premature luteinization during gnrh antagonists cycles in ivf adversely affects pregnancy and...

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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 vari- ability. 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 inter- cycle 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 Infertil- ity, 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. Cek- leniak, David B. Sable, Margaret G. Garrisi, Santiago Munne. Saint Barn- abas 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. 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 ad- versely 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 contro- versial 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. Statis- tical 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 out- come ( 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 proges- terone 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. FERTILITY & STERILITY S21

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stimulation in ART cycles has been shown to correlate well with multiplemeasures of in vitro fertilization (IVF) outcome. It is widely believed thatthe number of AFs correlates with the primordial follicle reserve. However,little is known about intercycle variability in antral follicle (AF) counts inpatients undergoing IVF. Additionally the effect of these differences uponstimulation 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 wereobtained during the pre-stimulation ultrasound. (In a separate group ofnormal women (n � 20) we found no significant change in AF count beforeand after treatment with a GnRH agonist.) Forty-seven patients (age 23–45)having undergone a total of 101 IVF cycles were identified. To evaluateintercycle variability, means and percent change from the mean in AFcounts were calculated and compared. Mean AF counts were also comparedto means of parameters of IVF stimulation quality, including oocytesrecovered, peak estradiol, length of stimulation, and gonadotropin dose.Comparisons of IVF stimulation quality were made between the low andhigh AF count cycle through a paired analysis. Comparisons were also madebetween the low and high AF count cycles and simulation quality inindividuals with greater intercycle AF count variability (�50% change fromthe mean), and between individuals with greater vs. lesser intercycle vari-ability. 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 oocytesretrieved (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 AFcounts (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 countcycle for each patient did not show a difference in oocytes retrieved, peakestradiol, gonadotropin dose, or biochemical and clinical pregnancy rates(p � NS). Stimulation quality was greater in individuals with lesser inter-cycle variability (p � 0.0036); however, no difference was detected incomparison of the lower to higher AF count cycle in individuals with greaterintercycle variability.

Conclusions: There is moderate intercycle variability in AF number, andthis variability is greater in individuals with lower AF counts. Although AFcount was well correlated with multiple parameters of IVF outcome; withinan individual patient, higher AF count in a given cycle was not predictiveof better stimulation quality compared to a lower count cycle. Therefore, itdoes not appear to be prudent to attempt to select an optimal cycle forstimulation in a particular patient. Greater intercycle variability is associatedwith decreased ovarian reserve.

Supported by: The Division of Reproductive Endocrinology and Infertil-ity, University of Washington.

Monday, October 14, 20023:45 P.M.

O-54

Maternal balanced translocation is a risk factor for poor response toovarian stimulation. Serena H. Chen, Tomas Escudero, Natalie A. Cek-leniak, David B. Sable, Margaret G. Garrisi, Santiago Munne. Saint Barn-abas Institute for Reproductive Medicine and Science (IRMS), Livingston,NJ.

Objective: To determine if maternal balanced translocation is a risk factorfor poor ovarian response to controlled ovarian hyperstimulation.

Design: A retrospective analysis of ovarian response to gonadotropinstimulation 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 autosomaltranslocation in either partner performed at Saint Barnabas IRMS from 1995through 2001 were analyzed: a total of 98 cycles in 76 women werecompleted. Stimulation and embryology outcomes were compared betweentwo groups: 59 cycles in 44 women with balanced translocations (femalecarrier) compared to 39 cycles in 32 women whose male partner had abalanced translocation (male carrier). Average female age, female smokinghistory, day 3 FSH, day 3 estradiol levels, and pregnancy rates were similarin both groups. Statistical analysis was performed comparing stimulationprotocols, estradiol level on day of hCG, and other cycle parameters.

Results: In couples undergoing IVF/PGD to avoid transmission of anunbalanced karyotype, a significantly higher proportion of women carryingbalanced translocations (female carrier) responded very poorly (estradiol onthe day of hCG less than 1000 pg/mL) to ovarian stimulation compared towomen whose partner had a balanced translocation (male carrier) (0.220 vs0.053, p �0.02). These differences in response occurred despite the fact thatthere were a significantly higher proportion of patients in the female carriergroup using aggressive stimulations, leading us to believe that the risk ofpoor 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 increasedwhen the female partner carries the balanced translocation compared towhen the male partner carries the translocation. The reasons for this findingare unknown. In some male translocation patients, a higher incidence ofgerm cell death has been noted. A similar mechanism should be investigatedin female translocation patients.

Supported by: No sponsors or grants.

Monday, October 14, 20024:00 P.M.

O-55

Premature luteinization during GnRH antagonists cycles in IVF ad-versely affects pregnancy and implantation rates. Ivan Valencia,Ernesto Bosch, Carlos Troncoso, Carlos Simon, Jose Remohi, AntonioPellicer. Inst Valenciano de Infertilidad, Valencia, Spain; Inst Valencianode Infertilidad and Dept of Pediatrics, Obstetrics and Gynecology, ValenciaUniv Sch of Medicine, Valencia, Spain.

Objective: The effect of premature luteinization has always been contro-versial in IVF cycles. A retrospective analysis of our data from antagonistscycles showed that a serum progesterone �1.2 ng/ml was significantlyassociated with a worse outcome in terms of pregnancy and implantationrate. Therefore we wanted to clarify this conclusion in a prospectivemanner.

Design: Prospective observational study.Materials/Methods: In October 2001 a prospective study was started

comparing GnRH antagonists cycles in IVF. All patients had a serumestradiol, 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 retrievedand embryos transferred. Pregnancy was defined as the presence of agestational sac with fetal hearbeat. Implantation rate was defined as thenumber of fetal heartbeats over the number of embryos transfered. Statis-tical analysis was done using the Fisher exact test, Mann-Whitney test,logistic regression analysis and ROC curve as appropriate. A p value �0.05was considered significant.

Results: Fifty-two ART cycles were included. One embryo transfer wascancelled because of risk of OHSS and all zygotes were frozen. Theincidence of premature luteinization, pregnancy and implantation rates aredetailed in Table 1. Premature luteinization on hCG day ocurred in 24/52cycles (46.2%). No difference was found in age, serum estradiol and LHlevel on hCG day, number of oocytes retrieved or in the number of embryostransferred between those cycles with and with-out premature luteinizationgroup. A statistically significant difference was only found in the number ofgestational sacs observed (0.28 vs 0.78 p � 0.0208). No LH surge (�10U/L) was noted in any cycle on hCG day. Logistic regression analysisshowed the progesterone level to be significantly correlated to cycle out-come ( �1.417 p � 0.026). The progesterone level of 1.2 ng/ml area underthe ROC curve was 0.721 with a 80% sensitivity, 55% specificity, 54%positive predictive value and a 80.4% negative predictive value assuming a40% pregnancy rate in the no premature luteinization group.

Conclusions: These preliminary data from this group of patients showedthat premature luteinization during GnRH antagonists IVF cycles was afrequent event and adversely affected the pregnancy and implantation rate.Progesterone elevations were not related to serum LH levels and may reflectthe mature granulosa cell response to exogenous FSH exposure. A proges-terone level �1.2 ng/ml is the best cut-off criteria for an adverse outcome.Probably GnRH antagonists cycles could benefit from additional routineprogesterone monitoring.

FERTILITY & STERILITY� S21

Table 1. Incidence of premature luteinization and cycle outcomeduring GnRH-antagonists IVF cycles.

P level ng/ml

p rr (95% C.I.)1.2 �1.2

Cycles (%) 24 (46.2%) 28 (53.6%)Embryo Transfers 23 28Pregnancies 5 15Pregnancy rate per

transfer (%)21.7% 53.6% 0.024 0.405

(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, 20024:15 P.M.

O-56

Elevated FSH�LH ratio in the presence of normal hormonal valuespredicts poor ovarian response in controlled ovarian hyperstimulation.Alon Shrim, Boaz Weizs, Salem Kiss, Jehoshua Dor. Tel Hashomer Med-ical 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 pres-ence of normal FSH and LH levels can predict ovarian response in patientsundergoing 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 FSHlevels �12 miu/ml were excluded. Patients were divided into three groupsaccording 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 wererecorded: age at treatment, basal day 3 FSH/LH levels, peak serum E2 level,pregnancy rate, number of IFV cycles and number of oocytes retrieved foreach cycle.

Results: 729 patients (with FSH �12) underwent 1776 cycles during thisperiod. In group 1, 144 patients underwent 352 cycles and achieved 74pregnancies. In group 2, 60 patients underwent 144 cycles and achieved 49pregnancies. In group 3, 518 patients underwent 1280 cycles and achieved322 pregnancies. Mean age at treatment was 34, 33 and 34 years for group1, 2 and 3 respectively (NS). Peak serum E2 level was significantly lowerin 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 comparedwith groups 2 and 3 (median oocytes retrieved 8, 10,10 in groups 1, 2 and3 respectively). Pregnancy rate per cycle (21%, 34% and 25% for groups 1,2and 3 respectively) and pregnancy rate per patient (52%, 81% and 62% forgroups 1, 2 and 3 respectively) were also significantly lower in group 1.

Conclusions: Elevated FSH/LH ratio predicts a poor outcome in patientsundergoing control ovarian hyperstimulation for IVF. FSH/LH ratio mayincrease before an increase in serum FSH is observed and thus can be usedas a predictor for ovarian response in patients undergoing controlled ovarianhyperstimulation in IVF.

Monday, October 14, 20024:30 P.M.

O-57

Is exogenous LH necessary when using GnRH antagonist in IVF ovar-ian hyperstimulation? Nicole Noyes, Karine Chung, Joseph Katz, LewisKrey. New York Univ, New York, NY.

Objective: To evaluate the role of exogenous LH in stimulated IVF cyclesutilizing GnRH antagonists.

Design: An association between LH and the triggering of human ovula-tion has been firmly established while any other role for LH in the mid- tolate-follicular phase remains speculative. Oocyte release is controlled in the

majority of IVF treatment cycles by suppression of the endogenous LHsurge. This has traditionally been accomplished via pre-follicular down-regulation by a GnRH-agonist. Late follicular LH inhibition has becomepossible with the newly available GnRH antagonists, which allow completeLH suppression. The concern in these patients is that there may be somedetrimental effect if gonadotropins containing no LH are used for stimula-tion. We reviewed pregnancy and implantation outcomes of groups whichwere stimulated with LH-containing agents and compared them to thosereceiving FSH only.

Materials/Methods: Retrospective analysis was performed of 153 IVFcycles between September 2000 and August 2001 that used a GnRHantagonist and achieved oocyte retrieval. Cycles were evaluated accordingto the particular gonadotropin utilized. Outcomes of cycles using purerecombinant FSH (Rec) were compared to cycles where LH-containinggonadotropin (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 exhibitingdiminished ovarian reserve. The GnRH antagonist was added to the stim-ulation regimen beginning on the day the lead follicle reached diameters of12–14 mm on transvaginal ultrasound.

Results: The mean number of days of GnRH antagonist administrationwas 3.4 and the mean day of drug initiation 8.1. The mean endometrialthickness on the day of hCG administration was 9.3 mm and the meansupplemented mid-luteal progesterone level was 71 ng/ml. The table com-pares outcome by gonadotropin utilized. Values are expressed as mean�SEM. Pregnancy is defined as a fetal heart on ultrasound. Implantationrate describes fetal heart per embryo replaced. Pregnancy and implantationrates in Rec- cycles (28% and 13.9%, respectively) are similar to those inwhich HMG (33% and 17.8%) or Rec � HMG is utilized (21% and 12.5%).

Outcome by gonadotropin utilized.

Ovarianstimulation

Agegroup n

Mean age(yrs)

Meanday 3FSH

Oocyteno.

2PNembryo

no.

Pregnancyper

retrievaln (%)

Implantationrate per

embryo repl.(%)

Rec- �40 35 35.7 � 0.4 6.4 � 0.4 9 � 1 5 � 1 14 (40%) 22/90 (24.4%)/�40 40 42.6 � 0.3 6.1 � 0.3 9 � 1 5 � 1 7 (18%) 11/147 (7.5%)

HMG �40 9 37.1 � 0.74 6.6 � 1 7 � 2 5 � 1 3 (33%) 3/18 (16.7%)/�40 3 42.3 � 0.3 6.3 � 1.5 5 � 1 4 � 1 1 (33%) 2/10 (20%)

Rec �HMG

�40 25 35.6 � 0.5 6.3 � 0.5 7 � 1 4 � 1 10 (40%) 19/72 (26.4%)

/�40 41 42.6 � 0.3 6.6 � 0.3 6 � 1 4 � 1 4 (9%) 6/128 (4.7%)

Conclusions: GnRH antagonist cycles using recombinant FSH have sim-ilar outcomes to those cycles in which an LH-containing gonadotropin isutilized. Mid- to late-follicular LH does not appear necessary to achieveappropriate endometrial thickness, maintain supplemented luteal progester-one concentrations or result in pregnancy.

Monday, October 14, 20024:45 P.M.

O-58

Plateau or drop in estradiol (E2) on the day after initiation of the GnRHantagonist Antagontm in in-vitro fertilization (IVF) treatment cyclesdoes 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 orplateau in Estradiol (E2) on the day following Antagon™ start in in-vitrofertilization (IVF) cycles.

Design: Retrospective analysis of 161 consecutive IVF cycles in whichE2 values were available on the day after AntagonTM start.

Materials/Methods: Women ranging in age from 23 to 41 underwent 161IVF cycles for a variety of indications. Treatment was started on cycle day2 with recombinant FSH (Follistim�, Organon Inc., West Orange, NJ orGonal-F�, Serono Inc., Norwell, MA) 225–600iu/day. Antagon was startedon the morning of stimulation day 6 or 7 when the lead follicle reached 1.2cm or the E2 level was greater than 400pg/ml. E2 was measured bysequential competitive chemiluminescent immunoassay (Immulite 2000,

S22 Abstracts Vol. 78, No. 3, Suppl. 1, September 2002