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Эффективность использования низких доз дроспиренона и 17b-эстрадиола у женщин в постменопаузе (обзор литературы)
Эффективность использования низких доз дроспиренона и 17b-эстрадиола у женщин в постменопаузе (обзор литературы)
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Аннотация
Вазомоторные симптомы, в том числе приливы, являются наиболее распространенными симптомами менопаузы, требующими коррекции гормональной терапией (ГТ) эстрогенами и/или с прогестагенами. Последние международные клинические рекомендации признают необходимость использования самых низких эффективных доз ГТ. В качестве ГТ для облегчения симптомов в постменопаузе и профилактики остеопороза используется 17b-эстрадиол в комбинации с дроспиреноном.
Целью данного обзора является метаанализ исследований, посвященных изучению эффективности и безопасности низких доз эстрадиола и дроспиренона с целью лечения вазомоторных симптомов климактерического синдрома, а также оценки состояния эндометрия у женщин в постменопаузе.
В обзоре представлены данные крупнейших рандомизированных контролируемых исследований, в которых была проведена оценка минимально эффективной дозы комбинации эстрадиол/дроспиренон на безопасность эндометрия, особенности фармакокинетики и фармакодинамики в зависимости от разных факторов.
Первое рандомизированное исследование показало, что для лечения приливов у женщин в постменопаузе комбинация дроспиренон 0,25 мг/эстрадиол 0,5 мг является минимально эффективной дозой. Эффективность низких доз дроспиренона/эстрадиола коррелировала с экспозицией эстрадиола и дроспиренона в сыворотке, в то время как курение отрицательно влияло на эффективность лечения.
Оценка рисков гиперплазии эндометрия и особенности кровотечения на фоне приема дроспиренона 0,25 мг/эстрадиола 0,5 мг в течение 12 мес не выявила гиперплазии или атипии эндометрия, что подтвердило безопасность приема дроспиренона 0,25 мг/эстрадиола 0,5 мг.
Таким образом, минимальной эффективной дозой для купирования приливов, не оказывая при этом значительного влияния на состояние эндометрия, является комбинация дроспиренон 0,25 мг/эстрадиол 0,5 мг, которая купирует вазомоторные проявления климактерического синдрома, снижает частоту симптомов вульвовагинальной атрофии, повышая качество жизни пациенток.
Ключевые слова: менопауза, дроспиренон, 17b-эстрадиол, приливы, фармакокинетика, фармакодинамика, гиперплазия эндометрия.
The aim of this review is a meta-analysis of studies examining the efficacy and safety of low-dose DR and E for the treatment of vasomotor symptoms in postmenopausal women.
The review presents data of 2 large randomized controlled studies that evaluated the lowest effective dose combination DR/E, the safety of this dose for endometrium, identified features of its pharmacodynamics and pharmacokinetics, depending on various factors.
In the first, a study of the lowest effective doses of DR/E for the treatment of HF in postmenopausal women was made. It led to the conclusion that the combination of DR 0,25 mg/E of 0,5 mg is the minimum effective dose. Efficacy of low doses of DR/E correlated with exposure DR and E in serum, while smoking had a negative impact on the Efficacy of treatment.
Another study assessed the risk of endometrial hyperplasia and bleeding pattern in patients receiving 0,25 mg DR/E of 0,5 mg for 12 months. At the end of the study no evaluable women in the DR/E2 group had an endometrial biopsy result of hyperplasia or worse, which endometrial confirmed the safety of receiving DR 0,25 mg/E of 0,5 mg.
Thus, the minimum effective dose for the relief of HF without causing any significant impact on the endometrium is DR of 0,25 mg/E of 0,5 mg. According to the results of the pharmacokinetic study a correlation between effectiveness of low dose DR/E with DR and E exposure levels was showed, and smoking reduces the effectiveness of hormonal therapy. This drug not only copes with moderate to severe hot flashes, but also reduces the incidence of symptoms of vulvovaginal atrophy, improving quality of life.
Key words: menopause, drospirenone, 17b-estradiol, hot flushes, pharmacokinetics, pharmacodynamics, endometrial hyperplasia.
Целью данного обзора является метаанализ исследований, посвященных изучению эффективности и безопасности низких доз эстрадиола и дроспиренона с целью лечения вазомоторных симптомов климактерического синдрома, а также оценки состояния эндометрия у женщин в постменопаузе.
В обзоре представлены данные крупнейших рандомизированных контролируемых исследований, в которых была проведена оценка минимально эффективной дозы комбинации эстрадиол/дроспиренон на безопасность эндометрия, особенности фармакокинетики и фармакодинамики в зависимости от разных факторов.
Первое рандомизированное исследование показало, что для лечения приливов у женщин в постменопаузе комбинация дроспиренон 0,25 мг/эстрадиол 0,5 мг является минимально эффективной дозой. Эффективность низких доз дроспиренона/эстрадиола коррелировала с экспозицией эстрадиола и дроспиренона в сыворотке, в то время как курение отрицательно влияло на эффективность лечения.
Оценка рисков гиперплазии эндометрия и особенности кровотечения на фоне приема дроспиренона 0,25 мг/эстрадиола 0,5 мг в течение 12 мес не выявила гиперплазии или атипии эндометрия, что подтвердило безопасность приема дроспиренона 0,25 мг/эстрадиола 0,5 мг.
Таким образом, минимальной эффективной дозой для купирования приливов, не оказывая при этом значительного влияния на состояние эндометрия, является комбинация дроспиренон 0,25 мг/эстрадиол 0,5 мг, которая купирует вазомоторные проявления климактерического синдрома, снижает частоту симптомов вульвовагинальной атрофии, повышая качество жизни пациенток.
Ключевые слова: менопауза, дроспиренон, 17b-эстрадиол, приливы, фармакокинетика, фармакодинамика, гиперплазия эндометрия.
________________________________________________
The aim of this review is a meta-analysis of studies examining the efficacy and safety of low-dose DR and E for the treatment of vasomotor symptoms in postmenopausal women.
The review presents data of 2 large randomized controlled studies that evaluated the lowest effective dose combination DR/E, the safety of this dose for endometrium, identified features of its pharmacodynamics and pharmacokinetics, depending on various factors.
In the first, a study of the lowest effective doses of DR/E for the treatment of HF in postmenopausal women was made. It led to the conclusion that the combination of DR 0,25 mg/E of 0,5 mg is the minimum effective dose. Efficacy of low doses of DR/E correlated with exposure DR and E in serum, while smoking had a negative impact on the Efficacy of treatment.
Another study assessed the risk of endometrial hyperplasia and bleeding pattern in patients receiving 0,25 mg DR/E of 0,5 mg for 12 months. At the end of the study no evaluable women in the DR/E2 group had an endometrial biopsy result of hyperplasia or worse, which endometrial confirmed the safety of receiving DR 0,25 mg/E of 0,5 mg.
Thus, the minimum effective dose for the relief of HF without causing any significant impact on the endometrium is DR of 0,25 mg/E of 0,5 mg. According to the results of the pharmacokinetic study a correlation between effectiveness of low dose DR/E with DR and E exposure levels was showed, and smoking reduces the effectiveness of hormonal therapy. This drug not only copes with moderate to severe hot flashes, but also reduces the incidence of symptoms of vulvovaginal atrophy, improving quality of life.
Key words: menopause, drospirenone, 17b-estradiol, hot flushes, pharmacokinetics, pharmacodynamics, endometrial hyperplasia.
Полный текст
Список литературы
1. Stearns V, Ullmer L, Lopez JF et al. Hot flushes. Lancet 2002; 360: 1851–61.
2. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004; CD002978.
3. Sturdee DW, Pines A. International Menopause Society Writing Group. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011; 14: 302–20.
4. The North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012; 19: 257–71.
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6. Archer DF, Thorneycroft IH, Foegh M et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005; 12: 716–27.
7. Schurmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric 2004; 7: 189–96.
8. Warming L, Ravn P, Nielsen T, Christiansen C. Safety and efficacy of drospirenone used in a continuous combination with 17A-estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004; 7: 103–11.
9. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric 2005; 8: 4–12.
10. Mueck AO, Seeger H. Smoking, estradiol metabolism and hormone replacement therapy. Curr Med Chem Cardiovasc Hematol Agents 2005; 3: 45–54.
11. Archer DF, Schmelter T, Schaefers M et al. A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17b-estradiol for moderate to severe vasomotor symptoms in postmenopausal women. Menopause 2014; 21.
12. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms – recommendations for clinical evaluation. Available at: http://www.fda. gov/downloads/Drugs /DrugSafety/InformationbyDrugClass/UCM135338.pdf
13. Rose DP, Vona-Davis L. Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas 2010; 66: 33–8.
14. Anttila S, Hakkola J, Tuominen P et al. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res 2003; 63: 8623–8.
15. Kisselev P, Schunck WH, Roots I, Schwarz D. Association of CYP1A1 polymorphisms with differential metabolic activation of 17A-estradiol and estrone. Cancer Res 2005; 65: 2972–8.
16. Genazzani AR, Schmelter T, Schaefers M et al. One-year randomized study of the endometrial safety and bleeding pattern of 0,25 mg drospirenone/0,5 mg 17b-estradiol in postmenopausal women. Climacteric 2013; 16: 490–8.
17. Gerlinger C, Gude K, Alincic-Kunz S, Schafers M. Recommendation for the collection and analysis of endometrial biopsies for hormone therapies. Climacteric 2012; 15: 52–8.
18. Kurman RJ, Ellenson HL, Ronnett BM. Blaustein’s Pathology of the Female Genital Tract, 6th edn. New York: Springer, 2011.
19. Hunter MS. The Women’s Health Questionnaire: a measure of mid-aged women’s perceptions of their emotional and physical health. Psychol Health 1992; 7: 45–54.
2. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004; CD002978.
3. Sturdee DW, Pines A. International Menopause Society Writing Group. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011; 14: 302–20.
4. The North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012; 19: 257–71.
5. Santen RJ, Allred DC, Ardoin SP et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010; 95: 1–66.
6. Archer DF, Thorneycroft IH, Foegh M et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005; 12: 716–27.
7. Schurmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric 2004; 7: 189–96.
8. Warming L, Ravn P, Nielsen T, Christiansen C. Safety and efficacy of drospirenone used in a continuous combination with 17A-estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004; 7: 103–11.
9. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric 2005; 8: 4–12.
10. Mueck AO, Seeger H. Smoking, estradiol metabolism and hormone replacement therapy. Curr Med Chem Cardiovasc Hematol Agents 2005; 3: 45–54.
11. Archer DF, Schmelter T, Schaefers M et al. A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17b-estradiol for moderate to severe vasomotor symptoms in postmenopausal women. Menopause 2014; 21.
12. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms – recommendations for clinical evaluation. Available at: http://www.fda. gov/downloads/Drugs /DrugSafety/InformationbyDrugClass/UCM135338.pdf
13. Rose DP, Vona-Davis L. Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas 2010; 66: 33–8.
14. Anttila S, Hakkola J, Tuominen P et al. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res 2003; 63: 8623–8.
15. Kisselev P, Schunck WH, Roots I, Schwarz D. Association of CYP1A1 polymorphisms with differential metabolic activation of 17A-estradiol and estrone. Cancer Res 2005; 65: 2972–8.
16. Genazzani AR, Schmelter T, Schaefers M et al. One-year randomized study of the endometrial safety and bleeding pattern of 0,25 mg drospirenone/0,5 mg 17b-estradiol in postmenopausal women. Climacteric 2013; 16: 490–8.
17. Gerlinger C, Gude K, Alincic-Kunz S, Schafers M. Recommendation for the collection and analysis of endometrial biopsies for hormone therapies. Climacteric 2012; 15: 52–8.
18. Kurman RJ, Ellenson HL, Ronnett BM. Blaustein’s Pathology of the Female Genital Tract, 6th edn. New York: Springer, 2011.
19. Hunter MS. The Women’s Health Questionnaire: a measure of mid-aged women’s perceptions of their emotional and physical health. Psychol Health 1992; 7: 45–54.
2. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004; CD002978.
3. Sturdee DW, Pines A. International Menopause Society Writing Group. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011; 14: 302–20.
4. The North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012; 19: 257–71.
5. Santen RJ, Allred DC, Ardoin SP et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010; 95: 1–66.
6. Archer DF, Thorneycroft IH, Foegh M et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005; 12: 716–27.
7. Schurmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric 2004; 7: 189–96.
8. Warming L, Ravn P, Nielsen T, Christiansen C. Safety and efficacy of drospirenone used in a continuous combination with 17A-estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004; 7: 103–11.
9. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric 2005; 8: 4–12.
10. Mueck AO, Seeger H. Smoking, estradiol metabolism and hormone replacement therapy. Curr Med Chem Cardiovasc Hematol Agents 2005; 3: 45–54.
11. Archer DF, Schmelter T, Schaefers M et al. A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17b-estradiol for moderate to severe vasomotor symptoms in postmenopausal women. Menopause 2014; 21.
12. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms – recommendations for clinical evaluation. Available at: http://www.fda. gov/downloads/Drugs /DrugSafety/InformationbyDrugClass/UCM135338.pdf
13. Rose DP, Vona-Davis L. Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas 2010; 66: 33–8.
14. Anttila S, Hakkola J, Tuominen P et al. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res 2003; 63: 8623–8.
15. Kisselev P, Schunck WH, Roots I, Schwarz D. Association of CYP1A1 polymorphisms with differential metabolic activation of 17A-estradiol and estrone. Cancer Res 2005; 65: 2972–8.
16. Genazzani AR, Schmelter T, Schaefers M et al. One-year randomized study of the endometrial safety and bleeding pattern of 0,25 mg drospirenone/0,5 mg 17b-estradiol in postmenopausal women. Climacteric 2013; 16: 490–8.
17. Gerlinger C, Gude K, Alincic-Kunz S, Schafers M. Recommendation for the collection and analysis of endometrial biopsies for hormone therapies. Climacteric 2012; 15: 52–8.
18. Kurman RJ, Ellenson HL, Ronnett BM. Blaustein’s Pathology of the Female Genital Tract, 6th edn. New York: Springer, 2011.
19. Hunter MS. The Women’s Health Questionnaire: a measure of mid-aged women’s perceptions of their emotional and physical health. Psychol Health 1992; 7: 45–54.
________________________________________________
2. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004; CD002978.
3. Sturdee DW, Pines A. International Menopause Society Writing Group. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011; 14: 302–20.
4. The North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012; 19: 257–71.
5. Santen RJ, Allred DC, Ardoin SP et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010; 95: 1–66.
6. Archer DF, Thorneycroft IH, Foegh M et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 2005; 12: 716–27.
7. Schurmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric 2004; 7: 189–96.
8. Warming L, Ravn P, Nielsen T, Christiansen C. Safety and efficacy of drospirenone used in a continuous combination with 17A-estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004; 7: 103–11.
9. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric 2005; 8: 4–12.
10. Mueck AO, Seeger H. Smoking, estradiol metabolism and hormone replacement therapy. Curr Med Chem Cardiovasc Hematol Agents 2005; 3: 45–54.
11. Archer DF, Schmelter T, Schaefers M et al. A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17b-estradiol for moderate to severe vasomotor symptoms in postmenopausal women. Menopause 2014; 21.
12. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms – recommendations for clinical evaluation. Available at: http://www.fda. gov/downloads/Drugs /DrugSafety/InformationbyDrugClass/UCM135338.pdf
13. Rose DP, Vona-Davis L. Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas 2010; 66: 33–8.
14. Anttila S, Hakkola J, Tuominen P et al. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res 2003; 63: 8623–8.
15. Kisselev P, Schunck WH, Roots I, Schwarz D. Association of CYP1A1 polymorphisms with differential metabolic activation of 17A-estradiol and estrone. Cancer Res 2005; 65: 2972–8.
16. Genazzani AR, Schmelter T, Schaefers M et al. One-year randomized study of the endometrial safety and bleeding pattern of 0,25 mg drospirenone/0,5 mg 17b-estradiol in postmenopausal women. Climacteric 2013; 16: 490–8.
17. Gerlinger C, Gude K, Alincic-Kunz S, Schafers M. Recommendation for the collection and analysis of endometrial biopsies for hormone therapies. Climacteric 2012; 15: 52–8.
18. Kurman RJ, Ellenson HL, Ronnett BM. Blaustein’s Pathology of the Female Genital Tract, 6th edn. New York: Springer, 2011.
19. Hunter MS. The Women’s Health Questionnaire: a measure of mid-aged women’s perceptions of their emotional and physical health. Psychol Health 1992; 7: 45–54.
Авторы
Е.Н.Андреева, О.Р.Григорян, Ю.С.Абсатарова
ФГБУ Эндокринологический научный центр Минздрава России, Москва
ФГБУ Эндокринологический научный центр Минздрава России, Москва
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