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A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the “follicle-stimulating hormone window” combined with the gonadotropin-releasing hormone antagonist cetrorelix
FERTILITY AND STERILITY威 VOL. 73, NO. 5, MAY 2000 Copyright ©2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the “follicle-stimulating hormone window” combined with the gonadotropin-releasing hormone antagonist cetrorelix Diederick de Jong, M.D., Nicholas S. Macklon, M.D., Ph.D., and Bart C. J. M. Fauser, M.D., Ph.D. Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
Received August 8, 1999; revised and accepted December 8, 1999. Supported by the “Stichting Voortplantingsgeneeskunde Rotterdam,” Rotterdam, the Netherlands. Reprint requests: Bart C. J. M. Fauser, M.D., Ph.D., Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands (FAX: 31-10-4367306; E-mail: [email protected]). 0015-0282/00/$20.00 PII S0015-0282(00)00414-3
Objective: To study whether minimal interference in the process of selection of the single dominant follicle may serve as the basis for a simplified ovarian stimulation regimen for IVF. Design: Single-center randomized pilot study. Setting: Tertiary referral fertility center. Patient(s): Fifteen normo-ovulatory patients with a regular indication for IVF. Intervention(s): Ovarian stimulation for IVF was begun with 100 or 150 IU/d recombinant FSH starting on cycle day 5. From cycle day 8 or later, cotreatment was begun with 0.25 mg/d GnRH antagonist. No luteal support was provided. Main Outcome Measure(s): Total number of dominant follicles and characteristics of the endocrine cycle. Result(s): Multiple follicle development occurred in five of eight patients in the 100-IU group and in all seven women in the 150-IU group. Follicular phase and luteal phase lengths were normal, but the endocrine profile was abnormal. Conclusion(s): A fixed daily dose of 150 IU recombinant FSH starting in the midfollicular phase resulted in ongoing growth of a restricted number of dominant follicles and sufficient oocytes retrieved to lead to ET. A marked reduction in the total amount of gonadotropins administered compared with standard treatment was achieved. Withholding luteal support did not exclude pregnancies. (Fertil Steril威 2000;73:1051– 4. ©2000 by American Society for Reproductive Medicine.) Key Words: IVF, recombinant FSH, GnRH antagonist, minimal ovarian stimulation
The concept of the “FSH window” emphasizes the importance of the duration of elevated FSH rather than the actual concentration for follicle recruitment. The follicular phase decrease in serum FSH levels, which secures selection of a single dominant follicle in normo-ovulatory women, can be prevented by the administration of low-dose exogenous FSH in the middle to late follicular phase (1, 2). Such an intervention in normo-ovulatory women results in ongoing growth of multiple dominant follicles (3). The recent availability of GnRH antagonists (GnRH-a) for acute sup-
pression of a premature rise in LH enables this concept to be tested clinically in IVF. The use of GnRH-a allows normal, undisturbed initiation of the menstrual cycle for IVF. In this pilot study, we investigated whether multiple dominant follicle development can be induced by instituting low doses of exogenous FSH from the midfollicular phase onward and whether such a regimen (including GnRH-a administration) might result in pregnancies in the absence of subsequent exogenous luteal support. 1051
MATERIALS AND METHODS The study protocol was approved by the local ethics review committee. Written informed consent was obtained from all participants. A total of 15 normo-ovulatory women ⬍38 years of age who enrolled in our IVF program were included in this prospective randomized pilot study. Subjects were studied during a single IVF treatment cycle. Three patients who had an insufficient response (defined as ⬍3 follicles ⱖ15 mm) to ovarian stimulation were excluded from analysis. Data obtained from 40 regularly cycling women, as published previously (1), served as controls. Before ovarian stimulation, the subjects were randomly assigned (with sealed envelopes) to one of the two stimulation regimens. Patients received either 100 IU (group A) or 150 IU (group B) of recombinant FSH (rFSH, Puregon; N.V. Organon, Oss, the Netherlands) as a daily s.c. injection from cycle day 5 onward until the day hCG was administered. Participants in both groups were also treated with a GnRH-a (cetrorelix, Cetrotide; Asta Medica AG, Frankfurt, Germany) at 0.25 mg/d s.c. from cycle day 8 onward when ⱖ1 follicle of 13 mm was present. Otherwise, cetrorelix administration was postponed. When ⱖ1 follicle of ⱖ18 mm and three follicles of ⱖ15 mm were observed on transvaginal ultrasound (US), 10,000 IU of hCG (Pregnyl; N.V. Organon) was administered by i.m. injection to trigger the final stages of oocyte maturation. No luteal phase support was provided. Oocytes were collected 36 hours after hCG administration. A maximum of two embryos was transferred on days 3–5 after oocyte retrieval. Repeated blood withdrawal was done during the entire cycle. When no pregnancy occurred, the time of onset of the next menstruation was documented. Viable pregnancy was defined as positive fetal heart activity observed by transvaginal US 5– 6 weeks after ET. Blood samples were centrifuged within 2 hours after withdrawal and stored at ⫺20°C until assayed. LH and FSH levels were measured by immunoradiometric assay; P and E2 levels were assessed by RIA. Intraassay and interassay coefficients of variation were ⬍3% and 8% for FSH, ⬍5% and 15% for LH, ⬍16% and 17% for P, and ⬍15% and 18% for E2, respectively. All samples from one subject were run in the same assay. Potential differences between groups in patients’ age, total amount of FSH administered, number of follicles on the day of hCG, number of oocytes retrieved, and number of embryos obtained were analyzed using the Mann-Whitney U test, as were differences in LH, FSH, E2, and P. Potential differences in cancellation rate and pregnancy rate were analyzed using Fisher’s exact test. Differences were considered statistically significant at P⬍.05.
RESULTS Patient characteristics, endocrine assessments, and treatment outcomes of patients during the intervention cycle are 1052 de Jong et al.
Communications-in-brief
shown in Table 1. Three patients in the 100-IU group exhibiting ⬍3 follicles of ⱖ15 mm were excluded from data analysis. Oocytes were retrieved from all remaining patients (n ⫽ 12). No embryos were obtained in three subjects. Three patients achieved a viable pregnancy. The total amount of rFSH administered in the 100-IU group was significantly less than that in the 150-IU group (700 vs. 1,200 IU; P⬍.005). No statistically significant difference was found in LH and FSH concentrations between the low-dose and high-dose group (data not shown). In both groups, serum LH concentrations fell to low levels during GnRH-a exposure compared with controls (⬍2 IU/L), whereas serum FSH concentrations remained steady (⫾6 IU/L) during the follicular phase. Treated subjects of both groups combined showed elevated FSH and suppressed LH levels 1 day before hCG compared with the natural cycle (6.5 and 1.9 vs. 3.8 and 4.8 IU/L, respectively; P⬍.0001). There were no statistically significant differences in follicle growth between the low-dose and high-dose groups. Significantly lower luteal phase LH and FSH concentrations were observed 5–7 days after hCG administration compared with the natural cycle (0.7 and 0.8 vs. 3.7 and 2.5 IU/L, respectively; P⬍.0001). No statistically significant difference was found in serum E2 and P concentrations between the low-dose and high-dose groups at any stage during this regimen. However, when compared with the control group, treated subjects of both groups combined showed elevated serum E2 levels on the day of hCG and 5–7 days after hCG (2,959 and 1,641 vs. 847 and 449 pmol/L, respectively; P⬍.0001) and elevated serum P levels 5–7 days after hCG (180 vs. 44 nmol/L; P⬍.05). The median duration of the luteal phase (number of days between the day of hCG and onset of menstruation) among the patients who did not conceive was 12 days (range, 10 –20 days) for the treated patients compared with 12 days (range, 5–16 days) for the controls.
DISCUSSION The aim of the present study was to determine whether a minimal intervention during the middle to late follicular phase, designed to extend the duration of the “FSH window,” results in multiple dominant follicle development sufficient for IVF. Although the mean number of follicles of ⬎15 mm observed on the day of hCG administration seems smaller than that observed in the standard long GnRH-a protocols for IVF, a median of 6 –9 oocytes were retrieved and a mean of three embryos were generated. In three patients receiving 100 IU/d rFSH, cycles were canceled because of a low response, suggesting that the FSH threshold of remaining cohort follicles was not surpassed in these patients. In the remaining five subjects receiving 100 IU/d, ovarian response Vol. 73, No. 5, May 2000
TABLE 1 Patient characteristics, steroid and gonadotropin levels, and treatment outcome of 12 IVF patients during minimal ovarian stimulation and of normo-ovulatory controls. IVF patients Characteristic
100 IU rFSH/d
150 IU rFSH/d
No. of subjects undergoing ovum pickup Age (y) Follicular phase Duration (d) Total dose of rFSH (IU) FSH 1 day before hCG (IU/L) LH 1 day before hCG (IU/L) E2 on day of hCG (pmol/L) No. of follicles ⬎10 mm on day of hCG administration Clinical outcome No. of oocytes retrieved per person No. of embryos obtained per person No. of pregnancies Luteal phase Duration (d) E2 5–7 days after hCG (pmol/L) P 5–7 days after hCG (nmol/L) FSH 5–7 days after hCG (IU/L) LH 5–7 days after hCG (IU/L)
5 34 (25–37)
7 30 (27–37)
12 (12–14) 700 (700–900) 5.7 (2.7–6.6) 2.4 (0.6–3.0) 3,248 (1,257–4,773) 7 (5–11)
14 (12–16) 1,200 (900–1,500) 7.6 (5.7–11.1) 1.5 (1.2–2.6) 2,899 (1,378–8,476) 10 (3–19)
6 (3–10) 3 (2–8)‡ 2 (2/4)㛳 12 (11–14)# 1,822 (939–3,094)†† 221.1 (96.3–409.2)†† 0.4 (0.3–1.6)†† 0.7 (0.2–0.7)††
9 (1–19) 3 (1–13)§ 1 (1/5)¶ 13 (11–21)** 1,641 (898–3,400)†† 179.0 (65.8–340.0)†† 1.1 (0.5–2.2)†† 1.0 (0.1–2.7)††
Controls 40 28 (20–36) 15 (10–20) — 3.8 (1.8–6.3)* 4.8 (1.3–10.3)* 820 (370–1,525)† — — — — 12 (5–16) 449 (253–940) 43.7 (11.7–74.9) 2.5 (0.7–7.1) 3.7 (0.2–12.1)
Note: Values are median (range) unless otherwise indicated. * One day before the spontaneous LH surge. † At day of the spontaneous LH surge. ‡ No embryos obtained in one subject. § No embryos obtained in two subjects. 㛳 Two of four patients who underwent ET conceived. ¶ One of five patients who underwent ET conceived. # Duration of the luteal phase for all subjects who did not conceive, including one without ET (n ⫽ 3). ** Duration of the luteal phase for all subjects who did not conceive, including those without ET (n ⫽ 6). †† In patients who did not conceive. de Jong. Minimal ovarian stimulation. Fertil Steril 2000.
was similar to that in the 150-IU/d group. The total amount of rFSH administered in this study (700 –1,200 IU) is substantially less than the amount of exogenous FSH usually administered in conventional ovarian stimulation regimens for IVF (approximately 2,200 IU). E2 concentrations in the late follicular phase were lower than those in conventional ovarian stimulation regimens for IVF, but 3.5 times higher than those in the natural cycle, consistent with multiple dominant follicular development. During the luteal phase, E2 and P levels were supraphysiologic, whereas LH and FSH levels were extremely low. The GnRH-a was an unlikely causative factor for the observed luteal gonadotropin suppression because its cessation in the follicular phase leads to a rapid recovery of the pituitarygonadal axis (4). Other possibilities include ovarian hyperstimulation or profound negative feedback due to high luteal phase steroid levels. The duration of the luteal phase in the treated patients was comparable to that in the controls even though no luteal support was provided, which suggests that FERTILITY & STERILITY威
the use of GnRH-a during ovarian stimulation for IVF may not compromise subsequent corpus luteum function (4). Using the described minimal ovarian stimulation regimen, it was possible to obtain pregnancies despite withholding luteal support. However, the number of patients included in this pilot study is too small for meaningful conclusions regarding clinical outcome. This study suggests that simplification of ovarian stimulation for IVF is feasible. This alternative approach deserves further attention with the focus toward overall clinical outcome vs. patient discomfort, risks, and cost.
Acknowledgment: The authors thank Dr. Linda J. van der Veer from ASTA Medica B.V., Amsterdam, the Netherlands, for providing the GnRH antagonist cetrorelix (Cetrotide).
1053
References 1. van Santbrink EJ, Hop WC, van Dessel TJ, de Jong FH, Fauser BC. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil Steril 1995;64: 37– 43. 2. Fauser BC, Van Heusden AM. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev 1997;18: 71–106. 3. Schipper I, Hop WC, Fauser BC. The follicle-stimulating hormone
1054 de Jong et al.
Communications-in-brief
(FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development. J Clin Endocrinol Metab 1998;83:1292– 8. 4. Ditkoff EC, Cassidenti DL, Paulson RJ, Sauer MV, Paul WL, Rivier J, et al. The gonadotropin-releasing hormone antagonist (Nal-Glu) acutely blocks the luteinizing hormone surge but allows for resumption of folliculogenesis in normal women. Am J Obstet Gynecol 1991;165: 1811–7.
Vol. 73, No. 5, May 2000
A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the “follicle-stimulating hormone window” combined with the gonadotropin-releasing hormone antagonist cetrorelix Diederick de Jong, M.D., Nicholas S. Macklon, M.D., Ph.D., and Bart C. J. M. Fauser, M.D., Ph.D. Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
Received August 8, 1999; revised and accepted December 8, 1999. Supported by the “Stichting Voortplantingsgeneeskunde Rotterdam,” Rotterdam, the Netherlands. Reprint requests: Bart C. J. M. Fauser, M.D., Ph.D., Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands (FAX: 31-10-4367306; E-mail: [email protected]). 0015-0282/00/$20.00 PII S0015-0282(00)00414-3
Objective: To study whether minimal interference in the process of selection of the single dominant follicle may serve as the basis for a simplified ovarian stimulation regimen for IVF. Design: Single-center randomized pilot study. Setting: Tertiary referral fertility center. Patient(s): Fifteen normo-ovulatory patients with a regular indication for IVF. Intervention(s): Ovarian stimulation for IVF was begun with 100 or 150 IU/d recombinant FSH starting on cycle day 5. From cycle day 8 or later, cotreatment was begun with 0.25 mg/d GnRH antagonist. No luteal support was provided. Main Outcome Measure(s): Total number of dominant follicles and characteristics of the endocrine cycle. Result(s): Multiple follicle development occurred in five of eight patients in the 100-IU group and in all seven women in the 150-IU group. Follicular phase and luteal phase lengths were normal, but the endocrine profile was abnormal. Conclusion(s): A fixed daily dose of 150 IU recombinant FSH starting in the midfollicular phase resulted in ongoing growth of a restricted number of dominant follicles and sufficient oocytes retrieved to lead to ET. A marked reduction in the total amount of gonadotropins administered compared with standard treatment was achieved. Withholding luteal support did not exclude pregnancies. (Fertil Steril威 2000;73:1051– 4. ©2000 by American Society for Reproductive Medicine.) Key Words: IVF, recombinant FSH, GnRH antagonist, minimal ovarian stimulation
The concept of the “FSH window” emphasizes the importance of the duration of elevated FSH rather than the actual concentration for follicle recruitment. The follicular phase decrease in serum FSH levels, which secures selection of a single dominant follicle in normo-ovulatory women, can be prevented by the administration of low-dose exogenous FSH in the middle to late follicular phase (1, 2). Such an intervention in normo-ovulatory women results in ongoing growth of multiple dominant follicles (3). The recent availability of GnRH antagonists (GnRH-a) for acute sup-
pression of a premature rise in LH enables this concept to be tested clinically in IVF. The use of GnRH-a allows normal, undisturbed initiation of the menstrual cycle for IVF. In this pilot study, we investigated whether multiple dominant follicle development can be induced by instituting low doses of exogenous FSH from the midfollicular phase onward and whether such a regimen (including GnRH-a administration) might result in pregnancies in the absence of subsequent exogenous luteal support. 1051
MATERIALS AND METHODS The study protocol was approved by the local ethics review committee. Written informed consent was obtained from all participants. A total of 15 normo-ovulatory women ⬍38 years of age who enrolled in our IVF program were included in this prospective randomized pilot study. Subjects were studied during a single IVF treatment cycle. Three patients who had an insufficient response (defined as ⬍3 follicles ⱖ15 mm) to ovarian stimulation were excluded from analysis. Data obtained from 40 regularly cycling women, as published previously (1), served as controls. Before ovarian stimulation, the subjects were randomly assigned (with sealed envelopes) to one of the two stimulation regimens. Patients received either 100 IU (group A) or 150 IU (group B) of recombinant FSH (rFSH, Puregon; N.V. Organon, Oss, the Netherlands) as a daily s.c. injection from cycle day 5 onward until the day hCG was administered. Participants in both groups were also treated with a GnRH-a (cetrorelix, Cetrotide; Asta Medica AG, Frankfurt, Germany) at 0.25 mg/d s.c. from cycle day 8 onward when ⱖ1 follicle of 13 mm was present. Otherwise, cetrorelix administration was postponed. When ⱖ1 follicle of ⱖ18 mm and three follicles of ⱖ15 mm were observed on transvaginal ultrasound (US), 10,000 IU of hCG (Pregnyl; N.V. Organon) was administered by i.m. injection to trigger the final stages of oocyte maturation. No luteal phase support was provided. Oocytes were collected 36 hours after hCG administration. A maximum of two embryos was transferred on days 3–5 after oocyte retrieval. Repeated blood withdrawal was done during the entire cycle. When no pregnancy occurred, the time of onset of the next menstruation was documented. Viable pregnancy was defined as positive fetal heart activity observed by transvaginal US 5– 6 weeks after ET. Blood samples were centrifuged within 2 hours after withdrawal and stored at ⫺20°C until assayed. LH and FSH levels were measured by immunoradiometric assay; P and E2 levels were assessed by RIA. Intraassay and interassay coefficients of variation were ⬍3% and 8% for FSH, ⬍5% and 15% for LH, ⬍16% and 17% for P, and ⬍15% and 18% for E2, respectively. All samples from one subject were run in the same assay. Potential differences between groups in patients’ age, total amount of FSH administered, number of follicles on the day of hCG, number of oocytes retrieved, and number of embryos obtained were analyzed using the Mann-Whitney U test, as were differences in LH, FSH, E2, and P. Potential differences in cancellation rate and pregnancy rate were analyzed using Fisher’s exact test. Differences were considered statistically significant at P⬍.05.
RESULTS Patient characteristics, endocrine assessments, and treatment outcomes of patients during the intervention cycle are 1052 de Jong et al.
Communications-in-brief
shown in Table 1. Three patients in the 100-IU group exhibiting ⬍3 follicles of ⱖ15 mm were excluded from data analysis. Oocytes were retrieved from all remaining patients (n ⫽ 12). No embryos were obtained in three subjects. Three patients achieved a viable pregnancy. The total amount of rFSH administered in the 100-IU group was significantly less than that in the 150-IU group (700 vs. 1,200 IU; P⬍.005). No statistically significant difference was found in LH and FSH concentrations between the low-dose and high-dose group (data not shown). In both groups, serum LH concentrations fell to low levels during GnRH-a exposure compared with controls (⬍2 IU/L), whereas serum FSH concentrations remained steady (⫾6 IU/L) during the follicular phase. Treated subjects of both groups combined showed elevated FSH and suppressed LH levels 1 day before hCG compared with the natural cycle (6.5 and 1.9 vs. 3.8 and 4.8 IU/L, respectively; P⬍.0001). There were no statistically significant differences in follicle growth between the low-dose and high-dose groups. Significantly lower luteal phase LH and FSH concentrations were observed 5–7 days after hCG administration compared with the natural cycle (0.7 and 0.8 vs. 3.7 and 2.5 IU/L, respectively; P⬍.0001). No statistically significant difference was found in serum E2 and P concentrations between the low-dose and high-dose groups at any stage during this regimen. However, when compared with the control group, treated subjects of both groups combined showed elevated serum E2 levels on the day of hCG and 5–7 days after hCG (2,959 and 1,641 vs. 847 and 449 pmol/L, respectively; P⬍.0001) and elevated serum P levels 5–7 days after hCG (180 vs. 44 nmol/L; P⬍.05). The median duration of the luteal phase (number of days between the day of hCG and onset of menstruation) among the patients who did not conceive was 12 days (range, 10 –20 days) for the treated patients compared with 12 days (range, 5–16 days) for the controls.
DISCUSSION The aim of the present study was to determine whether a minimal intervention during the middle to late follicular phase, designed to extend the duration of the “FSH window,” results in multiple dominant follicle development sufficient for IVF. Although the mean number of follicles of ⬎15 mm observed on the day of hCG administration seems smaller than that observed in the standard long GnRH-a protocols for IVF, a median of 6 –9 oocytes were retrieved and a mean of three embryos were generated. In three patients receiving 100 IU/d rFSH, cycles were canceled because of a low response, suggesting that the FSH threshold of remaining cohort follicles was not surpassed in these patients. In the remaining five subjects receiving 100 IU/d, ovarian response Vol. 73, No. 5, May 2000
TABLE 1 Patient characteristics, steroid and gonadotropin levels, and treatment outcome of 12 IVF patients during minimal ovarian stimulation and of normo-ovulatory controls. IVF patients Characteristic
100 IU rFSH/d
150 IU rFSH/d
No. of subjects undergoing ovum pickup Age (y) Follicular phase Duration (d) Total dose of rFSH (IU) FSH 1 day before hCG (IU/L) LH 1 day before hCG (IU/L) E2 on day of hCG (pmol/L) No. of follicles ⬎10 mm on day of hCG administration Clinical outcome No. of oocytes retrieved per person No. of embryos obtained per person No. of pregnancies Luteal phase Duration (d) E2 5–7 days after hCG (pmol/L) P 5–7 days after hCG (nmol/L) FSH 5–7 days after hCG (IU/L) LH 5–7 days after hCG (IU/L)
5 34 (25–37)
7 30 (27–37)
12 (12–14) 700 (700–900) 5.7 (2.7–6.6) 2.4 (0.6–3.0) 3,248 (1,257–4,773) 7 (5–11)
14 (12–16) 1,200 (900–1,500) 7.6 (5.7–11.1) 1.5 (1.2–2.6) 2,899 (1,378–8,476) 10 (3–19)
6 (3–10) 3 (2–8)‡ 2 (2/4)㛳 12 (11–14)# 1,822 (939–3,094)†† 221.1 (96.3–409.2)†† 0.4 (0.3–1.6)†† 0.7 (0.2–0.7)††
9 (1–19) 3 (1–13)§ 1 (1/5)¶ 13 (11–21)** 1,641 (898–3,400)†† 179.0 (65.8–340.0)†† 1.1 (0.5–2.2)†† 1.0 (0.1–2.7)††
Controls 40 28 (20–36) 15 (10–20) — 3.8 (1.8–6.3)* 4.8 (1.3–10.3)* 820 (370–1,525)† — — — — 12 (5–16) 449 (253–940) 43.7 (11.7–74.9) 2.5 (0.7–7.1) 3.7 (0.2–12.1)
Note: Values are median (range) unless otherwise indicated. * One day before the spontaneous LH surge. † At day of the spontaneous LH surge. ‡ No embryos obtained in one subject. § No embryos obtained in two subjects. 㛳 Two of four patients who underwent ET conceived. ¶ One of five patients who underwent ET conceived. # Duration of the luteal phase for all subjects who did not conceive, including one without ET (n ⫽ 3). ** Duration of the luteal phase for all subjects who did not conceive, including those without ET (n ⫽ 6). †† In patients who did not conceive. de Jong. Minimal ovarian stimulation. Fertil Steril 2000.
was similar to that in the 150-IU/d group. The total amount of rFSH administered in this study (700 –1,200 IU) is substantially less than the amount of exogenous FSH usually administered in conventional ovarian stimulation regimens for IVF (approximately 2,200 IU). E2 concentrations in the late follicular phase were lower than those in conventional ovarian stimulation regimens for IVF, but 3.5 times higher than those in the natural cycle, consistent with multiple dominant follicular development. During the luteal phase, E2 and P levels were supraphysiologic, whereas LH and FSH levels were extremely low. The GnRH-a was an unlikely causative factor for the observed luteal gonadotropin suppression because its cessation in the follicular phase leads to a rapid recovery of the pituitarygonadal axis (4). Other possibilities include ovarian hyperstimulation or profound negative feedback due to high luteal phase steroid levels. The duration of the luteal phase in the treated patients was comparable to that in the controls even though no luteal support was provided, which suggests that FERTILITY & STERILITY威
the use of GnRH-a during ovarian stimulation for IVF may not compromise subsequent corpus luteum function (4). Using the described minimal ovarian stimulation regimen, it was possible to obtain pregnancies despite withholding luteal support. However, the number of patients included in this pilot study is too small for meaningful conclusions regarding clinical outcome. This study suggests that simplification of ovarian stimulation for IVF is feasible. This alternative approach deserves further attention with the focus toward overall clinical outcome vs. patient discomfort, risks, and cost.
Acknowledgment: The authors thank Dr. Linda J. van der Veer from ASTA Medica B.V., Amsterdam, the Netherlands, for providing the GnRH antagonist cetrorelix (Cetrotide).
1053
References 1. van Santbrink EJ, Hop WC, van Dessel TJ, de Jong FH, Fauser BC. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil Steril 1995;64: 37– 43. 2. Fauser BC, Van Heusden AM. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev 1997;18: 71–106. 3. Schipper I, Hop WC, Fauser BC. The follicle-stimulating hormone
1054 de Jong et al.
Communications-in-brief
(FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development. J Clin Endocrinol Metab 1998;83:1292– 8. 4. Ditkoff EC, Cassidenti DL, Paulson RJ, Sauer MV, Paul WL, Rivier J, et al. The gonadotropin-releasing hormone antagonist (Nal-Glu) acutely blocks the luteinizing hormone surge but allows for resumption of folliculogenesis in normal women. Am J Obstet Gynecol 1991;165: 1811–7.
Vol. 73, No. 5, May 2000