in the menopausal transition were diagnosed with 1st degree obesity, 18 (33%) participants had abdominal obesity, and 20 (39%) women were diagnosed with metabolic syndrome. Table 3 presents the dynamics of anthropometric indicators of a group of women taking DRSP-containing hormonal contraceptives and comparison groups. Against the background of 12 months of treatment, a significant decrease in RT was observed in women taking COCs without a significant change in body weight and BMI. In control group 1a, a significant increase in all indicators was revealed (Table 3).

Table 3. Change in body weight, BMI, RT after 12 months in women in the menopausal transition, (M ± sd) 1 group 1a group Indicators Originally 12 months Originally 12 months Body weight 66.6 ± 10.8 65.5 ± 10.1 71.7 ± 13.9 73.5 ± 14.1 ** BMI, kg / m ² 24.8 ± 4.3 24.3 ± 4.0 26.5 ± 5.3 27.3 ± 5.2 ** From cm 77.7 ± 10.5 74.0 ± 10.5 * 81.5 ± 11.2 83.5 ± 11.9 ** Note: the table shows p values (* p <0.001, ** p <0.05) obtained by comparing the indicators after 12 months relative to the initial indicators separately for groups 1 and 1a.

When conducting an individual analysis in group 1, a decrease in body weight was detected in 14 (60.8%) patients by an average of 2.3 kg, in 5 (21.7%) body weight did not change, in 4 (17.4%) weight increased by 2 kg. In group 1a, in 20 (64.5%) the body weight increased by an average of 3.7 kg, in 4 (12.9%) the weight did not change, in 7 (22.6%) the body weight decreased on average by 2, 4 kg, differences in the magnitude of the decrease in body weight in the groups are significant (p <0.0001).

In group 1, a decrease in BMI was detected in 10 (43.5%) patients by 4.7% (relative to the initial level), in 11 (47.8%) BMI did not change, and in 2 (8.7%) an increase in BMI by 3.6%. In control group 1a, a decrease in BMI was found in 4 (12.9%) by 5% (relative to the initial level), unchanged in 12 (38.7%) and an increase in BMI was found in 15 (48.4%) by 7, 7%, frequency differences in the groups are statistically significant (p <0.0001).

In group 1, 19 (82.6%) showed a decrease in RT by an average of 4.8 cm, 2 (8.7%) did not change, and 2 (8.7%) showed an increase of 3.5 cm In control group 1a, 23 (74.2%) showed an increase in RT by an average of 3.5 cm, in 2 (6.5%) they did not change, and in 6 (19.4%) it decreased by an average of 3 , 0 cm, differences in the magnitude of the decrease in RT in groups are significant (p <0.0001).

Thus, while taking COCs containing 20 μg of ethinyl estradiol and 3 mg of DRSP, group 1 showed a tendency to weight loss, BMI and a significant decrease in RT, while in control group 1a of menopausal women who did not take hormones, it was revealed significant negative dynamics in the form of a significant deterioration of these indicators.

Initially, in women in the menopausal transition, hyperlipidemia was detected in 40 (75%) women in the menopausal transition: in 17 (31.5%) patients there was an increase in the level of total cholesterol, in 36 (69%) an increase in LDL, in 45 (86%) a decrease in HDL , hypertriglyceridemia in 13 (25%) (n = 54).

After 12 months in group 1, while taking hormonal contraceptives, a tendency to a decrease in the level of total cholesterol from 5.7 ± 1.1 mmol / l to 5.5 ± 1.1 mmol / l (p = 0.56), and LDL levels was revealed in blood serum from 3.4 ± 0.8 mmol / L to 3.2 ± 0.7 mmol / L (p = 0.24). The level of TG did not significantly change: initially it was 1.1 (0.8; 1.6) mmol / L, after 12 months - 1.4 (0.7; 1.7) mmol / L. The content of HDL in the blood serum of women with the use of COCs did not change, amounting to 1.7 ± 0.6 mmol / L before treatment and 1.7 ± 0.6 mmol / L after treatment. After 12 months, in group 1a of women who did not take hormone therapy, the level of total cholesterol was statistically significantly increased from 5.4 ± 0.9 mmol / L to 5.9 ± 1.0 mmol / L (p <0.05), LDL from 3.4 ± 0.7 mmol / L to 3.9 ± 1.0 mmol / L (p <0.05). The HDL content in the blood serum of women did not significantly change: initially 1.5 ± 0.3 mmol / L and after 12 months 1.5 ± 0.4 mmol / L (p = 0.34). The TG level also did not significantly change: initially 1.0 (0.8; 1.8) mmol / L, after 12 months - 1.1 (0.8: 1.6) mmol / L.

An individual analysis of the dynamics of the studied parameters in the 1st group revealed a decrease in the level of cholesterol in 12 (60%) patients, in 13 (72%) patients there was a decrease in the level of LDL, and the level of HDL increased in 8 (44%) patients. In group 1a of the control, the level of cholesterol increased in 25 (83%), in 24 (83%) patients there was an increase in the level of LDL, and in 17 (59%) women the level of HDL decreased. TG level did not significantly change in both groups.

When analyzing PHTT data, carbohydrate metabolism disorders were not detected in patients treated with COCs and in the control group. After 12 months, fasting glucose was 5.0 ± 0.7 mmol / L in group 1 and 5.0 ± 0.6 mmol / L in group 1a, 2 hours after glucose intake - 5.7 ± 1.7 mmol / l and 5.4 ± 1.6 mmol / l, respectively.

Thus, after 12 months, women taking combined hormonal contraceptives showed no significant dynamics in lipid metabolism. In the control group, there was a significant increase in the levels of total cholesterol and LDL. No significant effect of hormonal contraceptive on carbohydrate metabolism was found with initially normal fasting and postprandial glucose levels.

In women of the 1st group, while taking hormonal contraceptives, there was no significant change in clinical blood pressure: SAD initially averaged 120.8 ± 11.0 mm Hg. and after 12 months - 118.2 ± 7.9 mm Hg (p = 0.11), DBP initially averaged 76.4 ± 6.1 mm Hg. and after 12 months, 75.8 ± 8.0 mm Hg (p = 0.71). The control group showed a statistically significant increase in clinical SBP, but within the normal range: SBP increased on average from 119.1 ± 15.4 mm Hg. up to 125.5 ± 15.9 mmHg (p = 0.002), and DBP increased from 75.7 ± 12.2 mm Hg. up to 79.3 ± 12.5 mm Hg (p = 0.07).

Using a nonparametric frequency analysis, it was found that in group 1, a decrease in SBP was recorded in 15 (65%) patients, a decrease in DBP in 14 (61%) women, and in group 1a, an increase in SBP was detected in 22 (71%) (p = 0 , 0001), an increase in DBP - in 22 (71%) women.

It was found that the number of women with a high normal level of blood pressure (SBP 130-139 mm Hg and / or DBP 85-89 mm Hg) did not differ in groups 1 and 1a (p> 0.05). Initially, 4 (17%) women in group 1 and 6 (19%) women in group 1a had high normal blood pressure, after 12 months this ratio changed: only 11 (35%) in group 1a of control had high normal blood pressure and were not registered in group 1 of patients taking hormonal contraceptives (p <0.0001). Thus, in group 1, all 17% of high normal blood pressure returned to normal values; on the contrary, in control, the frequency of high normal blood pressure rose from 19% to 36%.

According to the results of the ABPM against the background of a 12-month intake of COCs containing 20 μg of ethinyl estradiol and 3 mg of DRSP, the group as a whole did not reveal significant changes for most of the ABPM parameters for the entire observation period (Table 4-5). In group 1 of women taking the combination of ethinyl estradiol with DRSP, only the DBPmin significantly decreased from 61.9 ± 7.2 mm Hg. up to 58.2 ± 6.6 mmHg (p = 0.015), SI SI DBP from 17.1 ± 5.1 to 10.4 ± 8.2 (p = 0.015). In control group 1a of women who did not take hormonal contraceptives, the maximum and average parameters of SBP significantly increased from 137.3 ± 21.7 mm Hg. up to 145.2 ± 19.4 mmHg (p = 0.034), from 115.7 ± 14.9 to 120.9 ± 13.2 mmHg (p = 0.026), respectively, but within normal values.

At night, in group 1 of women taking a combined hormonal contraceptive, there was an increase in the range of normal values of the maximum and minimum values of SBP from 121.3 ± 16.8 mm Hg. up to 129.6 ± 11.7 mmHg (p = 0.015), s 85.6 ± 13.9 mmHg up to 95.5 ± 14.7 mm Hg (p = 0.015), respectively, as well as the minimum DBP with 50.2 ± 7.0 mm Hg up to 58.1 ± 12.8 mmHg (p = 0.015).

Table 4. BP indicators in the daytime in women of the 1st group taking COCs and 1a of the control group according to the Smad, (M ± Std) Group 1 Group 1a Indicators Originally 12 months Originally 12 months GARDEN max,
mmHg. 142.2 ± 12.7 140.6 ± 8.9 137.3 ± 21.7 145.2 ± 19.4 * GARDEN
mmHg. 119.1 ± 9.0 121.8 ± 9.4 115.7 ± 14.9 120.9 ± 13.2 * GARDEN min,
mmHg. 99.9 ± 10.5 102.2 ± 10.1 94.5 ± 12.9 96.1 ± 11.7 IV garden,% 11.3 ± 17.4 10.4 ± 14.5 10.5 ± 22.8 11.4 ± 14.5 DBP max,
mmHg. 95.5 ± 12.3 92.6 ± 6.2 92.0 ± 9.7 95.2 ± 11.4 DBP cf.
mmHg. 77.8 ± 6.4 76.2 ± 4.9 74.8 ± 8.6 76.8 ± 7.4 DBP min,
mmHg. 61.9 ± 7.2 58.2 ± 6.6 * 56.4 ± 9.0 55.7 ± 8.4

IV DAD,% 10.7 ± Altern 17.9 10.7 ± 10.1 11.1 ± 12.9 10.6 ± 14.1 Wed HELL max
mmHg 110.6 ± 12.8 102.5 ± 24.8 108.9 ± 15.8 112.7 ± 14.2 Wed HELL Wed,
mmHg. 91.6 ± 7.2 91.4 ± 4.7 88.9 ± 9.7 91.7 ± 8.6 * Wed Hell min
mmHg 74.8 ± 8.3 73.8 ± 6.2 70.5 ± 8.7 70.6 ± 8.0 STD GARDEN 9.6 ± 2.0 9.6 ± 1.7 10.8 ± 3.7 12.2 ± 5.0 STD DAD 8.0 ± 2.1 8.1 ± 1.7 8.8 ± 2.1 9.6 ± 3.6 STD avg. 8.3 ± 2.3 8.5 ± 1.6 9.3 ± 2.6 10.2 ± 3.8 SI GARDEN,% 13.3 ± 7.3 9.2 ± 8.5 11.4 ± 6.9 11.6 ± 6.9 SI DAD,% 17.1 ± 5.1 10.4 ± 8.2 * 14.6 ± 6.3 13.2 ± 6.7 PAD, mmHg 41.2 ± 6.4 45.6 ± 9.6 41.6 ± 9.8 44.0 ± 8.9 Heart rate, beats / min 78.7 ± 7.8 78.8 ± 6.9 77.0 ± 8.2 76.4 ± 8.4 Note: * p <0.05

GARDEN max - maximum systolic blood pressure, GARDEN avg. - mean systolic blood pressure, SBP min - minimum systolic blood pressure, DBP max - maximum diastolic blood pressure, DBP cf. - average diastolic blood pressure, DBP min - minimum diastolic blood pressure, Avg. AD max - maximum average arterial pressure, Avg. - mean arterial pressure, Avg. arterial pressure mmin - minimum mean arterial pressure, IV - time index, STD - variability of arterial pressure, SI - daily index, PAD - pulse arterial pressure, heart rate - heart rate. The data in the table are presented as M ± Std.

Table 5. BP indicators at night in women of the 1st group taking COCs and 1a of the control group according to the ABPM Group 1 Group 1a Indicators Originally 12 months Originally 12 months GARDEN max,
mmHg. 121.3 ± 16.8 129.6 ± 11.7 * 121.5 ± 16.5 124.9 ± 19.5 GARDEN
mmHg. 104.4 ± 15.1 110.4 ± 11.4 103.7 ± 14.6 106.9 ± 15.0 GARDEN min,
mmHg. 85.6 ± 13.9 95.5 ± 14.7 * 87.8 ± 13.7 91.7 ± 13.9 IV garden,% 10.3 ± 9.4 10.4 ± 9.5 9.5 ± 11.8 10.4 ± 10.5 DBP max,
mmHg. 79.5 ± 9.0 84.5 ± 7.3 79.0 ± 12.0 81.7 ± 10.4 DBP cf.
mmHg. 64.8 ± 6.6 68.1 ± 6.0 64.5 ± 8.2 66.7 ± 8.6 * DBP min,
mmHg. 50.2 ± 7.0 58.1 ± 12.8 * 50.1 ± 7.2 52.5 ± 7.3 IV DAD,% 8.3 ± 10.4 8.4 ± 10.5 8.5 ± 10.8 8.8 ± 10.3

Avg. Max,
mmHg 93.3 ± 12.3 96.3 ± 7.7 93.3 ± 12.2 96.6 ± 13.7 Avg.
mmHg. 81.7 ± 9.8 81.4 ± 6.8 78.6 ± 9.4 80.4 ± 11.1 Avg. Min,
mmHg 65.6 ± 6.7 68.2 ± 7.9 64.6 ± 8.4 66.4 ± 8.9 STD GARDEN 9.5 ± 4.2 9.6 ± 4.0 9.4 ± 3.7 10.0 ± 2.4 STD DAD 8.1 ± 3.4 8.8 ± 3.2 8.1 ± 2.9 8.7 ± 2.0 STD avg. 8.5 ± 3.6 8.2 ± 3.5 8.2 ± 2.5 9.1 ± 2.1 PAD 39.6 ± 10.8 42.3 ± 10.3 39.2 ± 9.2 40.1 ± 8.8 Heart rate, beats / min 69.8 ± 8.4 69.9 ± 9.9 67.2 ± 8.7 61.2 ± 16.7 Note: * p <0.05

GARDEN max - maximum systolic blood pressure, GARDEN avg. - mean systolic blood pressure, SBP min - minimum systolic blood pressure, DBP max - maximum diastolic blood pressure, DBP cf. - average diastolic blood pressure, DBP mmin - minimum diastolic blood pressure, Avg. AD max - maximum average arterial pressure, Avg. - mean arterial pressure, Avg. arterial pressure mmin - minimum mean arterial pressure, IV - time index, STD - variability of arterial pressure, SI - daily index, PAD - pulse arterial pressure, heart rate - heart rate. The data in the table are presented as M ± Std.

In group 1a of women in the control, only the average DBP significantly increased from 64.5 ± 8.2 mm Hg. up to 66.7 ± 8.6 mmHg (p = 0.01). Heart rate (HR) on average did not significantly change in both groups. The blood pressure profile (the degree of nighttime decrease in SBP and DBP) did not statistically significantly change.

Thus, in the group of women in the menopausal transition, the use of combined hormonal contraceptives did not have a significant effect on the clinical numbers of blood pressure and indicators of BPM, which were within the normal range, as well as in the control group there were no significant changes in the level of blood pressure and indicators of BPM.

During the observation, there were no statistically significant changes in the parameters of the coagulogram in groups 1 and 1a of women in the menopausal transition, the indicators were within the reference values (Table 6).

Table 6. Coagulogram indices at baseline and after 12 months in groups 1 and 1a in women in the menopausal transition Group 1 Group 1a Originally 12 months Originally 12 months Fri Quick,% 87 (86-88) ¹ 114 (95-132) 99 (98-109) 101 (66-106) PTV, sec 12 (10-13) 11 (10-12) 11 (10-12) 16 (10-25) Mho 1.05 (1.00-1.08) 1.03 (0.85-2.12) 1.00 (0.99-1.01) 0.99 (0.96-1.71) Fibrinogen, g / l 2.6 (2.3-2.7) 3.6 (3.4-7.1) 3.5 (3.0-3.6) 2.8 (2.5-2.8) APTT, sec 35 (33-36) 38 (22-43) 32 (30-38) 32 (26-38) D-dimer, μg / ml 0.23 (0.19-0.33) 0.28 (0.24-0.35) 0.22 (0.18-0.26) 0.21 (0.18-0.25) Note: ¹ - median (25th-75th percentile); differences between groups

PT - prothrombin according to Quick (norm: 70-130%); PTV - prothrombin time (norm: 5.0-18.0 sec); MHO - international normalized ratio (norm: 0.98-1.15); APTT - activated partial thromboplastin time (norm: 30-45 sec); fibrinogen (norm: 2.0-4.0 g / l); D - dimer (norm 0-0.5 μg / ml).

All women were outpatiently monitored for 12 months. During this period, there were no cases of the development of arterial or venous thrombosis and thromboembolism, there were no newly detected cases of malignant oncological diseases. The subjective tolerance of taking a combination of ethinyl estradiol with DRSP was good. An increase in the activity of liver enzymes, levels of total bilirubin and blood creatinine, potassium has not been registered in any person.

An example of the use of HRT with drospirinone in postmenopausal women.

The study involved 84 postmenopausal women. The average age of the patients was 52.0 ± 5.03 years. All women were previously examined by a gynecologist, who determined the indications and contraindications for HRT. A group of women (2) who wished to take HRT, containing 1 mg of 17β-estradiol and 2 mg of DRSP, were 44 patients. The reception regimen is continuous at the same time of the day. Control group 2a included women who did not wish to take HRT.

Methods

All patients underwent a standard general clinical examination with the determination of anthropometric parameters, a gynecological examination (including a smear for oncocytology). Laboratory studies included the study of the lipid spectrum, glucose, uric acid, aspartic and alanine hepatic transaminases, creatine phosphokinases, an oral glucose tolerance test, a general blood count, a hormonal blood count, and a hemostasiogram was studied.

During a gynecological examination, mammography, an ultrasound of the pelvic organs were additionally performed to determine contraindications to the appointment of hormonal therapy. Also, during the examination, an office measurement of blood pressure and ECG was performed. All women were questioned using the Beck test to assess the severity of depressive disorders, the Spielberger test, a questionnaire to identify signs of autonomic changes, and a study of the modified menopausal index.

The parameters of the daily BP profile were determined by the SMAD method using the SpaceLabs 90217 non-invasive portable monitor (SPACELABS MEDICAL, USA). Measurements were carried out after 15 minutes during the day (from 7 to 23 hours) and after 30 minutes at night (from 23 to 7 hours). In the daily BP profile (SPAD), the time-averaged values of SBP and DBP were calculated for two time periods - day and night according to the formula

M = Σx / n,

 where M is the average value of blood pressure; x is the unit value of blood pressure; n is the number of measurements; pulse BP (PAD) was calculated as the difference between SBP and DBP (PAD> 53 mmHg was regarded as increased). "Pressure loading" for SBP and DBP (day, night) was evaluated by the index of time index (SI) BP; the time index was defined as the percentage of time during which blood pressure exceeded the normal level (during the day> 140/90 mm Hg, at night> 120/80 mm Hg). The daily rhythm of blood pressure was estimated by the degree of nighttime decline (SNA) of SBP and DBP, calculated by the difference between the average values of blood pressure for day and night, referred to the average daily values of blood pressure (%). As an indicator of blood pressure variability, the standard deviation (STD) from the mean values of SBP and DBP was calculated separately for day and night hours.

Ultrasound examination of the carotid arteries was performed in a patient position lying on the Philips iU-22 (9 MHz) with a slight deviation of the patient’s head in the opposite direction. The measurements were carried out in B-mode in a longitudinal section along the posterior wall of the artery at a distance of 1.0-1.5 cm proximal to the bifurcation of the OSA.

The stiffness of the great arteries was evaluated using an automated technique - volumetric sphygmography. It was performed on a Vasera VS 1000 instrument (Fukuda Denshi, Japan). SPVpl calculated automatically by the formula

SPV = (AL-AP) / ΔT,

 where AL is the length of the vessel from the beginning of the aorta to the place of application of the cuff to the ankle; AP - the length of the vessel from the beginning of the aorta to the place of application of the cuff on the shoulder;

ΔТ is the time between the beginning of the pulse wave recorded on the shoulder and the beginning of the pulse wave recorded on the ankle.

Vasera VS 1000 automatically calculates arterial stiffness index - cardio-vascular vascular index - CLSI (cardio-ankle vascular index, CAVI). Being a derivative of SST on the aorto-ankle segment, it allows one to judge the true stiffness of the arteries, minimizing the effect of blood pressure. Vasera VS 1000 automatically calculates the SPVpl and KLSI right and left. The IP index was automatically calculated - the growth index (augmentation, augmentationindex, AI) characterizing the magnitude of the reflected wave. It was calculated by the formula

IP = P1 / P2,

where P1 is the pressure at the peak of the shock wave and P2 is the pressure at the peak of the reflected wave. Additionally, volumetric sphygmography allows you to automatically determine the ankle-brachial index (LPI), which reflects the degree of stenosis or occlusion of the arteries of the lower extremities during atherosclerotic obliteration. LPI is calculated by the formula:

LPI = GARDEN on the ankle / GARDEN on the shoulder.

Traditionally, they are guided by the worst (lower) indicator. The magnitude of the LPI from 1.0 to 1.3 was considered normal, LPI <0.9 (with a sensitivity of 95% and a specificity of 100%) indicates vascular stenosis of the lower extremities.

The parameters of microcirculation in the skin were evaluated by laser Doppler flowmetry (LDF) using a single-channel laser blood flow analyzer LAKK-02 (LAZMA, Russia) with a wavelength of 630 nm, which allows penetrating to a depth of not more than 1 mm and assessing the nature of tissue perfusion in 1.0-1.5 mm ³ skin. The study was carried out in the following volume and sequence: 1) basal perfusion (BP); 2) respiratory constrictor test (DP); 3) constrictor test with venous occlusion (VO); 4) thermal dilator test (TP); 5) electrostimulation dilator test (EP); 6) dilator test with 5-minute arterial occlusion (OP). The total study time along with the adaptation period was 65-70 minutes.

The average level of tissue perfusion (M) was estimated, which represents the average blood flow in the time interval of registration and is proportional to the speed of the movement of red blood cells (Uer), the size of the hematocrit (Ht) and the number of functioning vessels (Nv) in the probed tissue volume: M = Vер × Ht × Nv.

To assess the functional state of the regulatory mechanisms of blood flow modulation at the level of microvessels, the amplitude-frequency wavelet analysis (ASF) of blood flow oscillations was used.

Statistical data processing was performed using the software package "StatSoftIns." (USA) Statistica 6.0 for MicrosoftWindows. All indicators were checked for compliance with the normal distribution. Student's parametric 1 test was used. The results are presented as the arithmetic mean and its standard deviation (M ± σ), as the median or as a percentage of the analyzed group. Comparison of groups by quantitative and ordinal signs was carried out by a nonparametric method using the Mann-Whitney criterion. Comparison of the results of treatment within groups was carried out using the Wilcoxon test. Differences were considered significant at a significance level of p≤0.05.

results

Assessment of changes in the severity of menopause syndrome (CS) in the studied groups of women 2 and 2a in postmenopausal women was carried out initially and after 12 months of observation. According to the results of this study, which included 84 postmenopausal patients, the frequency and severity of menopausal disorders according to the results of a MMI questionnaire, women in group 2 and group 2a were comparable. In the examined postmenopausal women, neurovegetative and psychoemotional symptoms predominated in the structure of CS (Tables 7, 8).

Table 7. Distribution of symptomatic complexes of CS in the studied groups 1 and 1a among postmenopausal women (average score for MMI) (M ± sd) Symptoms Points Group 2 (n = 44) Group 2a (n = 40) Neurovegetative 19.4 ± 0.4 20.0 ± 0.5 Metabolic endocrine 4.3 ± 0.4 4.8 ± 0.5 Psycho-emotional 13.0 ± 0.6 12.4 ± 0.5 Note: differences between groups are not significant (p> 0.05)

After 12 months, the severity of neuro-vegetative, metabolic-endocrine and psychoemotional symptoms with HRT decreased significantly. In the postmenopausal women control group, no positive dynamics were detected.

Table 8. The percentage of changes in the severity of symptoms of the COP in postmenopausal women,% Group 2 Group 2a Originally 12 months Originally 12 months Neurovegetative symptoms Mild 21 6 * fifteen 17 Medium grade 46 5* 36 39 Severe degree 12 0 * 8 10 Exchange-endocrine symptoms Mild 19 90 * 12 10

Medium grade 81 10* 88 90 Psychoemotional symptoms Mild thirty fifty* 25 fifteen Medium grade 55 3 * 56 68 Severe degree fifteen 0 * 17 17 Note: p values are marked in the table (* p <0.001)

Thus, after 12 months of HRT administration in postmenopausal women, there was a significant decrease in the severity of all symptom complexes of CS with a transition from severe and moderate severity to mild and / or absence of symptoms. In control group 2a, who did not take HRT, there were no significant changes in the frequency of complaints of women.

Initially, more than a third of postmenopausal women - 32 (38%) people - had 1 degree of obesity. Table 9 presents the dynamics of anthropometric indicators against a background of 12 months in the 2nd group of women taking HRT and in the control group. In postmenopausal women, on the background of HRT, a significant decrease in body weight, BMI, and visceral obesity (OT) was revealed. In control group 2a, a significant increase in indicators was revealed (Table 9).

Table 9. Change in body weight, BMI, RT after 12 months in postmenopausal women (M ± sd). 2 group 2a group Indicators Originally After 12 months Originally After 12 months Body weight 75.0 ± 14.6 73.6 ± 13.8 * 78.3 ± 15.6 80.6 ± 14.5 ** BMI, kg / m ² 28.0 ± 4.9 27.3 ± 4.8 * 29.3 ± 5.9 30.3 ± 5.5 ** From cm 85.0 ± 13.0 82.8 ± 11.3 * 89.0 ± 11.7 92.0 ± 12.7 ** Note: the table shows p values (* p <0.05, ** p <0.001) obtained by comparing the indicators after 12 months relative to the initial indicators separately for groups 1 and 1a.

When conducting an individual analysis of the dynamics of the studied parameters in the 2nd group of HRT administration, a decrease in body weight was detected in 25 (56.8%) patients by an average of 4 kg, in 5 (11%) the body weight did not change, in 14 (31.8%) ) Weight increased by 2.8 kg. In control group 2a, in 30 (75%) body weight increased on average by 3.8 kg, in 4 (10%) weight did not change, in 6 (15%) body weight decreased on average by 3.5 kg, differences in the magnitude of the decrease and increase in body weight in the groups are comparable (p <0.0001).

In group 2, a decrease in BMI was detected in 21 (47.7%) patients by an average of 2.3 kg / m ² (relative to the initial level), in 16 (36.3%) BMI did not change, and in 7 (16%) it was found increase in BMI. In the control group 2a of postmenopausal women who did not take HRT, an increase in BMI was found in 30 (75%) by an average of 2.3 kg / m ² (relative to the initial level), a decrease in BMI was found in 3 (8%), without change - in 7 (18%), differences in the magnitude of the decrease / increase in the groups are comparable (p <0.0001).

In a group of 2 women taking HRT, 29 (66%) showed a decrease in RT by an average of 4.5 cm, 4 (9%) did not change, and 11 (25%) showed an increase of 3.2 on average see. In control group 2a, 31 (78%) showed an increase in OT by an average of 4.8 cm, in 1 (3%) it did not change, in 8 (20%) it decreased on average by 3.3 cm, differences in the magnitude of the decrease and increase in the value of RT in the groups was comparable (p <0.0001).

Thus, while taking DRSP-containing HRT, a significant decrease in body weight, RT, and BMI was noted, while a statistically significant negative dynamics in the form of a significant increase in these indicators was found in the control group of women.

Initially, hyperlipidemia was diagnosed in 76 (91%) postmenopausal patients. An increase in total cholesterol was observed in 75 (89%) participants, an increase in LDL in serum was observed in 62 (83%), a decrease in HDL was observed in 68 (91%), and hypertriglyceridemia was observed in 17 (21.8%) (n = 84). .

After 12 months in group 2, while taking HRT, a significant decrease in the level of cholesterol was revealed from an average of 6.2 ± 0.9 mmol / L to 5.8 ± 0.9 mmol / L (p = 0.005), and LDL levels in serum - on average, from 3.8 ± 0.8 mmol / L to 3.5 ± 0.8 mmol / L (p = 0.027). The level of TG did not significantly change: initially it was 1.1 (0.8; 1.5) mmol / L, after 12 months - 1.3 (0.9; 1.5) mmol / L (p = 0.14) . The content of HDL in the blood serum of women during treatment with HRT did not significantly change, being 1.6 ± 0.4 mmol / L before treatment and 1.6 ± 0.5 mmol / L after treatment (p = 0.25). After 12 months, in group 2a of women who did not take HRT, there was a tendency to increase the level of cholesterol in the blood serum from 5.9 ± 1.2 mmol / L to 6.1 ± 1.0 mmol / L (p = 0.3) , the level of LDL significantly increased from 3.7 ± 1.0 mmol / L to 4.0 ± 1.1 mmol / L (p = 0.027). After 12 months, the HDL content in the blood serum of women significantly decreased: from 1.5 ± 0.3 mmol / L to 1.4 ± 0.3 mmol / L (p = 0.02). The TG level also did not significantly change: initially 1.3 (1.1; 1.8) mmol / L, after 12 months - 1.2 (0.9; 1.7) mmol / L (p> 0.05) .

In an individual analysis of the frequency dynamics in the group receiving HRT, 25 patients (61%) recorded a decrease in the level of total cholesterol by an average of 0.7 mmol / l, in 24 (69%) patients there was a significant decrease in LDL. The level of TG and HDL did not significantly change (p> 0.05).

It should be noted that in group 2 the magnitude of the decrease in total cholesterol was more than 2 times the magnitude of its increase (p = 0.018). In group 2a of control of women who did not take HRT, the level of cholesterol increased in an average of 0.61 mmol / l in 24 (65%) patients, an increase in LDL level occurred in 24 (75%) patients, and HDL level decreased in 21 (66%) women, the level of TG did not significantly change (p> 0.05).

When analyzing HRTT data, there were no violations of carbohydrate metabolism in patients treated with HRT and in the control group. After 12 months, fasting glucose was 5.2 ± 0.6 mmol / L in group 2 and 5.3 ± 0.7 mmol / L in group 2a, 2 hours after glucose intake - 6.0 ± 1.4 mmol / l and 6.2 ± 1.6 mmol / l, respectively.

Thus, in women taking the combination of estradiol with DRSP, there was a positive effect on lipid metabolism in the form of a significant decrease in total cholesterol, LDL. In group 2a of women who did not take HRT, a deterioration in lipid metabolism was observed, namely, a significant increase in LDL and a decrease in HDL.

After 12 months, women of the 2nd group, while taking HRT, showed a decrease in clinical blood pressure: from an average of 124.6 ± 16.8 mm Hg. up to 119.1 ± 12.3 mmHg (p = 0.0076), DBP decreased on average from 78.2 ± 10.8 mmHg. up to 73.4 ± 6.9 mmHg (p = 0.002). In the 2nd group of the control, a statistically significant increase in clinical blood pressure was noted, but within the normal range: SBP increased on average from 123.4 ± 13.4 mm Hg. up to 133.9 ± 12.6 mmHg (p <0.001), DBP increased on average from 78.9 ± 9.4 mm Hg. up to 85.7 ± 10.0 mmHg (p <0.001).

Using frequency non-parametric analysis, it was found that initially 15 (34%) women in group 2 and 11 (28%) women in group 2a had high normal blood pressure, after 12 months this ratio changed: only 6 (14%) remained high normal blood pressure, and in group 2a it was already registered in 25 (63%) women (p <0.0001). Thus, in group 2, the frequency of recorded high normal blood pressure decreased from 34% to 14%, and in group 2a of the control it increased from 28% to 63%, respectively.

In the HRT group, no significant changes in the ABPM parameters were revealed. In the control group of women, the maximum and average parameters of SBP significantly increased from 142.4 ± 16.4 mm Hg. up to 153.1 ± 18.0 mmHg (p <0.05), and from 117.9 ± 12.3 to 124.4 ± 13.3 mmHg. (p <0.05), respectively, the average maximum and average blood pressure, variability of DBP and PAD (Table 10-11). At night, in a group of 2 women taking 1 mg of estradiol and 2 mg of DRSP, there were no statistically significant changes. In group 2a, there was an increase in the maximum, average, and minimum values of SBP from 125.5 ± 18.0 mm Hg. up to 133.0 ± 18.5 mmHg, s 104.0 ± 13.4 mmHg up to 111.8 ± 15.0 mm Hg and with 85.2 ± 12.2 mmHg up to 93.3 ± 13.3 mmHg respectively, as well as the average indicator of average blood pressure and PAD.

Table 10. Daytime BP in women of group 2 taking HRT and group 2a of control according to the ABPM (M ± Std) Group 2 Group 2a Indicators Originally 12 months Originally 12 months GARDEN max,
mmHg. 139.8 ± 15.5 140.6 ± 12.0 142.4 ± 16.4 153.1 ± 18.0 * GARDEN
mmHg. 119.2 ± 12.2 119.5 ± 10.1 117.9 ± 12.3 124.4 ± 13.3 * GARDEN min,
mmHg. 99.5 ± 13.3 97.7 ± 13.8 92.7 ± 11.9 96.6 ± 14.8 IV garden,% 12.6 ± 22.1 11.4 ± 10.5 13.7 ± 17.6 14.4 ± 9.5 DBP max,
mmHg. 92.5 ± 12.3 93.6 ± 6.2 94.2 ± 10.1 100.5 ± 12.5 * DBP cf.
mmHg. 77.4 ± 7.9 76.6 ± 5.9 77.6 ± 10.9 78.7 ± 7.6 DBP min,
mmHg. 60.4 ± 8.4 58.3 ± 9.6 56.3 ± 10.2 57.2 ± 11.0 IV DAD,% 11.1 ± 12.9 10.7 ± 18.1 13.1 ± 14.9 12.7 ± 18.1 Avg. Max,
mmHg 109.3 ± 10.5 109.5 ± 9.3 111.3 ± 12.8 119.4 ± 12.9 * Avg.
mmHg. 92.6 ± 9.1 91.6 ± 6.7 90.7 ± 8.7 94.7 ± 8.3 * Avg BP min, mmHg 74.5 ± 10.2 72.3 ± 11.8 69.7 ± 9.5 69.6 ± 12.2 STD GARDEN 10.5 ± 2.5 10.3 ± 3.0 12.3 ± 3.1 13.5 ± 3.4 STD DAD 8.2 ± 2.2 8.4 ± 2.2 8.7 ± 2.4 10.4 ± 3.2 * STD avg. 8.7 ± 2.2 9.0 ± 2.3 9.7 ± 2.9 11.5 ± 3.1 SI GARDEN,% 10.4 ± 6.5 14.4 ± 20.9 11.4 ± 6.9 10.0 ± 8.6 SI DAD,% 13.8 ± 7.3 17.1 ± 21.1 14.8 ± 8.2 13.4 ± 8.6 PAD 42.3 ± 7.0 42.9 ± 7.4 41.4 ± 7.3 45.6 ± 9.9 * Heart rate, beats / min 75.5 ± 8.6 77.4 ± 7.7 74.8 ± 10.6 78.3 ± 10.5

Note: * p <0.05; GARDEN max - maximum systolic blood pressure, GARDEN avg. - mean systolic blood pressure, SBP mmin - minimum systolic blood pressure, DBP max - maximum diastolic blood pressure, DBP cf. - average diastolic blood pressure, DBP mmin - minimum diastolic blood pressure, Avg. AD max - maximum average arterial pressure, Avg. - mean arterial pressure, Avg. arterial pressure mmin - minimum mean arterial pressure, IV - time index, STD - variability of arterial pressure, SI - daily index, PAD - pulse arterial pressure, heart rate - heart rate. The data in the table are presented as M ± Std. Table 11. BP indicators at night in women of 2 groups taking HRT and 2a of the control group according to the Smad, (M ± Std) Group 2 Group 2a Indicators Originally 12 months Originally 12 months GARDEN max,
mmHg. 128.0 ± 17.7 129.2 ± 15.0 125.5 ± 18.0 133.0 ± 18.5 * GARDEN
mmHg. 108.2 ± 14.7 108.1 ± 10.8 104.0 ± 13.4 111.8 ± 15.0 * GARDEN min,
mmHg. 88.3 ± 11.3 90.4 ± 13.0 85.2 ± 12.2 93.3 ± 13.3 * IV garden,% 9.5 ± 6.8 9.4 ± 7.5 8.9 ± 10.2 9.4 ± 9.5 DBP max,
mmHg. 84.7 ± 9.1 82.6 ± 7.5 84.1 ± 12.0 84.0 ± 9.1 DBP cf.
mmHg. 67.1 ± 8.2 67.3 ± 7.5 65.7 ± 7.5 68.0 ± 8.5 DBP min,
mmHg. 51.0 ± 7.4 52.1 ± 8.6 49.0 ± 9.5 51.7 ± 8.2 IV DAD,% 9.3 ± 10.4 9.2 ± 9.6 9.1 ± 10.2 9.4 ± 10.4 Avg. Max,
mmHg 97.8 ± 12.2 97.5 ± 9.2 97.5 ± 11.4 100.7 ± 11.0 Avg.
mmHg. 81.7 ± 9.8 81.4 ± 6.8 78.9 ± 8.2 83.4 ± 10.2 * Avg. Min,
mmHg 65.3 ± 8.4 67.3 ± 8.4 62.2 ± 9.6 66.9 ± 9.1 STD GARDEN 10.9 ± 4.0 10.6 ± 2.7 10.8 ± 2.5 11.5 ± 2.9 STD DAD 9.5 ± 3.2 8.9 ± 2.2 10.1 ± 3.6 9.3 ± 2.0 STD avg. 8.6 ± 4.2 8.6 ± 2.5 10.2 ± 3.3 9.7 ± 2.4 PAD, mmHg 41.1 ± 8.6 40.8 ± 8.8 38.3 ± 8.1 43.8 ± 9.9 * Heart rate, beats / min 67.3 ± 8.9 66.8 ± 7.0 65.5 ± 8.0 67.7 ± 7.9 Note: * p <0.05

GARDEN max - maximum systolic blood pressure, GARDEN avg. - mean systolic blood pressure, SBP min - minimum systolic blood pressure, DBP max - maximum diastolic blood pressure, DBP cf. - average diastolic blood pressure, DBP mmin - minimum diastolic blood pressure, Avg. AD max - maximum average arterial pressure, Avg. - mean arterial pressure, Avg. arterial pressure min - minimum mean arterial pressure, IV - time index, STD - variability of arterial pressure, SI - daily index, PAD - pulse arterial pressure, heart rate - heart rate. The data in the table are presented as M ± Std.

Heart rate on average did not significantly change in both groups. The blood pressure profile (the degree of nighttime decrease in SBP and DBP) did not statistically significantly change.

In the group of postmenopausal women, with hypertension for the first time, after a few weeks out of 3 women with hypertension of the 2nd degree, blood pressure decreased to normal values in two women, and in one, it passed to 1st degree hypertension. A combination of perindopril and hydrochlorothiazide was prescribed for this patient; later, the patient's blood pressure level remained within the target values <140/90 mm Hg. Out of 13 women with grade 1 hypertension, in 12 patients blood pressure decreased to normal values, in 1 patient blood pressure decreased, but did not reach the target values, she was prescribed perindopril at a dose of 2.5 mg. In the control group, changes were observed in a negative direction: after several weeks, out of 9 patients with grade 1 hypertension, 3 went into grade 2 hypertension, and 6 patients with grade 2 hypertension did not change. A combination of perindopril and hydrochlorothiazide was also prescribed to all 15 women. After 12 months, 11 participants were diagnosed with newly diagnosed hypertension.

Thus, taking a combination of estradiol with DRSP as a whole did not have a significant effect on the clinical numbers of blood pressure and indicators of BPM, which were within the normal range; in the control group, a predominant increase in the levels of SBP, PAD, and variability, but within the normal range, was revealed.

An example of the effectiveness of a metabolic corrector - meldonium in postmenopausal women

The use of the domestic drug meldonium may become a new direction in the correction of systemic metabolic disorders in women with menopausal disorders and menopausal MS.

Meldonium is a structural analogue of gamma-butyrobetaine, a precursor to the synthesis of carnitine. When it is taken, the amount of gamma-butyrobetaine increases and the amount of carnitine decreases. It is carnitine that is the vehicle with which long-chain fatty acids are delivered to the mitochondria. The advantages of meldonium is that the latter indirectly inhibits the β-oxidation of free fatty acids in mitochondria, preventing their transport. Moreover, when taking meldonium in mitochondria, the concentration of under-oxidized, intermediate products of fatty acid metabolism does not increase, which, when activated, free radical processes serve as a source of the formation of toxic lipoperoxides.

Meldonium activates both of the most important enzymes in the aerobic glucose oxidation cycle:

- hexokinase, which involves not only glucose, but also other hexoses in the oxidation process;

- pyruvate dehydrogenase, which involves the formation of sugar from pyruvate in the Krebs cycle, thereby preventing the formation of lactate (acidosis).

With a decrease in the concentration of carnitine in the cytosol, the rate of transport of fatty acids to the mitochondria also decreases, which in turn helps to restore the transport of all ATP already produced to the cytosol. An increase in the concentration of fatty acids in the cytosol is a kind of signal to the cell that the oxidation of fatty acids is impossible for some reason. The body responds to such a signal by activating the mechanisms of glucose oxidation.

Thus, meldonium affects the energy metabolism associated with the switch of myocardial cells from fatty acid oxidation to oxygen-saving glucose oxidation.

Materials and methods

The study included 94 women in the period of early postmenopause with menopausal disorders at the age of 53.3 (50.0; 56.0) years.

The 1st group included 28 women who, together with the gynecologist for clinical indications, were prescribed HRT with the “Angelik” drug (1 mg of 17β-estradiol and 2 mg of drospirenone (DRSP)) once a day daily, the 2nd group included 36 patients for various reasons (woman’s reluctance, contraindications to taking the drug from the gynecologist) who did not receive HRT, who were prescribed the drug “Mildronat” at 500 mg 2 times a day. The control group consisted of 30 women who did not receive treatment with “Angelik” and “Mildronat” drugs. The follow-up was 16 weeks.

When included in the study and after 16 weeks of observation, all participants underwent a general clinical examination, determination of the main biochemical parameters of blood (bilirubin, aspartic and alanine aminotransferases, creatinine, uric acid, lipid profile testing and glucose tolerance test).

To assess the degree of overweight or obesity, a body mass index (BMI) was calculated - body weight (kg) / height (m ² ). The severity of abdominal obesity was determined indirectly by the size of the waist circumference (OT) and the coefficient - waist circumference / hip circumference (OT / AB). A value of RT> 80 cm and a coefficient of RT / OB> 0.8 were regarded as a sign of abdominal obesity. For the diagnosis of MS, the criteria of the International Diabetes Federation, 2005 were used.

Daily blood pressure monitoring (BPM) and arterial stiffness were studied by the oscillometric method using the MnSDP-2 apparatus and BPLab software in the expanded edition of Vasotens (LLC Petr Telegin, Russia).

BPM was performed for 24 hours with a measurement interval of 15 minutes in the daytime and 30 minutes in the night. Take into account the average systolic (SBP) and diastolic blood pressure (DBP) during the day, during the day and night; to quantify the magnitude of the pressure load, an index of the index of time of hypertension (IVH) was used; variability of blood pressure day and night. The type of circadian dynamics of blood pressure was determined.

In the study of arterial stiffness, the following indicators were evaluated:

1) the alternative propagation time of the aortic pulse wave (PTT2), based on the identification in the recording of the sphygmogram of reflection from the aortic bifurcation. The path length of the reflected wave differs from the path length of the straight line by twice the length of the aortic shaft, while the measured wave delay was taken to be the delay of the reflected wave, denoted as PTT2, which is determined by the propagation velocity of the pulse wave through the aorta (SRPV);

2) growth or augmentation index (AIx,%), which characterizes the ratio of the amplitudes of the pulse wave reflected and reflected from the aortic bifurcation;

3) the arterial stiffness index (ASI) and the ambulatory arterial stiffness index (AASI) were calculated.

To reduce the dependence of the stiffness indicators on blood pressure and heart rate, their normalized values were calculated - calculation of the values reduced to SBP = 100 mm Hg. and heart rate = 60 beats / min for PTT 100-60, ASI 100-60 and the "reduced" rate AIx-75, recalculated for heart rate = 75 beats / min.

Analysis of the variability of these indicators was carried out during the day.

All patients underwent an echocardiography study according to a unified protocol by one researcher on an ALOKA ultrasound scanner (Japan) with the determination of the main indicators of intracardiac hemodynamics.

As another indicator for assessing arterial stiffness, the aortic pulse wave propagation velocity (aoCTRP) was studied using the ultrasound method. To measure PWV using the ultrasonic method, we recorded the spectrum of flow rates in the descending aorta from the suprasternal access and then in the abdominal aorta at the level of its bifurcation, synchronized with the ECG. Next, we measured the distance from the jugular notch to the sensor at the installation site on the abdominal aorta (L). PWV was determined on the segment of the aorta from its arc to the bifurcation point. PWV was calculated as the ratio L / (T2-T1), where T1 is the time from the Q wave of the EGC to the beginning of the dopplera echo spectrum in the initial segment of the descending aorta, T2 is the time from Q on the ECG to the beginning of the dopplera echo spectrum in the abdominal aorta at the site of its bifurcation.

To determine the antithrombogenic (antiplatelet, anticoagulant and fibrinolytic) activity of the vascular wall, a cuff test was used, based on the creation of short-term local ischemia during occlusion of the vessels of the shoulder with a cuff of a sphygmomanometer according to the method of V.P. Baluda et al.

Platelet aggregation was determined using a Biola laser aggregation analyzer, Moscow. Adenosine diphosphate (ADP) at a final concentration of 2.5 μM was used as an aggregation inducer. The progressive activity of antithrombin III (ATIII) and fibrinolytic activity (stimulated XII-a dependent euglobulin lysis) of plasma was determined using a set of reagents from Tekhnologiya Standard. The total antiplatelet and fibrinolytic activity of the vascular wall was expressed as indices - the ratio of the degree of platelet aggregation and the time of fibrinolysis before and after occlusion of the vessels of the shoulder, the total anticoagulant activity of the vascular wall was expressed as a quotient from dividing the progressive activity of antithrombin III after applying the cuff to it cuff overlay.

To assess the functional state of the endothelium, a non-invasive method was used to determine the flow-induced endothelium-dependent vasodilation (EDVD) in a sample with reactive hyperemia (RG) using high-resolution ultrasound on a MEDISON ECO 7 apparatus.

EDVD was calculated as the relative change in the diameter of the brachial artery by 60 seconds after the RG, expressed as a percentage.

The reaction of the brachial artery was considered positive, in which the increase in its diameter was close to 10% or more from the initial level. Lesser significance or vasoconstriction were considered pathological.

Endothelium-independent vasodilation was evaluated in a sample with nitroglycerin. The change in the diameter of the brachial artery was evaluated at the 5th minute of the study and expressed as a percentage of the initial value.

The change in blood flow velocity in RG was also determined as a percentage of the initial value.

To identify the remodeling assessment of large elastic arteries, the thickness of the intima-media complex (TIM) of the common carotid artery (OCA) was calculated, which was determined 1 cm proximal to the bifurcation by the duplex method on the MEDISON ECO 7 apparatus.

Statistical data processing was performed using the program "Statistica 6.0". In the case of a normal distribution, the studied characters are presented in the form of M ± SD and in the form of a median and interquartile interval [Me (25%; 75%)] if the studied characters did not have a normal distribution. For qualitative indicators, absolute and relative frequencies were calculated. When analyzing intergroup differences in quantitative indicators, the nonparametric Mann-Whitney test was used. To identify existing differences in terms of quality, Fisher’s exact test, χ2 criterion, was used. The critical level of significance in testing statistical hypotheses in the study was p <0.05.

results

The main clinical characteristics of the examined women are presented in table 12.

Table 12. Clinical characteristics of women included in the study Indicators 1 group, n = 28 2 group, n = 36 control group, n = 30 age of patients, years 52.5 (49.0; 55.0) # 53.0 (49.0; 57.0) 54.5 (50.0; 56.0) age of menopause, years 48.5 (47.0; 50.0) # 49.0 (47.0; 52.0) 51.5 (50.0; 55.0) smoking, abs. /% 8 / 28.6 14 / 38.8 7 / 23.3 smoking duration, years 16 (10; 22) 17 (12; 25) 17 (12; 22) arterial hypertension, abs. /% 18 / 64.3 26 / 72.2 20 / 66.7 duration of arterial hypertension, years 3.0 (2.0; 4.0) 4.0 (2.0; 6.0) 5.5 (2.0; 9.0)

carbohydrate metabolism disorders, abs. /% 4 / 14.3 8 / 22.2 3/10 BMI, kg / m ² 29.0 (26.0; 33.3) # 29.2 (27.2; 33.1) && 32.0 (28.1; 36.2) From cm 94.5 (87.0; 106.0) 94.0 (86.0; 103.0) 100.4 (87.0; 110, 0) ITB 0.85 (0.81; 0.86) 0.86 (0.79; 0.90) 0.85 (0.82; 0.92) MS, abs. /% 16 / 57.1 22 / 61.0 16 / 53.3 * - significance of differences between the 1st and 2nd groups (* - p <0.05; ** - p <0.01; *** - p <0.001); # - significance of differences between the 1st group and the control group (# - p <0.05; ## - p <0.01; ### - p <0.001); & - significance of differences between the 1st group and the control group (& - p <0.05; && - p <0.01; &&& - p <0.001).

More than half of the women in the observed groups were diagnosed with MS. More than half of the women were diagnosed with hypertension (1 and 2 degree of increase in blood pressure prevailed) (Table 13).

Table 13. Metabolic profile of women included in the study Indicators 1 group, n = 28 2 group, n = 36 control group, n = 30 Total cholesterol, mmol / l 5.5 ± 0.5 5.6 ± 0.6 5.2 ± 0.9 LDL cholesterol, mmol / l 3.2 ± 0.6 3.3 ± 0.7 3.1 ± 0.5 HDL cholesterol, mmol / l 1.30 ± 0.10 1.26 ± 0.16 1.28 ± 0.13 TG, mmol / l 2.1 ± 0.3 2.3 ± 0.3 2.0 ± 0.3 TG / HDL 1.6 ± 0.2 2.0 ± 0.5 1.6 ± 0.4 Fasting venous blood glucose, mol / l 5.3 ± 0.6 5.5 ± 0.6 5.1 ± 0.5 Uric acid, mol / l 326.1 ± 71 286.5 ± 68 324 ± 70

Initial significant differences between the groups according to the studied indicators were not identified.

The most favorable changes in the blood lipid spectrum were noted in the group of women receiving HRT, and in the group of taking the drug "Meldonium".

In the 1st group, at the end of the study, a significant increase in HDL cholesterol was noted from 1.30 ± 0.10 to 1.34 ± 0.12 mmol / L (p <0.05), a decrease in blood TG level from 2.1 ± 0 , 3 to 1.9 ± 0.5 (p <0.05) and TG / HDL ratios from 1.60 ± 0.2 to 1.36 ± 0.15 (p <0.05), a decrease in the total Cholesterol and cholesterol.

In the 2nd group of women, at the end of the study, there was a significant decrease in the content of TG in the blood from 2.3 ± 0.3 to 1.9 ± 0.5 (p <0.01) and the ratio of TG / HDL from 2.0 ± 0 , 5 to 1.52 ± 0.6 (p <0.05), a tendency to a decrease in total cholesterol and LDL cholesterol and an increase in HDL cholesterol.

In the control group, by the end of the study, opposite changes were noted - an increase in total cholesterol from 5.2 ± 0.9 to 5.6 ± 0.8 mmol / l, LDL cholesterol from 3.1 ± 0.5 to 3.3 ± 0, 8 mmol / l, the ratio of TG / HDL from 1.60 ± 0.4 to 1.66 ± 0.5 and a decrease in HDL cholesterol from 1.28 ± 0.13 to 1.22 ± 0.18 mmol / l, ( differences are unreliable).

The initial significant differences in ADP-induced platelet aggregation before and after the cuff test between the studied groups of women were not identified.

The results of the cuff test indicate a decreased antiaggregatory activity of the vascular wall (AAACC).

By the end of the study, AAACC in women in different groups was significantly and significantly different - in women of the 1st group, while taking estradiol and DRSP after a cuff test, no significant platelet aggregation dynamics were detected, an insignificant decrease in the AAACC index was noted.

In the 2nd group of women, while taking meldonium, a decrease in the manifestations of ED and a restoration of the antiplatelet potential of the vascular wall were noted. In this group of women, after a cuff test, a decrease in platelet aggregation by 14.9% and a clear tendency to increase the AAACC index from 1.1 ± 0.4 to 1.3 ± 0.5 cu were revealed.

In women of the control group, at the end of the study, a further decrease in AAACC was noted - after the cuff test, an increase in platelet aggregation by 3% and a decrease in the AAACC index from 1.1 ± 0.2 to 0.95 ± 0.3 cu were noted.

Initially, the average values of the progressive activity of AT III in the studied groups did not significantly differ and corresponded to the normal values accepted in the laboratory.

In response to vascular occlusion in women of the examined groups, there was a significant increase in the progressive activity of AT III (by 4.6% in women of the 1st group, 2.2% in patients in the 2nd group). Significant differences in the anticoagulation activity of the vascular wall (AKASS) in women of the 1st and 2nd groups were not detected.

In the control group, after a cuff test, the greatest anticoagulant response of the vascular wall was noted - an increase in AT III activity by 9.2% and significantly higher values of the AKASS index compared to the 1st group of subjects.

Despite the similar reaction in response to vascular occlusion, the dynamics of these changes in the examined women was significantly lower than in healthy individuals, which may indicate a decrease in the anticoagulant properties of the vascular endothelium.

By the end of the AKASS study, the women in the studied groups did not differ significantly and was characterized by a significant increase in the progressive activity of AT III (by 8.6% in women of the 1st group, 6.4% in patients in the 2nd group and 5% in the control group) . There was a tendency to increase the AKASS index in women in the group of meldonium and estradiol and DRSP.

Initially, the fibrinolytic activity of blood plasma in women of the examined groups did not significantly differ and corresponded to the normal values accepted in the laboratory.

After short-term vascular occlusion, the fibrinolytic activity of blood in the examined women remained unchanged, which may indicate a reduced ability of the vascular wall to synthesize and excrete components of the fibrinolysis system that support its activity into the bloodstream.

By the end of the study, no reliable dynamics of the fibrinolytic activity of the vascular wall in women in the examined groups was revealed.

Initial differences in the level of fibrinonogen in the studied groups were not identified.

By the end of the study, there was a significant decrease in blood fibrinogen in women in the estradiol and DRSP group from 3.33.3 ± 0.5 to 2.8 ± 0.6 g / l (p <0.01), a clear tendency to decrease in patients in the meldonium administration group from 3.2 ± 0.4 to 3.0 ± 0.4 g / l and a significant increase in fibrinogen in women in the control group from 3.0 ± 0.6. 3.5 ± 0.9 g / l (P <0.01).

The results of SMAD in women with various therapies are presented in table. fourteen.

Table 14. The results of daily monitoring of blood pressure during estradiol therapy with drospirenone (angelica) and mildronate Indicators 1 group, n = 28 2 group, n = 36 Control group, n = 30 initially 16 weeks initially 16 weeks initially 16 weeks The average GARDEN day, mm Hg 130.1 ± 12.7 121.4 ± 7.8 *** 123.7 ± 15.0 118.6 ± 12.1 *** 129.5 ± 6.6 129.0 ± 9.0 Average GARDEN day, mmHg 135.8 ± 10.3 124.0 ± 7.5 *** 127.3 ± 15.8 121.1 ± 11.8 *** 132.3 ± 5.8 131.1 ± 6.9 The average GARDEN night, mm Hg 125.3 ± 17.0 116.4 ± 13.3 * 117.0 ± 14.2 115.1 ± 15.4 123.8 ± 9.8 128.0 ± 10.0 The average DBP day, mm Hg 82.6 ± 6.7 75.7 ± 4.1 *** 75.2 ± 6.3 72.9 ± 6.5 ** 78.0 ± 4.0 79.0 ± 5.3 Average DBP day, mmHg 84.8 ± 5.7 78.2 ± 4.8 *** 78.1 ± 6.4 74.2 ± 5.8 *** 80.0 ± 4.6 81.1 ± 3.3 Average DBP night, mmHg 73.6 ± 7.2 71.2 ± 5.9 67.9 ± 7.7 68.1 ± 8.0 75.5 ± 6.1 74.1 ± 6.1 GARDEN VARIABILITY,
mmHg. 13.8 ± 1.8 12.2 ± 2.3 *** 11.8 ± 2.5 10.9 ± 2.2 ** 12.1 ± 1.3 13.5 ± 1.2 Variability of GARDEN day,
mmHg. 13.0 ± 3.0 11.5 ± 2.8 *** 11.0 ± 2.7 10.3 ± 2.2 * 11.3 ± 1.3 11.6 ± 1.0 Variability of GARDEN night,
mmHg. 11.9 ± 2.7 11.6 ± 3.3 9.1 ± 2.1 8.7 ± 1.9 10.1 ± 2.9 12.3 ± 2.7 Variability of DBP day,
mmHg. 10.7 ± 1.2 9.2 ± 1.7 *** 10.4 ± 2.0 9.3 ± 2.0 ** 9.4 ± 1.3 9.1 ± 1.1 Variability of DBP day,
mmHg. 10.0 ± 2.0 8.2 ± 1.5 *** 9.6 ± 2.2 8.8 ± 2.1 8.7 ± 1.7 8.8 ± 1.7 Variability DBP night,
mmHg. 9.7 ± 1.3 8.9 ± 1.8 7.8 ± 1.9 7.5 ± 1.8 8.7 ± 1.1 8.0 ± 1.3

* - level of significance of differences at the end of the study (* - p <0.05; ** - p <0.01; *** - p <0.001)

Initially, there were no significant differences between the studied groups in terms of SBP and DBP during the day, day and night hours were not detected.

The average levels of SBP and DBP during BPM in women of both groups did not exceed generally accepted normal values.

By the end of the study, the dynamics of the indicators studied in SMAD in women in the 1st and 2nd groups was the same and significantly differed from the control group.

In the group of women taking HRT, there was a significant decrease in SBP during the day, day and night hours by 8.7, 11.8 and 8.9 mm Hg, respectively. In the group of women taking meldonium, a similar, but less pronounced dynamics was noted - a significant decrease in SBP during the day and daylight hours by 5.1 and 6.2 mm Hg. and a downward trend in SBP at night.

In women of the 1st group, at the end of the study, there was a significant decrease in DBP during the day and daytime hours by 6.9 and 6.6 mm Hg, respectively, and a tendency to a decrease in DBP at night. In women of the 2nd group, a similar, but less pronounced dynamics was noted - a significant decrease in DBP during the day and daytime hours by 2.3 and 3.9 mm Hg. and the lack of dynamics of DBP at night.

In women in the control group, there were no reliable dynamics of SBP and DBP during the day, day and night hours to the end of the study were not detected.

By 16 weeks, the HRT and meldonium therapy group showed a significant decrease in the variability of SBP and DBP during the day, daytime hours and the absence of such in women in the control group.

The results of our study, indicating a significant decrease in SBP and DBP, as well as blood pressure variability during the day and mainly during the daytime (active time period), are extremely important to us and may indirectly reflect a decrease in the manifestations of autonomic dysfunction and the restoration of central mechanisms of blood pressure regulation by background of ongoing therapy with HRT and meldonium.

Initial significant differences aoSPV was not identified.

By the end of the study, the dynamics of the studied parameter in women taking HRT and meldonium was of the same type and significantly differed from the control group.

Patients of the 1st group showed a decrease in aoSPV from 7.1 ± 1.2 to 6.3 ± 1.3 m / s, in women of the 2nd group - from 7.2 ± 1.6 to 6.9 ± 1 , 3 m / s and an increase in the studied parameter from 7.4 ± 1.8 to 8.0 ± 1.7 in the control group.

In our study, by the end of the observation, in the group of women taking HRT, there was a significant positive dynamics, characterized by a decrease in the amplitude of the reflected pulse wave (a decrease in the augmentation index and its “reduced” indicator).

A similar trend was observed in patients of the 2nd group on the background of taking meldonium and a clearly opposite dynamics in women of the control group — a significant increase in the augmentation index and its “reduced” indicator.

In women of the 1st and 2nd groups there was an increase in PTT ₂ (significantly in women of the 2nd group) and a decrease in this indicator in the control group.

Despite the absence of significant changes in this indicator in women of the examined groups, in patients of groups 1 and 2 there was a clear tendency to decrease this indicator and its slight increase in women of the control group.

In our study, a significant decrease in the outpatient rigidity index was observed only in the group of women taking HRT, in patients of the 2nd group there was a clear tendency to decrease this indicator. In the control group, on the contrary, a significant increase in AASI was noted.

1. Clinical example.

A 46-year-old woman turned to a cardiologist with complaints of hot flashes, palpitations and interruptions in heart function, sleep disturbance, irritability, depressive mood, and increased appetite.

From the anamnesis it is known: 2 normal births at 20 and 26 years old, followed by 4 abortions, the last at 39 years old, after which she began to gain weight dramatically. Married. Sexual life is active, protected by interruption of sexual intercourse. The menstrual cycle is regular.

Examination: abdominal obesity.

Examination data: weight - 98 kg, height - 158 cm, waist circumference (OT) - 98 cm, BMI - 31 kg / m ² , fasting plasma glucose - 5.5 mmol / l, 2 hours after loading with glucose inward - 7.6 mmol / L, total cholesterol (OXS) - 6.1 mmol / L, low-density lipoprotein cholesterol (HLPLP) - 3.9 mmol / L, high-density lipoprotein cholesterol (HLPVP) - 1.2 mmol / l triglycerides (TG) - 2.7 mmol / L.

Blood pressure (BP) - 136/88 mm Hg, heart rate - 102 in 1 min, single supraventricular extrasystoles.

Diagnosis: obesity of the 1st degree, abdominal (visceral type), hyperlipidemia, sinus tachycardia, supraventricular extrasystole, menopause.

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. By agreement with the gynecologist, contraception with pure progestin-based oral contraceptives (CPPO) is recommended.

Return visit after 4 months.

After 4 months, the weight decreased to 86 kg, BMI - 27 kg / m ² , OT - 92 cm.

HELL - 133/78 mm Hg, heart rate - 86 in 1 min.

Fasting blood glucose - 5.3 mmol / L, 2 hours after an oral glucose load - 7.4 mmol / L, OXS - 5.5 mmol / L, HLPLP - 3.2 mmol / L, HLPVP - 1.3 mmol / L; TG - 2.2 mmol / L.

Despite weight loss and a significant improvement in biochemical parameters, the patient still has complaints of flushing up to 10 per day, sleep disturbance, and poor mood.

It is recommended to continue to comply with the previous recommendations and, in agreement with the gynecologist, replace POPC with a combined oral contraceptive (COC) containing drospirenone.

The patient was on a follow-up visit after 1 month.

Well-being has improved significantly, tides do not bother, sleep has improved, interest in life has appeared, optimism, good mood, appetite has decreased.

Weight decreased to 82 kg, OT - 88 cm, BMI - 26 kg / m ² , BP - 128/72 mm Hg, heart rate - 76 in 1 min, fasting blood glucose - 4.9 mmol / L, through 2 hours after glucose loading by the inside - 7.1 mmol / L, total cholesterol - 5.0 mmol / L, HSLPNP - 2.9 mmol / L, HSLVP - 1.4 mmol / L, TG - 1.9 mmol / L.

On an ECG: sinus rhythm, without pathology.

It is recommended to continue non-pharmacological measures, cancel orlistat, continue taking COCs with drospirenone until menopause occurs.

A year later, the patient appeared on a follow-up visit.

He feels well, no complaints.

Weight - 78 kg, OT - 84 cm, BMI - 25 kg / m ² , BP - 125/70 mm Hg, heart rate - 74 in 1 min, fasting blood glucose - 4, 8 mmol / l, after 2 hours after loading by glucose inward - 7.3 mmol / L, OXS - 4.9 mmol / L, HLPLP - 2.8 mmol / L, HLPVP - 1.4 mmol / L, TG - 1.8 mmol / L.

On an ECG: sinus rhythm, without pathology.

Recommended: proper nutrition, taking into account the characteristics for a given age, walking 5 times a week for 40 minutes, strength exercises. Taking COC with drospirenone. Annual monitoring by a cardiologist and gynecologist.

2. Clinical example.

A 54-year-old woman turned to a cardiologist with complaints of a rapid heartbeat, interruptions in heart function, increased blood pressure to 160/90 mm Hg, hot flashes more than 10 per day, insomnia, depressed mood, and increased appetite.

Anamnesis: Before the onset of menopause, she considered herself practically healthy, did not consult doctors. Menses from 11 years, regular. Married. Two pregnancies in 21 and 24 years ended in normal birth. Protected by mechanical means, 1 abortion. Last menstruation 14 months ago. During this time, she began to dramatically gain weight, the figure changed, obesity mainly in the upper half of the body.

Objective examination: weight - 76 kg, height - 160 cm, RT - 94 cm, BMI - 29 kg / m ² , triglycerides - 2.4 mmol / l, OXC - 6.0, HLPLP - 3.7, HLPVP - 1 , 3, fasting glucose - 5.0, glucose after exercise - 8.2 mmol / L, blood pressure - 146/94 mm Hg, heart rate - 84 in 1 min. On the ECG - sinus tachycardia, single supraventricular extrasystoles.

Diagnosis: Menopause, menopause, visceral obesity, impaired glucose tolerance, arterial hypertension, supraventricular extrasystole, menopause.

Recommendations:

1. Moderately hypocaloric diet with a deficit of 600 kcal, increased physical activity, taking into account the characteristics for this age.

2. Orlistat 1 capsule 3 times a day with meals.

3. Acarbose 50 mg 3 times a day.

4. The combined preparation for HRT with drospirenone 1 time per day after examination and consultation of a gynecologist.

5. Meldonium 500 mg 2 times a day.

After 3 months at the second visit, the patient notes good health, lack of hot flashes, normalization of sleep, mood, appetite.

Body weight decreased to 68 kg, OT - 88 cm, BMI - 27 kg / m ² , triglycerides - 1.9 mmol / L, OXC - 5.5, HLPLP - 3.0, HLPVP - 1.4, fasting glucose - 5.1, glucose after loading - 7.7 mmol / L, blood pressure - 126/74 mm Hg, heart rate - 76 in 1 min. On the ECG - sinus rhythm.

It is recommended to continue non-pharmacological measures and HRT. Orlistat and acarbose cancel. Follow-up after 1 year with a cardiologist and gynecologist.

After a year at the doctor’s visit, the patient notes excellent health, the absence of any health complaints.

Body weight - 74 kg, OT - 66 cm, BMI - 26 kg / m ² , TG - 1.5 mmol / L, OXC - 5.0, HLPLP - 2.7, HLPVP - 1.4, fasting glucose - 5 , 0, glucose after loading - 7.3 mmol / L, blood pressure - 118/72 mm Hg, heart rate - 74 in 1 min. On the ECG - sinus rhythm.

Claims (6)

1. The method of personified prevention of estrogen-dependent diseases in women 45-60 years old with metabolic disorders, including measuring the waist circumference (OT), height and weight, to calculate body mass index (BMI), determining glucose and lipids; and for RTs over 80 cm, 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; 1000 mg of calcium per day for women taking hormonal contraception or hormone replacement therapy (HRT), and 1500-2000 mg not taking hormonal contraception or HRT; 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 at
a) BMI from 25 to 29.9 kg / m ² , the level of glucose and lipids corresponding to the norm, take combined oral contraceptives (COCs) with natural estrogen and dienogest or COC with drosperinone;
b) BMI from 30 kg / m ² and higher, glucose and lipid levels that correspond to the norm, take pure progestin 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 / or dyslipidemia take pure progestin contraceptives (POCC);
d) a BMI of not more than 30 kg / m ² and menopausal syndrome in postmenopausal women take combined hormone replacement therapy (HRT) containing drospirenone;
e) A BMI of more than 30 kg / m ² postmenopausal women take meldonium. 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, in which BMI more than 25 kg / m ² , fasting hyperglycemia and / or NTG and / or hyperlipidemia, and / or arterial hypertension - blood pressure more than 140/90 mm Hg, to reduce weight additionally take an inhibitor of gastrointestinal lipases. 4. The method according to claim 1, in which with fasting hyperglycemia, biguanides are additionally taken. 5. The method according to claim 1, in which, in case of NTG, an alpha glucosidase inhibitor is additionally taken. 6. The method according to claim 1, in which after weight loss less than 30 kg / m ² women in postmenopausal women with menopause take HRT with drospirenone.