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1 : 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 ( vs 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 :, ) , Tel: (02) , Fax: (02) , mkkoong@samsungcokr

2 (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 follitropin beta) 11~14 IU recombinant 15,16 rhfsh uhfsh, uhfsh 18,19,, 20,21 rhfsh

3 IU uhfsh,,,,, 150 IU HMG 30~ IU uhfsh 150 IU HMG , rhfsh (Puregon, Organon, Netherlands) 1772~4, rhfsh uhfsh (Metrodin-HP, Se- rono, Switzerland) HMG (Humegon, Organon, Hollandor, Menogon, Ferring, Germanyor, Pergonal, Serono, Switzerland) mm 3 2:1 matching 34, 35 39, I, 2 3,, II (geminal 10 mm lus cell IV (gonadotropin releasing hormone agonist, GnRH-a) nafarelin acetate (Synarel, Searl, Korea) µg, buserelin (suprefact, Hoechst AG, Germany) 05 mg/ml flare up 3, 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

4 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) Table 1 Characteristics of patients rhfsh (n=177) HMG+uhFSH-HP (n=331) p value Age of patients (yrs) NS Age of husbands (yrs) NS Duration of infertility (months) NS Endocrine profile Basal FSH (miu/ml) NS Basal LH (miu/ml) NS Basal E2 (miu/ml) NS Values are mean SD, NS : not significant

5 (IU) (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) NS Days of stimulation NS Total dose used (IU) p<0001 Gonadotropin units per oocyte (IU) p<0001 Mean fertilization rate per cycle (%) p<0005 Cancellation rate (%) p<005 hcg positive rate (%) NS Clinical pregnancy rate (%) 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 NS Mean number of mature oocytes NS Mean number of fertilized oocytes NS Mean number of high quality embryo NS Mean number of embryos transferred NS Mean number of embryos frozen NS Values are mean SD, NS: not significant

6 (Table 3), , , 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 Total No of mature oocytes Maturation rate (%) p<0001 Total No of fertilized oocytes Fertilization rate (%) 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) Basal FSH (miu/ml) Day of stimulation E2 on hcg injection day Total dose used (IU) * * * Gonadotropin units per oocyte (IU) * * * Mean number of oocytes Mean number of oocytes fertilized Mean number of embryos transferred Mean number of high quality embryos Fertilization rate per cycle (%) * * 687 Cancellation rate (%) ? -hcg positive rate (%) Clinical pregnancy rate (%) * p<

7 (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 (IU) ufsh rhfsh ufsh rhfsh uhfsh HMG hcg, , lenton rhfsh, 26~29,,,,,,, rhfsh Out 17 rhfsh rhfsh

8 rhfsh rhfsh ufsh vs IU) uhfsh 32~35 uhfsh meta-analysis uhfsh rhfsh Raga 39 De Placido (ICSI) 2 (167%), 11 (268%) 36 Out rhfsh (250 IU vs 150 IU, ) rhfsh rhfsh (200 IU vs 100 IU, ) ufsh 35 follitropin alpha 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

9 follitropin alpha follitropin beta immunopotency, in vitro potency, carbohyd- rate complexity 44,45 rhfsh uhfsh, 6 Homburg R, Armar NA, Eshel A, Adams J, Jacobs 508 rhfsh uhfsh uhfsh rhfsh isoform glycosylation pro- files, isohormone menopausal gonadotropin for in vitro fertilization rhfsh rhfsh uhfsh HMG, 1 Templeton A, Morris JK Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization N Engl J Med 1998; 339: Waterstone J, Parsons J, Bolton V Elective transfer of two embryos Lancet 1991; 337: Nijs M, Geerts L, van Roosendaal E, Segal-Bertin G, Vanderzwalmen P, Schoysman R Prevention of multiple pregnancies in an in vitro fertilization pro- gram Fertil Steril 1993; 59: Staessen C, Janssenswillen C, Van den Abbeel E, Devroey P, Van Steirteghem AC Avoidance of tri plet pregnancies by elective transfer of two good quality embryos Hum Reprod 1993; 8: Stanger JD, Yovich JL Reduced in-vitro fertiliza- tion of human oocytes from patients with raised basal luteinizing hormone levels during the follicu- lar phase Br J Obstet Gynaecol 1985; 92: HS Influence of serum luteinising hormone con- centrations on ovulation, conception and early pre- gnancy loss in polycystic ovarian syndrome Br Med J 1988; 297: Punnonen R, Ashorn R, Vilja P, Heinonen PK, Kujansuu E, Tuohimaa P Spontaneous luteinizing hormone surge and cleavage of in vitro fertilized embryos Fertil Steril 1988; 49: Daya S, Gunby J, Hughes EG, Collins JA, Sagle MA Follicle-stimulating hormone versus human cycles: a meta-analysis Fertil Steril 1995; 64: Howles CM, Loumaye E, Giroud D, Luyet G Mul- tiple follicular development and ovarian steroido- genesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European phase III study Hum Reprod 1994; 9: Wikland M, Borg J, Hamberger L, Svalander P Simplification of IVF: minimal monitoring and the use of subcutaneous highly purified FSH admini- stration for ovulation induction Hum Reprod 1994; 9: Chappel S, Kelton, C, Nugent N Expression of human gonadotropins by recombinant DNA me- thods In Genazzani, AR and Petraaglia, F (eds), Proceedings of the 3rd World Congress on Gyneco- logical Endocrinology Parthenon Publishing Group, Carnforth, UK, 1992 p Olijve W, de Boer W, Mulders JW, van Wezenbeek PM Molecular biology and biochemistry of human recombinant follicle stimulating hormone (Puregon)

10 Mol Hum Reprod 1996; 2: Balen AH, Hayden CJ, Rutherford AJ What are the clinical benefits of recombinant gonadotropins? Clinical efficacy of recombinant gonadotropins Hum Reprod 1999; 14: Howles CM Genetic engineering of human FSH (Gonal-F) Hum Reprod Update 1996; 2: Loumaye E The control of endogenous secretion of LH by gonadotropin-releasing hormone agonists during ovarian hyperstimulation for in-vitro fertilization and embryo transfer Hum Reprod 1990; 5: Recombinant Human FSH Product Development Group Recombinant follicle stimulating hormone: development of the first biotechnology product for the treatment of infertility Hum Reprod Update 1998; 4: Out HJ, Mannaerts BM, Driessen SG, Bennink HJ A prospective, randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle stimulating hormone (Puregon versus Metrodin) in in-vitro fertilization Hum Reprod 1995; 10: Redfearn A, Hughes EG, O'Connor M, Dolovich J Delayed-type hypersensitivity to human gonadotropin: case report Fertil Steril 1995; 64: Albano C, Smitz J, Camus M, Bennink HC, Van Steirteghem AC, Devroey P Pregnancy and birth in an in-vitro fertilization cycle after controlled ovarian stimulation in a woman with a history of allergic reaction to human menopausal gonadotropin Hum Reprod 1996; 11: Howles CM Role of LH and FSH in ovarian function Mol Cell Endocrinol 2000; 161: Levy DP, Navarro JM, Schattman GL, Davis OK, Rosenwaks Z The role of LH in ovarian stimulation: exogenous LH: let's design the future Hum Reprod 2000; 15: Bergh C, Howles CM, Borg K, Hamberger L, Josefsson B, Nilsson L, et al Recombinant human follicle stimulating hormone (r-hfsh; Gonal-F) versus highly purified urinary FSH (Metrodin HP): results of a randomized comparative study in women undergoing assisted reproductive techniques Hum Reprod 1997; 12: Hoomans EH, Andersen AN, Loft A, Leerentveld RA, van Kamp AA, Zech H A prospective, randomized clinical trial comparing 150 IU recombinant follicle stimulating hormone (Puregon ) and 225 IU highly purified urinary follicle stimulating hormone (Metrodin-HP ) in a fixed-dose regimen in women undergoing ovarian stimulation Hum Reprod 1999; 14: Frydman R, Howles CM, Truong F A double-blind, randomized study to compare recombinant human follicle stimulating hormone (FSH; Gonal-F) with highly purified urinary FSH (Metrodin-HP) in women undergoing assisted reproductive techniques including intracytoplasmic sperm injection The French Multicentre Trialists Hum Reprod 2000; 15: Lenton E, Soltan A, Hewitt J, Thomson A, Davies W, Ashraf N, et al Induction of ovulation in women undergoing assisted reproductive techniques: recombinant human FSH (follitropin alpha) versus highly purified urinary FSH (urofollitropin HP) Hum Reprod 2000; 15: Camier B, Avril C, Cohen J A multicentre, prospective, randomised study to compare a low dose protocol versus conventional administration of recombinant human follicle stimulating hormone (Gonal-F ) in normo-responder women undergoing IVF/ICSI (abstract) 14th Annual Meeting of the European Society of Human Reproduction and Embryology Gothenburg, Sweden, 1998 June Hum Reprod 13 (Abstract BK1), P Brinsden P, Akagbosu F, Gibbons LM, Lancaster S, Gourdon D, Engrand P, et al A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer Fertil Steril 2000; 73:

11 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 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Staessen C, Camus M, Clasen K, De Vos A, Van Steirteghem A Conventional in-vitro fertilization

12 versus intracytoplasmic sperm injection in sibling oocytes from couples with tubal infertility and normozoospermic semen Hum Reprod 1999; 14: Bukulmez O, Yarali H, Yucel A, Sari T, Gurgan T Intracytoplasmic sperm injection versus in vitro fertilization for patients with a tubal factor as their sole cause of infertility: a prospective, randomiz ed trial Fertil Steril 2000; 73: Horsman G, Talbot JA, McLoughlin JD, Lambert A, Robertson WR A biological, immunological and physico-chemical comparison of the current clinical batches of the recombinant FSH preparations Gonal- F and Puregon Hum Reprod 2000; 15: Tulppala M, Aho M, Tuuri T, Vilska S, Foudila T, Hakala-Ala-Pietila T, et al Comparison of two recombinant follicle-stimulating hormone preparations in in-vitro fertilization: a randomized clinical study Hum Reprod 1999; 14:

歯 PDF

歯 PDF * * The Effects of Oocyte Oocytes Intracytoplasmic ICSI) Kee TaekHoo Hai * SikChun Department of Obstetrics and Gynecology, School of Medicine, Kyungpook Taegu, *Department of Animal Science, Taegu Kyungbuk,