FERTILITY AND STERILITY
Vol. 56, No.5, November 1991
Printed on acid-free paper in U.S.A.
Copyright 0 1991 The American Fertility Society
Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin-releasing hormone antagonist, Nai-Giu, in controlled ovarian hyperstimulation* Rene Frydman, M.D.t:j: Cesar Cornel, M.D.t Dominique de Ziegler, M.D. t
Joelle Taieb, M.D.t Irving M. Spitz, M.D.§ Philippe Bouchard, M.D. II
Hopital Antoine Bectere, Clamart, Hopital Bicetre, Kremlin Bicetre, France, and Population Council, New York, New York
Objective: To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for preventing premature luteining hormone (LH) and progesterone (P) rise in controlled ovarian hyperstimulation using clomiphene citrate (CC) and human menopausal gonadotropin (hMG). Design: Participants in the study formed two groups. Both groups received CC-hMG and NalGlu. Group II differs from group I for receiving human chorionic gonadotropin (hCG) and blood samples for 10 days after the second Nal-Glu injection. Setting: Centre de Fecondation in Vitro, Hopital Antoine Beclere. Patients: Eleven women 25 to 34 years of age and having normal menstrual cycles using barrier method of contraception not attempting pregnancies participated in the study. Intervention: Daily blood samples, pelvic ultrasound, and CC-hMG/Nal-Glu/hCG administration. Main Outcome Measures: (1) Spontaneous LH surge and P rise, follicular growth, and plasma E 2 levels in cycles with CC-hMG/Nal-Glu administration and (2) luteal phase after hCG injection in subjects previously treated with CC-hMG/Nal-Glu. Results: Plasma E 2 level increased from 983 ± 80 pg/mL (mean ± SEM) on the day of the first Nal-Glu administration to 1,159 ± 102 and 1,610 ± 114 pg/mL (mean ± SEM) 24 and 48 hours later. In 10 women, LH and P remained low for at least 96 hours after the first Nal-Glu administration. In one subject, plasma LH was already elevated at the time of the first Nal-Glu injection. In women who received hCG, plasma E 2 and P reached a maximum of 1,258 ± 313 pg/mL and 50.3 ± 12.8 ng/mL (mean± SEM), respectively, on the 6th day of the luteal phase. Conclusion: Our results suggest that timely Nal-Glu injections can prevent LH and P rise for at least 96 hours, in spite of increasing levels of plasma E 2 • Moreover, Nal-Glu had no adverse effect on the kinetic of E 2 rise, the follicular growth, or on the post-hCG hormonal profile. Fertil Steril 56:923, 1991
Controlled ovarian hyperstimulation has been largely adopted for in vitro fertilization (IVF) because of the improved efficiency resulting from re-
-
Received November 7, 1990; revised and accepted June 24, 1991. * Presented in part at the 37th Annual Scientific Meeting, Society for Gynecologic Investigation, St. Louis, Missouri, March 21 to 24, 1990. t Service de Gynecologie-Obstetrique et Laboratoire de Biochimie, Hopital Antoine Beclere. :j: Reprint requests: Rene Frydman, M.D., Hopital Antoine Beclere, Maternite, 157 rue de laPorte de Trivaux, 92141 Clamart, France. Vol. 56, No.5, November 1991
trieving multiple oocytes at once. A common pitfall of controlled ovarian hyperstimulation using either a combination of clomiphene citrate (CC) and human menopausal gonadotropins (hMG) or hMG alone is the premature increases in plasma luteinizing hormone (LH) and progesterone (P) reported in up to 25% of the patients. 1 In the past few years, selective pituitary suppression using a long-acting
§ The Population Council. II Service d'Endocrinologie et des Maladies de la Reproduction Hopital Bicetre. Frydman et al.
GnRH antagonists in IVF
923
gonadotropin-releasing hormone agonist (GnRH-a) has gained general favor for selected patients, 2 or for all IVF candidates 3 •4 to prevent the unfavorable consequences of premature LH and P rise on IVF outcome. Pituitary desensitization with a GnRH -a increases, however, the need for hMG and augments the incidence of frank ovarian hyperstimulation. Recently, GnRH antagonists have become available for clinical use. 5•6 In a preliminary study, we have shown that administration of the GnRH antagonist (Ac-D2 NALl, 4C1D-Phe2,D3Pal3,Arg5,DGlu6 (AA), DAlalO) GnRH (Nal-Glu) during the follicular phase of the menstrual cycle resulted in delaying LH surge by 8 to 10 days but also interrupted the growth of the dominant ovarian follicle. 6 In the present study, we evaluated whether timely injections of this new antagonist analog of GnRH, Nal-Glu, deprived of the transitory stimulatory effect of GnRH -a, could be used to prevent LH and P rise when it is most worrisome, i.e., when plasma estradiol (E 2 ) exceeds LH triggering levels. This preliminary study also examined the effect of NalGlu on the maturation of ovarian follicles induced by exogenous hMG. MATERIALS AND METHODS
Eleven women 25 to 34 years of age were included in the study. All participants were normal cycling women using barrier method of contraception who volunteered for the study after being thoroughly informed and having signed appropriate consent forms. The study protocol had been reviewed and approved by the hospital ethic committee. All women received 100 mg of CC (Clomid; Merrell Dow, Neuilly-Sur-Seine, France) daily orally from cycle days 2 to 6. In addition, 150 IU of hMG (Humegon; Organon, St-Denis, France) were administered intramuscularly on days 4, 6, and 8. Starting on cycle day 9, the daily dose of hMG was determined in a standard fashion according to E 2 levels and ultrasound findings. Blood samples were obtained daily starting on cycle day 9. When serum E 2 exceeded 600 pg/mL, Nal-Glu (5 mg) was administered subcutaneously on the same day (P.M.). A second NalGlu injection was repeated 48 hours later. Starting on the morning after the first Nal-Glu injection, transvaginal pelvic US was performed daily, and blood samples were obtained twice a day. The administration of hMG was discontinued arbitrarily 48 hours after the second Nal-Glu injection. Six women continued daily blood sampling for 2 days after the discontinuation of hMG. The remaining 5 women received 5,000 IU of human chorionic go924
Frydman et al.
GnRH antagonists in IVF
nadotropin (hCG) (Gonadotrophine Chorionique "Endo"; Organon, St.-Denis, France) 48 hours after the second injection of Nal-Glu to study any possible impact of Nal-Glu on the luteal phase. In this latter group, blood samples were obtained 2, 4, 6, 8, and 10 days after hCG administration. Plasma E 2 and P were measured by radioimmunoassay as previously described. 1 Intra-assay and interassay coefficients ofvariation (CVs) were 4.8% and5.2%, respectively, for E 2 and 8.5% and 10.8% for P. Plasma LH was measured by an immunometric technique developed by Amersham Corporation (Amerline Laboratories, Paris, France). Results were expressed in miU/mL (First International Reference Preparation 68/40). Intra-assay and interassay CVs were 7% and 9.1 %, respectively. Results were expressed as means ± SEM. RESULTS
At the time of the first Nal-Glu injection, plasma LH was low (2.8 ± 0.4 miU /mL) P was
Vol. 56, No.5, November 1991
Printed on acid-free paper in U.S.A.
Copyright 0 1991 The American Fertility Society
Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin-releasing hormone antagonist, Nai-Giu, in controlled ovarian hyperstimulation* Rene Frydman, M.D.t:j: Cesar Cornel, M.D.t Dominique de Ziegler, M.D. t
Joelle Taieb, M.D.t Irving M. Spitz, M.D.§ Philippe Bouchard, M.D. II
Hopital Antoine Bectere, Clamart, Hopital Bicetre, Kremlin Bicetre, France, and Population Council, New York, New York
Objective: To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for preventing premature luteining hormone (LH) and progesterone (P) rise in controlled ovarian hyperstimulation using clomiphene citrate (CC) and human menopausal gonadotropin (hMG). Design: Participants in the study formed two groups. Both groups received CC-hMG and NalGlu. Group II differs from group I for receiving human chorionic gonadotropin (hCG) and blood samples for 10 days after the second Nal-Glu injection. Setting: Centre de Fecondation in Vitro, Hopital Antoine Beclere. Patients: Eleven women 25 to 34 years of age and having normal menstrual cycles using barrier method of contraception not attempting pregnancies participated in the study. Intervention: Daily blood samples, pelvic ultrasound, and CC-hMG/Nal-Glu/hCG administration. Main Outcome Measures: (1) Spontaneous LH surge and P rise, follicular growth, and plasma E 2 levels in cycles with CC-hMG/Nal-Glu administration and (2) luteal phase after hCG injection in subjects previously treated with CC-hMG/Nal-Glu. Results: Plasma E 2 level increased from 983 ± 80 pg/mL (mean ± SEM) on the day of the first Nal-Glu administration to 1,159 ± 102 and 1,610 ± 114 pg/mL (mean ± SEM) 24 and 48 hours later. In 10 women, LH and P remained low for at least 96 hours after the first Nal-Glu administration. In one subject, plasma LH was already elevated at the time of the first Nal-Glu injection. In women who received hCG, plasma E 2 and P reached a maximum of 1,258 ± 313 pg/mL and 50.3 ± 12.8 ng/mL (mean± SEM), respectively, on the 6th day of the luteal phase. Conclusion: Our results suggest that timely Nal-Glu injections can prevent LH and P rise for at least 96 hours, in spite of increasing levels of plasma E 2 • Moreover, Nal-Glu had no adverse effect on the kinetic of E 2 rise, the follicular growth, or on the post-hCG hormonal profile. Fertil Steril 56:923, 1991
Controlled ovarian hyperstimulation has been largely adopted for in vitro fertilization (IVF) because of the improved efficiency resulting from re-
-
Received November 7, 1990; revised and accepted June 24, 1991. * Presented in part at the 37th Annual Scientific Meeting, Society for Gynecologic Investigation, St. Louis, Missouri, March 21 to 24, 1990. t Service de Gynecologie-Obstetrique et Laboratoire de Biochimie, Hopital Antoine Beclere. :j: Reprint requests: Rene Frydman, M.D., Hopital Antoine Beclere, Maternite, 157 rue de laPorte de Trivaux, 92141 Clamart, France. Vol. 56, No.5, November 1991
trieving multiple oocytes at once. A common pitfall of controlled ovarian hyperstimulation using either a combination of clomiphene citrate (CC) and human menopausal gonadotropins (hMG) or hMG alone is the premature increases in plasma luteinizing hormone (LH) and progesterone (P) reported in up to 25% of the patients. 1 In the past few years, selective pituitary suppression using a long-acting
§ The Population Council. II Service d'Endocrinologie et des Maladies de la Reproduction Hopital Bicetre. Frydman et al.
GnRH antagonists in IVF
923
gonadotropin-releasing hormone agonist (GnRH-a) has gained general favor for selected patients, 2 or for all IVF candidates 3 •4 to prevent the unfavorable consequences of premature LH and P rise on IVF outcome. Pituitary desensitization with a GnRH -a increases, however, the need for hMG and augments the incidence of frank ovarian hyperstimulation. Recently, GnRH antagonists have become available for clinical use. 5•6 In a preliminary study, we have shown that administration of the GnRH antagonist (Ac-D2 NALl, 4C1D-Phe2,D3Pal3,Arg5,DGlu6 (AA), DAlalO) GnRH (Nal-Glu) during the follicular phase of the menstrual cycle resulted in delaying LH surge by 8 to 10 days but also interrupted the growth of the dominant ovarian follicle. 6 In the present study, we evaluated whether timely injections of this new antagonist analog of GnRH, Nal-Glu, deprived of the transitory stimulatory effect of GnRH -a, could be used to prevent LH and P rise when it is most worrisome, i.e., when plasma estradiol (E 2 ) exceeds LH triggering levels. This preliminary study also examined the effect of NalGlu on the maturation of ovarian follicles induced by exogenous hMG. MATERIALS AND METHODS
Eleven women 25 to 34 years of age were included in the study. All participants were normal cycling women using barrier method of contraception who volunteered for the study after being thoroughly informed and having signed appropriate consent forms. The study protocol had been reviewed and approved by the hospital ethic committee. All women received 100 mg of CC (Clomid; Merrell Dow, Neuilly-Sur-Seine, France) daily orally from cycle days 2 to 6. In addition, 150 IU of hMG (Humegon; Organon, St-Denis, France) were administered intramuscularly on days 4, 6, and 8. Starting on cycle day 9, the daily dose of hMG was determined in a standard fashion according to E 2 levels and ultrasound findings. Blood samples were obtained daily starting on cycle day 9. When serum E 2 exceeded 600 pg/mL, Nal-Glu (5 mg) was administered subcutaneously on the same day (P.M.). A second NalGlu injection was repeated 48 hours later. Starting on the morning after the first Nal-Glu injection, transvaginal pelvic US was performed daily, and blood samples were obtained twice a day. The administration of hMG was discontinued arbitrarily 48 hours after the second Nal-Glu injection. Six women continued daily blood sampling for 2 days after the discontinuation of hMG. The remaining 5 women received 5,000 IU of human chorionic go924
Frydman et al.
GnRH antagonists in IVF
nadotropin (hCG) (Gonadotrophine Chorionique "Endo"; Organon, St.-Denis, France) 48 hours after the second injection of Nal-Glu to study any possible impact of Nal-Glu on the luteal phase. In this latter group, blood samples were obtained 2, 4, 6, 8, and 10 days after hCG administration. Plasma E 2 and P were measured by radioimmunoassay as previously described. 1 Intra-assay and interassay coefficients ofvariation (CVs) were 4.8% and5.2%, respectively, for E 2 and 8.5% and 10.8% for P. Plasma LH was measured by an immunometric technique developed by Amersham Corporation (Amerline Laboratories, Paris, France). Results were expressed in miU/mL (First International Reference Preparation 68/40). Intra-assay and interassay CVs were 7% and 9.1 %, respectively. Results were expressed as means ± SEM. RESULTS
At the time of the first Nal-Glu injection, plasma LH was low (2.8 ± 0.4 miU /mL) P was
