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

Diagnostic Products Corp., Randolph, NJ)at the initiation of treatment, onthe day of AntagonTMstart and then daily thereafter until the day of hCGadministration. A rise or drop in E2 was recorded if the E2 rose or fell by10% or more on the day after Antagon start. A plateau was recorded if theE2 neither rose or fell by 10%. hCG 10,000u (Pregnyl, Organon Inc., WestOrange, NJ or Profasi, Serono Inc., Norwell, MA or Novarel, Ferring Inc.,Tarrytown, NY) was administered to initiate ovulation when at least 2follicles reached 1.8cm or greater. Ovum capture was performed 34–35hours after hCG. Insemination was performed by conventional means orintra-cytoplasmic sperm injection. 2–4 embryos were transferred on thethird or fifth day after ovum capture. Pregnancy was recorded if the patienthad an ongoing gestation past the ninth week. Statistical analysis wasperformed by Chi-square.

Results: 124/161 cycles were characterized by an E2 rise, 27/161 byplateau and 10/161 by a drop. PRs for the groups were 46%, 44.4% and 30%respectively. Implantation rates were similar as well with 21.8%, 19.3% and20.8% respectively. No statistical differences were noted between groups.

Conclusions: A drop or plateau in E2 on the day after AntagonTM startappears to have no prognostic significance in IVF. These E2 patterns likelyrepresent normal variants and are secondary to the inherent physiology ofthe GnRH antagonist AntagonTM. These data support the concept that nointervention (such as LH add-back) is necessary to guard an IVF cycleagainst an early drop or plateau in E2 during stimulation with recombinantFSH and AntagonTM.

Supported by: Organon Inc.

CONTRACEPTION SPECIAL INTEREST GROUP

Monday, October 14, 20022:00 P.M.

O-59

Chronic low-dose antiprogestin impairs preimplantation embryogene-sis, but not oocyte nuclear maturation or fertilization in rhesus mon-keys. Sherri M. Borman, Kristof Chwalisz, Richard L. Stouffer, Mary B.Zelinski-Wooten. Oregon National Primate Reseach Ctr-Oregon Health &Science Univ, Beaverton, OR; Research Lab of Schering AG, Berlin,Germany; Oregon National Primate Research Ctr-Oregon Health & ScienceUniv, Dept of Physiology and Pharmacology-OHSU, Beaverton, OR.

Objective: Continual administration of low doses of the antiprogestin ZK137 316 (Schering AG) permits ovarian/menstrual cyclicity, but preventspregnancy in female rhesus monkeys. The sites of contraceptive actionremain unknown. The objective of this study was to determine if chronic,low-dose antiprogestin exposure during follicular development impairs oo-cyte nuclear maturation in vivo, as well as fertilization and embryonicdevelopment in vitro.

Design: Twenty, adult, female rhesus monkeys exhibiting normal men-strual cycles received (n�10/group) vehicle or 0.03 mg ZK 137 316/kgbody weight IM daily for 3 months. Controlled ovarian stimulation withrecombinant (r) gonadotropins (Ares Serono) was initiated in the thirdmonth to obtain multiple oocytes for evaluation, as well as insemination andsubsequent embryonic development in vitro.

Materials/Methods: Follicles were aspirated 27 h after r-hCG adminis-tration. Oocytes were evaluated for nuclear maturity (germinal vesicle-intact, GV; metaphase I, MI; or metaphase II, MII), inseminated in vitro andco-cultured on BRL cells to the hatched blastocyst stage. The total numberof oocytes collected, percentage of oocytes at each nuclear stage, fertiliza-tion rates, developmental rates and the percentage of fertilized oocytes thatreached each embryonic stage were compared between groups using un-paired t-tests. Chi square or Fishers exact tests were used to compare theproportion of oocytes exhibiting abnormal fertilization or cleavage betweengroups.

Results: The total number of oocytes and percentage of oocytes collectedat GV, MI and MII were similar in both groups, except antiprogestin-treatedfemales had more (p �0.05) atretic oocytes than vehicle-treated females.The percentages of inseminated oocytes that fertilized as well as fertilizedoocytes that progressed to the morula stage were similar between groups.However, antiprogestin-treated females had a higher (p �0.05) rate ofabnormal cleavage. Embryonic development was delayed by one day (p�0.05) from the 16-cell to the morula stage in the antiprogestin grouprelative to vehicle. Despite this lag, the majority of embryos reached the

blastocyst stage by 6 days in vitro in the antiprogestin group, but fewerreached expanded blastocysts (p � 0.09) and less (p �0.05) developed tohatched blastocysts compared to vehicle.

Conclusions: During in vivo treatment with chronic, low dose antipro-gestin, oocytes retained their ability to resume and complete meiosis as wellas fertilize following insemination in vitro. However, embryogenesis invitro was impaired, particularly during the later stages of blastocyst devel-opment. Thus, exposure to chronic, low dose antiprogestin during the pre-and peri-ovulatory intervals altered oocyte functions that are critical fornormal preimplantation embryogenesis; this may contribute to pregnancyprevention.

Supported by: NIH grants HD31633, 2T32 HDO7133, U54 HD18185and RR00163.

Monday, October 14, 20022:15 P.M.

O-60

In vivo contraceptive activity of novel dual-function microbicides: Arylphosphate derivatives of bromo-methoxy zidovudine (compoundsWHI-05 and WHI-07). Osmond J. D’Cruz, Fatih M. Uckun. ParkerHughes Institute, St. Paul, MN.

Objective: The compounds WHI-05 (5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5-[p-methoxyphenyl] methoxyalaninyl phosphate) andWHI-07 (5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5-[p-bromo-phenyl] methoxyalaninyl phosphate) are aryl phosphate derivatives ofzidovudine (AZT) with potent, dual-function anti-HIV and spermicidalactivity without mucosal toxicity. This study sought to determine thevaginal contraceptive activity of WHI-05 and WHI-07 in the rabbit model.

Design: WHI-05 and WHI-07 were formulated via a nontoxic submicronparticle size (30–80 nm), lipophilic gel-microemulsion for intravaginal useas potential candidate anti-HIV spermicides. The in vivo contraceptivepotency of intravaginally applied 2% WHI-05 or WHI-07 in gel-microemul-sion was compared to those of detergent spermicide, nonoxynol-9 [N-9]containing formulations in the NZW rabbit model.

Materials/Methods: In Experiment I, aliquots of pooled rabbit semenobtained from fertile bucks (n � 24) were treated with vehicle alone,WHI-05 or WHI-07 at the time of artificial insemination (AI) of ovulatedNZW does (n � 10/subgroup) and the numbers of ovarian corpora lutea andimplanted embryos were determined on day 8. In Experiment II, ovulatedNZW does (n � 24/subgroup) with and without intravaginal administrationof gel formulations of 2% WHI-05, WHI-07 or N-9 were artificially insem-inated and allowed to complete their pregnancies. In Experiment III, NZWdoes (n � 16/subgroup) were artificially inseminated at 15, 30, and 60 minafter intravaginal application of 2% WHI-07-containing gel and the num-bers of implanted embryos were determined on day 8.

Results: Exposure of semen to WHI-05 and WHI-07 at the time of AIsignificantly inhibited pregnancy rates (90 and 100% inhibition, respec-tively) and embryo implantation (WHI-07-pretreated 0/117, WHI-05-pre-treated 2/110, control 38/111; p �0.0001). Intravaginal application of 2%WHI-05, WHI-07, and N-9-containing gel formulations before AI signifi-cantly inhibited pregnancy rates (90, 81, and 85% inhibition, respectively;p �0.0001) when compared to control. Furthermore, the 2% WHI-07-containing gel microemulsion provided �90% inhibition of fertility evenwhen insemination was delayed until 60 min after intravaginal application.

Conclusions: Taken together, our results demonstrate that WHI-05 andWHI-07 are potent contraceptive agents in vivo. Intravaginal use of gelformulations of WHI-05 and WHI-07 has clinical potential as contraceptiveagents in addition to their microbicide activity to curb the sexual transmis-sion of HIV.

Supported by: Supported in part by NIH Grant R01-HD37357 and amfARGrant 02667.

Monday, October 14, 20022:30 P.M.

O-61

Two-year toxicity and carcinogenicity study of the aryl phosphatederivative of bromo-methoxy zidovudine (compound WHI-07), a novel

FERTILITY & STERILITY� S23