Cyproterone-Teva

Pharmacological properties of the drug Cyproterone

Cyproterone refers to synthetic antiandrogens - antagonists of male sex hormones. It is an antiandrogenic agent with a steroid structure. Cyproterone acetate, through competitive binding, blocks tissue receptors of male sex hormones - androgens (testosterone, dihydroepiandrosterone, androstenedione, etc.). Designed to eliminate the phenomena of androgenization in women, correction of deviations in the sexual sphere in men, antiandrogen therapy for prostate carcinoma. Androgens are also produced in small quantities in the body of women, mainly in the adrenal glands, ovaries and skin. Androgen-dependent derivatives of the skin (sebaceous glands and hair follicles) with an increase in the level of androgen production increase sebum secretion, which is a pathogenetic factor in the development of seborrhea and acne (acne), there is excess hair growth in women according to the male type (hirsutism) with simultaneous hair loss on the head (androgenic alopecia). Cyproterone reduces these signs of androgenization in women, which is clinically manifested by healing or preventing the formation of acne, reducing excessive sebum secretion on the scalp and facial skin. Cyproterone also has gestagenic properties - it inhibits the secretion of gonadotropic hormones in the pituitary gland and inhibits ovulation, which determines its contraceptive effect. In men, excessive formation of androgens causes increased testicular function, increased potency and libido, and in such androgen-dependent diseases as prostate carcinoma, it contributes to the progression of the disease. The administration of the drug reduces excessive sexual desire, protects the prostate gland (the target organ for androgens) from the effects of androgens, and inhibits the growth of prostate tumors. Used in the form of tablets and prolonged depot form for intramuscular administration.

References

Clinical guidelines for diagnosis and treatment and preventive measures for congenital dysfunction of the adrenal cortex in adult patients, 2021. - 28 p.
Clinical guidelines for polycystic ovary syndrome, 2016. - 61 p.
Encyclopedia of clinical laboratory tests / ed. WELL. Titsa. - M.: Labinform, 1997. - P. 35-36.
Kumar, V., Abbas, A., Fausto, N. et al. Robbins and Cotran Pathologic Basis of Disease, 2014. - 1464 p.

Indications for use of the drug Cyproterone

Moderately pronounced phenomena of androgenization in women (hirsutism, severe or moderate forms of androgenetic alopecia and acne) with resistance to other types of therapy. Prescribed for severe androgenization phenomena. Men are prescribed antiandrogen therapy for inoperable prostate carcinoma, either without or after prior orchiectomy; in the treatment of prostate carcinoma with RF LH agonists; for the correction of painful or pathological abnormalities in the field of sexual desire, necessitating a reduction in sexual activity.

Use of the drug Cyproterone

Women with moderate androgenization phenomena are prescribed 10 mg/day orally, usually in combination with a gestagen-estrogen drug to simultaneously prevent pregnancy and prevent the development of intermenstrual bleeding. Both medications are taken from the 1st day of the menstrual cycle, cyproterone is taken 10 mg/day from the 1st to the 15th day of the menstrual cycle. The gestagen-estrogen drug is taken daily from the 1st to the 21st day of the cycle, 1 tablet per day. Then they take a 7-day break, during which menstrual-like bleeding occurs. If there is no bleeding, medication can be continued only after pregnancy has been ruled out. After the break, treatment is continued in the above manner. For amenorrhea, taking cyproterone begins on any day and the 1st day of taking the drug is conventionally taken as the 1st day of the menstrual cycle. The duration of treatment is usually several months. Acne and seborrhea are treatable faster than hirsutism and alopecia. After clinical improvement, stop taking cyproterone and continue to take only the gestagen-estrogen drug. In cases of severe androgenization in women, cyproterone is used from the 1st to the 10th day of the menstrual cycle, 100 mg once a day, in combination with taking a gestagen-estrogen drug from the 1st to the 21st day of the cycle. The treatment regimen is similar to that above. After clinical improvement, the dose of cyproterone can be reduced to 25–50 mg/day. In women after menopause or with a removed uterus, only cyproterone monotherapy is administered at a dose of 25–50 mg/day according to the following scheme: 21 days on, 7 days off. For inoperable prostate carcinoma (to exclude the influence of androgens of the adrenal cortex after orchiectomy), cyproterone is prescribed 100 mg 1-2 times a day or administered intramuscularly as a depot injection 300 mg once every 2 weeks. If orchiectomy has not been performed, cyproterone is prescribed 100 mg 2-3 times a day or administered intramuscularly once a week. If the condition improves or the disease remits, cyproterone is continued. The duration of therapy is determined individually and is about 6 months. When treating patients with inoperable prostate carcinoma with RF LH agonists, only cyproterone is first prescribed for 5–7 days, 100 mg 2 times a day, and in the next 3–4 weeks, an RF LH agonist is added. To limit the effect of adrenal cortex androgens during treatment with RF LH agonists, cyproterone continues to be taken at a dose of 100 mg 1–2 times a day. When treating pathological deviations of sexual desire, the dose of cyproterone is selected individually. Usually, at the beginning of the course, 50 mg is prescribed 2 times a day or injections of a depot form of 300 mg IM once every 10–14 days; if necessary, the oral dose is increased to 100 mg 2 times a day, and temporarily - up to 3 times a day or up to 600 mg of the depot form once every 10-14 days intramuscularly. In case of a satisfactory therapeutic effect, the single dose is reduced to the minimum maintenance dose. In most cases, 25 mg 2 times a day is enough for this. In this case, the dose reduction should be gradual over several weeks. To stabilize the therapeutic effect, cyproterone is usually used long-term, for several months.

Clinical aspects of the use of the combination of cyproterone acetate-ethinyl estradiol

In 1961, scientists from the Schering company (Wiechert et al.) successfully synthesized a new progestogen of the 17-acetoxyprogesterone series - cyproterone acetate (CPA). Due to its chemical structure, CPA does not have androgenic activity, unlike synthetic progestogens derived from 19-norsterone. In 1966, Neumann et al. first described the strong antiandrogenic, progestogenic and antigonadotropic properties of CPA. After Fan and Liao in 1969, using CPA as a tool, elucidated the mechanism of action of androgens at the molecular level, the mechanism of action of antiandrogens was explained by the competitive displacement of 5-dihydrotestosterone (DHT) by antiandrogen molecules from binding sites with cytoplasmic receptors (Fig. 1 ). This prevents the movement of the hormone-receptor complex into the cell nucleus and thus leads to a drop in the level of DHT in it. As a result, the stimulating effect of ovarian or adrenal androgens on androgen-dependent target organs, such as the skin, is weakened or stopped.

Rice. 1. In androgen-sensitive target tissues, circulating testosterone is converted to the strong androgen DHT, which binds to the nuclear androgen receptor. The resulting complex induces mRNA transcription, which leads to the synthesis of proteins and enzymes that cause androgenic effects. Antiandrogens, such as CPA, are antagonists of androgens by competing with them for binding to nuclear androgen receptors.

Initially, CPA was used in andrology for inoperable prostate cancer and for the correction of sexual disorders. Since the early 70s, the drug began to be used in gynecology, mainly in combination with ethinyl estradiol (EE2) for the treatment of hyperandrogenism in women. Currently, the most widely used combination in gynecological practice is the combination of 2 mg CPA and 35 mg EE2, present in the drug Diane-35, the only low-dose combined monophasic contraceptive with an antiandrogenic effect registered in Russia.

The contraceptive effect of Diane-35, like other estrogen-progestogen drugs, is based on the interaction of various factors, the most important of which are inhibition of ovulation, changes in the secretion and viscosity of cervical mucus, and transformation of the endometrium. Diane-35, due to the presence of antiandrogenic properties in CPA, is also indicated for the treatment of androgen-dependent diseases in women, such as acne, especially common and severe forms, androgenic alopecia and hirsutism.

The uniqueness of CPA lies in the fact that, along with the antiandrogenic effect, it also has pronounced gestagenic and antigonadotropic effects. CPA inhibits the activity of androgens regardless of their origin (ovarian or adrenal). This makes it possible to treat diseases caused by the formation of androgens or hypersensitivity to them. As a result of the antigonadotropic activity of CPA, the ovarian production of not only estrogen and progesterone, but also androgens is reduced. During treatment with Diane-35, the serum concentration of sex steroid binding globulin (GSBG) increases significantly, helping to reduce the level of free androgens, which enhances the therapeutic effect.

Hyperandrogenism can have clinical manifestations such as hirsutism, oligomenorrhea, acne, seborrhea. With an excessive content of active forms of male sex hormones in biological fluids or increased sensitivity of tissues to normal levels of androgens, virilization may develop, the components of which include balding of the temples, a change in the woman’s phenotype from isosexual to intersex (reduction of pelvic fat deposits and increase in muscularity of the upper half of the body), increase clitoris and decreased voice tone. The degree of virilization usually reflects the duration and severity of excessive secretion of androgens, although there are cases of significant virilization with minimal values of testosterone production and a significant increase in its production with minimal manifest signs of virilization. The presence of oligomenorrhea in women with hirsutism increases the likelihood of detecting excess androgen secretion.

Ovarian hyperandrogenism

Ovarian hyperandrogenism can be caused by polycystic ovary syndrome (PCOS), chyle cell hyperplasia, or virilizing ovarian tumors (arrhenoblastoma, theca cell, chyle cell tumor). As a result of clinical examination, it is necessary to exclude an ovarian tumor.

Polycystic ovary syndrome (PCOS) is a heterogeneous disease characterized by changes in the secretion of gonadotropins (LH/FSH>3), chronic anovulation, infertility and hyperandrogenism. The onset of the disease is early, often with menarche, progressing over time; The most typical are menstrual cycle disorders with delays in menstruation, initially from several days and weeks to several months and up to the development of amenorrhea. Both scanty (oligomenorrhea) and often heavy menstruation (menorrhagia) and uterine bleeding (UH) may be observed.

In 1988, G. Reaven first suggested that insulin resistance and compensatory hyperinsulinemia play a major role in the development of metabolic disorders. Women with PCOS experience varying degrees of insulin resistance, an increased incidence of type II diabetes mellitus, and lipid metabolism disorders. The presence of these risk factors is often combined with obesity, more pronounced in the upper part of the body in the shoulder girdle, darkening of the skin and the appearance of papillary melasma (acanthosis nigricans) in areas prone to increased sweating (armpits, back of the neck), with characteristic darkening and thickening and hypertrophy of skin folds. PCOS is considered a risk factor for the development of atherosclerosis and hormone-dependent tumors.

A very important measure is the suppression of excessive secretion of androgens by the ovaries and the induction of regular monthly menstrual-like bleeding, which is reliably achieved with the use of Diane-35. In studies performed by Golland and Elstein in 1993, it was shown that the administration of Diane-35 in patients with PCOS leads to a significant decrease in LH (84%), FSH (51%), estrogens (E1 - 69% and E2 by 62 %) and androgens (androstenedione – 67%, testosterone – 67%, free testosterone – 69%, DHEA-S – 62%). Sex steroid binding globulin (SHBG) levels increased by 530% due to the predominance of the estrogen component with the CPA/EE2 combination, while insulin levels did not change significantly compared to baseline values.

Favorable changes in ovarian morphology were also noted during treatment with Diane-35. According to Golland and Elstein (1993), Falsetti et al. (1993), Prelevic et al. (1993), Couzinet et al. (1986) noted a significant decrease in ovarian size to normal values.

Adrenal hyperandrogenism

Adrenal hyperandrogenism may be caused by congenital adrenal hyperplasia (CAH), acquired adrenal hyperplasia (Cushing's syndrome), or the presence of a virilizing tumor or adrenal cancer. When conducting a clinical examination, it is first necessary to exclude an adrenal tumor. Most often, the manifestation of the non-classical form of congenital adrenal hyperplasia (CAH) is caused by one of several disorders of the synthesis of adrenal steroids due to congenital enzymopathies. To date, defects in C-21, C-18, C-17 and C-11 hydroxylases, as well as 3b-ol-dehydrogenase, which are usually found separately, have been described. C-21 hydroxylase deficiency is associated with the expression of certain histocompatibility antigens on leukocytes (HLA-B locus of chromosome 6). Enzyme deficiency is caused by autosomal recessive mutations.

Partial adrenal enzyme deficiency, especially in women with hirsutism and oligomenorrhea but minimal virilization, may appear after puberty and is the cause of hyperandrogenism in up to 25% of women with hirsutism and oligomenorrhea.

Laboratory diagnosis of CAH is based on increased production of adrenal androgens in combination with decreased production of glucocorticoids, decreased or increased production of mineralocorticoids.

For CAH, Diane-35 is also used, which has a good therapeutic effect for such manifestations of virilization as acne, alopecia, and mild hirsutism. For more severe hirsutism (hirsut number on the Ferryman-Galwey scale 25–32), Androcur-10 is used, 1 tablet for 15 days, and Androcur-50 is used, 1-2 tablets per day according to a 10-day regimen, simultaneously with the prescription of Diane-35 .

Diane-35 therapy is effective for mild hirsutism and acne. For moderate and severe hirsutism, it is advisable to use Diane-35 in combination with Androcur-10.

Dysmenorrhea

Dysmenorrhea is the most common form of menstrual irregularities. Menometrorrhagia can be caused by disorders in the hypothalamus-pituitary-ovary-uterus system or caused by tumor and tumor-like processes of the uterus and appendages (uterine fibroids, adenomyosis, endometrial hyperplasia and polyps, etc.) or systemic disorders (impaired hemostasis, liver function, etc. .P.). To clarify the diagnosis, it is necessary to conduct an ultrasound examination of the pelvic organs, hemostasiogram, blood biochemistry, and hormonal blood profile. If large-scale processes and systemic diseases are excluded, hormone therapy may be performed to correct menstrual irregularities.

Adequate control of the cycle is an essential requirement for a contraceptive, since spotting or breakthrough bleeding during drug therapy are often the reason for stopping taking a hormonal contraceptive drug or switching to another, or even abandoning hormonal contraception altogether.

The positive effect of Diane-35 on the characteristics of the menstrual cycle, such as the duration and intensity of menstrual-like bleeding, low frequency of intermenstrual bleeding and other menstrual cycle disorders, has been scientifically proven (Aydinlik S. S. et al., 1986; Fugere P. et al., 1990).
With an increase in the duration of taking the drug, the menstrual cycle stabilized even in those women who had irregularities before taking the drug. In a large study that followed 1161 women over 36 cycles, excellent cycle control was confirmed by extremely low rates of menstrual irregularities (Table 1). The average cycle length was 28 days, menstruation - 5 days. At the same time, the amount of menstrual blood loss decreased in women with menorrhagia; the incidence of amenorrhea decreased to approximately 0.2%. Family planning
Contraception

Numerous studies have shown that 1 mg of CPA is sufficient to suppress ovulation, therefore a pronounced contraceptive effect appears already in the first cycle of use, demonstrating a high degree of contraceptive reliability. In a large clinical study (more than 21,000 documented cycles), only 2 pregnancies occurred as a result of missing doses of the drug. Disturbances in taking the drug were noted in 450 cycles, but the Pearl index was still 0.1.

Through central and peripheral mechanisms, Diane-35, in addition to suppressing ovulation, also induces a change in the viscosity of cervical mucus and causes secretory transformations of the endometrium. The results of endometrial biopsy showed that Diane-35 causes very minor proliferative changes in the endometrium during the first phase of the menstrual cycle. The secretory phase begins early, while the transformation of the endometrium remains incomplete; then the stroma loosens, and the glandular ducts undergo involution. Such changes make egg implantation extremely difficult.

Preparing for pregnancy

Diane-35 is widely used to treat infertility and normalize menstrual function in patients with PCOS to stimulate ovulation. The drug is prescribed as monotherapy on a 21-day regimen from days 1 to 21 of the cycle or in combination with CPA 10 mg from days 1 to 10 of the cycle. CPA is prescribed to ensure the optimal androgen/estrogens ratio during the selection of the dominant follicle. The stimulating effect is expected for 2–6 months after the end of taking the drug. If there is no effect, other ovulation stimulation schemes should be used.

Diane-35 can also be used as a means of preparing for a planned pregnancy in women with ovarian and/or adrenal hyperandrogenism or idiopathic (constitutional) hirsutism. The drug is prescribed for 3–6–9 months before the expected pregnancy.

It should be noted that a comparative study of the feminizing effects of various contraceptives showed that the risk when taking CPA is not higher than when using progestogens of a number of 19-norsteroids.

Cosmetology

The skin and its appendages (hair, sweat and sebaceous glands) are target tissues for sex steroid hormones and, above all, androgens. Hair growth (except on the scalp) and sebaceous gland secretion are largely androgen dependent. Being under the influence of androgens circulating in the peripheral blood, the skin, in addition, has the ability to convert testosterone or androstenedione into an even more active androgen - DHT, which is 2.5 times more active than testosterone.

Symptoms of virilization in women can be caused by increased production of androgens in the ovaries and/or adrenal glands. However, even with normal serum androgen levels, increased DHT formation as a result of increased 5a-reductase activity and/or end-organ hypersensitivity coupled with decreased estradiol levels may induce excessive androgenic effects.

Free, biologically active fractions of circulating androgens not associated with SHB, which is an estrogen-dependent protein, play an important role in the etiology of androgen disorders. Therefore, you should pay attention to the ratio of androgens and estrogens, in particular, testosterone / estradiol, since a decrease in estrogen levels, and as a consequence, an increase in the value of this ratio leads to more pronounced virilization.

When examining women with hirsutism, an increase in the level of testosterone production is determined from 200–300 mcg/day to 700–8000 mcg/day; an increase in testosterone clearance from 500 liters/day to 1000 liters/day, an increase in the free androgen fraction from 1% to 2% due to a decrease in the level of GSPC.

Hirsutism is defined as excessive growth of male-pattern terminal hair in women (upper lip, chin and sideburns on the face, linea alba, area around the nipple areola, upper limbs and thighs). It is necessary to distinguish between hirsutism and hypertrichosis - excessive growth of vellus hair, most often on the legs and forearms, which can be a manifestation of anorexia nervosa, hypothyroidism or taking certain medications (cyclosporine, diazoxide, minoxidil, phenytoin, etc.).

Hirsutism affects 5–8% of women, of which 40–80% have severe hyperandrogenemia. To adequately select treatment tactics, it is necessary to understand the pathophysiological mechanisms of regulation of androgen production in women. As a result of a significant number of studies, it has been revealed (in contrast to the situation with acne) that systemic androgen production increases in almost 50% of women with hirsutism. In women with normal androgen levels (idiopathic hirsutism), there is presumably an increase in 5a-reductase activity in the periphery. In addition, the metabolic clearance of androgens and their free fraction increase, and the concentration of SHB decreases.

Hirsutism has a significant psychological impact. Deviation from the established norm of hair growth leads to severe stress, anxiety and depression. A patient with hirsutism should be offered treatment, including cosmetic measures (depilation, hair removal) and hormonal correction.

The use of Diane-35 has been proven to be effective and safe in the long-term treatment of hirsutism, although in more severe cases the use of higher doses of CPA (20–100 mg) in the treatment regimen is recommended. Then, as soon as adequate control of hair growth is achieved, the dose of CPA is reduced and maintenance therapy with Diane-35 alone is continued. It is believed that hirsutism, compared to acne and seborrhea, is more difficult to treat. According to extensive research conducted by Aydinlik et al. (1990), positive therapeutic results are observed later due to the existence of a physiological hair growth cycle. Of 248 women with moderate severity of hirsutism on the face by the third cycle, the disappearance of symptoms occurred in only 17 (7%). However, by the end of the 9th cycle of taking the drug, 10 out of 20 women with severe hirsutism experienced complete remission, and 9 out of the remaining 10 women showed improvement by the 24th cycle.

Acne and seborrhea

Acne is the most common skin disease, especially among women during puberty (up to 80%). Acne is a multifactorial disease in which impaired secretion of the sebaceous glands and their inflammation are closely related. An increase in the activity of the sebaceous glands during seborrhea is the main etiological factor of the disease and closely correlates with the severity of manifestations in individuals of both sexes. Blockage of the sebaceous glands and the formation of comedones (with a white head, with a black head) occurs as a result of a violation of the drainage processes in the gland. Colonization of comedones by Propionibacterium acnes and other bacteria is accompanied by the release of bacterial fatty acids (together with the release of endogenous fatty acids) and leads to inflammation.

The earliest manifestation of acne - seborrhea - depends on the influence of androgens, which regulate hyperkeratinization of the ducts of the sebaceous glands. Interestingly, patients with acne tend to have normal serum androgen levels, and perhaps the majority of patients have sebaceous glands that are androgen hypersensitive.

Alopecia

Several factors influence scalp hair loss in women, so in order to provide effective therapy, it is important to determine the mechanisms that determine such disorders. The cause of alopecia may be a deficiency of vitamins and/or proteins as a result of malabsorption or an unbalanced diet. Endocrine causes (thyroid gland) or changes during pregnancy and lactation may be involved in the pathogenesis. Frequent washing and drying, perming, coloring, using hairsprays, and using medications can also lead to hair loss.

However, in a large number of cases, hair loss in women is associated with androgen exposure. This disorder, defined as diffuse androgen-dependent alopecia (ADA), has been shown to affect up to 30% of white women under 50 years of age (Dawber RPR et al., 1995). Determining hormone levels is of great importance, especially if there is a combination of several symptoms of hyperandrogenism, such as acne, hirsutism or PCOS. (Van Neste D., Rushton DH, 1997). As in the case of hirsutism, treatment of diffuse AZA requires more time and often larger doses of antiandrogens than in the treatment of acne and seborrhea. The work of Erdmann et al. (1994), who studied hormonal parameters in women with hyperandrogenism when prescribing Diana-35 and Diana-50, demonstrated significant improvement in all patients with AZA after 8-9 months of treatment. Another study, which included a control group and used a reverse cycling regimen, administered 50 mg CPA from cycle days 5 to 15 and 30 mcg EE2 from cycle days 5 to 25 for 12 months, showed significant improvement in 20 women with diffuse AZA . Interestingly, a significant (p < 0.01) increase in hair density was found in those patients who had serum ferritin levels exceeding 40 μg/L. In contrast, in the control group of untreated patients after 12 months of follow-up, there was a pronounced decrease in the values of both parameters. In this group of patients, no correlation was found between serum ferritin levels and the degree of hair loss.

Metabolic disorders

Lipid metabolism

Due to the high risk of developing atherosclerosis against the background of hyperandrogenism, it is of great interest to study changes in serum lipid levels along with other metabolic effects observed with the use of combined estrogen-progestagen drugs.

Estrogens reduce low-density lipoprotein (LDL) cholesterol, increase high-density lipoprotein (HDL) cholesterol, and stimulate the synthesis of triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL). Progestogens and especially androgens have the opposite effect on lipid metabolism: they increase LDL cholesterol, reduce HDL cholesterol, and also inhibit the production of TG and VLDL cholesterol.

The results obtained in a significant number of studies demonstrated, in general, the beneficial effect of Diane-35 on lipid metabolism. LDL levels tended to decrease slightly, while HDL and HDL cholesterol levels increased. At the same time, the LDL cholesterol/HDL cholesterol ratio, which is the main marker of atherosclerosis risk, remained stable.

Carbohydrate metabolism

The use of combined estrogen-progestogen drugs is accompanied by changes in carbohydrate metabolism in the form of a decrease in glucose tolerance and an increase in insulin release in response to a glucose load. The listed effects are caused by progestogenic components, derivatives of 19-norsteroids, which have both progestogenic and androgenic effects.

Similar effects were detected when using Diane-35, however, these changes should be considered as clinically insignificant, since the treatment had no effect on the ratio of the areas under the curves of insulin and glucose concentrations in the blood over time, as well as on the levels of glycosylated hemoglobin, a marker of long-term carbohydrate disorders. exchange (Miccoli et al., 1989; Vexiau et al., 1990; van den Ende and van Wayjen, 1995).

Diane-35 does not have an adverse effect on liver function. Liver biochemical levels remained within normal limits. Hepatic tolerability remained good even with long-term use. A study of the hemostasis system revealed a slight increase in coagulation processes, which are offset by the simultaneous activation of fibrinolytic activity. No significant changes in the rheological properties of blood were observed.

Conclusion

Thus, it has been established that with the simultaneous use of 2 mg of CPA and 35 mcg of EE2, the combination of estrogenic and progestogen components is optimal for the effective and safe treatment of androgenization symptoms in women. In an extensive study that included 1,000 patients with hyperandrogenism (a total of 21,000 treatment cycles), it was shown that in 3/4 of women, facial acne disappeared within the first 6 cycles of treatment. It should be noted that although the signs of hyperandrogenism disappear faster when using higher doses of CPA, the degree of relief of these symptoms after 12 months of use does not differ from that when using Diane-35 monotherapy.

It is generally accepted that Diane-35 is the drug of choice for the treatment of women with signs of hyperandrogenism who also require contraception, which is confirmed by the experience of using the drug in more than 20 million women worldwide.

The list of references can be found on the website https://www.rmj.ru

Ethinyl estradiol + cyproterone acetate

Diane-35 (trade name)

(Schering AG)
References:
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6. Holdaway M. et al. Cyproterone acetate as initial treatment and main–tenance therapy fir hyrsutism. Acta Endocr. 1985;109:522–529.

7. Nardi M. et al. Cyprotarone acetate–ethinylestradiol treatment of hirsutism, acne, seborrhea and alopecia. Acta eur. Fertil.1975;6:153–165.

8. Neumann F. The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research. Exp. Clin. Endocrinol.1994;102:1–32.

9. Aydinlenk S. Et al. Long-term therapy of signs of androgenization with a low-dosed antiandrogen-oestrogen combination. Clin. Trials J 1990;27:392–402.

10. Fugere P. et al. Cyproterone acetate/ethinyl estradiol in the treatment of acne. Contraception.1990;42:225–234.

11. Ferriman D., Gallwey JD Clinical assessment of body hair growth in women. J. Clin. Endocrinol. Metab. 1961;21:1440–1447.

12. Knochenhauer ES, Azziz R. Advances in the diagnosis and treatment of the hirsutism patient. Curr. Opin. Obstet. Gynecol.1995;7:344–360.

13. Conn JJ Jacobs HS The clinical management of hirsutism. Eur. J. Endocrinol. 1997;136:339–348.

14. Prelevic GM, Puzigaca Z., Balint–Peric LA Effects of an oral contraceptive containing cyproterome acetete (Diane–35) on the symptoms, hormone profile and ovarian volume of hirsute women with polycystic ovarian syndrome. Ann New York Acad. Sci. 1993;687:255–262.

15. Golland IM, Elstein ME, Results of an open one-year study with Diane–35 in women with polycystic ovarian syndrome. Ann. New York Acad. Sci. 1993;687:263–271.

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Contraindications to the use of the drug Cyproterone

Pregnancy, severe liver dysfunction, hereditary benign hyperbilirubinemia (Rotor syndrome, Dubin-Johnson syndrome), liver tumors, a tendency to thrombus formation, severe diabetes mellitus with vascular complications, sickle cell anemia, a history of herpes, idiopathic jaundice or itching during pregnancy, severe chronic depression. For prostate carcinoma, the diseases listed above (with the exception of primary liver tumors and severe depression) are a relative contraindication and the issue of using cyproterone is decided individually. The use of cyproterone is not recommended for people under the age of 18 (before the completion of puberty).

Side effects of the drug Cyproterone

Sometimes there may be changes in body weight and sexual desire, a feeling of anxiety, depressed mood, depression, increased fatigue, and decreased attention. In women, combination therapy using cyproterone causes temporary suppression of ovulation and prevents conception, sometimes - engorgement of the mammary glands, and very rarely - liver dysfunction. When using cyproterone in men, the ability to fertilize decreases, recovering 3-4 months after stopping treatment. Very rarely, liver dysfunction and gynecomastia are noted, sometimes together with increased tactile sensitivity of the nipples of the mammary glands. In rare cases, during the use of cyproterone, benign and, extremely rarely, malignant liver tumors develop.

Special instructions for the use of the drug Cyproterone

Before starting treatment for androgenization phenomena in women, it is recommended to conduct a general medical and gynecological examination (including the mammary glands), and pregnancy should also be excluded. If intermenstrual bleeding occurs, treatment should not be interrupted; it usually stops on its own. In case of heavy and repeated bleeding, a gynecological examination is necessary to exclude organic diseases of the female genital organs. During treatment, liver function, adrenal cortex, and peripheral blood composition should be regularly monitored. During pregnancy and breastfeeding, the use of cyproterone is contraindicated. Taking the drug during pregnancy may cause signs of feminization in male newborns.

Use strictly as prescribed by a doctor!

The patient should be informed of the need to inform the doctor about the use of any other medicinal product.

Before starting treatment with cyproterone, the patient is recommended to undergo a general medical examination, including determination of the peripheral blood formula, urine analysis, glucose concentration in blood plasma and urine, indicators of the blood coagulation system, blood pressure, body weight, determination of the functional state of the liver and adrenal glands. Women should undergo a comprehensive endocrinological and gynecological examination, including examination of the mammary glands, ovarian function, cytological examination of cervical mucus, and it is also necessary to exclude pregnancy. With long-term use of cyproterone, these diagnostic measures are recommended to be carried out every 6 months.

Overweight patients are advised to consult a nutritionist.

In patients with diabetes mellitus, treatment is carried out under constant medical supervision, because Dosage adjustment of insulin and other hypoglycemic drugs may be required. Monitoring of liver function in patients with diabetes mellitus should be performed approximately every 8 weeks.

Rare cases have been described after the use of cyproterone, when life-threatening intra-abdominal bleeding occurred in patients with benign and malignant liver tumors. Treatment with cyproterone should be stopped if there are signs of hepatoma - liver enlargement, pain and a feeling of heaviness in the epigastric region of the abdomen. With long-term use of cyproterone at a dose of 200-300 mg/day, its hepatotoxic effect (jaundice, hepatitis and liver failure) may occur, which in several cases has led to death. Most of the reported cases involved elderly patients with prostate cancer. The hepatotoxic effect of cyproterone is dose dependent and usually develops after several months of treatment. If the development of hepatotoxicity is suspected, a liver function test should be performed. If toxic liver damage is confirmed, the use of cyproterone should be discontinued, unless hepatotoxicity is due to another cause. for example, prostate cancer liver metastasis. In this case, continuation of treatment is possible provided that the expected benefit from the use outweighs the possible risk.

Cyproterone is not recommended for use in diseases accompanied by exhaustion (cachexia), due to the fact that catabolic reactions in the body may increase.

Isolated cases of vascular thromboembolism during treatment with cyproterone have been described. However, a cause-and-effect relationship with cyproterone has not been established. However, patients with a history of deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident or advanced malignancy are at high risk of recurrent thromboembolism while using cyproterone.

Several reports contained information about the occurrence of meningioma with long-term use of cyproterone at a dose of more than 25 mg/day. If a patient is diagnosed with meningioma, use of cyproterone should be discontinued.

Very rarely, when using the drug in high doses, shortness of breath may occur. This may be due to the stimulatory effect of progesterone and synthetic progestogens on respiration, which is accompanied by hypocapnia and compensatory respiratory alkalosis. Symptoms disappear after discontinuation of cyproterone without special treatment.

During the use of cyproterone, it is necessary to regularly evaluate the state of adrenocorticosteroid function due to the fact that in experimental studies using high doses of cyproterone, its decrease was noted due to the manifestation of the cortico-like effect of cyproterone.

Patients with rare hereditary diseases such as galactose intolerance, lactase deficiency, glucose-galactose malabsorption should not take the drug.

When cyproterone is used in men for several weeks, spermatogenesis is often suppressed due to the antiandrogenic and antigonadotropic effect of cyproterone - the number of sperm decreases and the volume of ejaculate decreases. Sexual desire and potency are also very often reduced. Spermatogenesis gradually recovers over 3-5 months. after discontinuation of cyproterone, in some patients, restoration of spermatogenesis may occur within 20 months. It is not yet known whether spermatogenesis can be restored after a very long period of treatment. In 10-20% of cases, men experience gynecomastia, which usually decreases when the drug is discontinued or reduced.

In men of reproductive age, before starting treatment with cyproterone, it is necessary to evaluate the spermatogram. During treatment with the drug, the decrease in spermatogenesis occurs gradually, so cyproterone should not be used as a male contraceptive.

With simultaneous consumption of alcohol in patients with pathologically increased sexual desire, a decrease in the effect of cyproterone therapy may be observed. In patients with alcoholism, treatment with cyproterone for hypersexuality and pathological deviations in sexual behavior is usually ineffective.

Since sexual and androgenic activity are not identical, suppression of androgenic activity is not always accompanied by suppression of sexual desire. Comprehensive treatment is required using psychotherapeutic and sociotherapeutic methods in close collaboration with the patient’s spouse. If appropriate measures are taken, the use of cyproterone to suppress sexual activity can produce positive results.

In patients with organic brain lesions or mental illnesses with deviations in sexual behavior, cyproterone has no clinical effectiveness.

In women, the use of cyproterone should only be carried out under the supervision of an experienced physician - a specialist in the field of hormonal therapy.

Cyproterone should not be used in young women who have not yet completed the formation of a normal menstrual cycle.

Before starting treatment, pregnancy must be completely excluded. If menstrual bleeding stops during treatment, the drug should be discontinued until pregnancy is completely ruled out. During treatment with the drug, pregnancy should not occur. In this regard, women of reproductive age should always use effective methods of contraception when taking cyproterone. It is recommended to take a combined estrogen-progestogen PC in the minimum possible dose of ethinyl estradiol 30-35 mcg. When taken in combination with a PC, you should read the appropriate instructions for medical use.

The use of cyproterone in women suffering from diseases that can aggravate the course of pregnancy (epilepsy, chorea, otosclerosis, multiple sclerosis, porphyria, diabetes mellitus and arterial hypertension) should only be carried out under the supervision of a physician, regardless of how cyproterone is used, as monotherapy or from PC.

In patients with gastrointestinal disorders accompanied by vomiting and/or diarrhea, it is not always possible to prevent pregnancy when using PCs. Despite this, treatment should not be stopped. Until the end of the treatment cycle, it is recommended to use barrier methods of contraception (condoms) as additional contraceptive measures. If there is no menstrual bleeding during a one-week pause in taking the drug, the drug should be discontinued until pregnancy is ruled out.

Taking cyproterone should not be stopped if bleeding in the form of “smearing” is observed outside the weekly break period. In case of heavy and repeated bleeding, a gynecological examination is necessary.

The use of cyproterone in combination with estrogens increases the risk of thrombosis. This fact must be taken into account when using cyproterone in women requiring surgical treatment. It is recommended to interrupt treatment with cyproterone 6 weeks before the planned surgery. During periods of prolonged bed rest, cyproterone should be suspended.

Women at the beginning of treatment with cyproterone often experience tenderness or a feeling of tension in the mammary glands or their enlargement, irregular menstrual bleeding or amenorrhea. There is often a decrease in sexual desire.

Due to decreased function of the sebaceous glands, dry skin may occur.

There were no negative effects of cyproterone on the fertility of patients after cessation of treatment.

Patients who have not reached puberty (the adverse effects of cyproterone on the growth of the patient and the formation of his endocrine system cannot be excluded) should not take cyproterone.

Considering the medical and social significance of the effects of cyproterone, it is recommended to obtain informed consent from the patient before starting treatment.