The effect of various progestogens on the antiandrogenic effect of modern combined oral contraceptives. Dosing and Administration of Desogestrel. Side effects of desogestrel

L.D. Zakhurdaeva, Department of Obstetrics, Gynecology and Fetal Medicine, NMAPE named after A.I. P.L. shupik

Today, in civilized countries, one of the most popular means of contraception are hormonal oral contraceptives. So, in Germany, these drugs are used by more than 30% of women aged 15 to 45 years, in the Netherlands - more than 45% of women in this age group, and in France and Belgium this figure reaches 50% (Prilepskaya V.N., 2009).

Fear of gaining weight is the most common female fear of taking hormonal contraceptives (HC). This fear is unfounded. In the vast majority of cases (about 97%), weight gain is due to improper diet and lack of physical activity, and not to the influence of HA. With the correct selection of modern drugs containing a low amount of synthetic hormones, the likelihood of a noticeable increase in body weight is significantly reduced. In 3% of cases, a slight weight gain is possible, but it can be easily corrected with a properly selected diet and fitness classes.

The latest generation of contraceptives contain a minimum amount of hormones and are safe for the body. A systematic review of randomized controlled trials (RCTs) showed no evidence of an association between weight gain and GC intake (Gallo M.F., Lopez L.M. et al., 2006). Initially, 570 RCTs were found for analysis comparing combined oral contraceptives (COCs) with placebo or with some other GC. After excluding studies with no more than three drug cycles of follow-up, and those with insufficient data on weight change, 44 RCTs were included in the final analysis. The COCs evaluated in these studies contained 18 types of progestins and three types of estrogens. The sample size ranged from 20 to 5654 patients (median 143). The duration of studies ranged from 6-12 cycles. Criteria for inclusion in the studies were different, but in most cases, participants were healthy women of reproductive age without contraindications to the use of oral contraceptives (OC). Three RCTs found no evidence for a causal relationship between the use of COCs or combined contraceptives (skin patches) and weight gain. In most cases, when comparing different COCs, there were no significant changes in weight gain. Despite this, in a study comparing drospirenone and desogestrel, there was a significant difference between the two groups. Comment: This difference may well be due to the ability of drospirenone to retain fluid in body tissues. However, the majority of women in both groups had weight fluctuations within 2 kg of baseline. The frequency of discontinuation of COCs due to weight gain did not differ between different contraceptives. Many researchers did not use strictly established methods for measuring body weight. Variation in scale graduation or difference in weighing technique may have affected the results. Similarly, weighing at different times of the day, on an empty stomach or on a full stomach, and the number of participants in the study may have accounted for some of the differences (International Center for Evidence-Based Medicine, 2008).

The reason for the fear of significant weight gain is the fact that earlier, while taking COCs with a high dose of estrogens (50 μg) and progestins, side effects such as metabolic disorders occurred, which were almost impossible to avoid (Samsioe G., 1990). Later, with the accumulation of clinical experience, it was proved that synthetic estrogens, especially ethinylestradiol (EE), induce some metabolic changes that are dose-dependent (Dobrokhotova Yu.E., 2008). Most progestogens of the 1st and 2nd generation are characterized by a rather high anabolic activity (Fig. 1). At the same time, the appearance of 3rd generation progestogens (gestodene, desogestrel), which practically do not have this effect, can largely determine the decrease in the frequency of this side effect. It has been established that in violation of carbohydrate tolerance and the development of hyperinsulinemia, the processes of energy utilization in fat depots are accelerated and fat accumulation increases, mainly in the abdominal type. Studies have shown that high doses of estrogen and

Rice. 1. The evolution of progestins

progestogens induce a decrease in glucose tolerance and increase the concentration of insulin in plasma (Rosenbaum H., 1990; Dobrokhotova Yu.E., 2008). Subsequently, with the appearance of new COCs with a lower dose of hormones, it was possible to minimize their effect on carbohydrate metabolism, which is confirmed by practically unchanged levels of glucose and insulin in the blood. Recent studies have shown that the use of highly selective 3rd generation progestogens in combination with low and ultra-low (20 and 15 μg EE) doses of estrogens did not reveal clinically significant changes in carbohydrate metabolism parameters.

Confirmation of the fact that certain eating behavior (eating more high-calorie, fatty foods) accelerates the accumulation of fat in the body are the results obtained by L.H. Eck and A.G. Bennet in 1997. Scientists conducted a comparative study of women taking OCs and not using them on the following parameters: basal metabolic rate, physical activity and dietary profile, i.e. the quality of food consumed. Comparative analysis showed that people using contraceptives (three-phase COC containing 35 mcg of EE and 0.5-0.75-1 mg of norethindrone), compared with those who did not use GC, ate much more fat than carbohydrates . At the same time, indicators of basal metabolism and physical activity did not differ significantly. The authors concluded that since the consumption of more fatty foods leads to a more active increase in body weight, the change in eating behavior that occurs against the background of COC use may itself be the cause of an increase in the percentage of adipose tissue in the body. In studies by Litchfield and Grunvald (1988), an absolute correlation of the dose of estrogen with body weight, hip and shoulder circumference and peripheral fat distribution in young women (18-26 years old) using OCs with a different dose of the estrogen component was established (Arefyeva M.O., 2009).

The Cochrane database in 2009 provides an overview of studies on the effect of COCs on body weight (Gallo M.F., Lopez L.M. et al., 2008). The data of some clinical trials, namely, quantitative changes in body weight indicators depending on the composition of the compared GCs, are presented in the table. Thus, the results of the conducted studies allow us to conclude that the effect of the estrogen component of contraceptives on eating behavior and peripheral fat distribution is dose-dependent, and in order to neutralize the effect of all metabolic pathways of weight gain, it is desirable to use contraceptives with minimal doses of the estrogen component (15-20 μg EE) in combination with highly selective 3rd generation progestogens (eg gestodene, desogestrel).

Thus, weight gain may be due to the following factors:

● estrogen component (fluid retention, metabolic effect);

● progesterone component (metabolic effect);

● change in diet and diet, reduced physical activity, stress factor, etc.

Based on many years of experience in the use of HA, various methods have been proposed to reduce or level the effect of side effects that occur when taking them:

● if the estrogen component is the cause of side effects, it is recommended to switch from a higher dosage of estrogens to a lower one (from triphasic to monophasic, from 30 mcg to 20 mcg);

● if weight gain is due to fluid retention, COCs with progestins with an antimineralocorticoid effect (gestodene and drospirenone) are recommended. Gestodene has a mild antimineralocorticoid effect. The pronounced antimineralocorticoid activity of drospirenone (3 mg of drospirenone is similar in activity to 25 mg of spironolactone) can contribute to the development of hyperkalemia (especially in patients with impaired renal function, liver and adrenal insufficiency), as well as while using potassium-sparing diuretics. Long-term use of COCs with a pronounced antimineralocorticoid effect requires regular assessment of water-salt metabolism and prevention of hyperkalemia (Arefyeva M.O., 2009);

● if the cause lies in the progestin component, it is recommended to prescribe COCs with a different type or at a lower dose of progestogens.

Table. Body weight changes with different GCs

Approaches to the route of administration of HA (oral, vaginal, transdermal, intrauterine) were also changed in order to reduce side effects. However, according to evidence-based medicine, the Cochrane Review (2007), drug instructions, they all have almost the same effect on body weight.

The effect of COCs on body weight, which are used in a prolonged regimen (24 + 4, 63 + 7, etc.), requires further study. This is primarily due to the fact that against the background of the prolonged regimen, the total hormonal load on the intake cycle increases in comparison with the cyclic regimen (21 + 7). The emergence of COCs with natural estrogens also requires further study of this issue. To date, no significant difference has been identified and there is insufficient data to show the benefits of EE over natural estrogens.

The results of studies conducted at the Scientific Center for Obstetrics, Gynecology and Perinatology named after. IN AND. Kulakova (Russia) (Simkin-Silverman L.R., Wing et al., 1998), showed that the effect of modern COCs on the lipid spectrum depends not only on their chemical structure, dosage and method of application, but also on the initial lipid level in a particular patient. It's in again confirms the significant influence of heredity factors and largely determines the change in body weight when prescribing COCs.

Analyzing the literature data, we can conclude that the constitutional approach in prescribing COCs allows patients to select the drug with the greatest accuracy, taking into account the entire spectrum of their genetically determined characteristics. Such an individualized choice of COCs for each specific woman makes it possible to significantly reduce the number of negative effects of drugs, incl. and their possible influence on fluctuations in body weight.

After summarizing the data of general clinical, gynecological, mental examinations, analysis of anamnestic data and somatometric measurements, we identified the constitutional types of the studied women: endomorphic - with a predominance of estrogen, opposite, mesomorphic - with a predominance of androgens and ectomorphic - with a predominance of progesterone. The hormonal background was confirmed by determining the level of sex steroids. The patients included in the study (100 people) were examined before the start of COC use and after 3-6 months of their regular use.

For persons with an endomorphic constitutional type (with a predominance of a fat component), we recommend using Lindinet 20, which includes 20 µg of EE and 75 µg of gestodene. Lindinet 20 contains the smallest amount of not only the estrogen component (20 μg), but also the progestin component (75 μg) in comparison with other COCs (Fig. 2).

Gestodene, which is part of Lindinet 20, is a 3rd generation progestin and has a pronounced antiestrogenic effect. It exhibits primary activity in blood plasma and has 100% bioavailability, tk. does not undergo metabolic transformation, which contributes to a rapid decrease in the level of estradiol (Fig. 3, 4). Gestodene has a pronounced anti-ovulatory index, which leads to a decrease in the levels of follicle-stimulating and luteinizing hormones, ethinyl estradiol in the blood to normal levels, corresponding to the early proliferative phase of the menstrual cycle. This is the only gestagen that does not stimulate the activity of two types of estrogen receptors in COS-7 cell culture (Rabe T., Bohlmann M.K. et al., 2000). Gestodene is the most powerful and highly selective progestin that does not have glucocorticoid activity (Kuhl H., Drugs, 1996; Tyrer L., 1999).

Gestodene also has an antimineralocorticoid effect, which causes a decrease in the level of circulating renin and relief of such symptoms of hyperestrogenism as breast tension, changes in blood pressure and body weight. Gestodene does not violate the exchange of sodium and potassium, does not affect body weight due to the redistribution of fluid, is not a derivative of 17-α spirolactone. This is a derivative of 19-nortestosterone, which in this group has the greatest similarity of antimineralocorticoid and other pharmacological effects with progesterone (Kirkman R.J.E., 1991; Asetskaya I.L., Belousov Yu.B., 2001).

The given pharmacological properties of gestodene and the minimum content of EE justify the use of Lindinet 20 in patients with hyperestrogenism.

During the study, it was found that an increase in body weight up to 1 kg was observed in 1% of cases, and a decrease up to 2 kg - in 6%. The increase to 1 kg was insignificant, associated with a change in the diet of women and did not serve as a reason for abandoning the method of contraception. These data were confirmed in a Polish study on the effect of Lindinet 20 on body mass index (BMI) (Fig. 5). The trial involved 800 women (predominant age - from 20 to 29 years), who were measured for 6 cycles of BMI. There was no increase in BMI; moreover, there was even a tendency to decrease it.

The fears of women and doctors about the possible effects of COCs on body weight are sometimes exaggerated. When such a side effect occurs, a specialist consultation is necessary.

To reduce the possible side effects of COCs, the following can be recommended:

1. In connection with the peculiarities of the mechanism of action of COCs for long-term use, it is necessary to carefully study the anamnesis and determine the constitutional type of women.

2. COCs should be selected according to the constitutional characteristics of the body. Women with an endomorphic constitutional type (estrogen predominance) can be recommended Lindinet 20.

3. It is desirable that the “starting” drug is a drug with a minimum hormonal load on the intake cycle, for example, Lindinet 20.

4. It is necessary to determine whether the patient belongs to the category of overweight or obese persons, and also to identify the presence of a predisposition to impaired lipid and carbohydrate metabolism.

5. It is very important to warn a woman about possible fluctuations in weight and methods for solving this problem.

7. When prescribing COCs, preference should be given to drugs containing low doses of hormones and progestins of the latest generations.

8. An increase in body weight up to 1 kg is not critical for women and can be observed even without the use of COCs. The benefits of using COCs (prevention of endometrial, ovarian, colorectal cancer, reduction of premenstrual syndrome, treatment of acne and seborrhea) are much higher than the risk of a slight increase in body weight against the background of COC use.

Medical aspects of women's health No. 7 (35) '2010

Endometriosis is a genetically determined, chronic, dyshormonal, immune-dependent disease caused by a benign growth of tissue, similar in morphological structure and function to the endometrium, outside the uterine mucosa.
In the structure of gynecological morbidity, endometriosis ranks third after inflammation and uterine fibroids, affecting up to 50% of women of reproductive age. Being one of the most urgent problems of gynecology, endometriosis leads to functional and structural changes in the reproductive system, often negatively affecting the psycho-emotional state of women, significantly reducing the quality of life.
The frequency of external genital endometriosis is up to 10-15% in the general population, 25-30% in women with infertility and 80% in patients with pelvic pain syndrome. In addition, endometriosis should be considered as a pathological process with a chronic, relapsing course, which is formed and develops against the background of an imbalance of immune, molecular genetic and hormonal mechanisms in the female body.
In recent years, a large number of studies have been conducted on the involvement of growth factors and cytokines in the development of external genital endometriosis. A special role in the pathogenesis of endometriosis is assigned to such growth factors as vascular endothelial (VEGF - vascular endothelial growth factor) and transforming (TGF- β - fibroblast growth factor), etc., which are found in endometrioid heterotopias, peritoneal fluid, blood plasma and are the most powerful angiogenic factors. With an increase in VEGF and a decrease in TGF- β there is an increase in proliferation in the elements of endometrioid heterotopias, proliferation of connective tissue, an increase in the adhesive process, which leads to a further spread of the process.
The modern approach to the treatment of patients with endometriosis consists in complex therapy, consisting of 2 stages: 1) surgical; 2) medication.
The goal of surgical treatment is to restore fertility in case of impaired reproductive function, the cause of which is a heterotopic proliferation of endometrioid tissue on the ovaries, peritoneum, pelvic organs, sacro-uterine ligaments. With the help of laparoscopic access using a variety of modern technologies (laser, electro- or ultrasound), a complete excision of all foci of endometriosis is performed. The next step is drug therapy aimed at inhibiting the activity of the hypothalamic-pituitary-ovarian system and the development of atrophic changes in the tissue of endometrioid heterotopias. For this purpose, combined estrogen-gestagen preparations, active antiestrogen or GnRH-a are used. Due to insufficient satisfactory tolerance in some young patients and the severity of such side effects as menopausal symptoms, atrophic colpitis, "hot flashes" with the use of GnRH, as well as the risk of developing osteoporosis, combined estrogen-progestogen and progestogen preparations have recently been increasingly used. within 3-6 months.
For the study, we chose the drug Charozetta® ("Organon"), which belongs to the class of purely progestogenic contraceptives and contains a minimum dose of progestogen - desogestrel 75 μg. Unlike other contraceptives containing only progestogens, the main mechanism of action of Charozetta® is the suppression of ovulation in 99%. The drug is characterized by a lesser degree of manifestation of estrogen-dependent symptoms, such as headache, breast engorgement, nausea, characteristic of estrogen-containing drugs, more characteristic of COCs. Oral desogestrel 75 mcg is successfully used in the complex therapy of PMS, inflammatory diseases of the pelvic organs, anemia, genital endometriosis. When taking desogestrel 75 mcg, there is no sharp decrease in hormone levels, and, as a result, there is no withdrawal bleeding. Many works describe the positive therapeutic effect of desogestrel as a highly selective progestogen in various gynecological diseases: uterine fibroids, endometriosis, endometrial hyperplastic processes, dysmenorrhea, premenstrual syndrome, fibrocystic mastopathy.
Purpose of the study. To study the dynamics of quantitative parameters of vascular endothelial growth factor (VEGF) and transforming growth factors (TGF- β - fibroblast growth factor) in the blood plasma (as markers of adhesions), the increase in levels of which is characteristic of endometriosis, before and after a 6-month intake of desogestrel, which is part of Charozetta®, and therefore the effectiveness of the drug Charozetta® at the second stage of treatment of patients with endometriosis . Comparison of these parameters with the parameters of the control group as indicators of the effectiveness of therapy.
Materials and methods
On the basis of GKB No. 1 im. N.I. Pirogov, 30 patients of reproductive age 18-45 years old (mean age was 26.4±6.2), with external endometriosis, mainly with the presence of endometrioid cysts of one or both ovaries, endometriosis of the pelvic peritoneum, adhesive process of the small pelvis, were examined. The control group included 30 patients aged 25-40 years with the presence of adhesions in the pelvic area of ​​inflammatory origin, who underwent operative laparoscopy, chromosalpingoscopy for infertility. In this group, peritoneal fluid was taken during operative laparoscopy, followed by quantitative determination and comparison of vascular endothelial growth factors (VEGF) and transforming growth factors (TGF- β - fibroblast growth factor), as markers of the adhesive process with the indicators of these factors in patients with endometriosis.
Upon admission, the hormonal status of the patients, the indicators of the CA-125 marker were examined. The study of blood hormones, the CA-125 marker was carried out on the basis of the laboratory of LLC "Medservice / Diagnostics +" of the City Clinical Hospital No. 1 named after. N.I. Pirogov (head of laboratory A.N. Mi-khal-tsov). Before and after the use of Charosetta, biochemical parameters of blood, general parameters of blood and urine were determined, and additional research methods were carried out - ultrasound of the pelvic organs on the LOGIQ-3 device. Surgical treatment was carried out on the basis of the City Clinical Hospital No. N.I. Pirogov, 18th gynecological department. Quantitative determination of growth factors (VEGF, TGF-

Statistics show that out of 100 women of reproductive age, 36 do not use contraceptives. Meanwhile, from the point of view of modern biology (genetics and embryology), the life of a person as an individual begins from the moment of the fusion of the nuclei of the male and female germ cells and the formation of a single nucleus containing a unique genetic material. During fetal development, the new human organism cannot be considered part of the mother's body. Therefore, artificial termination of pregnancy is the intentional termination of a person's life as a biological individual (http://medicinform.net).

According to official data, in 1999 in Ukraine the number of abortions was 36.7 per 1,000 women of childbearing age, which is significantly higher than in developed countries (Healthcare in Ukraine under permanent reform // Medichniy Rinok. - 2000. - No. 1. - pp. 3–5). This fact strongly dictates the need for a more responsible approach to family planning, including the rational use of natural factors and contraceptives for the purpose of birth control. For several decades, combined oral contraceptives have been effectively used for family planning. Unfortunately, a number of progestogens of the 1st and 2nd generations have a low selective effect on progesterone receptors, in addition, they cause a number of side effects - an increase in blood pressure, an increase in insulin resistance, dyslipidemia, etc. Desogestrel is practically devoid of these disadvantages. This active substance is part of modern monophasic combined oral contraceptives manufactured by the Hungarian pharmaceutical company Gedeon Richter S.A.: preparations NOVINET and REGULON.

Ethinylestradiol is the estrogenic component of these contraceptives. Desogestrel, a derivative of levonorgestrel, is a representative of third-generation progestogens. Desogestrel is characterized by high bioavailability of 80% when administered orally. In the liver, desogestrel is metabolized to form a highly active derivative, 3-ketodesogestrel. The latter, getting into the systemic circulation, interacts with blood proteins; 1/3 of the total 3-ketodesogestrel binds strongly to globulins, 2/3 is less strongly bound to albumins, 2-3% of the drug circulates in free form. Pharmacological activity has free 3-ketodesogestrel, which binds to the receptors of progesterone, testosterone, estrogen, mineralocorticoids. 3-Ketodesogestrel has a different degree of affinity for these receptors, so the specific stimulating effect of the drug in relation to each of the listed receptors is significantly different (Table 1). Desogestrel shows the highest affinity for progesterone receptors, which determines its pronounced progestogenic effect. To a lesser extent, desogestrel exhibits an antiestrogenic effect and practically does not have an androgenic and estrogenic effect (Rosenbaum H., 1996).

Table 1

The mechanism of action of progestogens according to Schindler A., ​​1999 with abbreviations

According to experimental studies, the level of binding of some representatives of progestogens of the 1st and 2nd generations with progesterone receptors, respectively, is 80 and 40% lower than that of 3-ketodesogestrel. At the same time, the level of binding of 3-ketodesogestrel to androgen receptors is lower than that of a number of other progestogens. The ratio of percent binding to progestogen receptors to percent binding to androgen receptors is called the selectivity index. To date, 3-ketodesogestrel has the highest selectivity index among known progestogens (Hoppen H., Hammann P., 1987; Pollow K., 1989; Philips A., 1990).

The clinical efficacy of desogestrel as part of combined oral contraceptives has been proven. More than 1500 scientific articles and more than 200 scientific reports are devoted to this problem. In table. 2 presents data confirming the high effectiveness of oral contraceptives containing desogestrel and ethinyl estradiol. These drugs include NOVINET (20 micrograms of ethinylestradiol and 150 micrograms of desogestrel) and REGULON (30 micrograms of ethinylestradiol and 150 micrograms of desogestrel). The effectiveness of these drugs is due to their ability to inhibit ovarian function, in particular to suppress the development of follicles. The results of a comparative analysis of the effectiveness of combined oral contraceptives indicate that monophasic oral contraceptives containing desogestrel (NOVINET, REGULON) are among the most effective drugs in terms of suppressing ovarian function (Van der Vange, 1986).

table 2

Efficacy of combined oral contraceptives containing ethinylestradiol and desogestrel

The most common side effects that may occur as a result of the use of oral contraceptives, including desogestrel-containing ones, are presented in Table. 3, 4. As follows from the above data, the frequency of side effects when taking desogestrel-containing oral contraceptives is low. Their appearance is most likely during the first 3 months of taking the drug, during the so-called adaptation period. As a rule, side effects do not pose a threat to a woman's health, do not require additional treatment and disappear by the 4th cycle of taking contraceptives.

Table 3

The frequency of menstrual irregularities by the 6th month of taking a monophasic oral contraceptive containing desogestrel and ethinyl estradiol

Table 4

Frequency of some subjective side effects

It is known that many oral contraceptives can contribute to weight gain. At the same time, almost all researchers note that when using desogestrel-containing combined oral contraceptives, changes in body weight are minimal.

The use of 1st and 2nd generation contraceptives is often associated with arterial hypertension. The results of studies devoted to the study of the effect of desogestrel-containing contraceptives on blood pressure indicate the absence of their significant impact on peripheral hemodynamic parameters.

As is known, a decrease in glucose uptake by cells causes an increase in insulin secretion and, accordingly, an increase in the level of the latter in the blood. This dysmetabolic disorder is an important risk factor for the development of cardiovascular diseases. Unfortunately, most oral contraceptives have an adverse effect on insulin secretion, mainly due to the progestogen component (Shoupe, 1993). Progestogens reduce tissue tolerance to carbohydrates and increase insulin resistance. At the same time, the effect of these drugs on carbohydrate metabolism is dose-dependent. According to the results of studies comparing the effect on carbohydrate metabolism of various combinations of active substances in oral contraceptives, combined preparations containing desogestrel at a dose of 150 mg have a minimal effect on both tissue tolerance to carbohydrates and their resistance to insulin. Thus, the experience of using the microdose desogestrel-containing drug NOVINET in women with uncomplicated type 1 diabetes mellitus indicates that the drug does not aggravate the disorder of carbohydrate, lipid and other types of metabolism, does not provoke the development of diabetic angiopathy. Increasing the dose of insulin by 8 units was required only in 1% of cases. In addition, in women with type 1 diabetes, NOVINET had a therapeutic effect, including a decrease in the severity of premenstrual syndrome, dysmenorrhea and mastopathy. The possibility of using NOVINET in women with compensated diabetes mellitus under the age of 35 years, in whom the duration of the disease ranges from 1 to 7 years, in the absence of obvious signs of damage to the cardiovascular system, is fully justified.

The use of a number of contraceptives is associated with their adverse effects on lipid metabolism. In a woman's body, estrogens have a positive effect on the distribution of lipoproteins in the blood plasma: they contribute to an increase in the number of high-density lipoproteins (HDL) and a decrease in low-density lipoproteins (LDL). Androgens and progestogens with androgenic influence cause the opposite effect - a decrease in HDL and an increase in LDL, which contributes to the development of the atherosclerotic process. According to a review of more than 50 clinical studies of oral contraceptives containing 30 mcg of ethinylestradiol and 150 mcg of desogestrel, the latter does not affect the effect of estrogen on plasma lipoproteins. This is due to the high selectivity of the effect of desogestrel on progesterone receptors. According to the results of the study of the clinical efficacy of NOVINET and REGULONA, both drugs contribute to an increase in HDL levels.

Some combined oral contraceptives can cause changes in the hemostasis system. Thus, the use of estrogen leads to an increase in the activity of certain blood coagulation enzymes and platelet aggregation. At the same time, estrogens activate the fibrinolytic system, increasing the concentration of plasminogen in the blood and reducing the level of fibrinolysis inhibitors. This effect is dose-dependent and is observed with the use of estrogens in high doses. Progestogens have practically no effect on the coagulation and anticoagulation systems of the blood. In the course of studying the effect of NOVINET and REGULON preparations containing low doses of estrogens on the hemostasis system, a slight increase in the activity of the blood coagulation system was noted, which, however, was balanced by a simultaneous increase in the activity of the anticoagulant system, as a result of which the overall hemostatic balance was not disturbed. Moreover, when using NOVINET (contains 20 μg of ethinylestradiol), these changes were less pronounced than when using REGULONA (contains 30 μg of ethinylestradiol).

Practice shows that the use of estrogen increases the concentration of many proteins of hepatic origin, including those that bind sex steroid hormones in the blood. Testosterone is an androgenic hormone, an increase in the amount of which in the blood leads to the appearance of signs of androgenization (acne, oily seborrhea, hypertrichosis, etc.). The greatest danger of hyperandrogenism is as an increased risk factor for the development of various diseases, such as diabetes, obesity, oncological and cardiovascular diseases. Unfortunately, a number of progestins have androgenic and antiestrogenic effects, as a result of which they can aggravate the manifestations of hyperandrogenism.

The use of a combination of ethinyl estradiol and desogestrel provides an increase in the level of testosterone-binding protein and a decrease in the free fraction of this hormone in the blood, which allows the use of REGULON in women with androgen-dependent skin changes. Many authors point to a significant decrease in the severity of signs of hyperandrogenization as a result of the use of combined oral contraceptives, which include ethinylestradiol and desogestrel. In 46-65% of patients with various types of skin rashes, a significant clinical improvement was noted, and in 18-48% a complete remission was achieved. REGULON and NOVINET have an almost equivalent therapeutic effect on hirsutism and acne.

Thus, these data indicate that NOVINET and REGULON preparations are highly effective and safe combined oral contraceptives containing low doses of active substances that do not significantly affect various metabolic links, and therefore these preparations can be recommended for protection from unwanted pregnancy for both practically healthy women and those with metabolic disorders (type I diabetes mellitus) and some hormonal disorders (hyperandrogenism syndrome).

Publication prepared
based on the article:
Mezhevitinova E.A. // Gynecology. - 2000. - V. 2, No. 4. - S. 104–110,
granted
representative office
"Richter Gideon" A.O. in Ukraine

Formula: C22H30O, chemical name: (17alpha)-13-ethyl-11-methylene-18,19-dinorpregn-4-en-20-yn-17-ol.
Pharmacological group: hormones and their antagonists / estrogens, gestagens; their homologues and antagonists.
Pharmachologic effect: contraceptive, progestogenic.

Pharmacological properties

Desogestrel promotes thickening of cervical mucus, suppresses ovulation, reduces the concentration of estradiol to levels that are characteristic of the early follicular phase. When using desogestrel, the pregnancy rate is comparable to that when using combined estrogen-gestagen drugs: the Pearl index (the number of pregnancies that occurred when using a contraceptive method in 100 women during the year) for desogestrel is 0.4, for drugs that contain 0 03 mg levonorgestrel, - 1.6. Desogestrel does not cause significant changes in hemostasis, lipid and carbohydrate metabolism.
After oral administration, desogestrel is rapidly absorbed. Desogestrel is rapidly and almost completely biotransformed by dehydrogenation and hydroxylation, with the formation of an active metabolite - etonogestrel, which is metabolized by the formation of glucuronide and sulfate conjugates. The bioavailability of desogestrel is 70%. The maximum concentration in blood serum is reached in 1.8 hours. Etonogestrel binds to plasma proteins: with albumin by 54 - 78%, with sex hormone-binding globulin by 19 - 43%. The equilibrium concentration is reached after 4-5 days of taking desogestrel. Desogestrel is excreted in breast milk in a ratio of 0.33 - 0.55; a newborn can receive 0.01 - 0.05 micrograms with a total milk intake of 150 ml / kg per day. On the 21st day, at steady state, the half-life is 20.6 - 35 hours. Etonogestrel and its metabolites are excreted as free steroids and conjugates with faeces and urine in a ratio of 1/1.5.

Indications

Contraception.

Dosing and Administration of Desogestrel

Desogestrel orally, with a small amount of liquid, 0.075 mg per day once every day, at the same time, for 4 weeks in the order indicated on the package. The reception of each subsequent package begins after the end of the previous one without any interruption.
In the absence of a previous (within the last month) intake of hormonal contraceptives, desogestrel should be started on the first day of the menstrual cycle (the first day of menstrual bleeding); you can start taking desogestrel on the 2nd - 5th day of the menstrual cycle, but then during the first cycle during the first week of taking the drug, an additional (barrier) method of contraception should be used.
When switching from a combined oral contraceptive, vaginal ring or transdermal contraceptive patch, desogestrel should be started the day after the last active tablet of the combined oral contraceptive is taken or on the day the vaginal ring or contraceptive patch is removed. Desogestrel can be started the day after the end of the usual interval of the previous oral contraceptive or the day after placebo, vaginal ring, contraceptive patch (i.e. the day you would start taking the pills from the new package of combined oral contraceptive , stick a new contraceptive patch or insert a new vaginal ring), but during the first week of taking desogestrel, it is recommended to use an additional barrier method of contraception.
When switching from contraceptives that contain only gestagens (mini-pill, implant, injectable forms), or when switching from an intrauterine contraceptive that releases progestogen, desogestrel can be started on any day - when using a mini-pill; on the day when the next injection is to be made - when using an injectable form of a contraceptive; on the day of their removal - when using an implant or intrauterine contraceptive.
After an abortion in the first trimester of pregnancy, it is recommended to start taking desogestrel immediately.
After childbirth or an abortion made in the second trimester of pregnancy, desogestrel can be taken no earlier than 6 weeks after birth and no earlier than 21-28 days after an abortion made in the second trimester of pregnancy. When you start taking desogestrel at a later date, you must additionally use a barrier method of contraception during the first week of taking the drug. If a woman had sexual intercourse after an abortion or childbirth before taking desogestrel, then before using the drug, it is necessary to wait for the first menstruation or exclude pregnancy.
The contraceptive effectiveness of desogestrel may decrease if the interval between taking two tablets is more than 36 hours. If the next dose of desogestrel is delayed by less than 12 hours, then it is necessary to take the drug as soon as the woman remembered this and use the subsequent tablets at the usual time. If the next intake of desogestrel is delayed for more than 12 hours, then it is necessary to adhere to the rules for taking pills, additionally using barrier methods of contraception for the next one week. If desogestrel was missed in the first week of their use and there was sexual intercourse during the one week that preceded the missed pills, then it is necessary to exclude the presence of a possible pregnancy.
With the development of severe gastrointestinal disorders (diarrhea, vomiting), the absorption of desogestrel may decrease and in this case it is necessary to use additional methods of contraception. If vomiting occurs within 3 to 4 hours after taking desogestrel, then its absorption may be incomplete. In this case, you should be guided by the recommendations that relate to taking the missed pills.
Before using desogestrel, it is necessary to carefully collect an anamnesis and conduct a gynecological examination to exclude pregnancy. Before prescribing desogestrel, it is necessary to establish the cause of the menstrual cycle disorder (oligomenorrhea, amenorrhea, and others), if any. During the use of desogestrel, control medical examinations are necessary at least once every 6 months. If desogestrel can affect an existing or latent disease, then an appropriate schedule of follow-up medical examinations should be established.
Against the background of the use of oral contraceptives, the risk of developing breast cancer increases with age, which does not depend on the duration of desogestrel use, but depends on the woman's age. The increased risk of developing breast cancer may be due to earlier diagnosis, the biological effects of the drug, or a combination of the two.
With the development of thrombosis against the background of the use of desogestrel, the drug must be discontinued. With prolonged immobilization, which is associated with surgery, injury or disease, desogestrel must be canceled.
When using desogestrel, it is possible to reduce the concentration of estradiol in the blood serum to an indicator that corresponds to the early follicular phase. Whether this has any clinically significant effect on bone mineral density is not known.
While taking the drug, irregular spotting is possible. If bleeding is sufficiently frequent and irregular, then consideration should be given to prescribing another contraceptive drug. If bleeding continues even after discontinuation of desogestrel, then it is necessary to exclude organic pathology.
With the development of amenorrhea while taking the drug, pregnancy must be excluded.
With the appearance of pain and amenorrhea in the process of taking desogestrel, it is necessary to remember the possibility of an ectopic pregnancy.
With the ineffectiveness of antihypertensive treatment or with a significant increase in blood pressure, the use of desogestrel should be discontinued.
With the development of violations of the functional state of the liver, a woman should consult a doctor for consultation and examination.
Women who are predisposed to chloasma should avoid prolonged exposure to the sun or ultraviolet radiation.
Women should be informed that desogestrel does not protect against human immunodeficiency virus and other sexually transmitted diseases.
The effectiveness of desogestrel may be reduced by omission of the drug, gastrointestinal disorders, or the concomitant use of other drugs.
When taking hepatic enzyme inducers (especially rifampicin), a barrier method of contraception should be used throughout the course of therapy and for 4 weeks after discontinuation of these drugs.
Women who take drugs that induce liver enzymes for an extended period of time should stop taking desogestrel and use non-hormonal methods of contraception.
During the use of progestogen-containing contraceptives in some women, menstrual bleeding may become rarer or even stop completely, while in others these bleeding may become more frequent or longer. Evaluation for irregular bleeding should be based on clinical presentation and may include testing to rule out pregnancy or malignancy.
When using desogestrel, the size of the follicles can sometimes reach sizes that exceed normal. Mostly they disappear on their own, but in some cases there is mild pain in the lower abdomen and surgical intervention is required.
Gestagens may affect glucose tolerance and peripheral tissue insulin resistance, but there is no evidence that diabetic patients need dose adjustment, but diabetic women should be under medical supervision during the entire period of therapy.
Desogestrel may affect the results of some laboratory tests, including thyroid, liver, kidney, adrenal function; fractions of lipids, lipoproteins; the content of transport proteins in the blood serum (for example, corticosteroid-binding globulin); indicators of blood clotting, fibrinolysis, carbohydrate metabolism. Usually these changes remain within the normal range.
No effect of desogestrel on the ability to perform actions that require increased concentration of attention and speed of psychomotor reactions was found.

Contraindications for use

Hypersensitivity, thromboembolism (including pulmonary embolism, deep vein thrombosis of the lower leg, including a history), liver failure (including a history), severe liver pathology (including a history; before normalization of liver function tests), vaginal bleeding of unclear origin, hormone-dependent tumors, liver tumors, breast cancer, prolonged immobilization, which is associated with surgery, injury or disease (risk of venous thromboembolism), established or suspected pregnancy.
Application restrictions
Uncontrolled arterial hypertension, systemic lupus erythematosus, porphyria, chloasma (especially if there is a history of chloasma during pregnancy), diabetes mellitus, herpes during a previous pregnancy.

Use during pregnancy and lactation

The use of desogestrel is contraindicated in pregnancy. Epidemiological studies have not revealed a teratogenic effect when using oral contraceptives in early pregnancy and an increase in the risk of having children with abnormalities. Desogestrel does not affect the quantity or quality of breast milk. A small amount of etonogestrel passes into breast milk. With the amount of breast milk consumed 150 ml / kg per day, the child can receive 0.01 - 0.05 mcg / kg of etonogestrel per day. When prescribed by a doctor, desogestrel can be used during breastfeeding, but careful monitoring of the development and growth of the child is necessary.

Side effects of desogestrel

Nervous system and sense organs: mood changes, fatigue, headache, discomfort when using contact lenses, otosclerosis, deafness.
Digestive system: nausea, vomiting, cholestatic jaundice, cholelithiasis,
Urogenital system: irregular bleeding, decreased libido, dysmenorrhea, amenorrhea, vaginitis, vaginal infection, ovarian cysts, breast tenderness, breast discharge, menstrual irregularities, ectopic pregnancy.
Allergic reactions: urticaria, rash, erythema nodosum.
Skin covers: pruritus, acne, alopecia, skin redness, urticaria, rash.
Others: weight gain, systemic lupus erythematosus, porphyria, hemolytic-uremic syndrome, chorea, herpes in pregnancy, hormone-dependent tumors, chloasma, venous and arterial thrombosis and thromboembolism, Sydenham's chorea, hereditary angioedema.

Interaction of desogestrel with other substances

Interactions between desogestrel and other medicinal products may result in breakthrough bleeding and/or decreased effectiveness of desogestrel.
With the combined use of desogestrel and inducers of microsomal liver enzymes (barbiturates, topiramate, phenytoin, carbamazepine, rifabutin, primidone, oxcarbazepine, rifampicin, griseofulvin and others), the effectiveness of desogestrel may decrease and the risk of breakthrough uterine bleeding may increase. Usually, the maximum level of enzyme induction is reached no earlier than after 14-21 days and can persist up to 28 days after the withdrawal of the concomitant inducer of microsomal liver enzymes.
In the conversion of desogestrel to etonogestrel, the CYP2C9 isoenzyme of cytochrome P450 plays an important role, therefore, interaction of desogestrel with inhibitors or substrates of CYP2C9 (for example, piroxicam, ibuprofen, naproxen, fluconazole, phenytoin, diclofenac, celecoxib, glipizide, sulfamethoxazole, irbesartan, isoniazid, losartan, valsartan) is possible. others); the clinical significance of this interaction is unknown.
Activated charcoal reduces the absorption and contraceptive effectiveness of desogestrel.
Antibiotics (for example, tetracycline, doxycycline, ampicillin and others) reduce the effectiveness of the contraceptive effect of desogestrel.
Desogestrel can weaken the effect of glipizide, metformin, can provoke hyperglycemia; when used together, constant monitoring of the level of glycemia is necessary.
Desogestrel increases fixation on thyroxine-binding globulin and reduces the effect of levothyroxine sodium; when used together, an increase in the dose of levothyroxine sodium may be required.
Nevirapine may decrease the plasma concentration of desogestrel; sharing is not recommended.
Desogestrel increases serum vitamin A concentrations.

Overdose

With an overdose of desogestrel, the development of nausea, vomiting, bloody discharge from the vagina is possible.
Symptomatic treatment is necessary; there is no specific antidote.

Trade names of drugs with the active ingredient desogestrel

Combined drugs:
Desogestrel + Ethinylestradiol: Marvelon®, Mercilon®, Tri-Merci®;
Ethinylestradiol + Desogestrel: Novinet®, Regulon.

Arzamastsev A.P., Sadchikova N.P.
Department of Pharmaceutical Chemistry
MMA them. THEM. Sechenov

In recent years, attitudes have changed Russian Federation to the use of contraceptives, in particular to oral hormonal contraceptives, which were introduced into medical practice 40 years ago. Impressive advances in the synthesis of new female sex steroid hormones, as well as extensive clinical and preclinical studies of their contraceptive reliability and safety, have led to the creation of low-dose drugs that provide the most convenient method of contraception for most women. According to experts, about 20% of all women of childbearing age worldwide take birth control pills, and if oral contraceptives are completely abandoned and only condoms are used, then 690,000 unplanned pregnancies will occur.

It is believed that approximately 50% of all pregnancies are accompanied by either abortions or unwanted births. The most important benefit of contraception is the improvement in women's health. At the same time, contraception also helps to solve the most important social problem associated with the birth of unwanted children.

The creation of new, safer contraceptives and the provision of them to the population has led to a decrease in the number of abortions in Russia over the past decade from 3 million 596 thousand in 1991 to 961 thousand in 2000. In addition, the use of hormonal contraceptives is accompanied by a number of positive non-contraceptive effects expressed in reducing the risk of developing ovarian and endometrial cancer, benign breast tumors, pelvic inflammatory disease, ectopic pregnancy, iron deficiency anemia, duodenal ulcers and rheumatoid arthritis, as well as the likelihood of developing premenstrual symptoms, dysmenorrhea, endometriosis, etc.

When choosing methods of contraception, their effectiveness, tolerability, safety and cost are taken into account. Therefore, it is important to have reliable and scientifically proven information about each method of contraception. All contraceptives can be divided into the following groups.

1. Combined oral contraceptives.
2. Contraceptives containing only progestogen.
3. Spermicidal contraceptives.
4. contraceptive coils.
5. Barrier contraceptives.

Hormonal contraception is the most effective method of fertility control (Table 1).

Combined oral contraceptives

Oral contraceptives containing estrogen and a progestin (syn. progestogen, progestin) are the most effective drugs for general use. Their main benefits include:

• reliability;
• abortion protection;
• protection against ectopic pregnancy;
• reduction in pregnancy-related mortality.

Additional benefits of oral contraception include:

• decrease in the intensity of premenstrual syndrome - 25%;
• reduction of inflammatory diseases of the pelvic organs - 50%;
• reduction of anemia caused by iron deficiency - 25%;
• reduction in the incidence of benign breast tumors - 50%;
• reduction in the incidence of benign ovarian tumors - 80%;
• reduction in the incidence of endometrial and ovarian cancer - 50%;
• improvement of the skin condition (in particular, with androgenization);
• reduction in bone loss with age (prevention of osteoporosis) and the incidence of hip fractures (25%).

Despite the fact that the history of the clinical use of oral contraceptives is only 40 years, this group of drugs, like no other, has made significant progress, which requires constant attention to new developments. During this period, the content of hormonal substances in oral contraceptives was reduced by more than 10 times, without reducing their contraceptive reliability. If almost all combined oral contraceptives contain ethinylestradiol (in rare cases, its precursor mestranol) as part of the estrogen component and differ only in its dose, then their progestogen component is different in structure. When classifying these drugs, based on the structure of the gestagen, in the 80s it was proposed to divide the combined oral contraceptives into drugs of the 1st (norethinodrel, nortestosterone, etinodiol, linestrenol), 2nd (levonorgestrel) and 3rd (desogestrel, gestodene, norgestimate ) generations. However, this classification does not include some other steroids with progestational activity used for contraceptive purposes. Moreover, in the last decade, new original gestagens have appeared - dienogest, drospirenone - with fundamentally new properties.

Therefore, it is best to separate gestagens according to the chemical structure, which determines the nature of their pharmacodynamics and pharmacokinetics. The spectrum of pharmacological activity of any progestogen is determined not only by the magnitude of the progestogen effect itself, but also by additional influences due to the presence or absence of partial androgenic, antiandrogenic, antimineralocorticoid and glucocorticoid activity (Table 2).

About the presence or absence of those listed in Table. The 2 additional effects of progestogens compared to progesterone are judged by their ability to inhibit or activate intracellular androgen, glucocorticoid, or mineralocorticoid receptors. Of these effects, antiandrogenic and antimineralocorticoid have the most important practical significance. The first of them is very important for women with androgenization and at the same time in need of contraception.

Currently, only one gestagen with a direct antiandrogenic effect, cyproterone acetate, is allowed for medical use in Russia (this gestagen, by a competitive mechanism, displaces androgens from their binding sites with intracellular receptors that mediate the development of androgenic effects), which, as part of the combined contraceptive Diane35, allows eliminating or markedly reduce the severity of signs of hyperandrogenism such as acne, seborrhea, alopecia and hirsutism. In addition, Diane35 allows you to solve not only cosmetic problems, but also has a preventive and therapeutic effect in polycystic ovary syndrome, the pathogenesis of which is also associated with hyperandrogenemia.

No less important physiological significance is the antimineralocorticoid activity of some gestagens (in this regard, the new gestagen drospirenone is unique), the mechanism of which is to block the binding of the endogenous steroid hormone aldosterone to mineralocorticoid receptors. These receptors are involved in the synthesis of kidney cell proteins that transport sodium ions (and hence water) from the primary urine back into the bloodstream. As a result of the normalization of the functional activity of these receptors, fluid retention in the body decreases, which is very important when taking combined oral contraceptives, since the estrogen component, on the contrary, helps to retain water in the body.

The successful balanced effect of ethinyl estradiol and drospirenone as part of the Yarina preparation on water metabolism contributes to the stabilization of body weight or even its decrease, and also reduces the incidence of breast tension, edema and the severity of premenstrual syndrome. In addition, the antimineralocorticoid effect of drospirenone is additionally manifested in the inhibition of the reninangiotensin system, which is especially beneficial for women prone to hypertension. Given that drospirenone also has a certain antiandrogenic activity, it should be considered that Yarina is most consistent with the physiology of the female body and contributes to maintaining excellent health and self-confidence.

Among the modern gestagens approved for use in Russia, the most powerful and selective in its specific pharmacological action is gestodene; its creation made it possible to reduce the dose of the progestogen component to the lowest value and to develop such combined oral contraceptives as Logest and Femoden.

The presence of some antimineralocorticoid action in gestodene, apparently, can explain the lower incidence of side effects such as breast tension, headaches, compared with desogestrel-containing contraceptives.

However, the most unique property of gestodene is its 100% bioavailability, since, unlike desogestrel and norgestimate, it does not need to be converted into active metabolites. Due to these features of the pharmacological properties of gestodene, its concentration in the blood is more predictable and, thereby, the possible risk of overdose or, conversely, insufficient dosage of the drug, is reduced, especially in women with a low or high metabolic rate. The high bioavailability of gestodene is also very important because only a stable blood level of the drug can provide good control of the menstrual cycle.

Conducted clinical studies have indeed shown that preparations containing gestodene in combination with ethinylestradiol, compared with desogestrel and norgestimate-containing preparations, provide better control of the menstrual cycle and cause fewer side effects such as headache, menorrhagia, nausea, vomiting, tension in the mammary glands and others. These properties of gestodene-containing drugs are of great clinical importance, since discontinuation of oral contraceptives usually occurs due to the occurrence of irregular uterine bleeding, weight gain or mastodynia.

According to the content of the estrogen component, until the early 90s, combined oral contraceptives were divided into high-dose (ethinylestradiol dose ≥ 50 μg) and low-dose (≤ 35 μg). However, when the dose of ethinyl estradiol was reduced to 20 μg, combined contraceptive preparations with this content of the estrogen component began to be called ultra-low-dose or micro-dose.

The addition of an estrogen component to the composition of an oral contraceptive leads to an increase in the contraceptive effect due to an increase in the ability of progestogens to inhibit the production of gonadotropins and to better cycle control. At the same time, estrogens change the synthesis of proteins in the coagulation system and affect the water balance in the body, causing fluid retention. Therefore, the desire to reduce the dose of the estrogen component in combined contraceptives is due to the desire to create the safest and most well-tolerated drug, while maintaining its contraceptive reliability.

The main mechanism of the contraceptive action of combined oral contraceptives is the inhibition of ovulation (in the implementation of this action, the effects of the estrogenic and progestogen components are summed up), which leads to the prevention of maturation of the follicle and the suppression of the positive feedback between estrogen and secretion of luteinizing hormone (LH). As a result, the production of the anterior pituitary gonadotropic hormones LH and follicle-stimulating hormone (FSH) is inhibited. In a normal menstrual cycle, FSH and LH levels rise rapidly between days 12 and 14, leading to ovulation. The gestagenic component of contraceptives, in addition, has peripheral contraceptive effects, expressed in an increase in the viscosity of cervical mucus, which makes it difficult for sperm to enter the uterus, and in a decrease in the ability of the endometrium to implant.

It should be noted that the contraceptive effect can be achieved by both the estrogenic and progestogen components separately, but only in combination with progestogen and estrogen can good control of the menstrual cycle be achieved. At the same time, the gestagen protects against excessive proliferation of the endometrium due to estrogens.

It is important to emphasize that reducing the dose of ethinylestradiol to 20 μg in combination with gestodene does not reduce the reliability of the contraceptive effect of the combined hormonal agent, but it reduces the risk of developing estrogen-dependent side effects - edema, changes in the rheological properties of blood, tension in the mammary glands, etc. This clinical fact, however, , cannot be transferred to oral contraceptives containing other progestogens.

For a woman to comply with an oral contraceptive regimen and reduce the number of refusals to continue its use, the ability of the drug to provide good control of the menstrual cycle, in particular a low frequency of intermenstrual bleeding, is very important. The results of numerous clinical studies have demonstrated good control of the menstrual cycle when prescribing a drug containing 20 μg of ethinyl estradiol in combination with 75 μg of gestodene.

The higher ability of gestodene compared to desogestrel to provide cycle control is indicated by data on a statistically significant low level of progesterone and estradiol in the blood of women who took the marked drugs with these gestagens.

The safety and high efficacy of gestodene-containing preparations have been proven in numerous preclinical and clinical trials. The daily oral dose of gestodene required to suppress ovulation (the main mechanism for the contraceptive effect) is the smallest - 0.03 mg / day, compared with other 19-nortestosterone derivatives used in modern hormonal contraceptives: desogestrel (0.06 mg / day). day), norgestimate (0.2 mg/day), levonorgestrel (0.05 mg/day) and norethisterone acetate (0.5 mg/day). At the same time, it should be emphasized that it is these data obtained in the whole organism, and not in in vitro experiments, that reflect the true activity of the listed gestagens.

The results of experiments conducted in vitro, moreover, on the tissues of experimental animals, and not on humans, are of some importance only for understanding certain aspects of the mechanism of action of gestagens, but they cannot be used as a justification for the preferential choice of one or another contraceptive, and not only from the point of view of contraceptive effectiveness and their tolerability, but also the presence of additional therapeutic effects (therapy of androgen-dependent diseases, protection from malignant and inflammatory diseases of the endometrium, etc.).

Recent studies of the mechanisms of the antitumor action of hormonal contraceptives have shown that it is based on the ability of the progestogen component (in particular, levonorgestrel) to induce apoptosis in the ovarian epthelial cells, and the higher the progestogen activity of the drug and the dose of the progestogen, the higher its ability to protect against the development of ovarian cancer ( Habeck M., 2001). Consequently, new opportunities are opening up in the scientifically based use of hormonal contraceptives to combat one of the most dangerous diseases in women (about 100,000 women die from ovarian cancer every year in the world).

In 1995, a new estrogen/gestagenic combination was introduced into clinical practice, containing as a progestogen component dienogest belonging to the group of estrans (13-methylgonanes). A particular advantage of this gestagen is its antiandrogenic activity, since other gonans have opposite androgenic activity. Unlike them, dienogest does not inhibit the activity of cytochrome P450 in rat liver microsomes and does not bind to specific blood transport proteins - globulins that transport sex steroids and glucocorticoids. Therefore, dienogest, combining the most favorable properties of pregnans (presence of antiandrogenic activity) and 19-norsteroids (high progestogenic activity), has optimal pharmacokinetic parameters (half-life - 9 hours) and excellent tolerability.

Currently, two hormonal preparations containing dienogest are allowed for medical use in Russia - the combined contraceptive Zhanin and Klimodien, a hormone replacement therapy agent.

Jeanine is a modern low-dose oral contraceptive with a mutually balanced ratio of estrogen and progestogen. A dose of 30 µg of ethinyl estradiol guarantees very good cycle stability. Jeanine has a high contraceptive reliability and tolerability due to the metabolic neutrality of dienogest. The use of Jeanine does not lead to statistically significant changes in body weight. The lack of androgenic effects, combined with the antiandrogenic properties of dienogest, has an effect on the skin and hair.

Pregnane (progesterone) derivatives have a progestogenic effect and, as a rule, do not have any significant estrogenic or androgenic effects on the body. However, some other properties of this group of gestagens have proven to be very important for their clinical use. In particular, the presence of pronounced antiandrogenic activity in cyproterone acetate, due to direct blockade of androgen receptors and inhibition of the conversion of testosterone to the more active androgen 5-beta-dihydrotestosterone, in addition to other mechanisms inherent in other combined contraceptives (increased levels of sex steroid-binding globulin, inhibition synthesis of androgens in the ovaries due to inhibition of secretion of gonadotropins by the pituitary gland), made it possible to create a combined contraceptive drug Diane35, which is also indicated for the treatment of androgen-dependent diseases - acne, seborrhea, alopecia and hirsutism. In our country, as in many countries of the world, this drug has gained great popularity and its use is growing every year.

The search for scientists in the field of new gestagens led to the creation of another unique compound, called drospirenone, which is an analogue of the aldosterone antagonist spironolactone and, like progesterone, has antimineralocorticoid and antiandrogenic effects. Due to this, drospirenone reduces the ability of estrogens to stimulate the action of aldosterone, which causes sodium and water retention in the body, increasing body weight. In addition, the presence of antiandrogenic activity in drospirenone leads to a decrease in the manifestations of acne, seborrhea and an improvement in skin condition.

Since fluctuations in the content of estradiol and progesterone in the blood occur during the menstrual cycle, scientists have tried to develop such regimens for taking oral contraceptives that would most closely approximate the physiological changes in the hormonal background. As a result, two-phase and three-phase drugs appeared, of which only three-phase contraceptives are quite widespread - Triquilar (synonymous with TriRegol), Triziston, TriMersi. However, the lack of comparative randomized clinical trials of these drugs does not give grounds to assert the preferential choice of any of them. Nevertheless, it should be noted that the total cyclic dose of hormones in Triquilar (TriRegol) or Trisiston is lower than that of TriMersi. Existing data on the pharmacological properties of these three-phase drugs do not allow us to talk about the possibility of any advantages of the latter.

The most common combined contraceptive hormonal drugs are presented in Table. 3.

In each case, only a doctor should choose one or another drug in accordance with the state of health of the woman, taking into account her hormonal profile. Every woman should choose a drug with such minimum doses of estrogen and progestogen that will provide good cycle control and will cause minimal side effects. Currently, the lowest-dose combined hormonal agent is Logest (20 μg ethinylestradiol, 75 μg gestodene), which, along with a reliable contraceptive effect, perfectly controls the cycle and has the least effect on lipid and carbohydrate metabolism, as well as body weight. Such properties of Logest make it possible to recommend it as a drug of choice for adolescents and young women for contraception after an abortion and for women of late reproductive age, as well as for smoking and the presence of diabetes mellitus.

• Preparations containing 20 micrograms of ethinyl estradiol (Logest, Mercilon) are especially suitable for obese or older women. It is recommended, however, that combined oral contraceptives should not be used by women over 50 years of age; they should use alternative methods of contraception.
• Preparations containing 30 or 35 mcg of ethinyl estradiol (Janine, Femoden, Marvelon, Microgynon, Minisiston, Diane35, Silest) in monophasic or 30/40 mcg (Trikvilar, Triziston, TriMersi) in triphasic preparations are suitable for general use, however, the order of administration Triphasic drugs are somewhat more complex than equivalent monophasic drugs, they inhibit the production of gonadotropins to a lesser extent, and their administration can lead to the development of ovarian cysts in case of insufficiency of endogenous female sex hormones.
• Monophasic drugs are best given to women who have a higher level of endogenous estrogens relative to progesterone, and triphasic drugs are best given to women with a relative deficiency of endogenous estrogens.
• Preparations with a high content of the active substance (50 micrograms of ethinyl estradiol or 50 micrograms of mestranol) provide high contraceptive reliability (Non-Ovlon, Ovidon), but increase the possibility of side effects. They are used mainly in case of reduced bioavailability (eg, in the case of long-term use of antiepileptic drugs that induce the activity of drug-metabolizing enzymes).

There is evidence that gestagens such as gestodene, desogestrel and norgestimate in combination with ethinylestradiol have a lesser effect on lipid metabolism than ethinodiol, levonorgestrel and norethisterone in combination with ethinylestradiol. Gestodene and desogestrel can be used by women who experience side effects (such as the appearance of acne-like rashes, headache, depression, weight gain, mastodynia and irregular uterine bleeding) of gestagens with pronounced androgenic activity. However, women who are going to use hormonal drugs should be informed that the use of modern drugs containing desogestrel and gestodene does not exclude the risk associated with venous thromboembolism in the presence of congenital disorders in the blood coagulation system.

Among women using oral contraceptives, there is an increased risk of developing venous thromboembolism, but the degree of this risk is much less than, for example, the risk of developing venous thromboembolism caused by pregnancy (approximately 60 cases of venous thromboembolism per 100,000 pregnancies). In all cases, the risk of developing venous thromboembolism increases with age and in the presence of other risk factors (eg, obesity).

The incidence of venous thromboembolism among healthy non-pregnant women who do not take oral contraceptives is approximately 5 cases per 100,000 women per year. For those women who use combined oral contraceptives containing levonorgestrel, this figure is approximately 15 cases per 100,000 women using drugs during the year. The absolute value of the risk of developing venous thromboembolism among women using combined oral contraceptives containing low doses of estrogens and modern gestagens (gestodene or desogestrel) is very small and significantly lower than the risk of developing venous thromboembolism associated with pregnancy. Nevertheless, every woman should be informed about the relative risk of developing thromboembolism, and the choice of contraceptive drug should be made by a doctor, taking into account all the individual characteristics of the woman.

Among women taking combined oral contraceptives, there is a slight increase in the risk of developing breast cancer; this relative risk may be wholly or partly related to an earlier diagnosis. The most significant risk factor appears to be age at which contraceptive use is discontinued compared to duration of use; the risk of breast cancer gradually decreases over 10 years after stopping contraceptives, and after 10 years after stopping contraceptives, no increased risk is observed. The possibility of a slight increase in the risk of breast cancer and the benefits associated with taking hormonal contraceptives, including taking into account their protective effect against the development of ovarian and endometrial cancers, should be carefully weighed when choosing a therapy or treatment.

In the specialized literature, you can find more information about all aspects of the use of hormonal contraceptives, primarily their therapeutic effect. Research continues in this area to clarify all the details of their safety and health benefits (protection against ectopic pregnancy, reduced risk of ovarian, uterine, colon cancer, ovarian cysts, androgen-dependent skin diseases, pelvic inflammatory disease, benign breast disease). glands, bone fractures, rheumatoid diseases).

emergency contraception. For emergency contraception, two hormonal methods are used, in which either levonorgestrel alone or a combined preparation containing ethinyl estradiol with levonorgestrel is used. Both methods are effective if the first dose of the drug is taken within 72 hours (3 days) after intercourse without contraception; the first dose should be taken as soon after intercourse as possible - the earlier the drug is used, the higher the effectiveness of contraception.

Both methods can be used more than 72 hours after intercourse without contraception (unapproved use), but in this case there is no guarantee of effective contraception.

Levonorgestrel is taken according to the following scheme. After taking the first tablet (750 mcg), the next tablet is taken 12 hours later. Emergency contraception using hormonal preparations containing only levonorgestrel has fewer side effects compared to emergency contraception using combined preparations.

When using a combined hormonal method of contraception (the Yuzpe method), you must take two tablets, each containing 50 micrograms of ethinylestradiol and 250 micrograms of levonorgestrel, and then take 2 more tablets 12 hours later.

For the purposes of emergency contraception, the drug Postinor (Gedeon Richter) is produced, each tablet of which contains levonorgestrel 750 mcg, in a package of 4 tablets.

It should be noted that in emergency cases, the use of intrauterine devices is a more effective means of contraception compared to hormonal contraception. A copper intrauterine device can be inserted into the uterus within 120 hours (5 days) after unprotected intercourse.

Contraceptives containing only progestogen. This group of drugs, in turn, consists of 3 subgroups.

1. Oral contraceptives containing only progestogen.
2. Parenteral contraceptives containing only progestogen.
3. Intrauterine contraceptives containing only progestogen.

Oral contraceptives containing only progestogen. Progestogen-only oral contraceptives are an acceptable alternative when estrogen use is contraindicated (including women with venous thrombosis or a predisposition to venous thrombosis). However, progestogen-only oral contraceptives provide less protection against pregnancy (Table 1) than combined preparations.

Progestogen-only oral contraceptives are acceptable for older women, heavy smokers, and those with hypertension, valvular disease, diabetes, and migraine. In the case of using oral contraceptives containing only progestogen, the appearance of irregular menstrual bleeding (oligomenorrhea, menorrhagia) is more frequent, but when using drugs for a long time, this irregularity gradually disappears.

The lowest-dose progestogen drug is Microlute (Schering AG), each tablet of which contains 30 μg of levonorgestrel, in a blister with a calendar scale of 35 pcs.

In Russia and some other countries, a more high-dose drug Exkluton (Organon) is also known, which includes linistrenol (500 μg).

Parenteral contraceptives containing only progestogen. Long-acting progestogen medroxyprogesterone acetate injectable (Depo Provera, Pharmacia; 150 mg/mL injection suspension, 1 mL single vial or syringe, or 500 mg/3.3 mL injection suspension, 3.3 mL vial, or injection 1000 mg / 6.7 ml, vial 6.7 ml) is administered intramuscularly. It is as effective as combined oral preparations, but due to its prolonged action, this form of contraceptive should never be used without detailed consultation based on the manufacturer's recommendations.

This form of hormonal contraception can be used for both short-term and long-term contraception for women who agree that after stopping contraception, there will be a high probability of menstrual irregularity and return to a fertile state will not occur immediately, but with a possible delay. A longer return to fertility and menstrual irregularities after the use of this type of contraception is possible and likely, but there is no evidence of permanent loss of fertility.

Severe bleeding has been reported in patients who used medroxyprogesterone acetate directly in the postpartum period (it is best to administer the first dose with a delay of 5-6 weeks after the birth of the child). If a woman is not breastfeeding, the first injection can be given within 5 days after delivery (but she must be warned that in this case severe and prolonged bleeding is possible).

There is evidence of a decrease in the level of mineralization of the bone skeleton when using a drug containing medroxyprogesterone acetate.

Intrauterine contraceptives containing only progestogen. Currently, an intrauterine system has been developed (Mirena, Schering AG, is a T-shaped plastic device with a polydimethylsiloxane reservoir, from which levonorgestrel is released at a rate of 20 μg / 24 hours, is effective for 5 years), capable of releasing the progestogen levonorgestrel directly into the cavity uterus. Therefore, the hormonal effect is mostly local and includes the prevention of endometrial cell proliferation, thickening of the cervical secretion, which makes it difficult for sperm to function, and the suppression of ovulation in some women (in some cycles).

The physical presence of the system in the uterus also has a small additional contraceptive effect. Fertility is fully restored immediately after removal of the system.

The system has advantages compared to copper intrauterine contraceptives, which are the absence of dysmenorrhea and a decrease in blood loss, which contributes to an increase in hemoglobin levels and iron stores in the body. There is also evidence that the use of Mirena reduces the incidence of pelvic inflammatory disease (especially among the youngest age groups, who have the highest risk of developing inflammatory diseases) and fibroids.

The high efficiency of Mirena in the treatment of endometrial hyperplasia has been established. In addition, since the progestogen is released in close proximity to the main contraceptive targets (cervical mucus and endometrium), the usual side effects associated with the use of a progestogen are less likely, in particular drugs that induce enzyme activity are unlikely to have a strong effect on the contraceptive effect. . This method of contraception can be chosen by women whose menstruation is very heavy. Since the formation of functional ovarian cysts (usually asymptomatic and most often spontaneously passing) is possible, it is recommended to carry out ultrasound monitoring for their occurrence.

It is important to emphasize that the cost of Mirena is not higher than modern oral contraceptives, if we calculate their cost for 5 years.

Intrauterine devices. IUDs are suitable for older women who have already given birth and as a second-line contraceptive method for younger women, which should be carefully evaluated because there is an increased underlying risk of pelvic infections.

Smaller coils have been created to reduce side effects. The spirals consist of a plastic carrier firmly bonded to copper wire or fitted with copper strips; some variants also have a central shaft made of silver to prevent fragmentation of the copper parts.

In the Russian Federation, the following intrauterine contraceptive devices are allowed:

• Copper-T KU-380-A (Schering AG, T-shaped device made of flexible polyethylene coated with a layer of copper with a total area of ​​380 mm 2; spiral size: vertical - 36 mm, horizontal - 32 mm; replacement every 6 years);
• Multiload KU-375 (Organon, is an intrauterine device, the surface of which is copper-coated with a surface of 375 mm 2, with a vertical rod approximately 3.5 cm high; replacement every 5 years);
• Nova-T KU-200-AG (Leiras, Finland, Schering AG group company), intrauterine device, copper wire with a silver core, surface area approximately 200 mm 2, wound on a vertical rod of a T-shaped supporting structure made of plastic, contains barium sulfate for radiopacity; change every 5 years).

Spermicidal contraceptives. Spermicidal contraceptives are a useful, complementary method of contraception, but they do not provide an adequate level of protection if used alone (unless fertility is already severely reduced). They are suitable for use in conjunction with barrier methods. Spermicidal contraceptives contain two components: a substance that destroys spermatozoa (spermicide) and a carrier, which itself may also have some inhibitory effect on the activity of spermatozoa. Products such as petroleum jelly, baby oil, and oil-based vaginal and rectal preparations are most likely to damage condoms and contraceptive diaphragms made from rubber latex, and thereby reduce their protective properties both in terms of barrier methods of contraception and as protection against sexually transmitted diseases.

Conclusion

Having considered all the main modern methods of contraception, one can see that their choice is quite wide and in each case an adequate choice can be made. The most reliable and convenient contraceptives currently remain oral hormonal agents. The ever-expanding use of such drugs will undoubtedly contribute to the preservation of women's health and the harmonization of family relationships.