Objective: To test diagnostic accuracy of lifetime high day 2 FSH in an unrestricted IVF population. Design: Retrospective analysis of lifetime high day 2 FSH with outcome measure: birth or ongoing pregnancy. Materials/Methods: 2,058 day 2 FSH measurements from 539 women aged 38 ± 4 years (mean ± SD) were studied. FSH standardization was WHO 2nd International Standard (IRP 78/549). Immunoassay was performed using Technicon Immuno 1 (Bayer, Tarrytown NY) (normal follicular phase range less than 9.6 mIU/mL). 730 consecutive IVF stimulations (lifetime IVF cycle 3 ± 2) were begun with flare GnRH-agonist/gonadotropin or clomiphene/gonadotropin/±GnRH-antagonist. All diagnoses were included. Prior to stimulation 80 cycles were deferred on account of elevated FSH (20 ± 7 mIU/mL). 81 cycles were not started on account of functional cysts, persistent luteal function or elevated estradiol. Results: Lifetime high day 2 FSH was greater than 10 mIU/mL in 40% of 730 cycles. Examined in increments of 2 mIU/mL for lifetime high FSH, confidence intervals for crude birth/ongoing pregnancy rates were not different from 4–16 mIU/mL. Receiver operator characteristic curves for cycle and lifetime high FSH had areas of 0.5, indicative of poor test accuracy. FSH greater than 16 mIU/mL gave positive likelihood ratios of 2.6 for cycle FSH (fair test) and 1.9 (poor to fair) for lifetime high FSH. With respect to outcome as the dependent variable, neither cycle FSH, nor lifetime high FSH, nor number of elevated FSHs, nor proportion of FSHs that were elevated were significant independent variables by multiple regression analysis. After starting treatment, 72 cycles (10%) were cancelled for poor response. Lifetime high FSH was greater in cancelled cycles 14.7 ± 8 versus 9.8 ± 4 in cycles completed to oocyte retrieval, (p = 0.001) and risk of cancellation was related to lifetime high FSH, (F = 74, r2 = 0.09, p = 0.001). Conclusions: Mild to moderate elevations of lifetime high day 2 FSH were frequent in an unrestricted IVF population (40%) but did not improve diagnostic accuracy with respect to birth-ongoing pregnancy in the range 4–16 mIU/mL. Using multiple regression, lifetime high day 2 FSH was weakly related to the intermediate endpoint, risk of cancellation. Given the major difficulties diagnosing ovarian reserve and the creative flexibility possible with ovarian stimulation, it may be appropriate to offer determined individuals IVF treatment despite mild to moderate elevations of lifetime high day 2 FSH.

Objective: Initial phase III clinical trials of ganirelix in IVF patients did not report an effect of BMI on LH surges; however, the patient population was limited to a BMI between 18 and 29 kg/m2. This study examines the incidence of LH surge in IVF patients on ganirelix with a BMI >29 kg/m2. Design: Retrospective analysis of IVF clinical data. Materials/Methods: Seventy-six infertility patients, ranging in age from 26–46, were enrolled in a ganirelix IVF protocol. Ovulation induction involved clomiphene citrate (100 mg cycle days 2–6) with recombinant FSH (cycle day 2 until hCG Rx). Ganirelix was administered on cycle day 8 at a dose of 0.25 mg and continued daily until hCG Rx. Blood samples were obtained on cycle days 2,5, and daily from cycle day 8 until oocyte retrieval. Concentrations of 17 [Szlig]-estradiol, progesterone, and LH were analyzed with electrochemicoluminescence immunoassays. The intra-assay coefficient of variation for LH was 1.6%. An LH surge was defined as >10 IU/L. BMI was calculated by measured height and weight. A scatterplot of BMI and LH was produced and incidence of LH surge compared by Student’s t-test. Results: LH surges while on ganirelix occurred in 6 of the 76 patients. Two of these cycles were cancelled. Oocytes were retrieved in the remaining 4 cycles. One of the four retrieved cycles resulted in an on-going pregnancy. The LH surges occurred with a BMI range of 19.8 to 44.8; however, LH surges were more likely to occur when BMI >34 kg/m2. Of the 8 patients with BMI >34, three (37.5%) were with LH surges. Conclusions: Accurate dosing of the GnRH antagonist ganirelix is critical for IVF patients. A balance is needed between efforts to minimize LH surges at low doses versus minimizing potential detrimental effects on endometrial receptivity at higher doses. Patients with BMI >34 kg/m2 may require higher than standard doses of ganirelix to prevent LH surges.

Objective: Initial phase III trials comparing the GnRH antagonist, ganirelix acetate, with the GnRH agonist, leuprolide acetate, showed similar pregnancy rates in IVF patients; however, inclusion criteria for this trial required patients to be ≤39 years old and with FSH levels ≤ 10 IU/L. Poor responder infertility patients, who may not meet these criteria, have previously benefited from the traditional clomiphene/FSH ovarian stimulation. This study compares clomiphene/FSH pregnancy outcomes in poor responder IVF patients, treated with or without ganirelix therapy. Design: Retrospective analysis of IVF clinical data. Materials/Methods: Two hundred fifty-five poor responder IVF patients with prior failed leuprolide treated cycles were enrolled in a clomiphene (100 mg cycle days 2–6), recombinant FSH (cycle day 2 until hCG Rx) protocol. Seventy-eight patients were additionally prescribed ganirelix (0.25 mg qD, cycle day 8 until hCG Rx); the remaining 177 patients did not use ganirelix. Blood samples were obtained on cycle days 2,5 and daily from cycle day 8 until oocyte retrieval. Some non-ganirelix patients required twice daily blood monitoring in the peri-ovulatory period. Pregnancy outcomes were calculated and compared by Student’s t-test. Results: Comparison between the ganirelix and non-ganirelix groups showed no statistically significant difference with regard to age (mean = 37.9 years), lifetime peak FSH (mean = 10.8 IU/L), cycle start FSH (mean = 8.2 IU/L), number of prior failed IVF cycles (mean = 3.6), or presenting diagnosis. Pregnancy outcomes between the ganirelix and non-ganirelix groups (see table) were not significantly different. Comparative pregnancy outcomes in poor responders. legendlegendP > 0.05 for all groupings.CC/FSH/GanirelixCC/FSHPositive hCG27/78 (34.6%)53/177 (29.9%)Chemical Preg7/78 (9.0%)11/177 (6.2%)Missed SAB4/78 (5.1%)9/177 (5.1%)Ongoing Preg16/78 (20.5%)33/177 (18.6%)legend P > 0.05 for all groupings. Open table in a new tab Conclusions: Use of the GnRH antagonist, ganirelix, in poor responder IVF patients provides similar pregnancy outcomes to those seen with traditional clomiphene/FSH stimulation protocols. In addition, ganirelix permits more convenient cycle monitoring and control of oocyte retrieval scheduling. Previous concerns of decreased embryo implantation rates at higher GnRH antagonist dosing are not supported by the comparative pregnancy outcome results.

Objective: To test the utility of day 2 estradiol measured during the IVF stimulation cycle. Design: To give external validity, an unrestricted population was chosen and analyzed retrospectively with the outcome measure birth/ongoing pregnancy. Materials/Methods: Day 2 estradiols were recorded in 895 consecutive IVF cycles with flare GnRH-agonist/gonadotropin or clomiphene combined with gonadotropin/±GnRH-antagonist. Female age was 37.7 ± 4.1 years (mean ± SD) and lifetime IVF cycles were 2.7 ± 1.7. All diagnoses were included. Treatment was deferred (n = 80) for elevated FSH (20 ± 7 IU/mL). After starting treatment, 72 cycles (10%) were cancelled for poor response. Predictive values and a receiver operator characteristic (ROC) curve were calculated for estradiol from 10–100 pg/mL in increments of 10. Results: In 730 treated cycles, outcome was not different by 10 pg/mL increments of day 2 estradiol in the range 10–100. Predictive values and likelihood ratios were non-significant and an ROC curve did not find day 2 estradiol to be a useful test in the subset of patients selected for treatment. In treated cycles there was no correlation between estradiol and FSH and FSH did not confound outcome. However, in cancelled cycles there was a negative correlation between FSH and estradiol (r2 = 0.14, p = 0.01). In cases of persistent luteal function (progesterone = 5.3 ± 5 ng/mL) or functional ovarian cysts treatment was not started. With estradiol elevation alone, treatment was started according to individual physician discretion. In 17 of the 33 estradiol elevation alone cycles treatment was started (estradiol 105 ± 50, median 90) and in four there was successful outcome (estradiol = 85 ± 6). In 16 of the 33 estradiol elevation alone cycles treatment was not started (estradiol = 140 ± 55, median 125). Circumstances of Estradiol >80 pg/mL. Tabled 1CircumstancenEstradiolPersistent luteal function16105 ± 210Functional cyst18260 ± 160Elevated estradiol alone33120 ± 50 Open table in a new tab Conclusions: It is biologically plausible that elevated day 2 estradiol reflects disorded ovarian function. In the present trial a population at risk for reduced ovarian reserve was studied in the cycle of stimulation. If estradiol exceeded 80 pg/mL, 50% of cycles were associated with non-structural ovarian cysts or persistent luteal function and treatment was deferred. In cycles proceeding to treatment, outcome was unimpaired for day 2 estradiol ranging from 10–100 pg/mL. However, small sample size in increments beyond 80 pg/mL severely limited power. If elevated day 2 estradiol is associated with a reduced IVF prognosis, the threshold is 80 pg/mL. At this threshold, derangements of the early follicular phase are frequently observed.