The climacteric period in a woman's life is considered as a transition from the reproductive phase of life to old age [12]. One of the earliest and most striking manifestations of the pathology of menopause is climacteric syndrome (CS), a symptom complex characterized by a combination of neuropsychic, vegetative-vascular, neuroendocrine disorders that sharply reduce the quality of life and are predictors of many later disorders, including cardiovascular and metabolic disorders. metabolic [2]. The most common symptom of CS is hot flashes, which, according to various authors, occur in 50-85% of women [5, 7, 11] and persist from 3 months to 15 years or more. Until recently, it was believed that hot flashes do not cause significant damage to health, but only reduce the quality of life. However, when using modern neuroimaging techniques at the time of tide, a sharp decrease in blood flow was revealed in certain areas of the brain, including the hippocampus, which is responsible for memory mechanisms [6]. In this regard, short-term but frequent episodes of ischemia can contribute to the development of degenerative processes in certain areas of the brain by reducing the number of neurons and synapses, which should especially be taken into account in women with unfavorable heredity: the risk of vascular dementia, Alzheimer's disease. In addition, it is believed that hot flashes may be indicators of latent cardiovascular diseases [10].
CS is a classic indication for traditional hormone therapy (HT) using natural estrogens or their analogues. However, there are contraindications and limitations to the use of HT due to the risk of developing pathology of the endometrium and mammary glands in some patients, and an adverse effect on the thrombogenic potential of the blood. In this regard, alternative methods of correction of CS, which primarily include herbal remedies, are becoming increasingly important. According to P. Albertazzi et al. [3], the number of cases of use of herbal medicines in the USA and England is 60-80%. For CS, herbal preparations belonging to the group of phytoestrogens are often used.
Phytoestrogens
- plant substances that can be divided into three main categories: isoflavones, lignans and coumestans. Phytoestrogens are found in many plants (legumes, soybeans, red clover) [1, 8]. Soy is a major dietary source of isoflavones, but it contains less estrogen-like substances compared to red clover. Among the Asian population, the incidence of breast, endometrial and prostate cancer, as well as the incidence of cardiovascular diseases, is lower than in Western countries [9]. It is believed that this is due to the consumption of large amounts of vegetable protein, which is an integral part of the national diet. It is possible that isoflavones, in addition to estrogenic activity, have other properties that are currently being actively studied.
The isoflavone of red clover extract (REC) has weak estrogenic activity, functionally close to 17β-estradiol, which allows it to bind to estrogen receptors, but 100-1000 times weaker. Such properties of phytoestrogens suggest a different degree of their effect on target organs than estrogens. EKC contains four types of isoflavone: biocanin A, formononetin, genistein and deidzein. The activity of all four substances is greater at estrogen receptor-β (ER-β) than at estrogen receptor-α (ER-α). This may underlie the tissue specificity of ECC [4]. Despite the relevance of phytoestrogens therapy, there is currently a lack of large studies assessing their effectiveness and safety during long-term use. In this regard, we conducted a randomized, blind, placebo-controlled study, the purpose of which was to evaluate the effectiveness and safety of long-term use of a drug containing EKC for the treatment of CS in comparison with placebo.
Material and methods
The study included 70 women suffering from symptoms of CS of moderate severity in the period of peri- and early postmenopause, whose average age was 51.3 ± 5.8 years, and the duration of postmenopause was 3.02 ± 1.4 years. All patients were randomly divided into two groups: Group 1 (main) consisted of 35 women with moderate CS who received EKK (feminal) at a dose of 40 mg once a day for 12 months. Group 2 included 35 patients with moderate CS who received placebo for 3 months. A comprehensive clinical and laboratory examination of patients included assessment of CS symptoms, results of hormonal, biochemical and lipid profile studies, endometrial thickness according to ultrasound, results of endometrial pipette biopsy, and the condition of the mammary glands according to mammographic examination. Determination of the levels of the main neurotransmitters in blood plasma and urine was carried out at zero (2 weeks before the start of the study), first (start of the study), second (3 months after the start of the study), third (6 months after the start of the study), fourth (after 12 months after the start of the study) visits.
Criteria for inclusion in the study.
The study included peri- and early postmenopausal patients aged 45 to 60 years with moderate CS symptoms, who signed an informed consent, had contraindications to classical HT, or refused to take classical HT.
The exclusion criteria from the study were the following:
— presence of estrogen-dependent tumors during the inclusion period;
— taking hormone replacement therapy for less than 3 months before inclusion in the study;
— the presence of diseases of the gastrointestinal tract and severe hepatobiliary complex;
— the presence of central nervous system diseases, mental illnesses that limit the correct adherence to the medication regimen;
- intolerance to the drug;
- pathology of the thyroid gland.
Methods for assessing effectiveness and safety.
The severity of CS symptoms was assessed using the modified menopausal index (MMI), calculated based on the score of CS symptoms
(Table 1).
At the first, second and fourth visits, blood was drawn to study the levels of estradiol, luteinizing hormone, follicle-stimulating hormone, prolactin using the chemiluminescence method. The levels of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, and atherogenic coefficient were assessed at the first and fourth visits using the spectrophotometric method. The levels of creatinine, total protein, glucose, total bilirubin, direct bilirubin, urea, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase were examined at the first and fourth visits using the spectrophotometric method. The levels of the main neurotransmitters in blood plasma and urine (serotonin, norepinephrine, dopamine) were determined using high-performance liquid chromatography during the first, second and fourth visits in the laboratory of the State Scientific Center for Social and Forensic Psychiatry named after. V.P. Serbian. Endometrial thickness was assessed using ultrasound at the first, second, and fourth visits. Endometrial biopsy was performed using a standard technique using vacuum sampling (endometrial aspiration biopsy using a Pipelle curette) at the first visit and at the end of the study (fourth visit). Height and body weight were measured at the first, second, third, and fourth visits. All patients underwent mammography to study breast density before inclusion in the study (if mammography was performed within 12 months before the patient was included in the study, it was not repeated) and 12 months after treatment with the study drug. All mammograms were evaluated centrally and retrospectively to identify any changes from baseline. The density of the mammary glands was assessed in accordance with the classification of J. Wolfe (1976).
Results and discussion
A decrease in the frequency and severity of all symptoms of CS was found in patients taking EKK at a dose of 40 mg/day (feminal), compared with those in patients in the placebo group (Table 2).
The dynamics of MMI in patients of group 1 when taking EKC showed a significant decrease in MMI values, lasting up to 6 months of treatment. In the placebo group, after 3 months of therapy, there was a tendency to increase MMI values, which was regarded as a negative dynamics of CS symptoms. CS therapy in these patients was subsequently continued with the active drug.
By the 6th month of treatment, the effectiveness of therapy in EKC patients, according to MMI, decreased to the initial value in 76% of observations and was maintained for 1 year in only 24% of patients. The data obtained indicate that the maximum effect of EKC use lasts for 6 months and lasts up to 12 months in only 24% of patients.
When comparing MMI in the main group and the placebo group, we found a statistically significant difference after 3 months of therapy (see Table 2):
respectively, MMI 34.85±6.77 and 42.92±6.3 (p<0.01).
To a greater extent, the drug had an effect on neurovegetative symptoms, the manifestations of which in patients of group 1 during 6-month therapy significantly decreased compared to those in the placebo group.
A positive effect was also achieved in relation to the “classical” manifestations of estrogen deficiency - hot flashes and sweating by the 6th month from the start of taking EKC. To a lesser extent, taking the drug affected increased fatigue, decreased memory and libido, which are traditionally classified as androgen-dependent manifestations. The severity of metabolic symptoms remained virtually unchanged.
Based on the results of the hormonal study we obtained, we did not detect significant changes in the levels of the main gonadotropins while taking EKC compared to these indicators in the placebo group.
The level of estradiol (E2) in the main group also did not change. However, in the placebo group, a significant decrease in E2 was detected, which indicates the progression of age-related changes. When comparing the dynamics of E2 levels in both groups, we did not establish any significant differences. The pathogenetic basis for the effectiveness of treatment of patients with CS with EKC may be changes in serotonin levels. An increase in serotonin levels was found in the first 3 months of taking EKC (Table 3).
However, by the 12th month of therapy, a tendency towards its decrease was noted, which coincided with the clinical manifestations in 76% of patients.
When comparing serotonin levels in both groups, significant differences were revealed after 3 months of therapy. Urinary serotonin levels changed similarly. There were no significant changes in the level of norepinephrine in the blood plasma and urine in patients of the main group and the placebo group. Positive dynamics were demonstrated by dopamine levels in blood plasma and urine (Table 4)
in the main group, which correlates with the effectiveness of therapy for 3 and 12 months. We did not find such changes in the placebo group.
When comparing the dynamics of changes in blood plasma dopamine levels in both groups, no significant differences were found.
Of particular interest was the study of the effect of EKC on the ratio of lipids in the blood plasma. When studying the dynamics of cholesterol, HDL, and LDL levels, no significant differences were found. However, by the 12th month of EKC therapy, triglyceride levels significantly decreased (p = 0.03), which apparently is the result of the positive effect of phytoestrogens on lipid metabolism.
The levels of other biochemical parameters (total protein, glucose, alkaline phosphatase, total bilirubin, liver enzymes) did not change throughout the observation period.
When analyzing ultrasound data for one year of taking red clover extract (Table 5)
A significant decrease in M-echo was detected 12 months after the start of therapy. When analyzing ultrasound data while taking placebo, no significant changes in endometrial thickness were detected.
Taking into account the data of the pathomorphological study, no negative effect of taking EKC on the endometrium was identified (see figure).
Figure 1. Results of pathomorphological examination of the endometrium (pipe biopsy) in patients of the main group (n=29).
All patients underwent a mammographic examination to determine breast density. As a result of a year of observation, mammographic density in patients of the main group in most cases did not change or there was a decrease in it.
Thus, the use of a drug containing EKC is effective for the treatment of moderate CS. Maximum effectiveness is observed by the 3rd month of taking the drug and persists up to 6 months of therapy in 76% of patients (p <0.01). However, in 76% of cases, the effectiveness of treatment decreases after 12 months of taking EKC, which requires an increase in the dose of the drug or its replacement.
Analyzing the results of our study, we suggested a possible mechanism of action of EKC, probably realized through the central serotonin and dopaminergic pathways with no effect on gonadotropin levels and insignificant estrogenic activity. In our opinion, phytoestrogens occupy their own niche in the treatment of CS symptoms and are not competitors to hormone replacement therapy.
conclusions
1. The results of our study allow us to conclude that treatment of patients with menopausal syndrome with red clover extract is safe with respect to the development of proliferative processes in the mammary gland and endometrium and does not require the addition of gestagens.
2. Additional positive changes in blood lipid composition obtained during therapy with red clover extract, combined with the absence of hepatotoxicity, expand the therapeutic possibilities of its use in patients with menopausal syndrome.
Effex Red root, 1 piece, 100 ml, oral solution
Composition and release form:
Red root tea drink
30 g per package.
Red root roots
30 g per package.
Red root tincture
(drops of hydroalcoholic extract) in bottles of 50, 100 or 250 ml.
100 ml drops Red root
contains: roots of the forgotten hedysarum neglectum (Hedysarum neglectum) 9 g, ethyl alcohol 20%.
Red root tablets
500 mg, 60 pcs.
packaged. 1 tablet Red root
contains: roots of the forgotten kopek (Hedysarum neglectum) 372 mg, vitamin E 4 mg (tocopherol equivalent), zinc oxide 6.25 mg.
Properties / Action:
Red root (tea kopeck, bear root) is a rare medicinal plant of the subalpine zone; herbaceous perennial from the legume family with a long (up to 5 m) powerful root. The roots are widely popular in Eastern medicine and are used as a general tonic. Red root preparations are biologically active additives (BAS). The red root has anti-inflammatory, antiexudative, vasoprotective, antioxidant, antispasmodic, vasodilating, diuretic, and general tonic effects. The action of the Red Root is due to the properties of the flavonoids, tannins, coumarins, triterpene saponins, free amino acids and other biologically active substances contained in the plant (quercetin, kaempferol, avicularin, hyperoside, catechins). Red root is a natural remedy to help solve men's problems. Helps reduce symptoms of benign prostatic hypertrophy. For inflammation of the prostate gland, urethritis and compression of the ducts due to prostate adenoma, the red root normalizes the activity of the urinary system, improves blood circulation and eliminates congestion in the prostate gland. In case of prostate adenoma, it reduces the symptoms of dysuria: improves urination, promotes more complete emptying of the bladder, reduces the frequency of urination, especially at night. Red root is a non-hormonal stimulant of sexual activity for men. Helps restore male sexual activity. The red root has high P-vitamin activity (see vitamin P): it strengthens the walls of capillaries and reduces their permeability. This explains the widespread use of red root in the treatment and prevention of various diseases. The red root heals the body as a whole: it normalizes the activity of the gastrointestinal tract and has a strengthening effect on the cardiovascular and respiratory systems. It also has a moderate stimulating effect on the heart muscle. There is evidence of the effectiveness of using Red Root for respiratory diseases (chronic obstructive pulmonary disease): it helps reduce the intensity of cough, improve psycho-emotional status, and blood counts. The ability of Red Root extract to stimulate the central nervous system, effectively relieve fatigue, and increase physical endurance has been established. Restores strength during heavy physical activity. Red root preparations are not addictive with long-term use.
Indications:
Red root dietary supplements are used in complex treatment:
- diseases of the genitourinary system in men: acute prostatitis, chronic prostatitis, urethritis, prostate adenoma, impotence, other urological diseases;
- as a general tonic (tincture of red root): normalizes the activity of the gastrointestinal tract, has a slight stimulating and strengthening effect on the cardiovascular, respiratory and nervous systems.
Directions for use and dosage:
Tincture.
50 g of dry raw materials are infused with 450 ml of 30-40 degree vodka for 7-14 days in a dark place at room temperature; then the tincture is filtered. Shake before use. Take for adults 2-3 times a day with meals, 50 drops (1/2 - 1 teaspoon; 2.5 ml) per 1/3 - 1/2 glass of water. Dilution of the ethyl alcohol present in the composition in water eliminates irritation of the urinary tract and mucous tissue of the gastrointestinal tract, which is very important in inflammatory processes. Duration of administration is from 1 to 3 months (depending on the type and severity of the disease, sensitivity to the drug). After a break of 1 month, the course can be repeated. It is recommended to conduct 2 to 4 courses per year.
Pills.
Adults: 1 tablet 2 times a day with meals. Duration of treatment is 1 month. If necessary, the course can be repeated with a 10-day break.
Infusion.
Pour 25 g of crushed root into 1 liter. boiling water, leave for 1 hour in a thermos and drink as tea 3 times a day before meals, 1/3 cup.
Red root tea.
Pour 1-2 teaspoons of red root into a glass of boiling water and leave for 20 minutes.Contraindications:
- hypersensitivity to the components of the dietary supplement Red Root.
Adverse reactions:Allergic reactions are possible.
Special instructions and precautions:
Before using the Red Root dietary supplement, it is recommended to consult a doctor. The red root dietary supplement is not a medicine. The opacity of the Red Root tincture and possible sedimentation during storage do not affect the quality and effectiveness of the drug. The effectiveness of the Red Root tincture is confirmed by clinical studies conducted at the Altai State Medical University and the St. Petersburg Chemical-Pharmaceutical Academy.
Storage conditions:
Store in a dry, cool place, protected from light. The expiration date is indicated on the packaging. Conditions for dispensing from pharmacies - without a doctor's prescription.
