В обзоре рассматриваются вопросы эффективности и безопасности фитоэстрогенов, преимущественно изофлавонов сои, в лечении симптомов климактерического синдрома. Особое внимание уделяется синтетическому генистеину. Наиболее высокая по сравнению с другими фитоэстрогенами эффективность генистеина подтверждается сравнительными и плацебо-контролируемыми исследованиями. Вместе с тем длительное применение генистеина не влияет на пролиферативные процессы в эндометрии и молочных железах. Генистеин можно считать достойной альтернативой гормональной терапии в случаях, когда она невозможна или нежелательна.
The review discusses the efficacy and safety of phytoestrogens, preferably soy isoflavones in treating the menopausal syndrome symptoms. Particular attention is paid to the synthetic genistein. The highest genistein efficacy, when compared to other phytoestrogens is confirmed by comparative and placebo-controlled trials. However, prolonged use of genistein does not affect the proliferate processes in the endometrium and breast. Genistein can be considered a good alternative to hormone therapy when it is proved to be impossible or undesirable.
Key words: postmenopause, phytoestrogens genistein, hot flushes, endometrial, breast, security.
1. Клинические рекомендации. Акушерство и гинекология. Вып. 2. Под ред. В.И.Кулакова. М.: ГЭОТАР-Медиа, 2008.
2. Nelson HD, Haney E, Humphrey et al. Management of menopause-related symptoms. Summary, Evidence Report/Technology Assessment No. 120 (Prepared by the Oregon Evidence-based Practice Center, under contract No. 290-02-0024). AHRQ Pub. No. 05-E016-1. Rockville, MD: Agency for Health Research Quality, 2005.
3. Maclennan AH, Broadbent JL, Lester S et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flashes. Cochrane Database Syst Rev 2004; 4: CD002978.
4. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419–27.
5. Gompel A, Rozenberg S, Barlow DH. The EMAS 2008 update on clinical recommendations on postmenopausal hormone replacement therapy. Maturitas 2008; 61: 227–32.
6. Hill DA, Hill SR. Counseling patients about hormone therapy and alternatives for menopausal symptoms. Am Fam Physician 2010; 82: 801–7.
7. Tsai SA, Stefanick ML, Stafford RS. Trends in menopausal hormone therapy use of US office-based physicians, 2000-2009. Menopause 2011; 18: 385–92.
8. Kronenberg F, Cushman LF, Wade CM et al. Race/ethnicity and women`s use of complementary and alternative medicine in the United States: results of national survey. Am J Public Health 2006; 96: 1236–42.
9. Melby MK. Chilliness: a vasomotor symptom in Japan. Menopause 2007; 14: 752–9.
10. Melby MK, Watanabe S, Whitten PL et al. Sensitive high-performance liquid chromatographic method using coulometric electrode array detection for measurement of phytoestrogens in dried blood spots. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 826: 81–90.
11. Rimbach G, Boesch-Saadatmandi C, Frank J et al. Dietary isoflavones in the prevention of cardiovascular disease – a molecular perspective. Food Chem Toxicol 2008; 46: 1308–19.
12. Oseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med 2008; 74: 1656–65.
13. Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas 2006; 55: 203–11.
14. Taku K, Melby MK, Kronenberg F et al. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012; 19 (7): 776–90.
15. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause 2006; 13: 831–9.
16. Jacobs A, Wegewitz U, Sommerfeld C et al. Efficacy of isoflavones in relieving vasomotor menopausal symptoms – a systematic review. Mol Nutr Food Res 2009; 53: 1084–97.
17. Lethaby A, Brown J, Marjoribanks J et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007: CD001395.
18. Nelson HD, Vesco KK, Haney E et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006; 295: 2057–71.
19. Krebs EE, Ensrud KE, MacDonald R et al. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol 2004; 104: 824–36.
20. Nedrow A, Miller J, Walker M et al. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med 2006; 166: 1453–65.
21. Tempfer CB, Bentz EK, Leodolter S et al. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril 2007; 87: 1243–9.
22. Bolanos R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment o climacteric vasomotor symptoms: systematic review and meta-analysis. Menopause 2010; 17: 660–6.
23. Messina M, Hughes C. Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively related to initial hot flush frequency. J Med Food 2003; 6: 1–11.
24. De Cremoux P, This P, Leclercq G, Jacquot Y. Controversies concerning the use of phytoestrogens in menopause management: bioavailability and metabolism. Maturitas 2010; 65 (4): 334–9.
25. Newton KM, Reed SD, LaCroix AZ et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006; 145: 869–79.
26. Geller SE, Shulman LP, van Breemen RB et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause 2009; 16: 1156–66.
27. Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med 2006; 355: 2338–47.
28. Nelson HD. Menopause. Lancet 2008; 371: 760–70.
29. Muthyala RS, Ju YH, Sheng S et al. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and
S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg Med Chem 2004; 12: 1559–67.
30. Takeuchi S, Takahashi T, Sawada Y et al. Comparative study on the nuclear hormone receptor activity of various phytochemicals and their metabolites by reporter gene assays using Chinese hamster ovary cells. Biol Pharm Bull 2009; 32: 195–202.
31. Crisafulli A, Marini H, Bitto A et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebocontrolled study. Menopause 2004; 11: 400–4.
32. Albertazzi P, Steel SA, Bottazzi M. Effect of pure genistein on bone markers and hot flushes. Climacteric 2005; 8: 371–9.
33. D’Anna R, Cannata ML, Atteritano M et al. Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study. Menopause 2007; 14: 648–55.
34. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer 2006; 55: 1–12.
35. Ullmann U, Oberwittle H, Grossmann M, Riegger C. Repeated oral once daily intake of increasing doses of the novel synthetic genistein product Bonistein in healthy volunteers. Planta Med 2005; 71: 891–6.
36. Ullmann U, Metzner J, Frank T et al. Safety, tolerability, and pharmacokinetics of single ascending doses of synthetic genistein (Bonistein) in healthy volunteers. Adv Ther 2005; 22: 65–78.
37. Ullmann U, Bendik I, Fllehmann B. Bonistein (synthetic genistein), a food component in development for a bone health nutraceutical. J Physiol Pharmacol 2005; 56: 79–95.
38. Metzner JE, Frank T, Kunz I et al. Study on the pharmacokinetics of synthetic genistein after multiple oral intake in post-menopausal women. Drug Res Arzneimittelforschung 2009; 59 (10): 513–20.
39. Evans M, Elliott JG, Sharma P et al. The effect of synthetic genistein on menopause symptom management in healthy postmenopausal women: A multi-center, randomized, placebo-controlled study. Maturitas 2011; 68: 196–214.
40. Marini H, Minutoli L, Polito F et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med 2007; 146: 839–47.
41. Marini H, Minutoli L, Polito F et al. OPG and sRANKL serum concentrations in osteopenic, postmenopausal women after 2-year genistein administration. J Bone Miner Res 2008; 23: 715–20.
42. Marini H, Bitto A, Altavilla D et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab 2008; 93 (12): 4787–96.
43. Hooper L, Ryder JJ, Kurzer MS et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update 2009; 15: 423–40.
44. Tempfer CB, Froese G, Heinze G et al. Side effects of phytoestrogens: a meta-analysis of randomized trials. Am J Med 2009; 122: 939–46, e9.
45. Unfer V, Casini ML, Costabile L et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized, doubleblind, placebo-controlled study. Fertil Steril 2004; 82: 145–8.
46. Foth D, Nawroth F. Effect of phytoestrogens on the endometrium? Fertil Steril 2005; 83: 256–7 [author reply 7], National Toxicology Program UDoHaHS. Center for the Evaluation of Risks to Human Reproduction. NTP-CERHR expert panel report on the reproductive and developmental toxicity of soy formula. http://cerhrniehsnihgov; 2006.
47. Alekel DL, van Loan MD, Koehler KJ et al. The Soy Isoflavones for Reducing Bone Loss. (SIRBL) Study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr 2009; 91: 218–30.
48. Horn-Ross PL, John EM, Canchola SL et al. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst 2003; 95: 1158–64.
49. McClain RM, Wolz E, Davidovich A et al. Acute, subchronic and chronic safety studies with genistein in rats. Food Chem Toxicol 2006; 44: 56–80.
50. McClain RM, Wolz E, Davidovich A et al. Reproductive safety studies with genistein in rats. Food Chem Toxicol 2007; 45: 1319–32.
51. McClain RM, Wolz E, Davidovich A et al. Subchronic and chronic safety studies with genistein in dogs. Food Chem Toxicol 2005; 43: 161–82.
52. McClain RM, Wolz E, Davidovich A et al. Genetic toxicity studies with genistein. Food Chem Toxicol 2006; 44: 42–55.
53. Sammartino A, Di Carlo C, Mandato VD et al. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol 2003; 17: 45–9.
54. Helferich WG, Andrade JE, Hoagland MS. Phytoestrogens and breast cancer: a complex story. Inflammopharmacology 2008; 16: 219–26.
55. Messina MJ, Wood CE. Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary. Nutr J 2008; 7: 17.
56. Shu XO, Zheng Y, Cai H et al. Soy food intake and breast cancer survival. JAMA 2009; 302: 2437–43.
57. Guha N, Kwan ML, Quesenberry CP et al. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the life after cancer epidemiology study. Breast Cancer Res Treat 2009; 118: 395–405.
________________________________________________
1. Клинические рекомендации. Акушерство и гинекология. Вып. 2. Под ред. В.И.Кулакова. М.: ГЭОТАР-Медиа, 2008.
2. Nelson HD, Haney E, Humphrey et al. Management of menopause-related symptoms. Summary, Evidence Report/Technology Assessment No. 120 (Prepared by the Oregon Evidence-based Practice Center, under contract No. 290-02-0024). AHRQ Pub. No. 05-E016-1. Rockville, MD: Agency for Health Research Quality, 2005.
3. Maclennan AH, Broadbent JL, Lester S et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flashes. Cochrane Database Syst Rev 2004; 4: CD002978.
4. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419–27.
5. Gompel A, Rozenberg S, Barlow DH. The EMAS 2008 update on clinical recommendations on postmenopausal hormone replacement therapy. Maturitas 2008; 61: 227–32.
6. Hill DA, Hill SR. Counseling patients about hormone therapy and alternatives for menopausal symptoms. Am Fam Physician 2010; 82: 801–7.
7. Tsai SA, Stefanick ML, Stafford RS. Trends in menopausal hormone therapy use of US office-based physicians, 2000-2009. Menopause 2011; 18: 385–92.
8. Kronenberg F, Cushman LF, Wade CM et al. Race/ethnicity and women`s use of complementary and alternative medicine in the United States: results of national survey. Am J Public Health 2006; 96: 1236–42.
9. Melby MK. Chilliness: a vasomotor symptom in Japan. Menopause 2007; 14: 752–9.
10. Melby MK, Watanabe S, Whitten PL et al. Sensitive high-performance liquid chromatographic method using coulometric electrode array detection for measurement of phytoestrogens in dried blood spots. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 826: 81–90.
11. Rimbach G, Boesch-Saadatmandi C, Frank J et al. Dietary isoflavones in the prevention of cardiovascular disease – a molecular perspective. Food Chem Toxicol 2008; 46: 1308–19.
12. Oseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med 2008; 74: 1656–65.
13. Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas 2006; 55: 203–11.
14. Taku K, Melby MK, Kronenberg F et al. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012; 19 (7): 776–90.
15. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause 2006; 13: 831–9.
16. Jacobs A, Wegewitz U, Sommerfeld C et al. Efficacy of isoflavones in relieving vasomotor menopausal symptoms – a systematic review. Mol Nutr Food Res 2009; 53: 1084–97.
17. Lethaby A, Brown J, Marjoribanks J et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007: CD001395.
18. Nelson HD, Vesco KK, Haney E et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006; 295: 2057–71.
19. Krebs EE, Ensrud KE, MacDonald R et al. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol 2004; 104: 824–36.
20. Nedrow A, Miller J, Walker M et al. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med 2006; 166: 1453–65.
21. Tempfer CB, Bentz EK, Leodolter S et al. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril 2007; 87: 1243–9.
22. Bolanos R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment o climacteric vasomotor symptoms: systematic review and meta-analysis. Menopause 2010; 17: 660–6.
23. Messina M, Hughes C. Efficacy of soyfoods and soybean isoflavone supplements for alleviating menopausal symptoms is positively related to initial hot flush frequency. J Med Food 2003; 6: 1–11.
24. De Cremoux P, This P, Leclercq G, Jacquot Y. Controversies concerning the use of phytoestrogens in menopause management: bioavailability and metabolism. Maturitas 2010; 65 (4): 334–9.
25. Newton KM, Reed SD, LaCroix AZ et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006; 145: 869–79.
26. Geller SE, Shulman LP, van Breemen RB et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause 2009; 16: 1156–66.
27. Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med 2006; 355: 2338–47.
28. Nelson HD. Menopause. Lancet 2008; 371: 760–70.
29. Muthyala RS, Ju YH, Sheng S et al. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and
S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg Med Chem 2004; 12: 1559–67.
30. Takeuchi S, Takahashi T, Sawada Y et al. Comparative study on the nuclear hormone receptor activity of various phytochemicals and their metabolites by reporter gene assays using Chinese hamster ovary cells. Biol Pharm Bull 2009; 32: 195–202.
31. Crisafulli A, Marini H, Bitto A et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebocontrolled study. Menopause 2004; 11: 400–4.
32. Albertazzi P, Steel SA, Bottazzi M. Effect of pure genistein on bone markers and hot flushes. Climacteric 2005; 8: 371–9.
33. D’Anna R, Cannata ML, Atteritano M et al. Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study. Menopause 2007; 14: 648–55.
34. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer 2006; 55: 1–12.
35. Ullmann U, Oberwittle H, Grossmann M, Riegger C. Repeated oral once daily intake of increasing doses of the novel synthetic genistein product Bonistein in healthy volunteers. Planta Med 2005; 71: 891–6.
36. Ullmann U, Metzner J, Frank T et al. Safety, tolerability, and pharmacokinetics of single ascending doses of synthetic genistein (Bonistein) in healthy volunteers. Adv Ther 2005; 22: 65–78.
37. Ullmann U, Bendik I, Fllehmann B. Bonistein (synthetic genistein), a food component in development for a bone health nutraceutical. J Physiol Pharmacol 2005; 56: 79–95.
38. Metzner JE, Frank T, Kunz I et al. Study on the pharmacokinetics of synthetic genistein after multiple oral intake in post-menopausal women. Drug Res Arzneimittelforschung 2009; 59 (10): 513–20.
39. Evans M, Elliott JG, Sharma P et al. The effect of synthetic genistein on menopause symptom management in healthy postmenopausal women: A multi-center, randomized, placebo-controlled study. Maturitas 2011; 68: 196–214.
40. Marini H, Minutoli L, Polito F et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med 2007; 146: 839–47.
41. Marini H, Minutoli L, Polito F et al. OPG and sRANKL serum concentrations in osteopenic, postmenopausal women after 2-year genistein administration. J Bone Miner Res 2008; 23: 715–20.
42. Marini H, Bitto A, Altavilla D et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab 2008; 93 (12): 4787–96.
43. Hooper L, Ryder JJ, Kurzer MS et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update 2009; 15: 423–40.
44. Tempfer CB, Froese G, Heinze G et al. Side effects of phytoestrogens: a meta-analysis of randomized trials. Am J Med 2009; 122: 939–46, e9.
45. Unfer V, Casini ML, Costabile L et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized, doubleblind, placebo-controlled study. Fertil Steril 2004; 82: 145–8.
46. Foth D, Nawroth F. Effect of phytoestrogens on the endometrium? Fertil Steril 2005; 83: 256–7 [author reply 7], National Toxicology Program UDoHaHS. Center for the Evaluation of Risks to Human Reproduction. NTP-CERHR expert panel report on the reproductive and developmental toxicity of soy formula. http://cerhrniehsnihgov; 2006.
47. Alekel DL, van Loan MD, Koehler KJ et al. The Soy Isoflavones for Reducing Bone Loss. (SIRBL) Study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr 2009; 91: 218–30.
48. Horn-Ross PL, John EM, Canchola SL et al. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst 2003; 95: 1158–64.
49. McClain RM, Wolz E, Davidovich A et al. Acute, subchronic and chronic safety studies with genistein in rats. Food Chem Toxicol 2006; 44: 56–80.
50. McClain RM, Wolz E, Davidovich A et al. Reproductive safety studies with genistein in rats. Food Chem Toxicol 2007; 45: 1319–32.
51. McClain RM, Wolz E, Davidovich A et al. Subchronic and chronic safety studies with genistein in dogs. Food Chem Toxicol 2005; 43: 161–82.
52. McClain RM, Wolz E, Davidovich A et al. Genetic toxicity studies with genistein. Food Chem Toxicol 2006; 44: 42–55.
53. Sammartino A, Di Carlo C, Mandato VD et al. Effects of genistein on the endometrium: ultrasonographic evaluation. Gynecol Endocrinol 2003; 17: 45–9.
54. Helferich WG, Andrade JE, Hoagland MS. Phytoestrogens and breast cancer: a complex story. Inflammopharmacology 2008; 16: 219–26.
55. Messina MJ, Wood CE. Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary. Nutr J 2008; 7: 17.
56. Shu XO, Zheng Y, Cai H et al. Soy food intake and breast cancer survival. JAMA 2009; 302: 2437–43.
57. Guha N, Kwan ML, Quesenberry CP et al. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the life after cancer epidemiology study. Breast Cancer Res Treat 2009; 118: 395–405.
Авторы
И.В.Кузнецова
ГБОУ ВПО Первый МГМУ им. И.М.Сеченова Минздрава РФ; ГОУ ВПО Российский университет дружбы народов, Москва