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Triggering of ovulation by a gonadotropin-releasing hormone (GnRH) agonist in patients pretreated with a GnRH antagonist
Vol. 66, No.1, July 1996
FERTILITY AND STERILITY@ Copyright
©
Printed on acid-free paper in U. S. A.
1996 American Society for Reproductive Medicine
Triggering of ovulation by a gonadotropin-releasing hormone (GnRH) agonist in patients pretreated with a GnRH antagonist Fran,.:ois Olivennes, M.D. *t Renato Fanchin, M.D. * Philippe Bouchard, M.D.:j:
Joelle Taieb, M.D. Ph.D.§ Rene Frydman, M.D.*
Antoine Beciere Hospital, Clamart, and St Antoine Hospital, Paris, France
Objective: To determine if GnRH-agonist (GnRH-a) could induce a LH surge in patients where a GnRH antagonist was used to prevent premature spontaneous LH surge. Design: Pilot study. Patients: Five patients treated with ovarian stimulation and lUI for idiopathic infertility. Main Outcome Measures: Luteinizing hormone, FSH, and P plasma levels. Results: A LH and FSH surge as well as a P rise were obtained in the five patients studied. Conclusion: A GnRH-a successfully can induce an LH surge after GnRH antagonist administration. The effect of the antagonist on the quality ofthe GnRH-a-induced LH surge as well as the oocyte quality remain to be evaluated. Fertil Steril® 1996;66:151-3 Key Words: GnRH agonist, GnRH antagonist, triggering of ovulation
Human chorionic gonadotropin is used routinely to induce the final oocyte maturation and ovulation because of its LH-like properties, However, the longer half-life of hCG compared with LH leads to the development of multiple corpus luteum and a sustained luteotropic effect, which are thought to contribute to the pathogenesis of the ovarian hyperstimulation syndrome (OHSS) (1). Administration of GnRH agonists (GnRH-a) has been proposed to trigger ovulation using the initial "flare-up" effect, inducing an endogenous surge of LH and FSH, which may reduce the risk of OHSS (1). Triggering ovulation with GnRH-a is possible only if they have not been used to obtain desensitization, and GnRH -a now are used widely in controlled ovarian stimulation (COH) to suppress premature
Received October 2, 1995; revised and accepted February 22, 1996. * Department of Obstetrics and Gynecology, Antoine Beclere Hospital. t Reprint requests: Fran~ois Olivennes, M.D., Department of Obstetrics and Gynecology, Antoine Beclere Hospital, 157, Rue de la porte de Trivaux, 92140 Clamart, France (FAX: 33-1-46-3094-93). :j: Department of Endocrinology, St. Antoine Hospital. § Department of Biochemistry, A. Beclere Hospital.
Vol. 66, No.1, July 1996
LH surges and to program the IVF cycles. However, GnRH-a have many drawbacks: a longer period may be necessary for desensitization in the "long protocol"; patients often complain of side effects (hot flushes, dysfunctional bleeding, irritability, and vaginal dryness); and the dose ofhMG needed is higher, which could by itself lead to an increased risk of OHSS. Recently, new GnRH antagonists, which apparently are free of the major histamine release effects that plagued the previous compounds, have became available for clinical studies. These antagonists can suppress and prevent LH surges and could be an alternative to GnRH-a. Gonadotropin-releasing hormone antagonists therefore could be very interesting in COH and could be administered in simple protocols (2, 3). Another advantage of GnRH antagonists is the fact that native GnRH or GnRH-a theoretically could displace the antagonist from the GnRH receptors at the pituitary level. This possibility could be of interest in the case of high risk of OHSS, and GnRH-a could be given instead of hCG to trigger ovulation. In this pilot study, we administered, in five patients treated for infertility with COH and lUI, a new GnRH antagonist to prevent premature LH surge and a GnRH -a to trigger ovulation.
Olivennes et a1.
Communications-in-brief
151
Table 1 Luteinizing Hormone, FSH, and P values Before and in the Evening of the GnRH-a Administration Patients
-24h
-12h
GnRH-a
+12h
LH FSH P
0.2 10.9 0.2
1 12.05 0.3
1.2 8.9 0.1
35.8 24.0 5.2
5.9 0.35 13.6 10.5 5.4 3.8
23.6
LH FSH P
4.4 6.6 0.1
0.45 9.9 0.1
0.15 7.9 0.1
125.2 26.9 1.05
10.5 6.9 14.1 12.0 0.6 1.3
5.2
LH FSH P
1.1 8.9 0.3
2.7 9.2 0.6
3.85 7.6 0.5
57.0 16.1 2.8
6.8 8.5 2.6
LH FSH P
1.2 9.9 0.5
2.0 9.7 0.9
2.30 9.8 0.7
38.4 22.9 5.6
1.1 0.2 9.7 7.6 6.1 12.5
LH FSH P
0.05 8.8 0.3
0.45 10.4 0.5
0.15 7.5 0.1
25.5 19.9 5.4
+24h
+36h
+48h
1
2
3 3.9 5.6 3.35
5.5
4 23
An LH surge was observed in all five patients studied. Luteinizing hormone plasma levels increased from 1.3 ± 1.0 to 56.3 ± 40.0 mIU/mL (conversion factor to SI unit, 1.00) from the evening before to 12 hours after GnRH-a administration. A rise was observed in the plasma P levels, which went from 0.49 ± 0.29 ng/mL (conversion factor to SI unit, 3.180) before GnRH-a administration to 4.04 ± 2.02 and 17.27 ± 4.12 ng/mL, respectively, 48 and 72 hours after the GnRH-a injection. A concomitant FSH surge also was observed in the five patients. The plasma FSH level, measured 12 hours after the GnRH-a administration, was 21.9 ± 4.1 mIU/mL (conversion factor to SI unit, 1.00). DISCUSSION
5 4.2 10.4 5.3
0.6 6.0 7.0
10.2
MATERIALS AND METHODS
All patients included in this study were required to sign a statement of informed consent. The use of the GnRH antagonist was approved by the ethical committee of University Paris-Sud. Five patients with idiopathic infertility undergoing COH for lUI were included in the study. The COH protocol consisted of two ampules per day of hMG started on day 2 of the menstrual cycle. An injection of 3 mg Cetrorelix (ASTA MEDICA, Frankfurt, Germany) was administered systematically on day 8 of the stimulated cycle to prevent premature LH surges according to the protocol described in IVF patients (2, 3). The patients were monitored with serum E2 and LH, daily from day 7 until the day when the triggering of ovulation was decided based upon the optimal follicle and E2 profile. Estradiol, LH, FSH, and P levels then were assessed twice a day for 4 days. The triggering of ovulation was obtained by single SC administration of 0.1 mg of GnRH-a (Triptoreline; Ipsen Biotech, Paris, France). The luteal phase was supported with natural P (600 mg/d) , administered vaginally and started 4 days after the GnRH-a injection. RESULTS
The plasma level of E2 on the day of GnRH-a administration was 1,568 ± 997 pg/mL (5,756 ± 3,660 pmollmL; mean ± SD). The hormonal profile of plasmatic LH and P in the five patients studied is presented in Table 1.
152
Olivennes et al.
Communications-in-brief
Significant LH and FSH surges as well as an increase in P levels were obtained after administration of the GnRH-a in the five patients pretreated with GnRH antagonist. The triggering of ovulation with GnRH -a is not common practice in IVF, because the majority of IVF cycles already involve GnRH-a as part of the stimulation protocol to obtain desensitization. The important role of GnRH in the onset of the LH surge has been demonstrated (4), and the use of GnRH-a offers a more physiological approach to triggering ovulation (1). The longer half-life, higher affinity, and longer interaction of hCG with the ovarian receptor sites could account for the luteinization of multiple follicles obtained in COH. The triggering of ovulation with GnRH-a has been credited with different advantages (1): [1] more physiological final maturation of the follicles with the simultaneous surge of LH and FSH; [2] reduction in the incidence ofluteinized unruptured follicle syndrome; [3] reduction in the incidence of OHSS, and [4] suppression of interference between the injected hCG and the pregnancy test (1). These advantages, however, remain to be confirmed by large randomized studies with special focus on the luteal phase modifications observed after administration of GnRH-a in the periovulatory period. Further studies must be done to prove that in this protocol, mature oocytes can be obtained through IVF and that the GnRH antagonist have not had a deleterious effect on the amplitude or duration ofthe GnRH-a-induced LH surge and therefore on oocyte maturity. The potential deleterious effects of this regimen on the functionnal integrity of the corpus luteum must also be studied and especially the possible lack of LH in the luteal phase, which therefore could require P and E2 replacement. Prevention of premature LH surge with GnRH an-
Fertility and Sterility®
tagonist could offer the possibility to use different options to induce the final oocyte maturation and ovulation (GnRH-a, native GnRH, and soon recombinant LH). These different compounds then could be studied to see their effects on IVF results. REFERENCES 1. Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil SterilI991;56:21320.
Vol. 66, No.1, July 1996
2. Olivennes F, Fanchin R, Bouchard P, de Ziegler D, Taieb J, Selva J, et al. The single or dual administration of the gonadotropin-releasing hormone antagonist Cetrorelix in an in vitro fertilization-embryo transfer program. Fertil Steril 1994; 62:468-76. 3. Olivennes F, Fanchin R, Bouchard Ph, Taleb J, Selva J, Frydman R. Scheduled administration of a GnRH antagonist (Cetrorelix) on day 8 of in vitro fertilization cycles: a pilot study. Hum Reprod 1995; 10:1382-6. 4. Leroy I, d'Acremont MF, Brailly-Tabard S, Frydman R, de Mouzon J, Bouchard P. A single injection of a gonadotropinreleasing hormone (GnRH) antagonist (Cetrorelix) postpones the luteinizing hormone (LH) surge: further evidence for the role of GnRH during the LH surge. Fertil Steril 1995; 62:461-7.
Olivennes et al.
Communications· in-brief
153
FERTILITY AND STERILITY@ Copyright
©
Printed on acid-free paper in U. S. A.
1996 American Society for Reproductive Medicine
Triggering of ovulation by a gonadotropin-releasing hormone (GnRH) agonist in patients pretreated with a GnRH antagonist Fran,.:ois Olivennes, M.D. *t Renato Fanchin, M.D. * Philippe Bouchard, M.D.:j:
Joelle Taieb, M.D. Ph.D.§ Rene Frydman, M.D.*
Antoine Beciere Hospital, Clamart, and St Antoine Hospital, Paris, France
Objective: To determine if GnRH-agonist (GnRH-a) could induce a LH surge in patients where a GnRH antagonist was used to prevent premature spontaneous LH surge. Design: Pilot study. Patients: Five patients treated with ovarian stimulation and lUI for idiopathic infertility. Main Outcome Measures: Luteinizing hormone, FSH, and P plasma levels. Results: A LH and FSH surge as well as a P rise were obtained in the five patients studied. Conclusion: A GnRH-a successfully can induce an LH surge after GnRH antagonist administration. The effect of the antagonist on the quality ofthe GnRH-a-induced LH surge as well as the oocyte quality remain to be evaluated. Fertil Steril® 1996;66:151-3 Key Words: GnRH agonist, GnRH antagonist, triggering of ovulation
Human chorionic gonadotropin is used routinely to induce the final oocyte maturation and ovulation because of its LH-like properties, However, the longer half-life of hCG compared with LH leads to the development of multiple corpus luteum and a sustained luteotropic effect, which are thought to contribute to the pathogenesis of the ovarian hyperstimulation syndrome (OHSS) (1). Administration of GnRH agonists (GnRH-a) has been proposed to trigger ovulation using the initial "flare-up" effect, inducing an endogenous surge of LH and FSH, which may reduce the risk of OHSS (1). Triggering ovulation with GnRH-a is possible only if they have not been used to obtain desensitization, and GnRH -a now are used widely in controlled ovarian stimulation (COH) to suppress premature
Received October 2, 1995; revised and accepted February 22, 1996. * Department of Obstetrics and Gynecology, Antoine Beclere Hospital. t Reprint requests: Fran~ois Olivennes, M.D., Department of Obstetrics and Gynecology, Antoine Beclere Hospital, 157, Rue de la porte de Trivaux, 92140 Clamart, France (FAX: 33-1-46-3094-93). :j: Department of Endocrinology, St. Antoine Hospital. § Department of Biochemistry, A. Beclere Hospital.
Vol. 66, No.1, July 1996
LH surges and to program the IVF cycles. However, GnRH-a have many drawbacks: a longer period may be necessary for desensitization in the "long protocol"; patients often complain of side effects (hot flushes, dysfunctional bleeding, irritability, and vaginal dryness); and the dose ofhMG needed is higher, which could by itself lead to an increased risk of OHSS. Recently, new GnRH antagonists, which apparently are free of the major histamine release effects that plagued the previous compounds, have became available for clinical studies. These antagonists can suppress and prevent LH surges and could be an alternative to GnRH-a. Gonadotropin-releasing hormone antagonists therefore could be very interesting in COH and could be administered in simple protocols (2, 3). Another advantage of GnRH antagonists is the fact that native GnRH or GnRH-a theoretically could displace the antagonist from the GnRH receptors at the pituitary level. This possibility could be of interest in the case of high risk of OHSS, and GnRH-a could be given instead of hCG to trigger ovulation. In this pilot study, we administered, in five patients treated for infertility with COH and lUI, a new GnRH antagonist to prevent premature LH surge and a GnRH -a to trigger ovulation.
Olivennes et a1.
Communications-in-brief
151
Table 1 Luteinizing Hormone, FSH, and P values Before and in the Evening of the GnRH-a Administration Patients
-24h
-12h
GnRH-a
+12h
LH FSH P
0.2 10.9 0.2
1 12.05 0.3
1.2 8.9 0.1
35.8 24.0 5.2
5.9 0.35 13.6 10.5 5.4 3.8
23.6
LH FSH P
4.4 6.6 0.1
0.45 9.9 0.1
0.15 7.9 0.1
125.2 26.9 1.05
10.5 6.9 14.1 12.0 0.6 1.3
5.2
LH FSH P
1.1 8.9 0.3
2.7 9.2 0.6
3.85 7.6 0.5
57.0 16.1 2.8
6.8 8.5 2.6
LH FSH P
1.2 9.9 0.5
2.0 9.7 0.9
2.30 9.8 0.7
38.4 22.9 5.6
1.1 0.2 9.7 7.6 6.1 12.5
LH FSH P
0.05 8.8 0.3
0.45 10.4 0.5
0.15 7.5 0.1
25.5 19.9 5.4
+24h
+36h
+48h
1
2
3 3.9 5.6 3.35
5.5
4 23
An LH surge was observed in all five patients studied. Luteinizing hormone plasma levels increased from 1.3 ± 1.0 to 56.3 ± 40.0 mIU/mL (conversion factor to SI unit, 1.00) from the evening before to 12 hours after GnRH-a administration. A rise was observed in the plasma P levels, which went from 0.49 ± 0.29 ng/mL (conversion factor to SI unit, 3.180) before GnRH-a administration to 4.04 ± 2.02 and 17.27 ± 4.12 ng/mL, respectively, 48 and 72 hours after the GnRH-a injection. A concomitant FSH surge also was observed in the five patients. The plasma FSH level, measured 12 hours after the GnRH-a administration, was 21.9 ± 4.1 mIU/mL (conversion factor to SI unit, 1.00). DISCUSSION
5 4.2 10.4 5.3
0.6 6.0 7.0
10.2
MATERIALS AND METHODS
All patients included in this study were required to sign a statement of informed consent. The use of the GnRH antagonist was approved by the ethical committee of University Paris-Sud. Five patients with idiopathic infertility undergoing COH for lUI were included in the study. The COH protocol consisted of two ampules per day of hMG started on day 2 of the menstrual cycle. An injection of 3 mg Cetrorelix (ASTA MEDICA, Frankfurt, Germany) was administered systematically on day 8 of the stimulated cycle to prevent premature LH surges according to the protocol described in IVF patients (2, 3). The patients were monitored with serum E2 and LH, daily from day 7 until the day when the triggering of ovulation was decided based upon the optimal follicle and E2 profile. Estradiol, LH, FSH, and P levels then were assessed twice a day for 4 days. The triggering of ovulation was obtained by single SC administration of 0.1 mg of GnRH-a (Triptoreline; Ipsen Biotech, Paris, France). The luteal phase was supported with natural P (600 mg/d) , administered vaginally and started 4 days after the GnRH-a injection. RESULTS
The plasma level of E2 on the day of GnRH-a administration was 1,568 ± 997 pg/mL (5,756 ± 3,660 pmollmL; mean ± SD). The hormonal profile of plasmatic LH and P in the five patients studied is presented in Table 1.
152
Olivennes et al.
Communications-in-brief
Significant LH and FSH surges as well as an increase in P levels were obtained after administration of the GnRH-a in the five patients pretreated with GnRH antagonist. The triggering of ovulation with GnRH -a is not common practice in IVF, because the majority of IVF cycles already involve GnRH-a as part of the stimulation protocol to obtain desensitization. The important role of GnRH in the onset of the LH surge has been demonstrated (4), and the use of GnRH-a offers a more physiological approach to triggering ovulation (1). The longer half-life, higher affinity, and longer interaction of hCG with the ovarian receptor sites could account for the luteinization of multiple follicles obtained in COH. The triggering of ovulation with GnRH-a has been credited with different advantages (1): [1] more physiological final maturation of the follicles with the simultaneous surge of LH and FSH; [2] reduction in the incidence ofluteinized unruptured follicle syndrome; [3] reduction in the incidence of OHSS, and [4] suppression of interference between the injected hCG and the pregnancy test (1). These advantages, however, remain to be confirmed by large randomized studies with special focus on the luteal phase modifications observed after administration of GnRH-a in the periovulatory period. Further studies must be done to prove that in this protocol, mature oocytes can be obtained through IVF and that the GnRH antagonist have not had a deleterious effect on the amplitude or duration ofthe GnRH-a-induced LH surge and therefore on oocyte maturity. The potential deleterious effects of this regimen on the functionnal integrity of the corpus luteum must also be studied and especially the possible lack of LH in the luteal phase, which therefore could require P and E2 replacement. Prevention of premature LH surge with GnRH an-
Fertility and Sterility®
tagonist could offer the possibility to use different options to induce the final oocyte maturation and ovulation (GnRH-a, native GnRH, and soon recombinant LH). These different compounds then could be studied to see their effects on IVF results. REFERENCES 1. Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil SterilI991;56:21320.
Vol. 66, No.1, July 1996
2. Olivennes F, Fanchin R, Bouchard P, de Ziegler D, Taieb J, Selva J, et al. The single or dual administration of the gonadotropin-releasing hormone antagonist Cetrorelix in an in vitro fertilization-embryo transfer program. Fertil Steril 1994; 62:468-76. 3. Olivennes F, Fanchin R, Bouchard Ph, Taleb J, Selva J, Frydman R. Scheduled administration of a GnRH antagonist (Cetrorelix) on day 8 of in vitro fertilization cycles: a pilot study. Hum Reprod 1995; 10:1382-6. 4. Leroy I, d'Acremont MF, Brailly-Tabard S, Frydman R, de Mouzon J, Bouchard P. A single injection of a gonadotropinreleasing hormone (GnRH) antagonist (Cetrorelix) postpones the luteinizing hormone (LH) surge: further evidence for the role of GnRH during the LH surge. Fertil Steril 1995; 62:461-7.
Olivennes et al.
Communications· in-brief
153