Journal of in Vitro Fertilization and Embryo Transfer, Vol. 8, No. 6, 1991
A Randomized Prospective Study on the Effect of Short and Long Buserelin Treatment in Women with Repeated Unsuccessful in Vitro Fertilization (IVF) Cycles Due to Inadequate Ovarian Response MARTHA DIRNFELD, 1,2 YAEL GONEN,1 ARIE LISSAK,1 SHLOMIT GOLDMAN,1 MARA KOIFMAN, 1 YORAM SOROKIN, 1 and HAIM ABRAMOVICI 1
Submitted: June 2, 1991 Accepted: August 4, 1991
INTRODUCTION The recognition that multiple embryo replacement is associated with an increased success rate in in vitro fertilization (IVF) treatment has led to several methods of ovarian stimulation, in order to obtain multiple fertilizable oocytes (1,2). With any regimen, a wide range of ovarian response can be expected and up to 35% of stimulated cycles may result in inadaquate response leading to cycle cancellation (3,4). Inadequate responders are difficult to manage since their poor response tends to be repetitive from cycle to cycle (5). An impaired response to ovarian stimulation by gondadotropins is often associated with premature luteinizing hormone (LH) surge and/or progesterone rise during the follicular phase (6). These hormonal derangements have detrimental effects on follicular maturation and functional viability of the oocyte, which lead to asynchrony between ovarian function and endometrial maturation (7). The results of several studies using gonadotropin releasing hormone agonist (GNRHa) and gonadotropins for ovulation induction in "normal" and poor responders are conflicting (812). The purpose of this prospective randomized study was to compare two modes of G N R H a treatment in a group of patients with previous inadaquate ovarian response undergoing gonadotropin induction of ovulation for IVF treatment.
Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I--long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group H (P < 0.01). Cancellation rate was significantly lower in Group I than in Group H (P < 0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos transferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response. KEY WORDS: poor responders; gonadotropin releasing hormone analogue; in vitro fertilization; ovulation induction.
1 Department of Obstetrics and Gynecology, Carmel Hospital Haifa, Israel. 2 To whom correspondence should be addressed at Department of Obstetrics and Gynecology, Carmel Hospital, 7 Michal Street, Haifa 34362, Israel.
MATERIALS AND METHODS Fifty-four women with long-standing infertility were included to participate in this study. Each pa339
0740-7769/91/1200-0339506.50/0 9 1991PlenumPublishingCorporation
DIRNFELD ET AL.
340
tient enrolled to the study had had at least one unsuccessful attempt of ovarian stimulation and oocyte pickup (OPU) cancellation, due to inadequate response. The mean age of the patients in this study was 33.5 years (range, 26-40 years). Thirty patients underwent two or more failed IVF cycles. Of 54 previous cycles stimulated with human menopausal gonadotropin (hMG), 70% were canceled, and in only 16 cycles was an OPU performed. None of them achieved a viable pregnancy. Early follicular-phase prolactin, follicle stimulating hormone (FSH), LH, testosterone, and thyroid function were within normal limits in all patients. Inadequate response was defined as (1) maximum rise of 17B-estradiol (Ez) below 300 pg/ml despite a high hMG dose; (2) early L H rise (above 180% of the mean) when the largest follicular diameter was below 16 mm and/or a rise in progesterone (P) concentration above 1.2 mg/ml during the follicular phase; or (3) combination of the above. Patients were randomly assigned to two groups using a table of random numbers. Group I (28 patients) received "long" treatment with daily Buserelin nasal spray (Buserelin-Superfact, Hoechst A.G, FRG), 1000 txg/day commencing 15-30 days prior to induction of ovulation, continuing with 600 p,g/day up to the human chorionic gonadotropin (hCG) administration day. hMG (Pergonal, Teva Laboratories, Kfar Sava, Israel), 2-3 ampoules (150--225 IU) per day, was started when serum 17Bestradiol was below 40 pg/ml. Group II (26 patients) received"short" treatment with Buserelin nasal spray, 600 p~g/day, starting on the first day of the menstrual cycle and continuing through the follicular phase until the evening of hCG (Chorigon, Teva, Israel) administration. Ovarian stimulation was started using hMG, 2-3 ampoules (150-225 IU) per day, from the third day of the menstrual cycle. Follicular maturation was monitored with daily s e r u m E2, P, and (LH) measurements and by daily ultrasound examinations. Hormonal assays were performed with commercialy available radioimmunoassay (RIA) kits. Serum E 2 and P were measured with a Coat a Count RIA kit (DPC Co, Los Angeles, CA). Serum L H was measured using a Maia Clone kit (Serono Diagnostics, Dover, Herzlia, Israel). Interassay variations were 12, 10, 7, and 9% for E2, progesterone, FSH, and LH, respectively. Ultrasonographic measurement of follicular di-
ameter was performed daily, starting on the seventh day of the menstrual cycle (Diasonics, 3.5 MHZ sector scan, USA). Ovulation was induced with 10,000 IU hCG when E 2 w a s above 300 pg/ml and ultrasound showed at least two follicles with a diameter of more than 17 ram. As mentioned above, Buserelin was stopped after hCG administration in all patients. OPU was performed 34-36 hr after hCG administration by laparoscopy or by ultrasonographically guided puncture. The methods for fertilization and embryo culture in vitro have already been described (13). Luteal support was given to all patients, starting on the day after OPU; progesterone in oil (Gestone, Paines and Byrne, Greenford, England), 100 mg per day, was administrated intramasculary daily and continued until the result of a positive or negative pregnancy test was available. In the case of a positive pregnancy test, treatment was continued until fetal heart beats were seen on ultrasound. Statistical analysis of the results was performed using Student's t test when comparing cycle parameters and Fisher's exact test when comparing pregnancy rates. P values of 0.05 or less were regarded as statistically significant. Data are presented throughout as mean + standard error of the mean (+SE).
RESULTS In comparison to previous treatment cycles both long and short GNRHa protocols gave improved results (Table I). The G N R H a treatment cycles gave statistically significant fewer cancellations, more oocytes, higher fertilization rates, and more embryos per patient (Table 1). Only the long G N R H a treatment group had significantly more pregnancies per cycle as compared with previous cycles (Table I). The long G N R H a treatment protocol gave significantly better results compared to the short GNRHa treatment protocol (Table I). The improvement was in fewer cancellations, more oocytes per cycle, more embryos per patient, and higher pregnancy rates (29 vs 8%) (Table I). Both long and short G N R H a treatment protocols gave significant suppression of the h y p o t h a l a m i c pitutary-ovarian (HPO) axis (Table II). Mean follicular-phase serum L H and progesterone were significantly lower in women undergoing ovulation induction with the long G N R H a protocol (Table II). Patients receiving long G N R H a treatment required
Journal o f in Vitro Fertilization and Embryo Transfer, Vol. 8, No. 6, 1991
SHORT VS LONG BUSERELIN TREATMENT OF INADEQUATE RESPONDERS
341
Table I. Results of R a n d o m i z e d L o n g or Short G N R H a T r e a t m e n t in 54 Patients with a Previous I n a d e q u a t e R e s p o n s e
Patients (cycles) Cancellations OPU No. o f oocytes b Fertilization rate E m b r y o s per patient b Pregnancies per cycle Pregnancies p e r O P U
Previous inadequate responders
Group I, long treatment
Group II, short treatment
54 38 (70%)* 16 2.8 --_ 1.7" 58%* 1.2 -+ 0.2* 1 (2%)** 1 (6%)
28 2 (7%) 26 7.0 - 0.6 81% 5.3 -+ 0.5 8 (29%)** 8 (36%)
26 10 (38%) 16 5.6 - 1 77% 4.0 - 0.8 2 (8%) 2 (12.5%)
Significance a
A Randomized Prospective Study on the Effect of Short and Long Buserelin Treatment in Women with Repeated Unsuccessful in Vitro Fertilization (IVF) Cycles Due to Inadequate Ovarian Response MARTHA DIRNFELD, 1,2 YAEL GONEN,1 ARIE LISSAK,1 SHLOMIT GOLDMAN,1 MARA KOIFMAN, 1 YORAM SOROKIN, 1 and HAIM ABRAMOVICI 1
Submitted: June 2, 1991 Accepted: August 4, 1991
INTRODUCTION The recognition that multiple embryo replacement is associated with an increased success rate in in vitro fertilization (IVF) treatment has led to several methods of ovarian stimulation, in order to obtain multiple fertilizable oocytes (1,2). With any regimen, a wide range of ovarian response can be expected and up to 35% of stimulated cycles may result in inadaquate response leading to cycle cancellation (3,4). Inadequate responders are difficult to manage since their poor response tends to be repetitive from cycle to cycle (5). An impaired response to ovarian stimulation by gondadotropins is often associated with premature luteinizing hormone (LH) surge and/or progesterone rise during the follicular phase (6). These hormonal derangements have detrimental effects on follicular maturation and functional viability of the oocyte, which lead to asynchrony between ovarian function and endometrial maturation (7). The results of several studies using gonadotropin releasing hormone agonist (GNRHa) and gonadotropins for ovulation induction in "normal" and poor responders are conflicting (812). The purpose of this prospective randomized study was to compare two modes of G N R H a treatment in a group of patients with previous inadaquate ovarian response undergoing gonadotropin induction of ovulation for IVF treatment.
Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I--long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group H (P < 0.01). Cancellation rate was significantly lower in Group I than in Group H (P < 0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos transferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response. KEY WORDS: poor responders; gonadotropin releasing hormone analogue; in vitro fertilization; ovulation induction.
1 Department of Obstetrics and Gynecology, Carmel Hospital Haifa, Israel. 2 To whom correspondence should be addressed at Department of Obstetrics and Gynecology, Carmel Hospital, 7 Michal Street, Haifa 34362, Israel.
MATERIALS AND METHODS Fifty-four women with long-standing infertility were included to participate in this study. Each pa339
0740-7769/91/1200-0339506.50/0 9 1991PlenumPublishingCorporation
DIRNFELD ET AL.
340
tient enrolled to the study had had at least one unsuccessful attempt of ovarian stimulation and oocyte pickup (OPU) cancellation, due to inadequate response. The mean age of the patients in this study was 33.5 years (range, 26-40 years). Thirty patients underwent two or more failed IVF cycles. Of 54 previous cycles stimulated with human menopausal gonadotropin (hMG), 70% were canceled, and in only 16 cycles was an OPU performed. None of them achieved a viable pregnancy. Early follicular-phase prolactin, follicle stimulating hormone (FSH), LH, testosterone, and thyroid function were within normal limits in all patients. Inadequate response was defined as (1) maximum rise of 17B-estradiol (Ez) below 300 pg/ml despite a high hMG dose; (2) early L H rise (above 180% of the mean) when the largest follicular diameter was below 16 mm and/or a rise in progesterone (P) concentration above 1.2 mg/ml during the follicular phase; or (3) combination of the above. Patients were randomly assigned to two groups using a table of random numbers. Group I (28 patients) received "long" treatment with daily Buserelin nasal spray (Buserelin-Superfact, Hoechst A.G, FRG), 1000 txg/day commencing 15-30 days prior to induction of ovulation, continuing with 600 p,g/day up to the human chorionic gonadotropin (hCG) administration day. hMG (Pergonal, Teva Laboratories, Kfar Sava, Israel), 2-3 ampoules (150--225 IU) per day, was started when serum 17Bestradiol was below 40 pg/ml. Group II (26 patients) received"short" treatment with Buserelin nasal spray, 600 p~g/day, starting on the first day of the menstrual cycle and continuing through the follicular phase until the evening of hCG (Chorigon, Teva, Israel) administration. Ovarian stimulation was started using hMG, 2-3 ampoules (150-225 IU) per day, from the third day of the menstrual cycle. Follicular maturation was monitored with daily s e r u m E2, P, and (LH) measurements and by daily ultrasound examinations. Hormonal assays were performed with commercialy available radioimmunoassay (RIA) kits. Serum E 2 and P were measured with a Coat a Count RIA kit (DPC Co, Los Angeles, CA). Serum L H was measured using a Maia Clone kit (Serono Diagnostics, Dover, Herzlia, Israel). Interassay variations were 12, 10, 7, and 9% for E2, progesterone, FSH, and LH, respectively. Ultrasonographic measurement of follicular di-
ameter was performed daily, starting on the seventh day of the menstrual cycle (Diasonics, 3.5 MHZ sector scan, USA). Ovulation was induced with 10,000 IU hCG when E 2 w a s above 300 pg/ml and ultrasound showed at least two follicles with a diameter of more than 17 ram. As mentioned above, Buserelin was stopped after hCG administration in all patients. OPU was performed 34-36 hr after hCG administration by laparoscopy or by ultrasonographically guided puncture. The methods for fertilization and embryo culture in vitro have already been described (13). Luteal support was given to all patients, starting on the day after OPU; progesterone in oil (Gestone, Paines and Byrne, Greenford, England), 100 mg per day, was administrated intramasculary daily and continued until the result of a positive or negative pregnancy test was available. In the case of a positive pregnancy test, treatment was continued until fetal heart beats were seen on ultrasound. Statistical analysis of the results was performed using Student's t test when comparing cycle parameters and Fisher's exact test when comparing pregnancy rates. P values of 0.05 or less were regarded as statistically significant. Data are presented throughout as mean + standard error of the mean (+SE).
RESULTS In comparison to previous treatment cycles both long and short GNRHa protocols gave improved results (Table I). The G N R H a treatment cycles gave statistically significant fewer cancellations, more oocytes, higher fertilization rates, and more embryos per patient (Table 1). Only the long G N R H a treatment group had significantly more pregnancies per cycle as compared with previous cycles (Table I). The long G N R H a treatment protocol gave significantly better results compared to the short GNRHa treatment protocol (Table I). The improvement was in fewer cancellations, more oocytes per cycle, more embryos per patient, and higher pregnancy rates (29 vs 8%) (Table I). Both long and short G N R H a treatment protocols gave significant suppression of the h y p o t h a l a m i c pitutary-ovarian (HPO) axis (Table II). Mean follicular-phase serum L H and progesterone were significantly lower in women undergoing ovulation induction with the long G N R H a protocol (Table II). Patients receiving long G N R H a treatment required
Journal o f in Vitro Fertilization and Embryo Transfer, Vol. 8, No. 6, 1991
SHORT VS LONG BUSERELIN TREATMENT OF INADEQUATE RESPONDERS
341
Table I. Results of R a n d o m i z e d L o n g or Short G N R H a T r e a t m e n t in 54 Patients with a Previous I n a d e q u a t e R e s p o n s e
Patients (cycles) Cancellations OPU No. o f oocytes b Fertilization rate E m b r y o s per patient b Pregnancies per cycle Pregnancies p e r O P U
Previous inadequate responders
Group I, long treatment
Group II, short treatment
54 38 (70%)* 16 2.8 --_ 1.7" 58%* 1.2 -+ 0.2* 1 (2%)** 1 (6%)
28 2 (7%) 26 7.0 - 0.6 81% 5.3 -+ 0.5 8 (29%)** 8 (36%)
26 10 (38%) 16 5.6 - 1 77% 4.0 - 0.8 2 (8%) 2 (12.5%)
Significance a
