Дисменорея: эффективность и приемлемость лечения препаратом, содержащим 2 мг хлормадинона ацетата и 0,03 мг этинилэстрадиола

Прилепская В.Н., Мгерян А.Н., Межевитинова Е.А. Дисменорея: эффективность и приемлемость лечения препаратом, содержащим 2 мг хлормадинона ацетата и 0,03 мг этинилэстрадиола. Гинекология. 2017; 19 (3): 84–89. DOI: 10.26442/2079-5696_19.3.84-89

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Prilepskaia V.N., Mgerian A.N., Mezhevitinova E.A. Dysmenorrhea. Dysmenorrhea: effectiveness and acceptability of treatment with a drug containing 2 mg of chloromadinone acetate and 0.03 mg of ethinyl estradiol. Gynecology. 2017; 19 (3): 84–89. DOI: 10.26442/2079-5696_19.3.84-89

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Аннотация

По данным разных исследователей, первичной дисменореей страдают от 20 до 91% женщин. Комбинированные оральные контрацептивы являются препаратами первого выбора у молодых женщин с первичной дисменореей. Они обладают высокой эффективностью, лечебными и протективными свойствами. С целью оценки приемлемости препарата, содержащего этинилэстрадиол и хлормадинона ацетат, у женщин с симптомами дисменореи в ФГБУ «НЦАГиП им. акад. В.И.Кулакова» под наблюдением находились 75 женщин в возрасте от 18 до 40 лет. Средний возраст составил 26,4±4,1 года. Средняя продолжительность менструального цикла – 27,4±1,3 дня. Длительность дисменореи в среднем составила 6,3 года. Всем пациенткам был назначен препарат Белара в классическом режиме (21+7). Исчезновение симптомов уже на третьем цикле использования препарата отметили 54 (72%) пациентки, и еще 15–20% – через 12 мес. Субъективная оценка, полученная при помощи визуальной аналоговой шкалы, показала, что после 3, 6 и 12 мес использования препарата Белара 72, 80 и 92% пациенток соответственно были удовлетворены или очень удовлетворены эффектом терапии. Анализ индивидуальных показателей артериального давления до и в процессе контрацепции свидетельствовал об отсутствии влияния данного препарата на эти параметры. Анализ динамики биохимических параметров, липидного спектра крови и некоторых параметров гемостаза не выявил клинически и статистически значимых изменений, выходящих за пределы нормативных значений. Проанализированы также побочные эффекты, возникшие на фоне использования препарата Белара, которые наблюдались в основном в первые 2 мес применения комбинированных оральных контрацептивов. Шесть пациенток отмечали скудные межменструальные кровянистые выделения, 3 женщины – ощущение тошноты, напряжение и тяжесть в молочных железах – 5 (6,7%), одна женщина в течение 1 курса лечения жаловалась на незначительное головокружение. Аллергических реакций выявлено не было. Все побочные эффекты исчезли самостоятельно и не потребовали дополнительной терапии. Контрацептивная эффективность препарата Белара составила 100%. Таким образом, данные литературы и наш опыт показали, что комбинированный оральный контрацептив, содержащий 2 мг хлормадинона ацетата и 0,03 мг этинилэстрадиола (Белара), является высокоэффективным, безопасным и патогенетически обоснованным препаратом в терапии дисменореи. При длительном применении он не оказывает негативного влияния на сердечно-сосудистую систему, параметры гемостаза и метаболические показатели обмена веществ.

Ключевые слова: дисменорея, комбинированные оральные контрацептивы, этинилэстрадиол, хлормадинона ацетат.

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According to various researchers, primary dysmenorrhea affects between 20% and 91% of women. Combined oral contraceptives (COCs) are the first choice drugs in young women with primary dysmenorrhea. They have high efficiency, therapeutic and protective effects. In order to assess the acceptability of a drug containing ethinylestradiol and chloromadinone acetate in women with symptoms of dysmenorrhea, 75 women aged 75 years were monitored at V.I.Kulakov Research Center for Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation. at the age of 18 to 40 years. The average age was 23.4±4.1 years. The average duration of the menstrual cycle is 27.4±1.3 years. The duration of dysmenorrhea averaged 6.3 years. All patients were prescribed the drug Belara in the classical mode (21+7). 54 (72%) patients noted the disappearance of symptoms already on the 3rd cycle of drug use and another 15–20% of patients in 12 months. Subjective evaluation, obtained with the help of visual analogue scale, showed that after 3, 6 and 12 months of using the drug Belara, 72, 80 and 92% of patients were respectively satisfied or very satisfied with the effect of therapy. Analysis of individual BP parameters before and during contraception testified to the lack of influence of this drug on these parameters. Analysis of the dynamics of biochemical parameters, lipid spectrum of blood and some parameters of hemostasis did not reveal clinically and statistically significant changes that go beyond the limits of normative values. Analyzed are also the side effects that arose on the background of using the drug Belara, which were observed mainly in the first 2 months use of COCs. Six patients noted meager intermenstrual bleeding, 3 women reported nausea, tension and heaviness in the mammary glands – 5 (6.7%), one woman complained of insignificant dizziness during 1 course of treatment. Allergic reactions were not identified. All the side effects disappeared on their own and did not require additional therapy. Contraceptive effectiveness of the drug Belara was 100%. Thus, literature data and our experience have shown that a combined oral contraceptive containing 2 mg of chloromadinone acetate and 0.03 mg of ethinyl estradiol (Belara) is a highly effective, safe and pathogenetically valid drug in the therapy of dysmenorrhea. With long-term use it does not have a negative effect on the cardiovascular system, parameters of hemostasis and metabolic metabolic rates. All women were from 18 to 39 years old with dysmenorrhea of varying severity.

Key words: dysmenorrhea, combined oral contraceptives, ethinyl estradiol, chloromadinone acetate.

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Список литературы

1. Schramm G, Heckes B. Switching hormonal contraceptives to a chlormadinone acetate-containing oral contraceptive. The Contraceptive Switch Study. Contraception 2007; 76; 84–90.
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5. Бюллетень ACOG №110. Неконтрацептивное использование гормональной контрацепции. Obstet Gynecol 2010; 115 (1): 206. / Biulleten' ACOG №110. Nekontratseptivnoe ispol'zovanie gormonal'noi kontratseptsii. Obstet Gynecol 2010; 115 (1): 206. [in Russian]
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7. Irvani M. The effect ZatariaMultiflora on primary Dysmenorrhea. J Herb Drugs 2009; 11 (2): 55–60.
8. O’Connell K, Westhoff C. Self-treatment patterns among adolescent girls with dysmenorrhea. J Pediatr Adolesc Gynecol 2006; 19 (4): 285–9.
9. Hillen TI, Grbavac SL, Johnston PJ et al. Primary dysmenorrhea in young Western Australian women: prevalence, impact, and knowledge of treatment. J Adolesc Health 1999; 25: 40–5.
10. Ju H, Jones M, Mishra G. The prevalence and risk factors of dysmenorrhea. Epidemiol Rev 2014; 36 (1): 104–13.
11. Thomas B, Magos A. Modern management of dysmenorrheal. Trends in Urology, Gynecology and Sexual Health 2009; 14 (5): 25–9.
12. National Library for Health. Dysmenorrhoea. Available from: http://www.cks.library.nhs.uk/ dysmenorrhoea
13. Rees MCP. Menstrual problems. In: Waller D, McPherson A, editors. Women's health. 5th ed. Oxford: Oxford University Press, 2003; p. 1–45.
14. Czekanowski R, Mosler KH, Schwalm H. Influence of prostaglandin F2-alpha on the contractility of the nonpregnant human uterus in vitro. Z Geburtshilfe Perinatol 1973; 177: 202–9.
15. Zahradnik H-P, Steiner H, Hillemanns HG et al. Prostaglandin F2alpha- and 15-methyl-prostaglandin F2alpha – application for the treatment of severe uterine bleedings (author's transl). Geburtshilfe Frauenheilkd 1977; 37: 493–5.
16. Jabbour HN, Kelly RW, Fraser HM et al. Endocrine regulation of menstruation. Endocr Rev 2006; 27: 17–46.
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18. Zahradnika H-P, Hanjalic-Becka A, Grothb K. Nonsteroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review. Contraception 2010; 81: 185–96.
19. Hanjalic-Beck A, Schafer WR et al. Chlormadinone acetate suppresses prostaglandin biosynthesis in human endometrial explants. Fertil Steril 2012; 98 (4): 1017–22.
20. Zahradnik H-P, Wetzka B, Schuth W. Zyklusabhängige Befindlichkeitsstörungen der Frau. Gynäkologe 2000; 33: 225–38.
21. Simopoulos AP. The importance of the ratio of omega-6/omega-3essential fatty acids. Biomed Pharmacother 2002; 56: 365–79.
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Wyndham Heron Ltd, 2008.
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24. Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs 2003; 63: 463–92.
25. Terlinden R, Uragg H, Gohler K et al. Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate. Contraception 2006; 74: 239–44.
26. René Druckmann. Profile of the progesterone derivative chlormadinone acetate – Pharmocodynamic properties and therapeutic application. Contraception 2009; 79: 272–81.
27. Lee HY, Acosta TJ, Tanikawa M et al. The role of glucocorticoid in the regulation of prostaglandin biosynthesis in non-pregnant bovine endometrium. J Endocrinol 2007; 193: 127–35.
28. Maia H, Casoy J, Pimentel K et al. Effect of oral contraceptives on vascular endothelial growth factor, Cox-2 and aromatase и expression in the endometrium of uteri affected by myomas and associated pathologies. Contraception 2008; 78: 479–85.
29. Maia H, Casoy J, Athayde C. The effect of a continuous regimen of drospirenone 3 mg/ethinylestradiol 30 microg on Cox-2 and Ki-67 expression in the endometrium. Eur J Contracept Reprod Health Care 2010; 15: 35–40.
30. Critchley HO, Jones RL, Lea RG et al. Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy. J Clin Endocrinol Metab 1999; 84: 240–8.
31. Sugino N, Karube-Harada A, Taketani T. Withdrawal of ovarian steroids stimulates prostaglandin F2-alpha production through nuclear factor-kappaB activation via oxygen radicals in human endometrial stromal cells: potential relevance to menstruation. J Reprod Dev 2004; 50: 215–25.
32. Lech MM, Ostrowska L. Risk of cancer development in relation to oral contraception. Eur J Contrasept Reprod Hlth Care 2006; 11 (3): 162‒8.
33. Pelissier C, Caby J. Contraception des femmes à hauts risques vasculaires et métaboliques: essai d'un dérivé de la 17 0H progestérone. Gynécologie 1983; 34: 131–8.
34. Vlieg H et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progesterone type results of the MEGA case-control study. BMJ 2009; 339: b2921.
35. Lidegaard Ø et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. SOGC Clinical Practice Guideline 2010: Oral Contraceptives and the Risk of Venous Thromboembolism: An Update. International Active Surveillance of Women Taking. BMJ 2009; 339: b2890.
36. Pelissier C, Basdevant A, Conard J et al. Administration prolongée d'acétate de chlormadinone: effets métaboliques, tensionnels et hormonaux. Gynécologie 1991; 42: 79–86.
37. Pelissier C, Basdevant A, Conard J et al. Progestogen contraception using chlormadinone acetate in women presenting high vascular risk. (A gynecoendocrine, metabolic and vascular study.). Contracept Fertil Sex (Paris) 1987; 15: 45–54.
38. Pelissier C. Tolérance clinique, métabolique et vasculaire de l'association 17b-estradiol et acétate de chlormadinone chez la femme ménopausée normale ou à risque artériel. Etude prospective contrôlée, randomisée, à long terme (18 mois). Rev Prat Gynecol Obstet 1999; 29: 35–40.
39. Winkler UH, Daume E, Sudik R et al. A comparative study of the hemostatic effects of two monophasic oral contraceptives containing
30 mu (g) ethinylestradiol and either 2 mg chlormadinone acetate or 150 mu (g) desogestrel. Eur J Contracept Reprod Health Care 1999; 4: 145–54.
40. Conard J, Plu-Bureau G, Bahi N et al. Progestogen-only contraception in women at high risk of venous thromboembolism. Contraception 2004; 70: 437–41.
41. Martinez F, Avecilla A. Combined hormonal contraception and venous thromboembolism. Eur J Contracept Reprod Health Care 2007; 12: 97–106.
42. Schramm G, Steffens D. Contraceptive efficacy and tolerability of chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (Belara®).
43. Results of a post-marketing surveillance study. Clin Drug Invest 2002; 22: 221–31.
44. Schramm G, Steffens D. A 12-month evaluation of the CMA containing oral contraceptive Belara: efficacy, tolerability and antiandrogenic properties. Contraception 2003; 67: 305–12.
45. Worret I, Arp W, Zahradnik H et al. Acne resolution rates: results of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon). Dermatology 2001; 203: 38–44.
46. Прилепская В.Н., Межевитинова Е.А., Абакарова П.Р. Возможности использования КОК, содержащего хлормадинона ацетат, у женщин с дисменореей и симптомами гиперандрогении. Medica mentle. Научно-образовательный проект для врачей. Гинекология. 2016; 18 (2): 22–8. / Prilepskaya V.N., Mezhevitinova E.A., Abakarova P.R. Vozmozhnosti ispol'zovaniia KOK, soderzhashchego khlormadinona atsetat, u zhenshchin s dismenoreei i simptomami giperandrogenii. Medica mentle. Nauchno-obrazovatel'nyi proekt dlia vrachei. Gynecology. 2016; 18 (2): 22–8. [in Russian]

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1. Schramm G, Heckes B. Switching hormonal contraceptives to a chlormadinone acetate-containing oral contraceptive. The Contraceptive Switch Study. Contraception 2007; 76; 84–90.
2. Ministerstvo zdravookhraneniia Rossiiskoi Federatsii “Osnovnye pokazateli akushersko-ginekologicheskoi sluzhby v 2015 g.” [in Russian]
3. Prilepskaya V.N., Khlebkova Yu.S. Prolonged contraception. Modern possibilities, efficiency and prospects (literature review). Gynecology. 2016; 18 (1): 88–91. [in Russian]
4. Hannaford PC, Selvaraj S, Elliott AM et al. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioners oral contraception study. BMJ 2007; 335: 651.
5. Biulleten' ACOG №110. Nekontratseptivnoe ispol'zovanie gormonal'noi kontratseptsii. Obstet Gynecol 2010; 115 (1): 206. [in Russian]
6. Chao-qin Gou, Gao J, Chen-xi Wu et al. Moxibution for primary Dysmenorrhea Interventional Times: A Systematic Review and Meta-Analysis. Evidence-based Complementary and Alternative Medicine 2016.
7. Irvani M. The effect ZatariaMultiflora on primary Dysmenorrhea. J Herb Drugs 2009; 11 (2): 55–60.
8. O’Connell K, Westhoff C. Self-treatment patterns among adolescent girls with dysmenorrhea. J Pediatr Adolesc Gynecol 2006; 19 (4): 285–9.
9. Hillen TI, Grbavac SL, Johnston PJ et al. Primary dysmenorrhea in young Western Australian women: prevalence, impact, and knowledge of treatment. J Adolesc Health 1999; 25: 40–5.
10. Ju H, Jones M, Mishra G. The prevalence and risk factors of dysmenorrhea. Epidemiol Rev 2014; 36 (1): 104–13.
11. Thomas B, Magos A. Modern management of dysmenorrheal. Trends in Urology, Gynecology and Sexual Health 2009; 14 (5): 25–9.
12. National Library for Health. Dysmenorrhoea. Available from: http://www.cks.library.nhs.uk/ dysmenorrhoea
13. Rees MCP. Menstrual problems. In: Waller D, McPherson A, editors. Women's health. 5th ed. Oxford: Oxford University Press, 2003; p. 1–45.
14. Czekanowski R, Mosler KH, Schwalm H. Influence of prostaglandin F2-alpha on the contractility of the nonpregnant human uterus in vitro. Z Geburtshilfe Perinatol 1973; 177: 202–9.
15. Zahradnik H-P, Steiner H, Hillemanns HG et al. Prostaglandin F2alpha- and 15-methyl-prostaglandin F2alpha – application for the treatment of severe uterine bleedings (author's transl). Geburtshilfe Frauenheilkd 1977; 37: 493–5.
16. Jabbour HN, Kelly RW, Fraser HM et al. Endocrine regulation of menstruation. Endocr Rev 2006; 27: 17–46.
17. Abel MH, Baird DT. The effect of 17 beta-estradiol and progesterone on prostaglandin production by human endometrium maintained in organ culture. Endocrinology 1980; 106: 1599–606.
18. Zahradnika H-P, Hanjalic-Becka A, Grothb K. Nonsteroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review. Contraception 2010; 81: 185–96.
19. Hanjalic-Beck A, Schafer WR et al. Chlormadinone acetate suppresses prostaglandin biosynthesis in human endometrial explants. Fertil Steril 2012; 98 (4): 1017–22.
20. Zahradnik H-P, Wetzka B, Schuth W. Zyklusabhängige Befindlichkeitsstörungen der Frau. Gynäkologe 2000; 33: 225–38.
21. Simopoulos AP. The importance of the ratio of omega-6/omega-3essential fatty acids. Biomed Pharmacother 2002; 56: 365–79.
22. Gowans G. Monthly Index of Medical Specialities. Maldon, Essex:
Wyndham Heron Ltd, 2008.
23. Marjoribanks J, Proctor ML, Farquhar C. Nonsteroidal anti-inflammatory drugs for primary dysmenorrhoea. Cochrane Database Syst Rev 2003: CD001751.
24. Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs 2003; 63: 463–92.
25. Terlinden R, Uragg H, Gohler K et al. Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate. Contraception 2006; 74: 239–44.
26. René Druckmann. Profile of the progesterone derivative chlormadinone acetate – Pharmocodynamic properties and therapeutic application. Contraception 2009; 79: 272–81.
27. Lee HY, Acosta TJ, Tanikawa M et al. The role of glucocorticoid in the regulation of prostaglandin biosynthesis in non-pregnant bovine endometrium. J Endocrinol 2007; 193: 127–35.
28. Maia H, Casoy J, Pimentel K et al. Effect of oral contraceptives on vascular endothelial growth factor, Cox-2 and aromatase и expression in the endometrium of uteri affected by myomas and associated pathologies. Contraception 2008; 78: 479–85.
29. Maia H, Casoy J, Athayde C. The effect of a continuous regimen of drospirenone 3 mg/ethinylestradiol 30 microg on Cox-2 and Ki-67 expression in the endometrium. Eur J Contracept Reprod Health Care 2010; 15: 35–40.
30. Critchley HO, Jones RL, Lea RG et al. Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy. J Clin Endocrinol Metab 1999; 84: 240–8.
31. Sugino N, Karube-Harada A, Taketani T. Withdrawal of ovarian steroids stimulates prostaglandin F2-alpha production through nuclear factor-kappaB activation via oxygen radicals in human endometrial stromal cells: potential relevance to menstruation. J Reprod Dev 2004; 50: 215–25.
32. Lech MM, Ostrowska L. Risk of cancer development in relation to oral contraception. Eur J Contrasept Reprod Hlth Care 2006; 11 (3): 162‒8.
33. Pelissier C, Caby J. Contraception des femmes à hauts risques vasculaires et métaboliques: essai d'un dérivé de la 17 0H progestérone. Gynécologie 1983; 34: 131–8.
34. Vlieg H et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progesterone type results of the MEGA case-control study. BMJ 2009; 339: b2921.
35. Lidegaard Ø et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. SOGC Clinical Practice Guideline 2010: Oral Contraceptives and the Risk of Venous Thromboembolism: An Update. International Active Surveillance of Women Taking. BMJ 2009; 339: b2890.
36. Pelissier C, Basdevant A, Conard J et al. Administration prolongée d'acétate de chlormadinone: effets métaboliques, tensionnels et hormonaux. Gynécologie 1991; 42: 79–86.
37. Pelissier C, Basdevant A, Conard J et al. Progestogen contraception using chlormadinone acetate in women presenting high vascular risk. (A gynecoendocrine, metabolic and vascular study.). Contracept Fertil Sex (Paris) 1987; 15: 45–54.
38. Pelissier C. Tolérance clinique, métabolique et vasculaire de l'association 17b-estradiol et acétate de chlormadinone chez la femme ménopausée normale ou à risque artériel. Etude prospective contrôlée, randomisée, à long terme (18 mois). Rev Prat Gynecol Obstet 1999; 29: 35–40.
39. Winkler UH, Daume E, Sudik R et al. A comparative study of the hemostatic effects of two monophasic oral contraceptives containing
30 mu (g) ethinylestradiol and either 2 mg chlormadinone acetate or 150 mu (g) desogestrel. Eur J Contracept Reprod Health Care 1999; 4: 145–54.
40. Conard J, Plu-Bureau G, Bahi N et al. Progestogen-only contraception in women at high risk of venous thromboembolism. Contraception 2004; 70: 437–41.
41. Martinez F, Avecilla A. Combined hormonal contraception and venous thromboembolism. Eur J Contracept Reprod Health Care 2007; 12: 97–106.
42. Schramm G, Steffens D. Contraceptive efficacy and tolerability of chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (Belara®).
43. Results of a post-marketing surveillance study. Clin Drug Invest 2002; 22: 221–31.
44. Schramm G, Steffens D. A 12-month evaluation of the CMA containing oral contraceptive Belara: efficacy, tolerability and antiandrogenic properties. Contraception 2003; 67: 305–12.
45. Worret I, Arp W, Zahradnik H et al. Acne resolution rates: results of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon). Dermatology 2001; 203: 38–44.
46. Prilepskaya V.N., Mezhevitinova E.A., Abakarova P.R. Vozmozhnosti ispol'zovaniia KOK, soderzhashchego khlormadinona atsetat, u zhenshchin s dismenoreei i simptomami giperandrogenii. Medica mentle. Nauchno-obrazovatel'nyi proekt dlia vrachei. Gynecology. 2016; 18 (2): 22–8. [in Russian]

Авторы

В.Н.Прилепская*, А.Н.Мгерян, Е.А.Межевитинова

ФГБУ «Научный центр акушерства, гинекологии и перинатологии им. акад. В.И.Кулакова» Минздрава России. 117997, Россия, Москва, ул. Академика Опарина, д. 4
*VPrilepskaya@mail.ru

________________________________________________

V.N.Prilepskaia*, A.N.Mgerian, E.A.Mezhevitinova

V.I.Kulakov Research Center for Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation. 117997, Russian Federation, Moscow, ul. Akademika Oparina, d. 4
*VPrilepskaya@mail.ru

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