Bridgett Mason, M.B., B.S. * Stuart Campbell, M.B.Ch.B.*

Transcription

1 FERTILITY AND STERILITY Cpyright 992 The American Fertility Sciety Vl. 57, N.4, April 992 Printed n ew-free paper in U.S.A. The rutine use f gnadtrpin-releasing hrmne agnists fr all patients underging in vitr fertilizatin. Is there any medical advantage? A prspective randmized study Charles Kingsland, M.B., B.S. *t Seang-Lin Tan, M.B., B.S.** Nigel Bickertn, M.B., B.S. t Bridgett Masn, M.B., B.S. * Stuart Campbell, M.B.Ch.B.* The Hallam Medical Centre, King's Cllege Schl f Medicine and Dentistry, Lndn, and Ryal Liverpl Hspital, Liverpl, United Kingdm Objective: T determine if the rutine use f gnadtrpin-releasing hrmne agnists (GnRH-a) fr all patients underging in vitr fertilizatin (IVF) prduces any significant medical advantage. Design: Prspective randmized study. Patients: Three hundred eight patients having their first ever IVF attempt. Interventins: Patients were randmly divided int fur grups and received either human menpausal gnadtrpin (hmg) alne fr varian simulatin (grup A, n = 8); clmiphene citrate and hmg (grup B, n = 77); a 3-day ultrashrt curse f GnRH-a and hmg (grup C, n = 74); r pituitary desensitizatin with GnRH-a fllwed by hmg (grup D, n = 76). Results: The indicatins fr IVF and mean age f all fur grups f patients were cmparable. There was a significant difference in the number f embrys cleaved and transferred amng the grups, but there were n significant differences in the cancellatin rate, mean number f cytes cllected r fertilized, and number f cases f failed fertilizatin. There were als n significant differences in the pregnancy and live birth rates per cycle cmmenced r per embry transfer. Cnclusin: The rutine use f GnRH -a fr all patients underging IVF has practical but n significant medical advantages. Fertil Steril 992;57:804-9 Key Wrds: Gnadtrpin-releasing hrmne agnists, in vitr fertilizatin Since the riginal descriptin f the use f gnadtrpins with gnadtrpin-r~leasing hrmne agnists (GnRH-a) fr varian stimulatin in IVF (), the methd has gained widespread ppularity, and many in vitr fertilizatin (IVF) prgrams Received August 9, 99; revised and accepted December 6, 99. * Hallam Medical Centre. t Department f Obstetrics and Gynaeclgy, Ryal Liverpl Hspital. :j: Department f Obstetrics and Gynaeclgy, King's Cllege Schl f Medicine and Dentistry. Reprint requests: Seang-Lin Tan, M.R.C.O.G., Department f Obstetrics and Gyneclgy, King's Cllege Schl f Medicine and Dentistry, Denmark Hill, Lndn SE5 BRX, United Kingdm. presently use this apprach as the predminant, if nt the nly methd f varian stimulatin. Hwever, the majrity f studies advcating the superirity f GnRH-a ver cnventinal stimulatin regimens have been in patients wh were pr respnders in previus treatment cycles (), and they have either been retrspective analyses f data r nnrandmized studies (2-4). Prspective randmized studies cmparing the use f GnRH -a with cnventinal stimulatin regimens in patients wh d nt have a specific indicatin fr the use f GnRH-a have been very few in number, and their results have been cntradictry. Althugh sme studies have reprted significantly increased pregnancy rates (PRs) with the use f GnRH-a (5, 6), ther studies have suggested that there is n bvius su- 804 Kingsland et al. GnRH-a and IVF Fertility and Sterility

2 peririty f regimens incrprating GnRH -a ver cnventinal stimulatin prtcls (7, 8). If there are n disadvantages in using GnRH -a, this lack f cnsensus perhaps des nt matter. Hwever, in cmparisn with varian stimulatin by human menpausal gnadtrpin (hmg) and clmiphene citrate (CC), the use f GnRH-a cmbined with hmg leads t a prlnged treatment cycle and increased exgenus gnadtrpin requirements (3, 9) that, in turn, results in a higher cst f treatment. It has als been suggested that mderate and severe varian hyperstimulatin syndrme is significantly mre frequent when GnRH-a are used (6). We, therefre, designed a prspective randmized study t determine if the rutine use f GnRH-a fr all patients underging IVF prduces any significant medical advantage. MATERIALS AND METHODS Three hundred eight patients wh were underging their first attempt at IVF at the Hallam Medical Centre in Lndn and wh had nt been treated with IVF at any ther centre were recruited int the study. They were prspectively randmized by drawing serially numbered sealed envelpes, each f which cntained a study grup number ( t 4) that were allcated by reference t randm tables. In this manner, the patients (with infrmed cnsent) were assigned t receive ne f fur varian stimulatin regimens, tw f which incrprated the use f GnRH-a. Grup A Tw ampules per day f hmg (Pergnal; Sern, Welwyn Garden City, United Kingdm) were administered by deep intramuscular injectin starting n the 2nd day f the menstrual cycle if the cycle length was ::5: 26 days r frm the 4th day if the cycle length was >26 days. Three ampules f hmg were administered if the patient was ver 35 years f age and fur ampules if she was ver 40 years. GrupB The identical regimen f hmg administratin was given as in grup A. In additin, the patients were given CC, 00 mg/d frm days 2 t 6 fthe menstrual cycle. Grupe An ultrashrt regimen f GnRH -a was used. This cnsisted f the administratin f buserelin acetate (Suprefact; Hechst, Hunslw, United Kingdm), 500 ~g/d subcutaneusly (SC) n days 2, 3, and 4 f the menstrual cycle. Starting n day 3 f the menstrual cycle, three ampules f hmg were administered daily if the patient was up t 35 years f age, and fur and five ampules were given if the patient was ver 35 and 40 years ld, respectively. GrupD This cnsisted f a lng prtcl f GnRH -a administratin. Buserelin acetate, 200 ~g/d was administered SC frm day f the menstrual cycle; this was cntinued until pituitary desensitizatin was achieved. This was deemed t have ccurred when the cncentratin f ttal urinary estrgen (E) was <00 nml/d and a pelvic ultrasund (US) scan revealed n fllicular activity. Once pituitary desensitizatin had ccurred, the administratin f hmg was cmmenced at the identical daily dse as fr patients in grup C while the administratin f buserelin acetate was cntinued until, and including, the day f human chrinic gnadtrpin (hcg) administratin. Mnitring f varian stimulatin was by daily US assessment f fllicular grwth tgether with estimatin f daily ttal urinary E cncentratin. The dse f hmg was increased if fllicular grwth was pr. The cycle was canceled if there was pr fllicular respnse r if the patient had vulated befre cyte recvery as evidenced n US. Human chrinic gnadtrpin (Prfasi; Sern), 5,000 IU, was administered when the mean diameter f the largest varian fllicle was at least 7 mm and at least tw ther fllicles were larger than 4 mm in diameter with satisfactry urinary E levels. Transvaginal US-directed cyte recvery was scheduled 35 hurs after the administratin f hcg. Embry transfer (ET) was perfrmed 48 hurs after cyte retrieval, and a maximum f fur embrys were transferred fr each patient. The luteal phase in all fur grups f patients was supprted by the administratin fhcg, 2,000 IU n the day fet and repeated 3 days later. The techniques f IVF, embry culture, and ET have been previusly described (0). All patients in the study had mnitring f varian stimulatin, cyte cllectin, and ET by the same team f physicians, and all labratry prcedures were handled by the same team f scientific staff. The age, diagnstic categry, number f cytes cllected, fertilized and cleaved, and the pregnancy utcme were recrded fr each patient. The Shapir-Wilk W test was used t test fr the nrmality Vl. 57, N.4, Aprii992 Kingsland et ai. GnRH-a and IVF 805

3 Table Etilgy f Infertility f Patients in Study Grup A B C D Ttal n. f cycles (n. f patients) Tubal factr Unexplained infertility Male factr infertility Endmetrisis Others f distributin f each patient variable. Analyses f differences in the fur grups were perfrmed using either ANOVA r Kruskal-Wallis ne-way ANOVA, depending n whether the data were nrmally distributed, whereas prprtins were cmpared using X2 test. A prbability level f 0.05 was used t indicate statistical significance. RESULTS The indicatins fr IVF and the age f the patients in the fur grups were cmparable (Tables and 2). The percentage f patients having cyte recverywere86.4%, 90.9%, 89.2%, and 88.2% in the fur grups, respectively, reflecting the bradly similar cancellatin rate in the fur grups f patients. Althugh the mean amunt f hmg used was greater in grups C and D (24.6 and 27.4 ampules, respectively) than in grups A and B (8.2 and 6.9 ampules, respectively), the differences did nt reach statistical significance. There was n significant difference in the mean number f cytes cllected, which were 6.5 ± 4.99, 6.37 ± 4.3, 6.35 ± 4.66, and 7.59 ± 4.0 in the fur grups, respectively. The mean number f cytes fertilized and number f cases f failed fertilizatin were cmparable in all fur grups. There was a marginally significant difference in the mean number f embrys cleaved (P = 0.05) and a significant difference in the mean number f embrys transferred (P = 0.0) (Table 2). There were n significant differences in the PRs per cycle cmmenced, per cyte retrieval, r per ET (Table 3) when the results f all fur grups were cmpared r when cmparisns were made between grups A and D, Band D, and A + Band D. The live birth rates per cycle cmmenced and per ET were als nt significantly different in the fur grups. Finally, the verall pregnancy and live birth rates btained in the patients wh had buserelin acetate incrprated int the varian stimulatin regimen (grups C and D) were cmpared with thse btained in thse wh had either hmg alne r in cmbinatin with CC (grups A and B). The results are shwn in Table 4. The PRs per cycle cmmenced and per ET were 7.72% and 24.56% in thse wh had did nt have buserelin acetate as cmpared with 8.67% and 26.7% in thse wh had buserelin acetate. The live birth rates per cycle cmmenced and per ET were 2.03% and 6.67% in grups A + B and 6.00% and 22.43% in grups C + D, respectively. Nne f these differences were statistically significant. DISCUSSION Gnadtrpin-releasing hrmne agnists, which act by desensitizing the pituitary after an initial Table 2 Clinical Respnse f Patients in Study Grup A B C D N. f patients/cycles Age N. f cyte recveries N. f canceled cycles Cancellatin rate (%) N. f cytes cllected N. f cytes fertilized N. f failed fertilizatin N. f embrys cleaved N. f embrys transferred II 8 33 (23 t 43) * 70 (4)t ± 4.99* 3.26 ± ± ± (25 t 4) 70 7 (4) ± ± ± ± (25 t 42) 66 8 (0) ± ± ± ±.7 * Values are medians (ranges). t Values in parentheses are the number f spntaneus vulatins. * Values are means ± SD. P = 0.05, significant. II P = 0.Q, significant (22 t 44) 67 9 (0) ± ± ± ± Kingsland et al. GnRH-a and IVF Fertility and Sterility

4 Table 3 Pregnancy and Live Birth Rates in the Fur Grups f Patients Grup A B C D PR per cycle cmmenced (%)* PR per cyte retrieval (%) PRperET (%) N. f singletns N. f first trimester abrtins N. f ectpic pregnancies N. f secnd trimester abrtins Live birth rate per cycle cmmenced (%) Live birth rate per ET (%) (8)t (6) (8) (9) * Nt significant in all categries. t Values in parentheses are number nging. stimulatry phase, are nw widely used in IVF prgrams. Since the initial publicatin f its use (), a number f studies have suggested that the use f GnRH-a prevents a spntaneus luteinizing hrmne (LH) surge, leading t a lwer cancellatin rate (5), and imprves the fllicular respnse s that a successful utcme after IVF may be achieved in previusly abnrmal respnders. Mre recently, it has been suggested that GnRH -a shuld be rutinely used fr pituitary suppressin befre varian stimulatin fr IVF (4). Hwever, there have been very few prspective randmized studies cmparing the use f GnRH -a with cnventinal stimulatin regimens in patients wh d nt have a specific indicatin fr the use f GnRH -a, and their results have been cntradictry. Neveu et al. (5) randmly divided 20 nrm-vulatry wmen t receive either fllicle-stimulating hrmne (FSH) alne r buserelin acetate in the lng prtcl and FSH. One pregnancy was bserved in the first grup and six in the latter grup. Antine et al. (9) reprted a prspective randmized study in 80 patients wh were cnsidered nrm-vulatry and fund that thse wh received GnRH-a and hmg had a significantly Table 4 Cmparisn f Pregnancy and Live Birth Rates in Patients Wh Received and Wh Did Nt Receive Buserelin Acetate A+B C+D Significance PR per cycle cmmenced P = 0.95 PRperET P = 0.90 Live birth rate per cycle cmmenced P = 0.40 Live birth rate per ET P = 0.36 % higher prprtin reaching cyte recvery and had mre cytes recvered as cmpared with thse wh received hmg nly, but the dse f hmg required was significantly higher when GnRH-a was used. The fertilizatin and cleavage rates were the same in bth grups, and there was n significant difference in the PRs. In the third prspective randmized study, Rn-EI et al. (6) fund that patients wh received GnRH-a and hmg yielded significantly mre cytes and embrys per retrieval, and they had a significantly higher PR per cycle. In cntrast, Ferrier et al. (7) reprted in a prspective randmized study f 93 cycles cmparing CC and hmg and GnRH-a and hmg that there was n difference in the cancellatin rates, mean number f cytes per retrieval, r fertilizatin rates. In fact, in their grup f IVF patients, the PR per retrieval was significantly higher in thse wh received CC/hMG (7). Similarly, Marulis and clleagues (8), in a prspective randmized study, fund n differences in fertilizatin and implantatin rates between thse wh had GnRH-a and FSH/hMG and thse wh had nly FSH/hMG. The PRs per cycle initiated, per aspiratin, and per ET were slightly higher in thse wh had FSH/hMG withut GnRH -a, but the differences were nt significant. In the present study, we cmpared the use fhmg ± CC with tw prtcls incrprating the use f GnRH-a. The reasn the 3-day ultrashrt prtcl f GnRH-a was included as ne arm f the study was because f the recent suggestin that the administratin f 3 days f GnRH -a at the cmmencement f the cycle suffices t suppress the endgenus LH surge and wuld result in a significantly higher PR as cmpared with that prduced by the standard CC/hMG regimen (). In the present study, all fac- Vl. 57, N.4, April 992 Kingsland et al. GnRH-a and IVF 807

5 trs that culd affect the utcme ftreatment were cntrlled. The patients were cmparable in terms f age and indicatins fr IVF, and nly patients having their first ever IVF attempt were recruited s that the starting dse f hmg culd be fixed withut reference t the patients' respnse in previus treatment cycles. The reasn why ne additinal ampule f hmg was given in grups C and D was because f the bservatin that there is a decreased varian respnse t hmg caused by GnRHa (2, 3). Mnitring f varian stimulatin, cyte cllectin, and ET were all undertaken by the same team f physicians, and all labratry prcedures were handled by the same scientific staff. Althugh there was a marginally significant difference in the number f embrys cleaved and a significant difference in the number f embrys transferred amng the fur grups, with the highest numbers being btained in thse n the lng prtcl f GnRH -a, there were n significant differences in any f the ther parameters studied. The cnclusin f the present prspective randmized study that there is n verall significant medical advantage f using GnRH -a rutinely fr all patients underging IVF is similar t that f Ferrier et al. (7) and Marulis et al. (8) but different frm that f Neveu et al. (5), Antine et al. (9), and Rn-EI et al. (6). The reasn fr the disparity in the results f the varius studies is nt precisely clear. One pssible reasn is that in the studies by Rn EI et al. (6) and Antine et al. (9) there were significantly higher cancellatin rates when hmg was used alne as cmpared with GnRH-a and hmg (27.2% versus 3.3% [6] and 28.9% versus 3.3% [9]) which, in turn, was reflected in the relatively lw PRs btained in the absence f agnists (3% [6] and 2.2% [9]). In the light f these cnflicting r~prts, it wuld appear that the medical advantage f using GnRH-a rutinely fr all IVF patients remains unprven by prspective randmized studies. It may well be that extremely large studies, beynd the capacity f anyne center t perfrm, are required t reslve the questin f whether the rutine use f GnRH-a fr all patients underging IVF prduces any significant medical advantage. Hwever, pari passu, this implies that any difference in results is unlikely t be very dramatic. If there were n ptential disadvantages f using GnRH -a rutinely, perhaps this wuld nt be an imprtant cnsideratin. Hwever, cmpared with CCjhMG, the use f GnRH-a cmbined with hmg results in a prlnged treatment cycle and generally increased exgenus gnadtrpin requirements (2, 3). This, in turn, leads t a higher cst f treatment. Mrever, GnRH-a d nt prtect against varian hyperstimulatin, and, in fact, it has been suggested that the risk f hyperstimulatin may be slightly higher when GnRH-a are used (6, 4). Ntwithstanding these cmments, the practical advantages f using GnRH -a fr all patients underging IVF may verwhelm any ther cnsideratin. Mnitring f the treatment cycle des nt need t be as rigrus as when hmg ± CC is used, and the timing f cyte recvery can be regulated t sme extent fr the cnvenience f bth patients and staff. Bth these factrs are bviusly very attractive fr many IVF prgrams. In cnclusin, the use f GnRH -a therapy has bradened the ptins available fr varian stimulatin in IVF and ther assisted cnceptin techniques. The majr advantage f using GnRH -a fr all patients underging IVF is fr practical cnsideratins rather than because f any significant medical advantage prduced. REFERENCES. Prter RN, Smith W, Craft IL, Abdulwahid NA, Jacbs HS. Inductin f vulatin fr in vitr fertilisatin using buserelin and gnadtrpins. Lancet 984;2: Rutherfrd AJ, Subak-Sharpe RJ, Dawsn KJ, Margara RA, Franks S, Winstn RML. Imprvement f in-vitr fertilisatin after treatment with buserelin, an agnist f luteinising hrmne releasing hrmne. Br Med J 988;296: Lejeune B, Barlw P, Puissant F, Delvigne A, Vanrysselberge M, Lery F. Use f bus ere lin acetate in an in vitr fertilizatin prgram: a cmparisn with classical clmiphene citrate-human menpausal gnadtrpin treatment. Fertil Steril 990;54: Meldrum DR, Wist A, Hamiltn F, Gutlay AL, Kemptn W, Huynh D. Rutine pituitary suppressin with leuprlide befre varian stimulatin fr cyte retrieval. Fertil Steril 989;5: Neveu S, Hedn B, Bringer J, Chinchle J-M, Arnal F, Humeau C, et a. Ovarian stimulatin by a cmbinatin f a gnadtrpin releasing hrmne agnist and gnadtrpins fr in-vitr fertilisatin. Fertil Steril987;47: Rn-EI, Herman A, Glan A, Nachum H, Sffer Y, Caspi E. Gnadtrpins and cmbined gnadtrpin-releasing hrmne agnist-gnadtrpins prtcls in a randmised prspective study. Fertil Steril99;55: Ferrier A, Rasweiler JJ, Bedfrd JM, Prey K, Berkeley AS. Evaluatin f leuprlide acetate and gnadtrpins versus clmiphene citrate and gnadtrpins fr in vitr fertilizatin r gamete intrafallpian transfer. Fertil Steril990;54: Marulis GB, Emery M, Verkauf BS, Saphier A, Bernhisel M, Yek TR. Prspective randmized study f human mentrpin versus a fllicular and a luteal phase gnad- 808 Kingsland et a. GnRH-a and IVF Fertility and Sterility

6 trpin-releasing hrmne analg-human mentrpin stimulatin prtcls fr in vitr fertilizatin. Fertil Steril 99;55: Antine JM, Salat-Barux J, Alvarez S, Crnet D, Tibi Ch, Mandelbaum J, et al. Ovarian stimulatin using human menpausal gnadtrphins with r withut LHRH analgues in a lng prtcl fr in-vitr fertilizatin: a prspective randmised cmparisn. Hum Reprd 990;5: Riddle A, Sharma V, Masn BA, Frd NT, Pampigline JS, Parsns J, et al. Tw years' experience f ultrasund-directed cyte retrieval. Fertil Steril 987;48: Macnamee M, Hwles CM, Edwards RG, Taylr PJ, Elder KT. Shrt term luteinizing hrmne-releasing hrmne treatment: prspective trial f a nvel varian stimulatin regimen fr in vitr fertilizatin. Fertil Steril 989;52: Barnes RB, Scmmegna A, Schreiber JR. Decreased varian respnse t human menpausal gnadtrpin caused by subcutaneusly administered gnadtrpin -releasing hrmne agnist. Fertil Steril987;47: Hrvath FM, Styler M, Hammnd JM, Sheldn RM, Kemmann E. Exgenus gnadtrpin requirements are increased in leuprlide suppressed wmen underging varian stimulatin. Fertil Steril988;49: Glan A, Rn-EI R, Herman A, Weinraub Z, Sffer Y, Caspi E. Ovarian hyperstimulatin fllwing D-Trp-6 luteinizing hrmne-releasing hrmne micrcapsules and mentrpin fr in vitr fertilizatin. Fertil Steril 988;50:92-7. Vl. 57, N.4, April 992 Kingsland et al. GnRH-a and IVF 809