Ukrainian Scientific and Practical Center of Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine
L.M. Semenyuk, O.V. Larina
The article provides new data on the prevention of reproductive losses in PCOS. The role of various adverse environmental factors in the formation of functional hormonal imbalance in PCOS is shown. Scleropolycystosis of the ovaries is considered from the position of a multifactorial disease. Improving the quality of the reproductive function of women, which is possible by reducing the toxic effect of drugs prescribed at the pre-gravid stage, with the combined introduction into the body of substances of plant origin and oral contraceptives with an antiandrogen effect.
The paper presents new data on the prevention of reproductive losses in PCOS. The role of various environmental factors on the formation of functional hormonal imbalance in PCOS. PCOS considered from the perspective of multifactorial diseases. Improving the quality of women's reproductive function in which it is possible by reducing the toxic effects of prescribed drugs on Pregravidarnaja stage in the combined administration to a plant-derived substances and oral contraceptives with antiandrogenic effect.
High mortality rates together with low birth rates are the cause of a serious demographic crisis in our country. Despite the achievements of medical science in establishing the causes of pregnancy loss, as well as infertility, this problem remains far from being solved. It is an indisputable fact that various factors affecting the success of future pregnancies depend on the success of the first gestational debut - from uterine to endocrine, since almost 50% of menstrual cycle disorders and secondary infertility manifest after the loss of the first pregnancy [3,5].
Functional hormonal imbalance, which is the basis of spontaneous abortions of the 1st trimester, is more often associated with hypoestrone, hypoprogesteronemia at the stage of selection of the dominant follicle, cytokine imbalance, which is the resulting indicator of malfunctioning of xenobiotic detoxification systems. from a violation of the sleep-rest rhythm, to a violation of the nutrition culture, a hypodynamic lifestyle, as a result, it is accompanied by functional hypercortisolemia, hyperprolekinemia, dyspituitarism, insufficient progesterone-inhibiting blocking factor levels, a decrease in the synthesis of secretory immunoglobulin A, and an increase in pro-inflammatory cytokines. flora and its increased contamination of various biotopes of the body, which closes the pro-inflammatory cascade immune mechanism .
The formation of the menstrual function of a modern woman takes place against the background of psycho-emotional stress that accompanies modern life, environmental pollution and imperfections in food technology, etc. - factors that provoke an increase in consumption and a decrease in the supply of vitamin and mineral compounds to the body of a modern person. The result of the combined effect of adverse external factors and individual features of the genome is the development of multifactorial (combined or complex) diseases (MFD). Today, a large group of diseases is distinguished, in the pathogenesis of which the influence of toxic food, man-made and other harmful factors is considered to be the leading link. They are often defined as "ecogenetic diseases". The reason for their occurrence lies not only in the deterioration of environmental conditions, but also in increased individual sensitivity to the action of damaging factors. Mutant genes (alleles) that are compatible with birth and life, but under certain unfavorable conditions contribute to the development of one or another MFZ, have been called "susceptibility genes" [5,6].
One of the most common diseases of a multifactorial nature in endocrine gynecology is PCOS. Having a hereditary predisposition, the disease manifests itself with a clinical picture of various pathological processes - from a violation of the menstrual cycle with chronic anovulation and hyperandrogenism, infertility or miscarriage, to a tendency to tumor formation, an early manifestation of the metabolic syndrome 
Ways to prevent MFZ diseases today are divided into several levels:
Primary prevention is also called preconception prevention. It is aimed at preventing the conception of a sick child and includes a set of measures and recommendations related to planning childbirth. Preconception prevention includes informing the couple about marital hygiene, planning a child, prescribing therapeutic doses of folic acid and multi-vitamins before conception and during the first months of pregnancy. As world experience shows, such prevention reduces the risk of having children with chromosomal abnormalities and neural tube defects.
Secondary prevention includes the entire complex of screening programs, invasive and non-invasive methods of examining the fetus, special laboratory analyzes of fetal material using cytogenetic, molecular and biochemical research methods in order to prevent the birth of children with severe chromosomal, genetic and congenital malformations.
Tertiary prevention refers to the creation of conditions for the non-manifestation of hereditary and congenital defects, methods of correction of already existing pathological conditions. It includes various options for standard copying. In particular, such as the use of special diets in case of congenital disorders of metabolic processes, drugs that remove toxins from the body or replace missing enzymes, operations to correct the function of damaged organs, etc.
Improving the quality of reproductive function can also be achieved by preventing future serious reproductive and gestational disorders by reducing the toxic effect of drugs prescribed in the pre-gravid stage, by introducing substances of plant origin into the body.
At the same time, it is necessary to take into account the composition of such drugs, since the results of scientific research in recent years indicate that in order to achieve the full biological value of nutrition, it is necessary to introduce into the diet not vitamins taken separately, but correctly selected in the quantitative and qualitative ratio of their combinations between themselves and other substances. This is due to the fact that many chemical processes take place with the participation of several interacting substances at the same time.
Mastolek is a new domestic drug, a plant-vitamin complex that has a positive effect on the metabolism of estrogens. Undoubtedly, the main component of "Mastolek" is indole-3-carbinol (IZK), which effectively affects all types of estrogen-dependent tumors, including malignant, affecting the organs of the female genital sphere (including the mammary gland, uterus, ovaries), inhibits their growth, regulates the metabolism of estrogens, preventing the formation of aggressive 16-hydroxysterone with the formation of hyperestrogenemia. ISK blocks the intracellular signaling pathway coming from growth factors and cytokines, which in turn inhibits excessive proliferation characteristic of diseases such as uterine fibroids, mastopathy, endometriosis, etc., induces apoptosis in tumor cells, selectively inhibiting the transformation and infected with the human papilloma virus (HPV). Prophylactic intake of ISK forms a stable defense of the body at the cellular level.
The use of indole-3-carbinol in polycystic ovaries is associated with its ability to activate a certain form of cytochrome P-450 (CYP 1A1), which is responsible for the formation of 2-hydroxy derivatives of estradiol, and thus restores the normal balance of hydroxy derivative estrogens: weak estrogen2 -E1) and pathological metabolite 16α-hydroxyestrone (16-α-OH-E1), which stimulates cell proliferation. The mechanisms of antiproliferative action of I3K are realized by means of I3K-dependent inhibition of phosphorylation of tyrosine residues of cytoplasmic proteases that transmit a signal from the cell surface to the cell nucleus (growth factors EGF and IGF, nuclear transcription factor NFckF) and inhibition of the response to the action of pro-inflammatory cytokines - tumor necrosis factor alpha (TNF-α) and its "partner" interleukin IL-1 .
The combination of IKA with the extract of broccoli (BrassicaOleraceaItalica) is important in terms of enhancing the effect of broccoli to inhibit the growth of cancer cells. In the course of a study conducted by doctors from John Hopkins College, it was established that broccoli is a source of glucoraphanin, which in the body turns into sulforaphane, which kills bacteria that cause some types of stomach ulcers, and also prevents the development of malignant tumors of this organ. At the same time, it was noted that sulforaphane kills even bacteria that are resistant to antibiotics. Studies conducted by Japanese scientists have shown that sulforaphane stops the growth of skin cancer cells. Broccoli also has the above-described indole-3-carbinol (I3K), which is recognized by scientists as an effective tool for fighting cancer cells, acting on them both directly and capable of stimulating immune anti-cancer protection. Another component of broccoli is sinegrin, a substance that stops the division of cancer cells and causes their death. Women who use broccoli products regularly later note not only a decrease in pain in the mammary gland, but also the dissolution of its small lumps. Broccoli can also affect cardiovascular and neurological diseases and affect the aging process. Currently, mammological oncologists can reasonably recommend the use of broccoli to women with breast diseases. They include this variety in the diet for mastopathy. And not by chance. Broccoli is rich in iodine and is an excellent preventive measure against breast cancer. The combination of the above-mentioned substances with the extract of sacred Vitex (Vítexagnus-castus) allows "Mastolek" to influence the function of the corpus luteum (iron that regulates the menstrual cycle). I would like to note that two plants are widely used in gynecological endocrinology, for the preparations based on which double-blind placebo-controlled studies were conducted, which confirmed their compliance with the criteria of evidence-based medicine. Cimicifugaracemosa, which has been successfully used for the treatment of climacteric disorders, and an extract from the fruits of the common barberry, which has been recommended for the treatment of temporary disorders of the menstrual cycle, as well as for the purpose of eliminating the symptoms of premenstrual syndrome, including premenstrual mastodynia . is used to alleviate premenstrual mastodynia associated with hyperproduction of prolactin, functional hyperandrogenism associated with chronic stress, which is the basis of many endocrine imbalances that lead, as a result, to insufficiency of the luteal phase of the menstrual cycle, infertility, pregnancy losses [ 25].
The next important component of Mastoleka is dandelion root (Taráxacum), which contains a number of plant antiandrogens that help:
• normalize the hormonal background;
• reduce excessive production of testosterone;
• block the production of 5-alpha-reductase and the conversion of testosterone to dehydrotestosterone (DHT);
• increase the level of globulin, which binds sex hormones;
• normalize blood sugar levels and increase insulin sensitivity (insulin resistance is often the cause of polycystic disease and increased DHT production).
Dandelion roots contain terpenes, sterols, polysaccharide inulin (up to 40%), choline, bitter substance lactucopyrin, carotenoids - precursors of vitamin A, vitamins of group B, E, ascorbic acid, minerals (potassium, calcium, manganese, iron, magnesium, zinc, cobalt ), asparagine, tannins, vegetable protein (up to 5%), fatty oil (consisting of glycerides of oleic, melisic, palmitic, linoleic and keratin acids), simple carbohydrates (sugars). And also a significant amount of inulin, taraxasterol, pseudotaraxasterol, homotaraxasterol, beta-amyrin, beta-sitosterol, stigmasterol, taraxal, laculin, clugthionol, inositol, asparagine, P-phenylacetic acid, 3-4-dioxy, linoleic and keratin acids in its complex also provide support for hormonal diseases and mastopathy.
It was important, and in our opinion, pathogenetically justified, to include L-methionine (L-Methionine) in the composition of the drug - an irreplaceable amino acid that improves metabolic processes in the liver, which is necessary for maintaining the body's growth and nitrogen balance. L-methionine contains a methyl group, which is involved in the process of permethylation and is necessary for the synthesis of choline. Due to this, the synthesis of phospholipids from fats is normalized and the deposition of neutral fat in the liver is reduced. L-methionine participates in the exchange of sulfur-containing amino acids, the synthesis of epinephrine, creatinine and other biologically active substances, activates the action of hormones, vitamins (B12, ascorbic, folic acids), enzymes, and proteins. Participates in reactions of permethylation, deamination, decarboxylation. Necessary for the detoxification of xenobiotics, which is especially relevant for most women who use oral contraceptives or undergo a course of estrogen replacement therapy, due to the weakening of the enzymatic processes of their body, estrogen is metabolized into carcinogenic estradiol, which causes pathological prodrugs. ovaries, mammary glands). L-methionine converts carcinogenic estradiol into a less dangerous form of the female hormone - estriol. Also, this amino acid is necessary for the proper functioning of the nervous system, eliminates increased irritability, nervous lability in PMS and climacteric syndrome. L-methionine has a pronounced antioxidant effect, as it is a source of sulfur that inactivates free radicals. The sulfhydryl group of methionine protects cells from the ingress of toxic substances, and also provides transport of selenium and zinc .
The plant-vitamin complex "Mastoleka" contains ascorbic acid, vitamins A, E, D, B2, B6, B12. Ascorbic acid (vitamin C) is an active participant in the regulation of redox processes in the body, has antiaggregant and pronounced antioxidant properties. Strengthens the detoxification function of the liver, increases the body's resistance to infections. Reduces the toxicity of medicines and increases the effectiveness of chemotherapy and radiation therapy during the treatment process. Vitamins A, E, D are necessary for the full functioning of the ovaries, normalize the work of the female reproductive system, and support sexual activity.[20,21,22]
Vitamin A affects human growth, improves the condition of the skin, contributes to the body's resistance to infection, ensures the growth and development of epithelial cells, is part of the visual pigment of the rods of the retina - rhodopsin and the visual pigment of the cones - iodopsin. These pigments regulate the dark adaptation of the eye. Biological action of vitamin A: antioxidant, immunomodulatory, ensuring normal structure and function of epithelium and mucous membranes, reparative and wound healing, regulating blood glucose level, regulating gonadal functions, ensuring metabolism in the retina of the eye, oncoprotective. With a lack of vitamin A, there are disturbances in the work of the immune system, failures in the functioning of the endocrine system and in protection against infections. By affecting the mucous membranes, retinol increases their resistance to viruses, increases the activity of leukocytes, and is also able to protect the genitourinary system, respiratory tract, and gastrointestinal tract from infections .
Vitamin D is a set of biologically active substances that are similar in chemical structure. All D vitamins regulate the level of phosphorus and calcium in the human body. In modern medicine, vitamin D is considered to be vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). In recent years, many works have appeared on the influence of vitamin D on the development of insulin resistance and hyperandrogenism. There is growing evidence of a link between vitamin D deficiency and obesity. The search for genetic markers of predisposition to polycystic ovary syndrome among vitamin D receptor gene polymorphisms is underway. Taking into account the revealed relationship, therapy with vitamin D drugs can become an effective method of treating this disease. In addition to the effect on reproductive function, vitamin D is involved in the regulation of circadian rhythms, the violation of which can also lead to the development of anovulation, i.e. vitamin D deficiency can contribute to the realization of the multifactorial nature of diseases of the female reproductive system [13,15,20].
Vitamin E (tocopherol) - according to its chemical structure, belongs to the group of alcohols. Tocopherol is a reproduction vitamin that has a beneficial effect on the work of the sex glands and some other glands, restores reproductive functions, promotes the development of the fetus during pregnancy and the newborn child. It is a natural antioxidant that prevents the oxidation of vitamin A and has a beneficial effect on its accumulation in the liver. Prevents the development of processes of formation of free radicals and peroxides of fatty acids toxic to the body, oxidative damage of lipid membranes and cellular structures. Vitamin E promotes the assimilation of proteins and fats, participates in the processes of tissue respiration, affects the functioning of the brain, blood, nerves, and muscles, improves wound healing, and delays aging .
In gynecological practice, it deserves attention due to its high antioxidant qualities, it stimulates the production of prostacyclin and thereby prevents the aggregation of platelets in people with diabetes, neutralizing the effects of prostaglandins, it has a clinical effect in the case of threatened abortion, dysmenorrhea, premenstrual syndrome. The antitumor activity of tocopherol is related to its ability to block the conversion of nitrites to nitrosamines, which are strong tumor promoters. The immunomodulating properties of vitamin E are also known.
Vitamins B2, B6, B12 – B vitamins in combination with selenium prevent nervous exhaustion and strengthen the nervous system. Vitamin B2 (riboflavin) stimulates the processes of regeneration and hematopoiesis, regulates the functions of the liver and the central nervous system, participates in the exchange of carbohydrates, fats and proteins, cellular respiration and redox processes.
Vitamin B6 (pyridoxine) improves the functioning of the brain, regulates the functions of the gonads, adrenal glands, thyroid gland, blood glucose level. It has a diuretic, antidepressant, anti-anemic, hypotensive, anti-atherosclerotic, anti-inflammatory, immunostimulating effect. Vitamin B6 helps increase the level of the female hormone - progesterone - in the blood. Promotes the synthesis of endorphins - natural stimulators of mood and emotions, thus having a beneficial effect on the symptoms of menopause and PMS.
Vitamin B12 (cyanocobalamin) improves concentration and memory, increases resistance to colds and viral infections, has an antisclerotic effect, participates in the formation of amino acids, hematopoiesis, enzyme synthesis, protein, fat and carbohydrate metabolism. Many studies have established that vitamins A, C, E and group B are involved in the estrogen exchange and directly affect the reproductive function during menstrual cycle disorders.
Selenium was chosen as the mineral included in the Mastolek complex. According to modern ideas, the biological role of selenium is primarily determined by its antioxidant and immunomodulatory effect . As is known, the influence of external oxidants (radiation, ultraviolet light, chemical pollutants of air, water, food, cold effects and many other factors), as well as the activation of endogenous mechanisms for the generation of active oxygen metabolites and intensification of lipid peroxidation (LPO) processes in various pathological conditions lead to the development of the so-called oxidative stress - an important pathogenic factor of many diseases. The list of these diseases is constantly expanding and includes such socially significant diseases as cardiovascular, bronchopulmonary, oncological and others. In conditions of oxidative stress, there is tension in the body's antioxidant protection system, which needs to replenish antioxidants through their intake with food. That is why it is extremely important that our diet provides the daily needs of the human body in antioxidants, and in certain extreme situations these needs can increase significantly. The circle of natural antioxidants is known to be very wide, and a special place in it is occupied by the glutathione system, the key components of which are enzymes containing selenium - glutathione peroxidases I, II, III and IV . Selenoproteins P and W also have antioxidant functions . The selenoenzyme responsible for thyroid hormone metabolism is 5-iodothyronine deiodinase I, which indicates a close connection between selenium metabolism and iodine metabolism [13,23]. Knowledge of the connection explains the high frequency of thyroid gland pathology in women of Ukraine. Selenium-dependent thyredoxin reductase, the main biological function of which is the catalysis of oxidation/reduction of thyredoxin, a protein responsible for maintaining redox homeostasis in the cell, was relatively recently isolated and identified. In particular, selenium deficiency in the body reduces the production of antibodies, disrupts the differentiation of thymocytes (reduces the number of CD8 + CD4-CD8-thymocytes). At the same time, it was shown in invitro and invivo systems that the addition of selenium increases the mitogenic activity of T cells and the phagocytic activity of macrophages . (Including adhesion processes in the pelvis). All over the world, the problems of using selenium in the diet of a healthy person and therapeutic and preventive nutrition are being discussed very actively.
The results of epidemiological and clinical studies accumulated today in global practice allow us to conclude that selenium deficiency in the environment, which causes its low content in the body, can cause progressive damage to the myocardium (one example is selenium-deficient cardiopathy), impaired reproductive function, pancreatic fibrosis, bronchial asthma and a number of other pathologies . With a reduced supply of selenium and a low content of this element in the blood, the risk of oncological diseases increases. Selenium has a detoxifying effect on heavy metals . The supply of selenium is very important for people who have been exposed to radioactive iodine and are at risk of developing thyroid adenoma.
Numerous studies indicate a decrease in the content of selenium in the blood serum of residents of large industrial cities. Selenium deficiency is observed in old age, in children receiving low-calorie and low-protein food, during pregnancy .
The purpose of the study was to study the effectiveness of the plant-vitamin complex "Mastolek" in the prevention of reproductive losses in women of reproductive age.
MATERIALS AND RESEARCH METHODS
We examined 67 women aged 18–24 years with PCOS (group I), biochemical hyperandrogenism, who, along with hormonal correction (COC with anti-androgenic effect), received the plant-vitamin complex "Mastolik" 1 tab x 2 times a day, and 45 women who received only COCs (group II). The control group consisted of 31 healthy women preparing for pregnancy. All examined had no history of pregnancy.
The state of the hormonal background before treatment and after 6 months of therapy was studied. In order to study the functional state of the pituitary-ovary system, the level of gonadotropic hormones (follicle-stimulating (FSH) and luteinizing (LH)) was studied by the immunoenzymatic method using special test systems UBI (USA), as well as the levels of estradiol and progesterone (ar-systems) Italy ). The level of FSH, LH, prolactin and estradiol was determined on day 5–7 of the menstrual cycle.
Dynamics of indicators of hormonal status before and after treatment on days 5-7 of the menstrual cycle
Hormones 5-7 d.m.c.
(after treatment) (p=67)
Control group (p=31)
P * <0.05 (significant differences of the values before treatment compared to the indicators after treatment) P ** (significant differences of the indicator after treatment compared to the data of the control group.)
When evaluating the data of the central regulation of the reproductive system against the background of the therapy in group I, it was determined that the level of LH and dissociation of LH/FSH significantly decreased by 43.1 and 40.3%, respectively, which is significantly lower than the data obtained before treatment (p<0.05) and corresponds to the level of women in the control group.
The analysis of the prolactin level significantly decreased only in women who received the herbal-vitamin complex "Mastolek" in complex treatment (group I), at the initial level of 618.32±23.54 μU/ml - after treatment it was 313.81±32.08 ( p <0.05), which practically corresponded to the indicator of the control group 316.29±31.
The prolactin index in women with traditional treatment (II group) before treatment was 598.65±18.34, after - 417.08±14.4μU/m (p>0.05)
Within a year after the end of the treatment, 27 women of the I group and 4 women of the II group realized their reproductive function independently. There were reproductive losses in the group that received complex therapy of COC + "Mastolek". In the second group, 3 pregnancies ended with spontaneous abortions in the period of 8-11 weeks, in one case - premature birth occurred in the period of 34 weeks of gestation.
The results of the study indicate the good effectiveness of the plant-vitamin complex "Mastolek", which in combination with other types of medical measures necessary in each specific case (hormone therapy, homeopathic remedies, herbal preparations, drugs that improve blood circulation in organs that regulate reproductive function, anti-stress therapy etc.). ) significantly increases a woman's chances of getting pregnant on her own and, accordingly, allows her to give birth to a healthy child.
The data we received provide grounds for recommending the drug "Mastolek" in the complex therapy of women with PCOS during pregnancy planning.
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