: 29 1 2002 Kor J Fertil Steril, Vol 29, No 1, 2002, 3,, The Efficacy of Recombinant Human Follicle Stimulating Hormone (rhfsh) in Human IVF-ET Program Kuk Sun Han, Hong Bok Lee, In Ok Song, Yong Seog Park, Hye Kyung Byun, Jin Hyun Jun, Mi Kyoung Koong Division of Reproductive Endocrinology & Infertility Department of Obstetrics and Gynecology, Samsung Cheil Hospital Sungkyunkwan University School of Medicine, Seoul, Korea Objectives: Recently, recombinant FSH (rfsh) has been manufactured using a Chinese hamster ovary cell line transfected with the gene encoding human FSH Both rfsh and urinary gonadotropin (ufsh) could be used for controlled ovarian hyperstimulation (COH) However, ufsh implies a number of disadvantages, such as batch-to-batch inconsistency, no absolute source control, dependence on large amounts of urine, low specific activity, and low purity The purpose of this study was to evaluate the efficacy of rfsh in human IVF-ET program Materials and Methods: A total of 508 infertile women was enrolled in this study They are classified into rfsh group (n=177) or ufsh group (n=331), and all of them were matched by age and cause of infertility in same period The Puregon (Organon, Holland) was used as rfsh, and the Metrodin-HP (Serono, Switzeland) and Humegon (Organon, Holland) was used as ufsh We subdivided the patients into three age groups The outcomes of IVF-ET program were analyzed using the statistical package for social sciences (SPSS) Results: There was no significant differences in the level of estradiol on hcg injection day, the numbers of retrieved oocytes, matured oocytes, fertilized oocytes, transferred embryos, frozen embryos between the two groups The total dose (IU) of gonadotropin for COH was significantly lower in the rfsh group compared to ufsh group (1339 54911 vs 25278 10752 IU, p<0001) Clinical pregnancy rate per embryo transfer in the rfsh group showed increasing tendency, compared to the ufsh group, but there was no statistical significance (352% vs 293%) Our results demonstrated that the relative efficiency of rfsh compared with ufsh is higher in older patients Conclusions: The ovarian stimulatory effect and clinical outcome of recombinant FSH was similar to that of the urinary gonadotropin The IVF-ET cycles with significantly lower dose of gonadotropin in rfsh group showed comparable results Therefore, we suggest that recombinant FSH is more potent and effective than urinary gonadotropin Key Words: Recombinant human follicle stimulating hormone (rfsh), Urinary gonadotropin (ufsh), IVF-ET, Total dose of gonadotropin, Pregnancy rate :, ) 100-380 1-19, Tel: (02) 2000-7522, Fax: (02) 2000-7790, e-mail: mkkoong@samsungcokr - 45 -
(in vitro fertilization, IVF) rhfsh uhfsh 1~4 (follicle stimulating hormone, FSH),, (glycoprotein) human menopausal gonadotropin ( HMG, menotropin) 1 mg 10,000 (luteinizing hormone, LH), 17 5~8 monoclonal rhfsh (urinary human FSH, uhfsh, urofol- litropin), (highly purified uhfsh, highly purified urofollitropin) HMG 8~10,,,, 1960 rhfsh 1988 Chinese hamster ovary (CHO) cell line a ß subunit encoding expression vector (recom- binant human FSH, rhfsh, follitropin alpha and - 46 - follitropin beta) 11~14 IU recombinant 15,16 rhfsh uhfsh, uhfsh 18,19,, 20,21 rhfsh 1999 5 2001 5
30 150 IU uhfsh,,,,, 150 IU HMG 30~35 225 IU uhfsh 150 IU HMG 35 508, rhfsh (Puregon, Organon, Netherlands) 1772~4, rhfsh uhfsh (Metrodin-HP, Se- rono, Switzerland) HMG (Humegon, Organon, Hollandor, Menogon, Ferring, Germanyor, Pergonal, Serono, Switzerland) 331 18 mm 3 2:1 matching 34, 35 39, 40 508 I, 2 3,, II (geminal 10 mm lus cell IV (gonadotropin releasing hormone agonist, GnRH-a) nafarelin acetate (Synarel, Searl, Korea) 1 500 µg, buserelin (suprefact, Hoechst AG, Germany) 05 mg/ml flare up 3, - 47-225 IU uhfsh 225 IU HMG rhfsh 5 16 mm (human chorionic gonadotropin, hcg, Pregnyl, Organon, Ne- therlands) 10,000 IU 36 (polar body) cumulus mass corona radiate (first polar body) corona cell sun-burst cumulus mass vesicle break down), III corona cell cumu-, V cumulus cell corona cell, V
48~72 3~4 HMG 331 (luteal phase support) (proge- sterone in oil, Progest, Samil Phar, Korea) 50 mg (Utroge- stan, Hanwha Phar, Korea) 300 mg 12 ß- hcg 3 miu/ml ß-hCG (gestational sac) SPSS (statistical package for social science) 100 Student's t-test, chi-square test Fisher's Exact test, (efficacy criteria),, p 005, (, ) 508 (91 19 vs 93 17) 2:1 matching rhfsh 177 uhfsh 2 (167%), 11 (268%) 13,,,, 12 (68%) 41 (124%),,, (Table 1), 93 (525%), 194 (593%) 84 (475%), 133 (407%) 356%, 29%, (Table 2) 13395 4911 Table 1 Characteristics of patients rhfsh (n=177) HMG+uhFSH-HP (n=331) p value Age of patients (yrs) 327 38 330 43 NS Age of husbands (yrs) 352 49 359 50 NS Duration of infertility (months) 507 395 524 388 NS Endocrine profile Basal FSH (miu/ml) 77 26 84 50 NS Basal LH (miu/ml) 35 21 34 19 NS Basal E2 (miu/ml) 184 80 196 93 NS Values are mean SD, NS : not significant - 48 -
(IU) 25278 10752 (IU) (p<0005) (p<0001) (p<0001) 719%, 656%, hcg, Table 2 Indication of infertility rhfsh (n=177) HMG+uhFSH-HP (n=331) p value Tubal factor 63 (356%) 96 (29% ) NS Male factor 56 (316%) 94 (284%) NS Endometriosis 24 (136%) 54 (163%) NS Immune factor 2 ( 11%) 4 ( 12%) NS Peritoneal factor 10 ( 56%) 20 ( 60%) NS Old age 3 ( 17%) 14 ( 42%) NS Uterine factor 3 ( 17%) 5 ( 15%) NS NS: not significant Table 3 Results of controlled ovarian hyperstimulation, and in vitro fertilization rhfsh (n=177) HMG+uhFSH-HP (n=331) p value E2 on hcg injection day (pg/ml) 21053 13771 25369 30612 NS Days of stimulation 91 19 93 17 NS Total dose used (IU) 13395 4911 25278 10752 p<0001 Gonadotropin units per oocyte (IU) 2177 2956 4358 7169 p<0001 Mean fertilization rate per cycle (%) 719 656 p<0005 Cancellation rate (%) 68 124 p<005 hcg positive rate (%) 40 341 NS Clinical pregnancy rate (%) 352 293 NS Values are mean SD, NS: not significant Table 4 Results of retrieved oocytes and embryo parameters rhfsh (n=177) HMG+uhFSH-HP (n=331) p value Mean number of retrieved oocytes 122 88 119 81 NS Mean number of mature oocytes 102 60 91 51 NS Mean number of fertilized oocytes 87 62 79 52 NS Mean number of high quality embryo 17 14 16 13 NS Mean number of embryos transferred 36 14 34 17 NS Mean number of embryos frozen 84 63 81 45 NS Values are mean SD, NS: not significant - 49 -
(Table 3), 122 88, 119 81 60, 91 51 first polar body I II 102,,, Table 5 Comparision of oocyte parameters rhfsh (n=177) HMG+uhFSH-HP (n=331) p value Total No of retrieved oocytes 2167 3950 Total No of mature oocytes 1515 2470 Maturation rate (%) 699 625 p<0001 Total No of fertilized oocytes 1469 2299 Fertilization rate (%) 678 582 p<0001 Table 6 Treatment parameters and outcome in the rhfsh and HMG+uhFSH groups when patients were subdivided according to age Less than 35 years 35 to 39 years More than 40 years rhfsh (n=131) HMG+uhFSH-HP (n=224) rhfsh (n=35) HMG+uhFSH-HP (n=78) rhfsh (n=11) HMG+uhFSH-HP (n=29) Mean age (yrs) 309 23 307 24 367 14 364 13 413 10 420 20 Basal FSH (miu/ml) 74 22 80 46 87 38 88 53 88 16 103 72 Day of stimulation 90 18 93 17 95 25 94 18 92 18 93 17 E2 on hcg injection day 22117 14057 28009 35524 19183 13873 22030 16366 14255 6156 14449 10829 Total dose used (IU) 12738 4622 * 23488 10634 15357 5806 * 28356 10322 14909 3216 * 30828 9215 Gonadotropin units per oocyte (IU) 2038 3155 * 3697 6851 2485 2390 * 4697 5539 2834 2033 * 8614 11299 Mean number of oocytes 132 90 131 84 101 83 103 68 74 38 78 69 Mean number of oocytes fertilized Mean number of embryos transferred Mean number of high quality embryos Fertilization rate per cycle (%) 95 67 85 54 65 32 65 48 59 37 60 40 36 14 34 17 36 14 35 16 40 15 30 12 24 16 23 15 24 17 22 14 30 15 20 18 705 663 744 * 627 803 * 687 Cancellation rate (%) 76 125 57 90 0 207? -hcg positive rate (%) 397 367 424 31 364 217 Clinical pregnancy rate (%) 355 301 364 296 273 217 * p<005-50 -
(Table 4) Table 5 (maturation rate) 699%, 625% (p<0001) (p<0001) 34, 35 39, 40 (p<005) 35 17,30~33,, (Table 6) rhfsh uhfsh HMG uhfsh rhfsh ufsh Bennink 31 rhfsh 22~24 Lenton 25 150 (IU) ufsh rhfsh ufsh rhfsh uhfsh HMG hcg, - 51 -, lenton rhfsh, 26~29,,,,,,, rhfsh Out 17 rhfsh rhfsh
rhfsh rhfsh ufsh vs 15357 IU) uhfsh 32~35 uhfsh meta-analysis uhfsh rhfsh Raga 39 De Placido (ICSI) 2 (167%), 11 (268%) 36 Out 37 30 33 rhfsh (250 IU vs 150 IU, ) rhfsh rhfsh (200 IU vs 100 IU, ) 38 35 ufsh 35 follitropin alpha - 52-40 35 39 rhfsh (14909 IU rhfsh 40 Daya 8 pub-med rhfsh rhfsh uhfsh rhfsh 40 ufsh rfsh Ravhon 30 ufsh rfsh 41~43 rhfsh folli- tropin alpha (Gonal-F ) follitropin beta (Puregon ) follitropin beta
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28 Khalaf Y, Taylor A, Pettigrew R The relative clinical efficacy of recombinant follicle stimulating hormone to the highly purified urinary preparation Assist Reprod Rev In press 2000 29 Mannaerts BM, Rombout F, Out HJ, Coelingh Bennink H Clinical profiling of recombinant follicle stimulating hormone (rfsh; Puregon): relationship between serum FSH and efficacy Hum Reprod Update 1996; 2: 153-61 30 Ravhon A, Lavery S, Aurell R, Trew G, Margara R, Winston R Clinical experience with recombinant follicle-stimulating hormone (FSH) and urinary FSH: a retrospective case- controlled analysis Fertil Steril 2001; 75: 920-5 31 Bennink HJTC, Fauser BCJM, Out HJ Recombinant follicle-stimulating hormone (FSH; Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene citrate-res istant, normogonadotropic, chronic anovulation: a prospective, multicenter, assessor-blind, randomized, clinical trial Fertil Steril 1998; 69: 19-25 32 Recombinant Human FSH Study Group Clinical assessment of recombinant human follicle-stimulating hormone in stimulating ovarian follicular development before in vitro fertilization Fertil Steril 1995; 63: 77-86 33 Jansen CA, van Os HC, Out HJ, Coelingh Bennink HJ A prospective randomized clinical trial comparing recombinant follicle stimulat ing hormone (Puregon) and human menopausal gonadotropins (Humegon) in non-down-regulated in-vitro fertilization patients Hum Reprod 1998; 13: 2995-9 34 Hedon B, Out HJ, Hugues JN, Camier B, Cohen J, Lopes P, et al Efficacy and safety of recombinant follicle stimulating hormone (Puregon) in infertile women pituitary -suppressed with triptorelin undergoing in-vitro fertilization: a prospective, randomized, assessor-blind, multicentre trial Hum Reprod 1995; 10: 3102-6 35 Yarali H, Bukulmez O, Gurgan T Urinary folliclestimulating hormone (FSH) versus recombinant FSH in clomiphene citrate-resistant, normogonadotropic, chronic anovulation: a prospective randomized study Fertil Steril 1999; 72: 276-81 36 Delvigne A, Dubois M, Battheu B, Bassil S, Meuleman C, De Sutter P, et al The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study II Multiple discriminant analy - sis for risk prediction Hum Reprod 1993; 8: 1361-6 37 Out HJ, Braat DD, Lintsen BM, Gurgan T, Bukulmez O, Gokmen O, et al Increasing the daily dose of recombinant follicle stimulating hormone (Puregon) does not compensate for the age-related decline in retrievable oocytes after ovarian stimulation Hum Reprod 2000; 15: 29-35 38 Out HJ, Lindenberg S, Mikkelsen AL, Eldar-Geva T, Healy DL, Leader A, et al A prospective, randomized, double-blind clinical trial to study the efficacy and efficiency of a fixed dose of recombinant follicle stimulating hormone (Puregon) in women undergoing ovarian stimulation Hum Reprod 1999; 14: 622-7 39 Raga F, Bonilla-Musoles F, Casan EM, Bonilla F Recombinant follicle stimulating hormone stimulation in poor responders with normal basal concentrations of follicle stimulating hormone and oestradiol: improved reproductive outcome Hum Reprod 1999; 14: 1431-4 40 De Placido G, Alviggi C, Mollo A, Strina I, Varricchio MT, Molis M Recombinant follicle stimulating hormone is effective in poor responders to highly purified follicle stimulating hormone Hum Reprod 2000; 15: 17-20 41 Aboulghar MA, Mansour RT, Serour GI, Amin YM, Kamal A Prospective controlled randomized study of in vitro fertilization versus intracytoplasmic sperm injection in the treatment of tubal factor infertility with normal semen parameters Fertil Steril 1996; 66: 753-6 42 Staessen C, Camus M, Clasen K, De Vos A, Van Steirteghem A Conventional in-vitro fertilization - 55 -
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