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Клинические результаты применения высокоочищенного человеческого менопаузального гонадотропина и рекомбинантного фолликулостимулирующего гормона для стимуляции яичников у пациенток, проходящих процедуру экстракорпорального оплодотворения (рандомизированно
Клинические результаты применения высокоочищенного человеческого менопаузального гонадотропина и рекомбинантного фолликулостимулирующего гормона для стимуляции яичников у пациенток, проходящих процедуру экстракорпорального оплодотворения (рандомизированно
Андерс Ныбое Андерсен, Паул Деврое, Еан-Царлес Арце. Клинические результаты применения высокоочищенного человеческого менопаузального гонадотропина и рекомбинантного фолликулостимулирующего гормона для стимуляции яичников у пациенток, проходящих процедуру экстракорпорального оплодотворения (рандомизированное слепое контролируемое исследование). Гинекология. 2017; 19 (3): 12–22. DOI: 10.26442/2079-5696_19.3.12-22
a randomized assessor-blind controlled trial. Hum Reprod. 2006; 21 (12): 3217–27. DOI: https://doi.org/10.1093/humrep/del284
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a randomized assessor-blind controlled trial. Hum Reprod. 2006; 21 (12): 3217–27. DOI: https://doi.org/10.1093/humrep/del284
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Аннотация
Введение. Активность лютеинизирующего гормона (ЛГ) может повлиять на ответ на проводимое лечение и результаты экстракорпорального оплодотворения.
Методы. Осуществлено рандомизированное слепое международное исследование по сравнению частоты наступления беременности (основной критерий оценки) у 731 женщины, проходящей процедуру экстракорпорального оплодотворения после проведения стимуляции яичников высокоочищенным человеческим менотропином (высокоочищенным человеческим менопаузальным гонадотропином – ЧМГ; n=363) или рекомбинантным фолликулостимулирующим гормоном – рФСГ (n=368), которая проводилась после длительного введения агонистов гонадотропин-рилизинг-гормона. Всем пациенткам выполнены одинаковые процедуры до и после рандомизации. Пересадка одного или двух эмбрионов выполнялась на 3-й день.
Результаты. В группе женщин, которым назначен рФСГ (11,8), удалось получить большее количество ооцитов (p<0,001) по сравнению с группой пациенток, получающих высокоочищенный ЧМГ (10,0), но там же отмечена большая доля получения эмбрионов высокого качества (11,3%; p=0,044) по сравнению с группой женщин, получающих рФСГ (9,0%). К концу проведения стимуляции у пациенток, получающих рФСГ, после введения поправки на фолликулярный ответ обнаружены более низкие показатели уровня эстрадиола (p=0,031) и более высокий уровень прогестерона (p<0,001). В показателях распространенности гипо-, изо- и гиперэхогенного эндометрия отмечен статистически достоверный сдвиг (p=0,023) в сторону развития гиперэхогенного эндометрия в группе женщин, получающих рФСГ. Частота наступления беременности составила 27% в группе, получающей высокоочищенный ЧМГ, и 22% в группе женщин, которым назначен рФСГ (отношение шансов 1,25; 95% доверительный интервал 0,89–1,75).
Выводы. На основании полученных результатов нельзя сделать вывод о преимуществе применения высокоочищенного ЧМГ или рФСГ с точки зрения частоты наступления беременности, установлено отсутствие превосходства какого-либо препарата. Обнаружены фармакодинамические различия применения высокоочищенного ЧМГ и рФСГ и их влияние на развитие фолликулов, качество полученных ооцитов/эмбрионов, эндокринный ответ и эхогенность эндометрия, что может оказаться значимым для результатов лечения.
Ключевые слова: качество эмбрионов, высокоочищенный менотропин, экстракорпоральное оплодотворение, беременность, рекомбинантный ФСГ.
Methods. A randomized, assessor-blind, multinational trial compared ongoing pregnancy rates (primary end-point) in 731 women undergoing IVF after stimulation with highly purified menotrophin (HP-hMG) (n=363) or recombinant FSH (rFSH) (n=368) following a long GnRH agonist protocol. Patients received identical pre- and post-randomization interventions. One or two embryos were transferred on day 3.
Results. More oocytes were retrieved (p<0.001) after rFSH treatment (11.8) compared with HP-hMG treatment (10.0), but a higher proportion developed into top quality embryos (p=0.044) with HP-hMG (11.3%) than with rFSH (9.0%). At the end of stimulation, lower estradiol (E2) (p=0.031) and higher progesterone (p<0.001) levels were found with rFSH, even after adjusting for follicular response. The distribution of hypo-, iso- and hyper-echogenic endometrium showed a significant (p=0.023) shift towards the hyperechogenic pattern after rFSH treatment. The ongoing pregnancy rate per cycle was 27% with HPhMG and 22% with rFSH [odds ratio (95% confidence interval): 1.25 (0.89–1.75)].
Conclusions. Superiority of HP-hMG over rFSH in ongoing pregnancy rate could not be concluded from this study, but non-inferiority was established. Pharmacodynamic differences in follicular development, oocyte/embryo quality, endocrine response and endometrial echogenicity exist between HP-hMG and rFSH preparations, which may be relevant for treatment outcome.
Key words: embryo quality/highly purified menotrophin/IVF/pregnancy/recombinant FSH.
Методы. Осуществлено рандомизированное слепое международное исследование по сравнению частоты наступления беременности (основной критерий оценки) у 731 женщины, проходящей процедуру экстракорпорального оплодотворения после проведения стимуляции яичников высокоочищенным человеческим менотропином (высокоочищенным человеческим менопаузальным гонадотропином – ЧМГ; n=363) или рекомбинантным фолликулостимулирующим гормоном – рФСГ (n=368), которая проводилась после длительного введения агонистов гонадотропин-рилизинг-гормона. Всем пациенткам выполнены одинаковые процедуры до и после рандомизации. Пересадка одного или двух эмбрионов выполнялась на 3-й день.
Результаты. В группе женщин, которым назначен рФСГ (11,8), удалось получить большее количество ооцитов (p<0,001) по сравнению с группой пациенток, получающих высокоочищенный ЧМГ (10,0), но там же отмечена большая доля получения эмбрионов высокого качества (11,3%; p=0,044) по сравнению с группой женщин, получающих рФСГ (9,0%). К концу проведения стимуляции у пациенток, получающих рФСГ, после введения поправки на фолликулярный ответ обнаружены более низкие показатели уровня эстрадиола (p=0,031) и более высокий уровень прогестерона (p<0,001). В показателях распространенности гипо-, изо- и гиперэхогенного эндометрия отмечен статистически достоверный сдвиг (p=0,023) в сторону развития гиперэхогенного эндометрия в группе женщин, получающих рФСГ. Частота наступления беременности составила 27% в группе, получающей высокоочищенный ЧМГ, и 22% в группе женщин, которым назначен рФСГ (отношение шансов 1,25; 95% доверительный интервал 0,89–1,75).
Выводы. На основании полученных результатов нельзя сделать вывод о преимуществе применения высокоочищенного ЧМГ или рФСГ с точки зрения частоты наступления беременности, установлено отсутствие превосходства какого-либо препарата. Обнаружены фармакодинамические различия применения высокоочищенного ЧМГ и рФСГ и их влияние на развитие фолликулов, качество полученных ооцитов/эмбрионов, эндокринный ответ и эхогенность эндометрия, что может оказаться значимым для результатов лечения.
Ключевые слова: качество эмбрионов, высокоочищенный менотропин, экстракорпоральное оплодотворение, беременность, рекомбинантный ФСГ.
________________________________________________
Methods. A randomized, assessor-blind, multinational trial compared ongoing pregnancy rates (primary end-point) in 731 women undergoing IVF after stimulation with highly purified menotrophin (HP-hMG) (n=363) or recombinant FSH (rFSH) (n=368) following a long GnRH agonist protocol. Patients received identical pre- and post-randomization interventions. One or two embryos were transferred on day 3.
Results. More oocytes were retrieved (p<0.001) after rFSH treatment (11.8) compared with HP-hMG treatment (10.0), but a higher proportion developed into top quality embryos (p=0.044) with HP-hMG (11.3%) than with rFSH (9.0%). At the end of stimulation, lower estradiol (E2) (p=0.031) and higher progesterone (p<0.001) levels were found with rFSH, even after adjusting for follicular response. The distribution of hypo-, iso- and hyper-echogenic endometrium showed a significant (p=0.023) shift towards the hyperechogenic pattern after rFSH treatment. The ongoing pregnancy rate per cycle was 27% with HPhMG and 22% with rFSH [odds ratio (95% confidence interval): 1.25 (0.89–1.75)].
Conclusions. Superiority of HP-hMG over rFSH in ongoing pregnancy rate could not be concluded from this study, but non-inferiority was established. Pharmacodynamic differences in follicular development, oocyte/embryo quality, endocrine response and endometrial echogenicity exist between HP-hMG and rFSH preparations, which may be relevant for treatment outcome.
Key words: embryo quality/highly purified menotrophin/IVF/pregnancy/recombinant FSH.
Полный текст
Список литературы
1. Van Wely M, Westergaard LG, Bossuyt PMM, Van der Veen F. Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles (Cochrane review). The Cochrane Library, Issue 1. Update Software, Oxford, 2003.
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3. Westergaard LG, Erb K, Laursen SB et al. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotrophic women down-regulated with a gonadotropinreleasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril 2001; 76: 543–9.
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14. Wolfenson C, Groisman J, Couto AS et al. Batch-to-batch consistency of human-derived gonadotrophin preparations ompared with recombinant preparations. Reprod Biomed Online 2005; 10: 442–54.
15. Filicori M, Cognigni GE, Pocognoli P et al. Modulation of folliculogenesis and steroidogenesis in women by graded menotropin administration. Hum Reprod 2002; 17: 2009–15.
16. Fanchin R, Righini C, Olivennes F et al. Computerized assessment of endometrial echogenicity: clues to the endometrial effects of premature progesterone elevation. Fertil Steril 1999; 71: 174–81.
17. Fanchin R, Righini C, Ayoubi J-M et al. New look at endometrial echogenicity: objective computer-assisted measurements predict endometrial receptivity in in vitro fertilizationembryo transfer. Fertil Steril 2000; 74: 274–81.
18. Weston AM, Zelinski-Wooten MB, Hutchinson JS et al. Evelopmental potential of embryos produced by in-vitro fertilization from gonadotrophin-releasing hormone antagonist-treated macaques stimulated with recombinant human follicle stimulating hormone alone or in combination with luteinising hormone. Hum Reprod 1996; 11: 608–13.
19. Lisi F, Rinaldi L, Fishel S et al. Evaluation of two doses of recombinant luteinising hormone supplementation in an unselected group of women undergoing follicular stimulation for in vitro fertilization. Fertil Steril 2005; 83: 309–15.
20. Assou S, Anahory T, Pantesco V et al. The human cumulus-oocyte complex gene-expression profile. Hum Reprod 2006; 21 (7): 1705–19.
21. Platteau P, Nyboe Andersen A, Balen A et al. Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO group II anovulatory infertility: a randomized controlled study. Hum Reprod 2006; 21 (7): 1798–804.
22. Helmgaard L, Sørensen P, Arce J-C. Children born after controlled ovarian stimulation with HP-hMG or recombinant FSH: results of the EISG pregnancy outcome follow-up. Fertil Steril 2004; 82 (Suppl. 2): S232.
23. ESHRE. The European IVF-monitoring programme (EIM) for the European Society for Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2002. Results generated from European registers by ESHRE. Hum Reprod 2006; 21 (7): 1680–97.
2. Platteau P, Smitz J, Albano C et al. Exogenous luteinizing hormone activity may influence the treatment outcome in in vitro fertilization but not in intracytoplasmic sperm injection cycles. Fertil Steril 2004; 81: 1401–4.
3. Westergaard LG, Erb K, Laursen SB et al. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotrophic women down-regulated with a gonadotropinreleasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril 2001; 76: 543–9.
4. Arce J-C, Nyboe Andersen A, Collins J. Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies: a mini-review. Hum Reprod 2005; 20: 1757–71.
5. Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 2003; 18: 1005–9.
6. Vail A, Gardener E. Common statistical errors in the design and analysis of subfertility trials. Hum Reprod 2003; 18: 1000–4.
7. The European and Israeli Study Group on highly purified hMG versus rFSH. Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil Steril 2002; 78: 520–8.
8. Filicori M, Cognigni GE. Roles and novel regimens of luteinizing hormone and follicle-stimulating hormone in ovulation induction. J Clin Endocrinol Metab 2001; 86: 1437–41.
9. Golan A, Ron-El R, Herman A et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44: 430–40.
10. European Medicines Agency. Guideline on the choice of the noninferiority margin. EMEA/CPMP/EWP/2158/99, 2005.
11. European Medicines Agency. Points to consider on switching between superiority and non-inferiority. CPMP/EWP/482/99, 2000.
12. European Medicines Agency. ICH Topic E9. Note for guidance on statistical principles for clinical trials. CPMP/ICH/363/96, 1998.
13. European Medicines Agency. ICH Topic E10. Note for guidance on choice of control group in clinical trials. CPMP/ICH/364/96, 2001.
14. Wolfenson C, Groisman J, Couto AS et al. Batch-to-batch consistency of human-derived gonadotrophin preparations ompared with recombinant preparations. Reprod Biomed Online 2005; 10: 442–54.
15. Filicori M, Cognigni GE, Pocognoli P et al. Modulation of folliculogenesis and steroidogenesis in women by graded menotropin administration. Hum Reprod 2002; 17: 2009–15.
16. Fanchin R, Righini C, Olivennes F et al. Computerized assessment of endometrial echogenicity: clues to the endometrial effects of premature progesterone elevation. Fertil Steril 1999; 71: 174–81.
17. Fanchin R, Righini C, Ayoubi J-M et al. New look at endometrial echogenicity: objective computer-assisted measurements predict endometrial receptivity in in vitro fertilizationembryo transfer. Fertil Steril 2000; 74: 274–81.
18. Weston AM, Zelinski-Wooten MB, Hutchinson JS et al. Evelopmental potential of embryos produced by in-vitro fertilization from gonadotrophin-releasing hormone antagonist-treated macaques stimulated with recombinant human follicle stimulating hormone alone or in combination with luteinising hormone. Hum Reprod 1996; 11: 608–13.
19. Lisi F, Rinaldi L, Fishel S et al. Evaluation of two doses of recombinant luteinising hormone supplementation in an unselected group of women undergoing follicular stimulation for in vitro fertilization. Fertil Steril 2005; 83: 309–15.
20. Assou S, Anahory T, Pantesco V et al. The human cumulus-oocyte complex gene-expression profile. Hum Reprod 2006; 21 (7): 1705–19.
21. Platteau P, Nyboe Andersen A, Balen A et al. Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO group II anovulatory infertility: a randomized controlled study. Hum Reprod 2006; 21 (7): 1798–804.
22. Helmgaard L, Sørensen P, Arce J-C. Children born after controlled ovarian stimulation with HP-hMG or recombinant FSH: results of the EISG pregnancy outcome follow-up. Fertil Steril 2004; 82 (Suppl. 2): S232.
23. ESHRE. The European IVF-monitoring programme (EIM) for the European Society for Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2002. Results generated from European registers by ESHRE. Hum Reprod 2006; 21 (7): 1680–97.
2. Platteau P, Smitz J, Albano C et al. Exogenous luteinizing hormone activity may influence the treatment outcome in in vitro fertilization but not in intracytoplasmic sperm injection cycles. Fertil Steril 2004; 81: 1401–4.
3. Westergaard LG, Erb K, Laursen SB et al. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotrophic women down-regulated with a gonadotropinreleasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril 2001; 76: 543–9.
4. Arce J-C, Nyboe Andersen A, Collins J. Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies: a mini-review. Hum Reprod 2005; 20: 1757–71.
5. Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 2003; 18: 1005–9.
6. Vail A, Gardener E. Common statistical errors in the design and analysis of subfertility trials. Hum Reprod 2003; 18: 1000–4.
7. The European and Israeli Study Group on highly purified hMG versus rFSH. Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil Steril 2002; 78: 520–8.
8. Filicori M, Cognigni GE. Roles and novel regimens of luteinizing hormone and follicle-stimulating hormone in ovulation induction. J Clin Endocrinol Metab 2001; 86: 1437–41.
9. Golan A, Ron-El R, Herman A et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44: 430–40.
10. European Medicines Agency. Guideline on the choice of the noninferiority margin. EMEA/CPMP/EWP/2158/99, 2005.
11. European Medicines Agency. Points to consider on switching between superiority and non-inferiority. CPMP/EWP/482/99, 2000.
12. European Medicines Agency. ICH Topic E9. Note for guidance on statistical principles for clinical trials. CPMP/ICH/363/96, 1998.
13. European Medicines Agency. ICH Topic E10. Note for guidance on choice of control group in clinical trials. CPMP/ICH/364/96, 2001.
14. Wolfenson C, Groisman J, Couto AS et al. Batch-to-batch consistency of human-derived gonadotrophin preparations ompared with recombinant preparations. Reprod Biomed Online 2005; 10: 442–54.
15. Filicori M, Cognigni GE, Pocognoli P et al. Modulation of folliculogenesis and steroidogenesis in women by graded menotropin administration. Hum Reprod 2002; 17: 2009–15.
16. Fanchin R, Righini C, Olivennes F et al. Computerized assessment of endometrial echogenicity: clues to the endometrial effects of premature progesterone elevation. Fertil Steril 1999; 71: 174–81.
17. Fanchin R, Righini C, Ayoubi J-M et al. New look at endometrial echogenicity: objective computer-assisted measurements predict endometrial receptivity in in vitro fertilizationembryo transfer. Fertil Steril 2000; 74: 274–81.
18. Weston AM, Zelinski-Wooten MB, Hutchinson JS et al. Evelopmental potential of embryos produced by in-vitro fertilization from gonadotrophin-releasing hormone antagonist-treated macaques stimulated with recombinant human follicle stimulating hormone alone or in combination with luteinising hormone. Hum Reprod 1996; 11: 608–13.
19. Lisi F, Rinaldi L, Fishel S et al. Evaluation of two doses of recombinant luteinising hormone supplementation in an unselected group of women undergoing follicular stimulation for in vitro fertilization. Fertil Steril 2005; 83: 309–15.
20. Assou S, Anahory T, Pantesco V et al. The human cumulus-oocyte complex gene-expression profile. Hum Reprod 2006; 21 (7): 1705–19.
21. Platteau P, Nyboe Andersen A, Balen A et al. Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO group II anovulatory infertility: a randomized controlled study. Hum Reprod 2006; 21 (7): 1798–804.
22. Helmgaard L, Sørensen P, Arce J-C. Children born after controlled ovarian stimulation with HP-hMG or recombinant FSH: results of the EISG pregnancy outcome follow-up. Fertil Steril 2004; 82 (Suppl. 2): S232.
23. ESHRE. The European IVF-monitoring programme (EIM) for the European Society for Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2002. Results generated from European registers by ESHRE. Hum Reprod 2006; 21 (7): 1680–97.
________________________________________________
2. Platteau P, Smitz J, Albano C et al. Exogenous luteinizing hormone activity may influence the treatment outcome in in vitro fertilization but not in intracytoplasmic sperm injection cycles. Fertil Steril 2004; 81: 1401–4.
3. Westergaard LG, Erb K, Laursen SB et al. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotrophic women down-regulated with a gonadotropinreleasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril 2001; 76: 543–9.
4. Arce J-C, Nyboe Andersen A, Collins J. Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies: a mini-review. Hum Reprod 2005; 20: 1757–71.
5. Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 2003; 18: 1005–9.
6. Vail A, Gardener E. Common statistical errors in the design and analysis of subfertility trials. Hum Reprod 2003; 18: 1000–4.
7. The European and Israeli Study Group on highly purified hMG versus rFSH. Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil Steril 2002; 78: 520–8.
8. Filicori M, Cognigni GE. Roles and novel regimens of luteinizing hormone and follicle-stimulating hormone in ovulation induction. J Clin Endocrinol Metab 2001; 86: 1437–41.
9. Golan A, Ron-El R, Herman A et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44: 430–40.
10. European Medicines Agency. Guideline on the choice of the noninferiority margin. EMEA/CPMP/EWP/2158/99, 2005.
11. European Medicines Agency. Points to consider on switching between superiority and non-inferiority. CPMP/EWP/482/99, 2000.
12. European Medicines Agency. ICH Topic E9. Note for guidance on statistical principles for clinical trials. CPMP/ICH/363/96, 1998.
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Авторы
Андерс Ныбое Андерсен*1, 2, Паул Деврое3, Еан-Царлес Арце4 для Merit Group*
1. Rigshospitalet, Fertility Clinic, Copenhagen, Denmark;
2. Rigshospitalet, Fertility Clinic, Blegdamsvej 9, 2100 Copenhagen, Denmark;
3. Center for Reproductive Medicine of the Vrije Universiteit Brussel, Brussels, Belgium;
4. Ferring Pharmaceuticals A/S, Obstetrics & Gynaecology, Clinical Research & Development, Copenhagen, Denmark
*anders.nyboe.andersen@rh.hosp.dk
1. Rigshospitalet, Fertility Clinic, Copenhagen, Denmark;
2. Rigshospitalet, Fertility Clinic, Blegdamsvej 9, 2100 Copenhagen, Denmark;
3. Center for Reproductive Medicine of the Vrije Universiteit Brussel, Brussels, Belgium;
4. Ferring Pharmaceuticals A/S, Obstetrics & Gynaecology, Clinical Research & Development, Copenhagen, Denmark
*anders.nyboe.andersen@rh.hosp.dk
1. Rigshospitalet, Fertility Clinic, Copenhagen, Denmark;
2. Rigshospitalet, Fertility Clinic, Blegdamsvej 9, 2100 Copenhagen, Denmark;
3. Center for Reproductive Medicine of the Vrije Universiteit Brussel, Brussels, Belgium;
4. Ferring Pharmaceuticals A/S, Obstetrics & Gynaecology, Clinical Research & Development, Copenhagen, Denmark
*anders.nyboe.andersen@rh.hosp.dk
________________________________________________
1. Rigshospitalet, Fertility Clinic, Copenhagen, Denmark;
2. Rigshospitalet, Fertility Clinic, Blegdamsvej 9, 2100 Copenhagen, Denmark;
3. Center for Reproductive Medicine of the Vrije Universiteit Brussel, Brussels, Belgium;
4. Ferring Pharmaceuticals A/S, Obstetrics & Gynaecology, Clinical Research & Development, Copenhagen, Denmark
*anders.nyboe.andersen@rh.hosp.dk
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