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XXI CENTURY - THE ERA OF NEW ACHIEVEMENTS OF HORMONAL CONTRACEPTION
Hormonal contraception over the nearly 40-year period of its rapid development has established itself not only as one of the most effective methods of preventing an unplanned pregnancy, but also as a new, very promising area of medicine.
A lot of studies on this problem, conducted in a number of foreign countries and in our country, revealed a number of its healing and protective properties, which subsequently led to even greater popularity of hormonal contraceptives among practitioners.
During the period that has passed since the synthesis of the first hormonal contraceptive "Ewed" (1960), a number of new compounds were created with different chemical structures and modes of administration, which were the basis for creating new types and forms of hormonal drugs.
The minimum content of the components in tableted oral forms has significantly reduced the number of adverse reactions and practically minimized them. The synthesis of new highly selective progestogens has also determined their higher acceptability.
The development of injection, implantation methods and intrauterine hormonal systems has expanded the possibilities of an individual approach in the appointment of contraception.
Thanks to the achievements in the field of hormone biochemistry, as well as the results of experimental and clinical studies, the qualitative and quantitative composition of hormonal contraceptives has continued to improve and expand to date.
Various combined oral contraceptives as progestogen component contain different compounds and therefore differ from each other in terms of overall metabolic and clinical effects.
A new type of 19-norprogestin used as a progestogen component of COCs is dienogest, which is highly selective for progesterone receptors, highly bioavailable, and has a pronounced progestogen effect on the endometrium.
Dienogest (17? -Cyanomethyl-17? -Hydroxy-4,9-estradien-3-on) is a progestin of the 19-nortestosterone group, which has no androgenic effect, and only one of this series of hormones has a 17? -Cyanomethyl group instead of 17 ? -ethynyl group. The antiandrogenic effect of dienogest is especially significant at the cellular level and it is much stronger than that of cyproterone acetate. Dienogest does not bind to SHBG and remains in a free, biologically active state, in a rather high (9%) amount, which ensures penetration into the tissue.
The antiandrogenic effect of dienogest is due to the following processes: competitive or non-competitive antagonism to the level of androgen receptors; local suppression of androgen biosynthesis or acceleration of androgen metabolism and excretion; blockade of the enzymatic transformation of testosterone into 5β-dehydrotestosterone (DHT) as a result of the suppression of 5β-reductase; decreased secretion of gonadotropic pituitary hormones, including endogenous testosterone production (Oettel M. et al., 1995).
The great advantage of dienogest in the composition of COCs is its anti-androgenic effect on target cells due to competitive binding to androgen receptors. The therapeutic effect of dienogest was revealed for such symptoms of hyper-androgenia as seborrhea, acne. So, in the treatment of patients with symptoms of hyperandrogenism, improvement in patients receiving OK containing dienogest was noted in 87% after 6 months. (Moore C. etal., 1999).
The effect of OK containing 0.03 mg of ethinyl estradiol and 2 mg of dienogest (Janine preparation) on the concentration of sex hormones androgens and globulins that bind sex hormones (SHBG) in young healthy women after three cycles of OK was studied, as well as the antiandrogen effect of this drug was studied. combinations in patients with acne compared with OC containing 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate after 6 cycles of therapy. The use of these two combinations of hormonal preparations had a beneficial effect on androgen-dependent skin disorders, mainly acne. The improvement of clinical symptoms was associated with a marked decrease in the concentration of total and free testosterone in the blood serum and a significant increase in the level of SHBG. A moderately pronounced decrease in the level of 5β-dehydrotestosterone and the androgen precursor dehydroepiandrosterone sulfate also has a positive therapeutic effect. Despite the fact that it is impossible to determine the level of androgens in the hair follicles, a significant decrease in the concentration of androstenediol indicates a suppression of the local formation of 5β-dehydrotestosterone. These results correlate with data from morphological studies: the number of sebaceous glands in the connective tissue is significantly reduced. No statistically significant difference in the anti-androgenic properties of the two combinations of hormonal drugs was found.
Dienogest has a pronounced therapeutic effect at a lower dose than other progestins in patients with endometriosis. The effectiveness of dienogest treatment for pain syndrome is 50-90% and does not differ from patients using nafarelin (73-77%), buserelin (72%) and goserelin (70%) (Moore C. et al., 1999).
The gestagen chlormadinone, which is part of Belar's new monophasic combined oral contraceptive (ethinyl estradiol 30 μg and chlormadinone 2 mg), has antiandrogenic properties.
Drospirenone, a new progestogen that is part of the Yarina preparation, is very close to endogenous progesterone in its biological properties. Unlike other modern gestagens, it is an analogue of spironolactone. Drospirenone has biological properties similar to those of endogenous progesterone, and antimineralocorticoid activity. Drospirenone counteracts the retention of sodium and water caused by aldosterone, which contributes to some side effects of estrogens (including weight gain and breast engorgement). It must be emphasized that the loss of sodium caused by drospirenone is not accompanied by a clinically significant increase in potassium levels. Studies have shown that the drug Yarin due to the antiandrogenic properties of drospirenone has a positive effect on mild and moderate acne in young women.
Other surrogate markers, such as levels of free (unbound) testosterone and SHG G, also indicate favorable changes during therapy with Yarin. It provides excellent control of the menstrual cycle, rarely causing intermenstrual bleeding and amenorrhea. There is convincing evidence that Yarin's contraceptive is effective in treating premenstrual syndrome, and also has a positive effect in general on women's well-being and quality of life associated with health. In addition, the drug Yarina has a beneficial effect on acne and other skin diseases (Foidart J.-M., 2000; Mansour D., 2002). Composition of the drug: 30 μg ethinyl estradiol and 3 mg drospirenone.
A new, extremely interesting form of hormonal contraception is the combined transdermal contraceptive system (ORTO EVRA), which contains 6.0 mg of norelgestromine and 0.75 mg of ethinyl estradiol (EE). The area of its contact with the skin surface is 20 cm2, and about 24 μg of norelgestromin and 20 μg of ethinyl estradiol are released in 24 hours.
Norelgestromin is an active progestogen, with almost no androgenic effect. The norelgestromin entering the woman’s body transdermally does not affect the levels of sex hormone-related globulins, and therefore low levels of free testosterone remain that do not differ from the norm (AudetM.C. etal., 2001).
The active ingredients of the transdermal contraceptive system, unlike oral contraceptives, are absorbed through the skin and therefore there is no primary metabolism (in the gastrointestinal tract, liver), which causes a significantly smaller number of adverse reactions.
Large clinical trials (3300 women) have shown that the transdermal system is not inferior to COC in its contraceptive effectiveness. Its effectiveness can only be reduced in women with a body weight of 90 kg (Smallwood G. et al., 2001; Abrams L. et al., 2002; and others).
Thus, women of reproductive age, including teenage girls, can use the transdermal contraceptive system.
Progestin-only oral contraceptives are a reliable alternative to COCs. Today they are supplemented with another new drug containing 75 micrograms of desogestrel (Charozetta, Organon, Netherlands).
The main goal in the development of Charozet’s preparation was to produce an oral contraceptive that did not contain an estrogen component, but which could permanently block ovulation in the same way as COCs, and therefore its contraceptive reliability was comparable to COCs. Charozetta has a high selectivity for progesterone receptors, low androgenic activity, and therefore will cause fewer adverse reactions.
In a double-blind comparative study of the effectiveness of 75 mcg / day of desogestrel and 30 mcg / day of levonorgestrel (Rice et al., 1999), a higher contraceptive effectiveness of desogestrel was found (the Perl index was 0.14 for desogestrel and 1.17 for left, respectively nor-gestral). For comparison, it should be said that the Pearl index for low-dose COCs varies from 0.12 to 0.5 (Trussell et al., 1987); for traditional progestin-containing contraceptives, the Pearl index is 0.5–3.0 (McCann, Potter, 1994). Therefore, the contraceptive reliability of the Charozet drug is similar to COC.
In 1991, a new NovaRing contraceptive ring was designed, tested through numerous clinical studies, and subsequently introduced into clinical practice.
NovaRing is a flexible, transparent ring made of evatan (ethinyl vinyl acetate), 54 mm in diameter and 4 mm in thickness. Each ring contains 2.7 mg of ethinyl estradiol and 11.78 mg of etonogestrel. According to the biological gradient, by diffusion from the ring into the vagina, 15 μg of ethinyl estradiol and 120 μg of ethonogestrel are released daily. The combination of these hormones provides the level of steroid hormones in the blood, optimal for achieving a contraceptive effect. The maximum concentration of hormones in blood plasma is reached within a few days after the introduction of NovaRing, and due to the constant continuous release of hormones from the membrane of the ring, there are no differences in their concentration in blood plasma.
According to the daily release of the estrogen component (15 mcgetininyl estradiol), NovaRing corresponds to ultramicrocosed oral contraceptives.
Each ring is intended for use during 1 menstrual cycle, including 3 weeks. its use and 1 week. a break. An important advantage is that the ring is easily inserted and removed by the woman herself, while the elasticity and softness of the ring allows both the woman and the partner not to experience any unpleasant sensations.
The contraceptive mechanism of NovaRing is due to the suppression of ovulation and an increase in the viscosity of cervical mucus. It has been found that NovaRing suppresses ovulation as effectively as combined oral contraceptives.
The results of clinical trials conducted from 1997 to 1999. confirmed not only the high contraceptive effectiveness and acceptability of NovaRing, but also good cycle control during contraception, the absence of a negative effect on hemostasis, blood lipid spectrum, blood pressure, body weight. Implanone is a new contraceptive implant (1 capsule for subcutaneous administration), contains etonogestrel, which is an active metabolite of desogestrel and has a high selective activity to progesterone receptors and minimal androgenic effect. The introduction of the implant is less traumatic compared to the norplant (5 capsules). The contraceptive effect persists for 3 years. After removal of the implant, a rapid restoration of fertility is observed (Urbancsel J., 1998; Bennink H., 2000).
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XXI CENTURY - THE ERA OF NEW ACHIEVEMENTS OF HORMONAL CONTRACEPTION
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