Premature luteinization during GnRH antagonists cycles in IVF adversely affects pregnancy and implantation rates

stimulation in ART cycles has been shown to correlate well with multiple measures of in vitro fertilization (IVF) outcome. It is widely believed that the number of AFs correlates with the primordial follicle reserve. However, little is known about intercycle variability in antral follicle (AF) counts in patients undergoing IVF. Additionally the effect of these differences upon stimulation quality has not been investigated. Design: Retrospective study; university ART clinic. Materials/Methods: Patients experiencing two or more IVF cycles within a one-year interval between 2000 –2002 were included if AF counts were obtained during the pre-stimulation ultrasound. (In a separate group of normal women (n ⫽ 20) we found no significant change in AF count before and after treatment with a GnRH agonist.) Forty-seven patients (age 23– 45) having undergone a total of 101 IVF cycles were identified. To evaluate intercycle variability, means and percent change from the mean in AF counts were calculated and compared. Mean AF counts were also compared to means of parameters of IVF stimulation quality, including oocytes recovered, peak estradiol, length of stimulation, and gonadotropin dose. Comparisons of IVF stimulation quality were made between the low and high AF count cycle through a paired analysis. Comparisons were also made between the low and high AF count cycles and simulation quality in individuals with greater intercycle AF count variability (⬎50% change from the mean), and between individuals with greater vs. lesser intercycle variability. Statistical analysis included Wilcoxon signed-rank, Mann-Whitney (rank-sum) tests, and Spearman Correlation Coefficients. Results: AF count was positively correlated with the number of oocytes retrieved (r ⫽ 0.71, p ⫽ ⬍0.0001), peak estradiol (r ⫽ 0.50, p ⫽ 0.0007), and negatively correlated with gonadotropin dose (r ⫽ ⫺0.66, p ⫽ ⬍0.0001). Intercycle variability in AF number was greater at lower AF counts (r ⫽ ⫺0.31, p ⫽ 0.036), but was not correlated with age (p ⫽ NS). Paired analysis of stimulation quality between the low and high AF count cycle for each patient did not show a difference in oocytes retrieved, peak estradiol, gonadotropin dose, or biochemical and clinical pregnancy rates (p ⫽ NS). Stimulation quality was greater in individuals with lesser intercycle variability (p ⫽ 0.0036); however, no difference was detected in comparison of the lower to higher AF count cycle in individuals with greater intercycle variability. Conclusions: There is moderate intercycle variability in AF number, and this variability is greater in individuals with lower AF counts. Although AF count was well correlated with multiple parameters of IVF outcome; within an individual patient, higher AF count in a given cycle was not predictive of better stimulation quality compared to a lower count cycle. Therefore, it does not appear to be prudent to attempt to select an optimal cycle for stimulation in a particular patient. Greater intercycle variability is associated with decreased ovarian reserve. Supported by: The Division of Reproductive Endocrinology and Infertility, University of Washington.

Monday, October 14, 2002 3:45 P.M. O-54 Maternal balanced translocation is a risk factor for poor response to ovarian stimulation. Serena H. Chen, Tomas Escudero, Natalie A. Cekleniak, David B. Sable, Margaret G. Garrisi, Santiago Munne. Saint Barnabas Institute for Reproductive Medicine and Science (IRMS), Livingston, NJ. Objective: To determine if maternal balanced translocation is a risk factor for poor ovarian response to controlled ovarian hyperstimulation. Design: A retrospective analysis of ovarian response to gonadotropin stimulation in patients undergoing in vitro fertilization (icsi and non-icsi) and preimplantation genetic diagnosis (IVF/PGD) at a single center. Materials/Methods: All cycles for couples with a balanced autosomal translocation in either partner performed at Saint Barnabas IRMS from 1995 through 2001 were analyzed: a total of 98 cycles in 76 women were completed. Stimulation and embryology outcomes were compared between two groups: 59 cycles in 44 women with balanced translocations (female carrier) compared to 39 cycles in 32 women whose male partner had a balanced translocation (male carrier). Average female age, female smoking history, day 3 FSH, day 3 estradiol levels, and pregnancy rates were similar in both groups. Statistical analysis was performed comparing stimulation protocols, estradiol level on day of hCG, and other cycle parameters.

FERTILITY & STERILITY威

Results: In couples undergoing IVF/PGD to avoid transmission of an unbalanced karyotype, a significantly higher proportion of women carrying balanced translocations (female carrier) responded very poorly (estradiol on the day of hCG less than 1000 pg/mL) to ovarian stimulation compared to women whose partner had a balanced translocation (male carrier) (0.220 vs 0.053, p ⬍0.02). These differences in response occurred despite the fact that there were a significantly higher proportion of patients in the female carrier group using aggressive stimulations, leading us to believe that the risk of poor ovarian response in this group may be underestimated by this data (0.356 vs 0.158, p ⬍0.039). Conclusions: In couples undergoing IVF/PGD for balanced translocation, the risk for poor response to ovarian stimulation is significantly increased when the female partner carries the balanced translocation compared to when the male partner carries the translocation. The reasons for this finding are unknown. In some male translocation patients, a higher incidence of germ cell death has been noted. A similar mechanism should be investigated in female translocation patients. Supported by: No sponsors or grants.

Monday, October 14, 2002 4:00 P.M. O-55 Premature luteinization during GnRH antagonists cycles in IVF adversely affects pregnancy and implantation rates. Ivan Valencia, Ernesto Bosch, Carlos Troncoso, Carlos Simon, Jose Remohi, Antonio Pellicer. Inst Valenciano de Infertilidad, Valencia, Spain; Inst Valenciano de Infertilidad and Dept of Pediatrics, Obstetrics and Gynecology, Valencia Univ Sch of Medicine, Valencia, Spain. Objective: The effect of premature luteinization has always been controversial in IVF cycles. A retrospective analysis of our data from antagonists cycles showed that a serum progesterone ⬎1.2 ng/ml was significantly associated with a worse outcome in terms of pregnancy and implantation rate. Therefore we wanted to clarify this conclusion in a prospective manner. Design: Prospective observational study. Materials/Methods: In October 2001 a prospective study was started comparing GnRH antagonists cycles in IVF. All patients had a serum estradiol, LH and progesterone determination on the day of hCG injection. Premature luteinization was defined as a progesterone level ⬎1.2 ng/ml. Cycles with and without premature luteinization were compared for age, serum estradiol, progesterone and LH level, number of oocytes retrieved and embryos transferred. Pregnancy was defined as the presence of a gestational sac with fetal hearbeat. Implantation rate was defined as the number of fetal heartbeats over the number of embryos transfered. Statistical analysis was done using the Fisher exact test, Mann-Whitney test, logistic regression analysis and ROC curve as appropriate. A p value ⬍0.05 was considered significant. Results: Fifty-two ART cycles were included. One embryo transfer was cancelled because of risk of OHSS and all zygotes were frozen. The incidence of premature luteinization, pregnancy and implantation rates are detailed in Table 1. Premature luteinization on hCG day ocurred in 24/52 cycles (46.2%). No difference was found in age, serum estradiol and LH level on hCG day, number of oocytes retrieved or in the number of embryos transferred between those cycles with and with-out premature luteinization group. A statistically significant difference was only found in the number of gestational sacs observed (0.28 vs 0.78 p ⫽ 0.0208). No LH surge (⬎10 U/L) was noted in any cycle on hCG day. Logistic regression analysis showed the progesterone level to be significantly correlated to cycle outcome ( ⫺1.417 p ⫽ 0.026). The progesterone level of 1.2 ng/ml area under the ROC curve was 0.721 with a 80% sensitivity, 55% specificity, 54% positive predictive value and a 80.4% negative predictive value assuming a 40% pregnancy rate in the no premature luteinization group. Conclusions: These preliminary data from this group of patients showed that premature luteinization during GnRH antagonists IVF cycles was a frequent event and adversely affected the pregnancy and implantation rate. Progesterone elevations were not related to serum LH levels and may reflect the mature granulosa cell response to exogenous FSH exposure. A progesterone level ⬎1.2 ng/ml is the best cut-off criteria for an adverse outcome. Probably GnRH antagonists cycles could benefit from additional routine progesterone monitoring.

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Table 1. Incidence of premature luteinization and cycle outcome during GnRH-antagonists IVF cycles. P level ng/ml 1.2

⬍1.2

p

rr (95% C.I.)

Cycles (%) 24 (46.2%) 28 (53.6%) Embryo Transfers 23 28 Pregnancies 5 15 Pregnancy rate per 21.7% 53.6% 0.024 0.405 transfer (%) (0.173 to 0.948) Implantation rate (%) 10.6% 30.1% 0.006 0.351 (0.160 to 0.769) Supported by: IVI Valencia

Monday, October 14, 2002 4:15 P.M. O-56 Elevated FSH⶿LH ratio in the presence of normal hormonal values predicts poor ovarian response in controlled ovarian hyperstimulation. Alon Shrim, Boaz Weizs, Salem Kiss, Jehoshua Dor. Tel Hashomer Medical Ctr, Hod-hasharon, Israel; Tel Hashomer Medical Ctr, Tel Aviv, Israel; Tel Hashomer Medical Ctr, Ramat Gan, Israel. Objective: To determine whether an elevated FSH/LH ratio in the presence of normal FSH and LH levels can predict ovarian response in patients undergoing IVF treatment. Design: A retrospective study. Materials/Methods: Study groups consisted of all patients who underwent IVF treatment during a three year period. Patients with basal day 3 FSH levels ⬎12 miu/ml were excluded. Patients were divided into three groups according to basal day 3 FSH/LH level: ratio ⫽ or ⬎2 (group 1), ratio ⫽ or ⬍0.5 (group 2), ratio 0.5–2 (group 3). For each group the following were recorded: age at treatment, basal day 3 FSH/LH levels, peak serum E2 level, pregnancy rate, number of IFV cycles and number of oocytes retrieved for each cycle. Results: 729 patients (with FSH ⬍12) underwent 1776 cycles during this period. In group 1, 144 patients underwent 352 cycles and achieved 74 pregnancies. In group 2, 60 patients underwent 144 cycles and achieved 49 pregnancies. In group 3, 518 patients underwent 1280 cycles and achieved 322 pregnancies. Mean age at treatment was 34, 33 and 34 years for group 1, 2 and 3 respectively (NS). Peak serum E2 level was significantly lower in group 1 (1321 pg/ml) versus groups 2 (1775 pg/ml) and 3 (1629 pg/ml). Number of oocytes retrieved was significantly lower in group 1 compared with groups 2 and 3 (median oocytes retrieved 8, 10,10 in groups 1, 2 and 3 respectively). Pregnancy rate per cycle (21%, 34% and 25% for groups 1,2 and 3 respectively) and pregnancy rate per patient (52%, 81% and 62% for groups 1, 2 and 3 respectively) were also significantly lower in group 1. Conclusions: Elevated FSH/LH ratio predicts a poor outcome in patients undergoing control ovarian hyperstimulation for IVF. FSH/LH ratio may increase before an increase in serum FSH is observed and thus can be used as a predictor for ovarian response in patients undergoing controlled ovarian hyperstimulation in IVF.

Monday, October 14, 2002 4:30 P.M. O-57 Is exogenous LH necessary when using GnRH antagonist in IVF ovarian hyperstimulation? Nicole Noyes, Karine Chung, Joseph Katz, Lewis Krey. New York Univ, New York, NY. Objective: To evaluate the role of exogenous LH in stimulated IVF cycles utilizing GnRH antagonists. Design: An association between LH and the triggering of human ovulation has been firmly established while any other role for LH in the mid- to late-follicular phase remains speculative. Oocyte release is controlled in the

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Abstracts

majority of IVF treatment cycles by suppression of the endogenous LH surge. This has traditionally been accomplished via pre-follicular downregulation by a GnRH-agonist. Late follicular LH inhibition has become possible with the newly available GnRH antagonists, which allow complete LH suppression. The concern in these patients is that there may be some detrimental effect if gonadotropins containing no LH are used for stimulation. We reviewed pregnancy and implantation outcomes of groups which were stimulated with LH-containing agents and compared them to those receiving FSH only. Materials/Methods: Retrospective analysis was performed of 153 IVF cycles between September 2000 and August 2001 that used a GnRH antagonist and achieved oocyte retrieval. Cycles were evaluated according to the particular gonadotropin utilized. Outcomes of cycles using pure recombinant FSH (Rec) were compared to cycles where LH-containing gonadotropin (HMG) was utilized: Rec-only (n⫽75), HMG– only (n⫽12), and Rec ⫹ HMG (n⫽66). At the time of the study, GnRH antagonist was “second-line” therapy in our program, used only in patients exhibiting diminished ovarian reserve. The GnRH antagonist was added to the stimulation regimen beginning on the day the lead follicle reached diameters of 12–14 mm on transvaginal ultrasound. Results: The mean number of days of GnRH antagonist administration was 3.4 and the mean day of drug initiation 8.1. The mean endometrial thickness on the day of hCG administration was 9.3 mm and the mean supplemented mid-luteal progesterone level was 71 ng/ml. The table compares outcome by gonadotropin utilized. Values are expressed as mean ⫾SEM. Pregnancy is defined as a fetal heart on ultrasound. Implantation rate describes fetal heart per embryo replaced. Pregnancy and implantation rates in Rec- cycles (28% and 13.9%, respectively) are similar to those in which HMG (33% and 17.8%) or Rec ⫹ HMG is utilized (21% and 12.5%). Outcome by gonadotropin utilized.

Ovarian Age stimulation group n RecHMG Rec ⫹ HMG

Mean age (yrs)

Mean day 3 FSH

2PN Oocyte embryo no. no.

Pregnancy per retrieval n (%)

14 (40%) 22/90 (24.4%) 7 (18%) 11/147 (7.5%) 3 (33%) 3/18 (16.7%) 1 (33%) 2/10 (20%) 10 (40%) 19/72 (26.4%)

⬍40 35 35.7 ⫾ 0.4 /⫽40 40 42.6 ⫾ 0.3 ⬍40 9 37.1 ⫾ 0.74 /⫽40 3 42.3 ⫾ 0.3 ⬍40 25 35.6 ⫾ 0.5

6.4 ⫾ 0.4 6.1 ⫾ 0.3 6.6 ⫾ 1 6.3 ⫾ 1.5 6.3 ⫾ 0.5

9⫾1 9⫾1 7⫾2 5⫾1 7⫾1

5⫾1 5⫾1 5⫾1 4⫾1 4⫾1

/⫽40 41 42.6 ⫾ 0.3

6.6 ⫾ 0.3 6 ⫾ 1

4⫾1

4 (9%)

Implantation rate per embryo repl. (%)

6/128 (4.7%)

Conclusions: GnRH antagonist cycles using recombinant FSH have similar outcomes to those cycles in which an LH-containing gonadotropin is utilized. Mid- to late-follicular LH does not appear necessary to achieve appropriate endometrial thickness, maintain supplemented luteal progesterone concentrations or result in pregnancy.

Monday, October 14, 2002 4:45 P.M. O-58 Plateau or drop in estradiol (E2) on the day after initiation of the GnRH antagonist Antagontm in in-vitro fertilization (IVF) treatment cycles does not affect pregnancy outcome. Daniel Shapiro, Melinda Carter, Dorothy Mitchell-Leef, David Wininger. Reproductive Biology Assoc, Atlanta, GA. Objective: To determine if pregnancy rates (PR) are affected by a drop or plateau in Estradiol (E2) on the day following Antagon™ start in in-vitro fertilization (IVF) cycles. Design: Retrospective analysis of 161 consecutive IVF cycles in which E2 values were available on the day after AntagonTM start. Materials/Methods: Women ranging in age from 23 to 41 underwent 161 IVF cycles for a variety of indications. Treatment was started on cycle day 2 with recombinant FSH (Follistim威, Organon Inc., West Orange, NJ or Gonal-F威, Serono Inc., Norwell, MA) 225– 600iu/day. Antagon was started on the morning of stimulation day 6 or 7 when the lead follicle reached 1.2 cm or the E2 level was greater than 400pg/ml. E2 was measured by sequential competitive chemiluminescent immunoassay (Immulite 2000,

Vol. 78, No. 3, Suppl. 1, September 2002