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Медикаментозное лечение лейомиомы матки антигестагенами: возможности и перспективы
Медикаментозное лечение лейомиомы матки антигестагенами: возможности и перспективы
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Аннотация
Предпосылки: лейомиомы – самый распространенный вид опухолей женских половых путей, почти 1/3 гистерэктомий проводятся в связи с лейомиомой.
Цель: оценка эффективности мефипристона для неоадъювантной терапии лейомиомы.
Материалы и методы: 90 женщин репродуктивного возраста с лейомиомой матки рандомизировали в 3 группы: 1-я группа – 30 больных получали мифепристон 50 мг ежедневно в течение 3 мес, 2-я группа – 30 больных получали золадекс 3,76 мг подкожно каждые 28 дней в течение 3 мес, после чего в 1 и 2-й группах проводили лапароскопическую миомэктомию, как и в 3-й группе – 30 больных, не получавших неоадъювантной терапии. В 1 и 2-й группах исследовали влияние терапии на рецепторы к эстрогенам и прогестерону, факторы клеточного роста и ангиогенеза, рецепторы к ним, антигены клеточной пролиферации и ингибиторы апоптоза.
Результаты: на неоадъювантной терапии уменьшились кровотечения, боли, объем матки и доминантных узлов, причем в 1-й группе в большей мере, чем во 2-й, а частота неэффективности терапии (около 10%) была одинаковой в обеих группах. По критерию длительности оперативного вмешательства и объема внутриоперационной кровопотери различий между 1 и 2-й группами не было, но каждая из них была достоверно лучше, чем в 3-й группе. На фоне терапии понижалась экспрессия эстрогеновых и прогестероновых рецепторов, индекс пролиферации и васкуляризация лейомиомы. В 1-й группе дистрофические изменения проявлялись преимущественно нарушением сосудистой проницаемости, а во 2-й – накоплением фиброзной ткани.
Заключение: снижение влияний прогестерона в ходе неоадъювантной терапии сопровождается уменьшением активаторов ангиогенеза, что расширяет возможности выполнения органосохраняющих операций.
Ключевые слова: лейомиома, неоадъювантная терапия, мифепристон, гозерелин.
Objective: to evaluate the effecacy of mefipristone in neoadjuvant therapy of leiomyoma (LM).
Materials and methods: ninety nonpregnant women of reproductive age with uterine leiomyomas were enrolled into this study. Patients from Group I (n=30) were administered Mifepristone 50 mg once daily for 3 months, patients from Group II (n=30) were administered Zoladex 3,76 mg subcutaneously every 28 days for 3 months and patients from Group III (n = 30) were not administered any therapy. Laparoscopic myomectomy was performed after 3 months from the initiation of the study in all three groups. Effects of neoadjuvant therapy on estrogen and progesterone receptors, cell growth factors and angiogenesis, as well as associated receptors, antigens of cell proliferation and inhibitors of apoptosis were studied in Groups I and II.
Results: the neoadjuvant therapy reduced bleeding, pain intensity, size of uterus and dominant nodes to a greater extent in Group I, than in Group II, while treatment failure rates of ≈10% were similar in both groups. There were no differences between Groups I and II when it comes to duration of surgeryand intraoperative blood loss, but these two criteria performed significantly better in Groups I and II as compared to Group III. During neoadjuvant treatment decrease of estrogen and progesterone receptors expression, of proliferation index and of LMsvascularization were observed. Degenerative changes manifested predominantly in impaired vascular permeability in Group I, while in Group II -in accumulation of fibrous tissue.
Conclusion: inhibition of progesterone effects in the course of neoadjuvant therapy is accompanied by suppression of angiogenesis activators, which extends the potential for organ-sparing surgery.
Key words: leiomyoma, neoadjuvant therapy, Mefipristone, Goserelin.
Цель: оценка эффективности мефипристона для неоадъювантной терапии лейомиомы.
Материалы и методы: 90 женщин репродуктивного возраста с лейомиомой матки рандомизировали в 3 группы: 1-я группа – 30 больных получали мифепристон 50 мг ежедневно в течение 3 мес, 2-я группа – 30 больных получали золадекс 3,76 мг подкожно каждые 28 дней в течение 3 мес, после чего в 1 и 2-й группах проводили лапароскопическую миомэктомию, как и в 3-й группе – 30 больных, не получавших неоадъювантной терапии. В 1 и 2-й группах исследовали влияние терапии на рецепторы к эстрогенам и прогестерону, факторы клеточного роста и ангиогенеза, рецепторы к ним, антигены клеточной пролиферации и ингибиторы апоптоза.
Результаты: на неоадъювантной терапии уменьшились кровотечения, боли, объем матки и доминантных узлов, причем в 1-й группе в большей мере, чем во 2-й, а частота неэффективности терапии (около 10%) была одинаковой в обеих группах. По критерию длительности оперативного вмешательства и объема внутриоперационной кровопотери различий между 1 и 2-й группами не было, но каждая из них была достоверно лучше, чем в 3-й группе. На фоне терапии понижалась экспрессия эстрогеновых и прогестероновых рецепторов, индекс пролиферации и васкуляризация лейомиомы. В 1-й группе дистрофические изменения проявлялись преимущественно нарушением сосудистой проницаемости, а во 2-й – накоплением фиброзной ткани.
Заключение: снижение влияний прогестерона в ходе неоадъювантной терапии сопровождается уменьшением активаторов ангиогенеза, что расширяет возможности выполнения органосохраняющих операций.
Ключевые слова: лейомиома, неоадъювантная терапия, мифепристон, гозерелин.
________________________________________________
Objective: to evaluate the effecacy of mefipristone in neoadjuvant therapy of leiomyoma (LM).
Materials and methods: ninety nonpregnant women of reproductive age with uterine leiomyomas were enrolled into this study. Patients from Group I (n=30) were administered Mifepristone 50 mg once daily for 3 months, patients from Group II (n=30) were administered Zoladex 3,76 mg subcutaneously every 28 days for 3 months and patients from Group III (n = 30) were not administered any therapy. Laparoscopic myomectomy was performed after 3 months from the initiation of the study in all three groups. Effects of neoadjuvant therapy on estrogen and progesterone receptors, cell growth factors and angiogenesis, as well as associated receptors, antigens of cell proliferation and inhibitors of apoptosis were studied in Groups I and II.
Results: the neoadjuvant therapy reduced bleeding, pain intensity, size of uterus and dominant nodes to a greater extent in Group I, than in Group II, while treatment failure rates of ≈10% were similar in both groups. There were no differences between Groups I and II when it comes to duration of surgeryand intraoperative blood loss, but these two criteria performed significantly better in Groups I and II as compared to Group III. During neoadjuvant treatment decrease of estrogen and progesterone receptors expression, of proliferation index and of LMsvascularization were observed. Degenerative changes manifested predominantly in impaired vascular permeability in Group I, while in Group II -in accumulation of fibrous tissue.
Conclusion: inhibition of progesterone effects in the course of neoadjuvant therapy is accompanied by suppression of angiogenesis activators, which extends the potential for organ-sparing surgery.
Key words: leiomyoma, neoadjuvant therapy, Mefipristone, Goserelin.
Полный текст
Список литературы
1. Cook JD, Walker CL. Treatment strategies for uterine leiomyoma: the role of hormonal modulation. Reprod Med 2004; 22: 2.
2. Healy DL, Vollenhoven B, Weston G. Uterine fibroids. In: Shaw RW, Soutter WP, Stanton SL eds. Gynecology, Philadelphia. Churchill Livingstone 2003; p. 479–94.
3. Azici A, Sozen I. Transforming growth factor – beta-3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril 2000; 73 (5): 1006–11.
4. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990–1997. Obstet Gynecol 2002; 99 (2): 229–34.
5. Manyonda I, Sinthamoney A-M, Belli E. Controversies and challenges in the modern management of uterine fibroids. Br J Obstet Gynaecol 2004; 111: 95–102.
6. Vercellini P, Trespidi L, Zaina B et al. Gonadotropin-releasing hormone agonist treatment before abdominal myomectomy: a controlled trial. Fertil Steril 2003; 79: 1390–5.
7. Di Lieto A, De Falco M, Pollio F et al. Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone analogue-treated women with uterine myomas. J Soc Gynecol Investig 2005; 12 (2): 123–8.
8. Steinauer J, Pritts E, Jackson R et al. Systematic review of Mifepristone for the treatment of uterine leiomyomata. J Obstet Gynecol 2004; 103 (6): 1331–6.
9. Young SL, Al-Hendy A. Potential Nonhormonal Therapeutics for Medical Treatment of Leiomyomas. In: Uterine Leiomyomas: Options and Choices. Ed. in Chief B.Carr. Seminars in Reproductive Medicine 2004; 22 (2): 121–30.
10. Ganesan, S, Michelle S. Identification and Characterization of Novel Estrogen Reseptor-β-Sparing Antiprogestins. Endocrinology 2002; 143 (8): 3071–82.
11. Bodner K, Bodner-Adler B, Kimberger O et al. Bcl-2 receptor expression in patients with uterine smooth muscle tumors. J Soc Gynecol Invest 2004; 11: 187–91.
12. Martel KM, Ko AC, Christman GM et al. Apoptosis in Human Uterine Leiomyomas. Semin Reprod Med 2004; 22 (2): 91–102.
13. Liang Y, Hyder SM. Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects. Endocrinology 2005; 146 (8): 3632–41.
14. Ratherford AJ Molecular pharmacology. In: Reproductive Medicine. Molecular, Cellular and Genetic Fundamentals. Ed. O.Bart, M.Fauser, 2003; p. 313–62.
15. Poncelet C, Madelanat P, Feldman G et al. Expression of von Willebrand's factor, CD34, CD31, and vascular endothelial growth factor in uterine leiomyomas. Fertil Steril 2002; 78: 581–6.
16. Smith SK. Angiogenesis and reproduction. Br J Obstet Gynecol 2001; 108: 777–83.
17. Степанова Е.В. Антиангиогенная терапия: новые возможности лечения злокачественных заболеваний. Практическая онкология.
2002; 4 (3): 246–52.
18. Wu JJ, Richer J, Horwitz KB et al. Progestin-dependent induction of vascular endothelial growth factor in human breast cancer cells: preferential regulation by progesterone receptor B. Cancer Res 2004; 64 (6): 2238–44.
19. Spitz IM. Progesterone antagonists and progesterone receptor modulators. Expert Opin Investig Drugs 2003; 12 (10): 1693–1707.
20. Chwalisz K, DeManno D. Therapeutic potential for the selective progesterone reseptor modulator asoprisnil in the treatment of leiomyomata. Semin Reprod Med 2004; 22 (2): 113–9.
2. Healy DL, Vollenhoven B, Weston G. Uterine fibroids. In: Shaw RW, Soutter WP, Stanton SL eds. Gynecology, Philadelphia. Churchill Livingstone 2003; p. 479–94.
3. Azici A, Sozen I. Transforming growth factor – beta-3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril 2000; 73 (5): 1006–11.
4. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990–1997. Obstet Gynecol 2002; 99 (2): 229–34.
5. Manyonda I, Sinthamoney A-M, Belli E. Controversies and challenges in the modern management of uterine fibroids. Br J Obstet Gynaecol 2004; 111: 95–102.
6. Vercellini P, Trespidi L, Zaina B et al. Gonadotropin-releasing hormone agonist treatment before abdominal myomectomy: a controlled trial. Fertil Steril 2003; 79: 1390–5.
7. Di Lieto A, De Falco M, Pollio F et al. Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone analogue-treated women with uterine myomas. J Soc Gynecol Investig 2005; 12 (2): 123–8.
8. Steinauer J, Pritts E, Jackson R et al. Systematic review of Mifepristone for the treatment of uterine leiomyomata. J Obstet Gynecol 2004; 103 (6): 1331–6.
9. Young SL, Al-Hendy A. Potential Nonhormonal Therapeutics for Medical Treatment of Leiomyomas. In: Uterine Leiomyomas: Options and Choices. Ed. in Chief B.Carr. Seminars in Reproductive Medicine 2004; 22 (2): 121–30.
10. Ganesan, S, Michelle S. Identification and Characterization of Novel Estrogen Reseptor-β-Sparing Antiprogestins. Endocrinology 2002; 143 (8): 3071–82.
11. Bodner K, Bodner-Adler B, Kimberger O et al. Bcl-2 receptor expression in patients with uterine smooth muscle tumors. J Soc Gynecol Invest 2004; 11: 187–91.
12. Martel KM, Ko AC, Christman GM et al. Apoptosis in Human Uterine Leiomyomas. Semin Reprod Med 2004; 22 (2): 91–102.
13. Liang Y, Hyder SM. Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects. Endocrinology 2005; 146 (8): 3632–41.
14. Ratherford AJ Molecular pharmacology. In: Reproductive Medicine. Molecular, Cellular and Genetic Fundamentals. Ed. O.Bart, M.Fauser, 2003; p. 313–62.
15. Poncelet C, Madelanat P, Feldman G et al. Expression of von Willebrand's factor, CD34, CD31, and vascular endothelial growth factor in uterine leiomyomas. Fertil Steril 2002; 78: 581–6.
16. Smith SK. Angiogenesis and reproduction. Br J Obstet Gynecol 2001; 108: 777–83.
17. Степанова Е.В. Антиангиогенная терапия: новые возможности лечения злокачественных заболеваний. Практическая онкология.
2002; 4 (3): 246–52.
18. Wu JJ, Richer J, Horwitz KB et al. Progestin-dependent induction of vascular endothelial growth factor in human breast cancer cells: preferential regulation by progesterone receptor B. Cancer Res 2004; 64 (6): 2238–44.
19. Spitz IM. Progesterone antagonists and progesterone receptor modulators. Expert Opin Investig Drugs 2003; 12 (10): 1693–1707.
20. Chwalisz K, DeManno D. Therapeutic potential for the selective progesterone reseptor modulator asoprisnil in the treatment of leiomyomata. Semin Reprod Med 2004; 22 (2): 113–9.
2. Healy DL, Vollenhoven B, Weston G. Uterine fibroids. In: Shaw RW, Soutter WP, Stanton SL eds. Gynecology, Philadelphia. Churchill Livingstone 2003; p. 479–94.
3. Azici A, Sozen I. Transforming growth factor – beta-3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril 2000; 73 (5): 1006–11.
4. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990–1997. Obstet Gynecol 2002; 99 (2): 229–34.
5. Manyonda I, Sinthamoney A-M, Belli E. Controversies and challenges in the modern management of uterine fibroids. Br J Obstet Gynaecol 2004; 111: 95–102.
6. Vercellini P, Trespidi L, Zaina B et al. Gonadotropin-releasing hormone agonist treatment before abdominal myomectomy: a controlled trial. Fertil Steril 2003; 79: 1390–5.
7. Di Lieto A, De Falco M, Pollio F et al. Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone analogue-treated women with uterine myomas. J Soc Gynecol Investig 2005; 12 (2): 123–8.
8. Steinauer J, Pritts E, Jackson R et al. Systematic review of Mifepristone for the treatment of uterine leiomyomata. J Obstet Gynecol 2004; 103 (6): 1331–6.
9. Young SL, Al-Hendy A. Potential Nonhormonal Therapeutics for Medical Treatment of Leiomyomas. In: Uterine Leiomyomas: Options and Choices. Ed. in Chief B.Carr. Seminars in Reproductive Medicine 2004; 22 (2): 121–30.
10. Ganesan, S, Michelle S. Identification and Characterization of Novel Estrogen Reseptor-β-Sparing Antiprogestins. Endocrinology 2002; 143 (8): 3071–82.
11. Bodner K, Bodner-Adler B, Kimberger O et al. Bcl-2 receptor expression in patients with uterine smooth muscle tumors. J Soc Gynecol Invest 2004; 11: 187–91.
12. Martel KM, Ko AC, Christman GM et al. Apoptosis in Human Uterine Leiomyomas. Semin Reprod Med 2004; 22 (2): 91–102.
13. Liang Y, Hyder SM. Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects. Endocrinology 2005; 146 (8): 3632–41.
14. Ratherford AJ Molecular pharmacology. In: Reproductive Medicine. Molecular, Cellular and Genetic Fundamentals. Ed. O.Bart, M.Fauser, 2003; p. 313–62.
15. Poncelet C, Madelanat P, Feldman G et al. Expression of von Willebrand's factor, CD34, CD31, and vascular endothelial growth factor in uterine leiomyomas. Fertil Steril 2002; 78: 581–6.
16. Smith SK. Angiogenesis and reproduction. Br J Obstet Gynecol 2001; 108: 777–83.
17. Степанова Е.В. Антиангиогенная терапия: новые возможности лечения злокачественных заболеваний. Практическая онкология.
2002; 4 (3): 246–52.
18. Wu JJ, Richer J, Horwitz KB et al. Progestin-dependent induction of vascular endothelial growth factor in human breast cancer cells: preferential regulation by progesterone receptor B. Cancer Res 2004; 64 (6): 2238–44.
19. Spitz IM. Progesterone antagonists and progesterone receptor modulators. Expert Opin Investig Drugs 2003; 12 (10): 1693–1707.
20. Chwalisz K, DeManno D. Therapeutic potential for the selective progesterone reseptor modulator asoprisnil in the treatment of leiomyomata. Semin Reprod Med 2004; 22 (2): 113–9.
________________________________________________
2. Healy DL, Vollenhoven B, Weston G. Uterine fibroids. In: Shaw RW, Soutter WP, Stanton SL eds. Gynecology, Philadelphia. Churchill Livingstone 2003; p. 479–94.
3. Azici A, Sozen I. Transforming growth factor – beta-3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril 2000; 73 (5): 1006–11.
4. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990–1997. Obstet Gynecol 2002; 99 (2): 229–34.
5. Manyonda I, Sinthamoney A-M, Belli E. Controversies and challenges in the modern management of uterine fibroids. Br J Obstet Gynaecol 2004; 111: 95–102.
6. Vercellini P, Trespidi L, Zaina B et al. Gonadotropin-releasing hormone agonist treatment before abdominal myomectomy: a controlled trial. Fertil Steril 2003; 79: 1390–5.
7. Di Lieto A, De Falco M, Pollio F et al. Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone analogue-treated women with uterine myomas. J Soc Gynecol Investig 2005; 12 (2): 123–8.
8. Steinauer J, Pritts E, Jackson R et al. Systematic review of Mifepristone for the treatment of uterine leiomyomata. J Obstet Gynecol 2004; 103 (6): 1331–6.
9. Young SL, Al-Hendy A. Potential Nonhormonal Therapeutics for Medical Treatment of Leiomyomas. In: Uterine Leiomyomas: Options and Choices. Ed. in Chief B.Carr. Seminars in Reproductive Medicine 2004; 22 (2): 121–30.
10. Ganesan, S, Michelle S. Identification and Characterization of Novel Estrogen Reseptor-β-Sparing Antiprogestins. Endocrinology 2002; 143 (8): 3071–82.
11. Bodner K, Bodner-Adler B, Kimberger O et al. Bcl-2 receptor expression in patients with uterine smooth muscle tumors. J Soc Gynecol Invest 2004; 11: 187–91.
12. Martel KM, Ko AC, Christman GM et al. Apoptosis in Human Uterine Leiomyomas. Semin Reprod Med 2004; 22 (2): 91–102.
13. Liang Y, Hyder SM. Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects. Endocrinology 2005; 146 (8): 3632–41.
14. Ratherford AJ Molecular pharmacology. In: Reproductive Medicine. Molecular, Cellular and Genetic Fundamentals. Ed. O.Bart, M.Fauser, 2003; p. 313–62.
15. Poncelet C, Madelanat P, Feldman G et al. Expression of von Willebrand's factor, CD34, CD31, and vascular endothelial growth factor in uterine leiomyomas. Fertil Steril 2002; 78: 581–6.
16. Smith SK. Angiogenesis and reproduction. Br J Obstet Gynecol 2001; 108: 777–83.
17. Степанова Е.В. Антиангиогенная терапия: новые возможности лечения злокачественных заболеваний. Практическая онкология.
2002; 4 (3): 246–52.
18. Wu JJ, Richer J, Horwitz KB et al. Progestin-dependent induction of vascular endothelial growth factor in human breast cancer cells: preferential regulation by progesterone receptor B. Cancer Res 2004; 64 (6): 2238–44.
19. Spitz IM. Progesterone antagonists and progesterone receptor modulators. Expert Opin Investig Drugs 2003; 12 (10): 1693–1707.
20. Chwalisz K, DeManno D. Therapeutic potential for the selective progesterone reseptor modulator asoprisnil in the treatment of leiomyomata. Semin Reprod Med 2004; 22 (2): 113–9.
Авторы
Т.Е.Самойлова
Перинатальный медицинский центр, Москва
Perinatal Medical Centre, Moscow
Перинатальный медицинский центр, Москва
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Perinatal Medical Centre, Moscow
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