Elena H. Yanushpolsky, M.D., a Shelley Hurwitz, Ph.D., b Eugene Tikh, B.S., c and Catherine Racowsky, Ph.D. a

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1 FERTILITY AND STERILITY VOL. 80, NO. 1, JULY 2003 Copyright 2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Predictive usefulness of cycle day 10 follicle-stimulating hormone level in a clomiphene citrate challenge test for in vitro fertilization outcome in women younger than 40 years of age Elena H. Yanushpolsky, M.D., a Shelley Hurwitz, Ph.D., b Eugene Tikh, B.S., c and Catherine Racowsky, Ph.D. a Center for Reproductive Medicine, Department of Obstetrics and Gynecology, and Center for Clinical Investigation, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts Received June 26, 2002; revised and accepted December 2, Reprint requests: Elena H. Yanushpolsky, M.D., Department of Obstetrics and Gynecology, Brigham and Women s Hospital, 75 Francis Street, Boston, Massachusetts (FAX: ; eyanushpolsky@ partners.org). a Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Brigham and Women s Hospital. b Center for Clinical Investigation, Brigham and Women s Hospital. c University of Massachusetts Medical School, Worcester, Massachusetts /03/$30.00 doi: /s (03) Objective: To determine the usefulness of the day 10 FSH level of a clomiphene citrate challenge test in predicting IVF outcome in women younger than 40 years of age. Design: Retrospective chart review. Setting: Academic fertility center. Patient(s): Three hundred fifty-three women younger than 40 years of age undergoing 483 IVF cycles. Main Outcome Measure(s): Delivery rates. Result(s): An inverse relationship was observed between the likelihood of successful pregnancy and both cycle day 3 and cycle day 10 FSH levels. In women with a normal day 3 FSH level, elevated day 10 FSH levels predicted similarly poor IVF outcomes as for women with an abnormal day 3 FSH level. There was no specific threshold FSH level beyond which pregnancies failed to occur. Successful pregnancies were achieved with aggressive stimulation even in women with FSH levels greater than 20 miu/ml. Conclusion(s): The clomiphene citrate challenge test (CCCT) correlates with IVF outcomes in women younger than 40 years of age. Stimulated day 10 FSH levels are strongly predictive of decreased IVF success even when day 3 FSH levels are normal. Results of the CCCT are useful for patient counseling before the IVF cycle and for choosing the optimal gonadotropin regimen. (Fertil Steril 2003;80: by American Society for Reproductive Medicine.) Key Words: Clomiphene citrate challenge test, FSH, ovarian reserve, IVF success Before infertile patients commit their physical, emotional, and financial resources to the IVF process, most wish to know their realistic chance of a successful outcome. Accurate counseling based on established predictive variables is thus of paramount importance. Ovarian reserve relative to patient age and FSH level is one of the most important predictive variables of IVF success (1). However, the best method for evaluation of ovarian reserve remains controversial. The value of basal FSH levels independent of age has been vigorously debated. Some investigators assert that cycle day 3 FSH levels are superior predictors of IVF performance compared with age (2, 3), whereas others have found no evidence to support routine screening for basal FSH levels (4, 5). The clomiphene citrate challenge test (CCCT) has been described as a provocative endocrine evaluation of ovarian reserve in women with unexplained infertility and apparently normal ovarian function (1). Loumaye et al. (6) demonstrated a correlation between abnormal CCCT results and poor IVF outcomes, and Scott et al. (7) showed an increase in the incidence of abnormal CCCT with advancing reproductive age. Both sets of investigators reported, however, that women of advanced reproductive age with normal results on the CCCT had lower pregnancy rates from IVF than did their younger counterparts. This find- 111

2 ing suggests that the relative predictive value of abnormal results on a CCCT may depend on a woman s age. Although elevated day 3 and day 10 FSH levels have been associated with unsuccessful outcomes in women older than 40 years of age (8), no previous study has explored this relationship in younger women. We therefore sought to determine the relationship between FSH levels on the CCCT and IVF outcome in younger women ( 40 years of age) and to identify the usefulness of day 10 FSH levels in predicting IVF success in this age group. MATERIALS AND METHODS This retrospective review was approved by the Institutional Review Board of Brigham and Women s Hospital. The sample consisted of 353 patients undergoing IVF (age range, 25.2 to 39.9 years; mean age [ SD], years) who underwent 483 oocyte retrievals between January 1998 and December Two hundred forty-six patients underwent one cycle of IVF, 85 had two cycles, 21 had three cycles, and 1 had four cycles. Infertility diagnoses included male factor (138 patients [39%]); tubal factor (99 patients [28%]); and other diagnoses, including endometriosis, cervical factor, and unexplained. All patients underwent a CCCT before starting their first IVF cycle. The test was performed by measurement of baseline blood FSH level on menstrual cycle day 3, followed by administration of clomiphene citrate, 100 mg (Clomid; Marion Merrell Dow, Inc., Kansas City, MO) on menstrual cycle days 5 through 9 and measurement of stimulated blood FSH levels on menstrual cycle day 10. The FSH levels were measured by using a Technicon Immuno 1 System (Bayer Corp., Tarrytown, NY). The interassay and intraassay coefficients of variation were 3.3% and 1.9%, respectively. Controlled ovarian hyperstimulation was performed with luteal down-regulation using 1.0 to 0.5 mg of leuprolide acetate (Lupron; TAP Pharmaceuticals, Inc., Deerfield, IL). The standard IVF protocol for follicular stimulation was performed with hmg (Humegon; Organon, Inc., West Orange, NJ, or Repronex; Ferring Pharmaceuticals Inc., Tarrytown, NY), FSH (Follistim, Organon Inc., West Orange, NJ, or Fertinex or Gonal-F; Serono Laboratories, Rockland, MA), or a combination of hmg and FSH, depending on individual patient characteristics. The intracytoplamic sperm injection (ICSI) procedure was performed in 151 cycles (31%), and assisted hatching was undertaken in 182 cycles (38%). Statistical analyses were performed by using mixedmodel logistic regression to account for varying number of cycles per woman (statistical analysis system [SAS] genmod procedure [9]). To determine the association between delivery rate and the results of both day 3 and day 10 FSH levels together, patients were dichotomized in different ways to account for all possible combinations of day 3 and day 10 TABLE 1 Oocyte retrieval and delivery rates according to FSH results on day 3 and day 10. Type of result FSH level (miu/ml) levels after stratification into standard categories of 10 miu/ml and 10 miu/ml. Odds ratios for delivery and 95% confidence intervals are presented. The odds ratio for failure is the reciprocal of the odds ratio for delivery. Statistical significance was P.05. RESULTS No. of oocyte retrievals Delivered pregnancy (%) Single day Day Day Day Day Concordant Both days Other Both days Other Discordant Day 3 10 and Day Other Day 3 10 and Day Other The median day 3 FSH level was 7.9 miu/ml (range, 0.2 to 26.5 miu/ml), and the median day 10 FSH level was 8.1 miu/ml (range 2.4 to 34.8 miu/ml). There was no significant correlation between CCCT results and patient age (mean age [ SD], years). The rate of cycle cancellation was 6% and was similar across all categories of FSH results. An inverse relationship was observed between the likelihood of delivered pregnancy and day 3 or day 10 FSH level (Fig. 1). The most significant decrease in delivered pregnancy rates was observed when the FSH level was 10 miu/ml or greater. This association held for day 3 (delivered pregnancy rate, 41% vs. 25% for patients with FSH level 10 miu/ml and 10 miu/ml, respectively; P.005) and day 10 values (delivered pregnancy rate, 44% vs. 24% for patients with FSH 10 miu/ml and 10 miu/ml; P.0001). However, deliveries occurred even when day 3 or day 10 FSH levels were greater than 20 miu/ml (23% and 22%, respectively) (Fig. 1). When both cycle day 3 and cycle day 10 FSH results were considered, the lowest delivery rates were observed in women with FSH levels 10 miu/ml or greater on both days (23.5%), whereas the highest delivery rates were seen in women with both day 3 and day 10 FSH levels less than 10 miu/ml (45.9%) (Fig. 2, Table 1). When day 3 FSH levels 112 Yanushpolsky et al. CCCT results and IVF outcomes under 40 Vol. 80, No. 1, July 2003

3 FIGURE 1 In vitro fertilization delivery rates per oocyte retrieval with respect to day 3 and day 10 FSH levels on a clomiphene citrate challenge test. were less than 10 miu/ml but the day 10 FSH level was 10 miu/ml or greater, pregnancy rates were significantly reduced and similar to those observed when the day 3 FSH level was 10 miu/ml or greater or when levels on both days were elevated (P.004). Therefore, an elevated day 10 FSH level alone indicates compromised pregnancy rates even when the day 3 FSH level is normal. Table 2 shows the odds ratios for the likelihood of pregnancy for the various combinations of day 3 and day 10 FSH values. There was a 2.63-fold increase in the probability of pregnancy when both day 3 and day 10 FSH levels were less than 10 miu/ml (P.0001). Conversely, there was a 53% reduction in the probability of pregnancy when both day 3 and day 10 FSH levels were 10 miu/ml or greater (odds ratio, 0.47; P.03) and a 55% reduction when only the day 10 FSH level was elevated (odds ratio, 0.45; P.002). Of note, when the day 3 FSH level was elevated but the day 10 FSH was normal, there was a 42% reduction in the probability of pregnancy (odds ratio, 0.58; P.12). The above relationships between FSH levels and delivery rates remained after stratification of cycles by age ( 35 years, 35 to 37 years, and 38 to 40 years) (data not shown). The groups did not differ significantly with regard to the incidence of chemical pregnancy, spontaneous abortion, or ectopic pregnancy. TABLE 2 Usefulness of day 3 and day 10 FSH levels for predicting pregnancy outcome. FSH level (miu/ml) Day 3 Day 10 Odds ratio (95% CI) P value Any ( ).0001 Any ( ) Reciprocal to Any 0.48 ( ) Any 2.09 ( ) Reciprocal to ( ) ( ) ( ) ( ).03 FERTILITY & STERILITY 113

4 FIGURE 2 Comparison of IVF delivery rates per oocyte retrieval with respect to basal and stimulated FSH levels. **P.004. DISCUSSION We found that some women younger than 40 years of age with day 3 and day 10 FSH levels 20 miu/ml were able to achieve successful pregnancies. These data suggest that there may be a difference in IVF success rates in younger women compared to older women even if results of the CCCT are similarly abnormal. Watt et al. (8) found no pregnancies in women older than age 40 years with basal FSH levels greater than 11.1 miu/ml or stimulated FSH levels greater than 13.5 miu/ ml. They proposed that those levels should be used as cut-offs for offering IVF services to women in that age group. We were not able to identify cut-off FSH levels for women younger than 40 years of age. Pregnancies were achieved even in women with maximal FSH levels when treated with aggressive ovulation induction regimens, albeit at lower rates than in women with normal CCCT results. Aggressive ovulation induction protocols included high doses of FSH and hmg up to 600 miu twice daily, as well as microflare use of diluted leuprolide acetate instead of a down-regulation regimen. Taken together, both age and CCCT results should be considered when selecting an optimal ovulation induction protocol. Our data also confirm previous observations (4, 5) that basal FSH levels alone do not accurately predict the chance of IVF success. Although elevated day 3 FSH levels indicate poor prognosis, normal levels do not assure optimal ovarian reserve. Our data indicate that stimulated cycle day 10 FSH levels are necessary for accurate assessment of both ovarian reserve and chances for IVF success. Women with normal basal FSH levels but elevated day 10 FSH levels had similarly low pregnancy rates as women with elevated basal FSH levels. Both of these groups of women had significantly lower pregnancy rates than did women with low basal and stimulated FSH levels ( 10 miu/ml). These observations show that an elevated day 10 FSH level, regardless of the day 3 value, predicts compromised ovarian reserve, as demonstrated by reduced success rates following IVF in women under 40 years of age. Reduced success rates do not mean, however, that ongoing pregnancies can never be achieved in patients younger than 40 years of age with abnormal CCCT results. In fact, we could not identify any FSH threshold value beyond which no pregnancy could be achieved and have observed successful delivery outcomes in women with abnormal CCCT results. 114 Yanushpolsky et al. CCCT results and IVF outcomes under 40 Vol. 80, No. 1, July 2003

5 We propose that all women younger than 40 years of age who are planning to undergo IVF be screened with a CCCT. Information derived from this test has direct application for counseling patients on their likelihood of success and for selecting the optimum regimen for controlled ovarian stimulation. References 1. Navot D, Rosenwaks Z, Margalioth EJ. Prognostic assessment of female fecundity. Lancet 1987;11: Toner JP, Philput CB, Jones GS, Muasher SJ. Basal follicle-stimulating hormone level is a better predictor of in vitro fertilization performance than age. Fertil Steril 1991;55: Scott RT, Hofmann GE, Oeninger SC, Muasher SJ, Rosenwaks Z. Follicle stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51: van Montfrans JM, Hoek A, van Hooff MH, de Koning CH, Tonch N, Lambalk C. Predictive value of basal follicle-stimulating hormone concentrations in a general subfertility population. Fertil Steril 2000;74: Bancsi LF, Huijus AM, den Ouden CT, Broekmans FJ, Looman CW, Blankenstein MA, et al. Basal follicle-stimulating hormone levels are of limited value in predicting ongoing pregnancy rates after in vitro fertilization. Fertil Steril 2000;73: Loumaye E, Billion JM, Milne JM, Palti I, Pensis M, Thomas K. Prediction of individual response to controlled hyperstimulation by means of a clomiphene citrate challenge test. Fertil Steril 1990;53: Scott RT, Leonardi MR, Hofmann GE, Illions EH, Neal GS, Navot D. A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population. Obstet Gynecol 1993;82: Watt AH, Legedza ATR, Ginsburg ES, Barbieri RL, Clarke RN, Hornstein MD. The prognostic value of age and follicle-stimulating hormone levels in women over forty years of age undergoing in vitro fertilization. J Asst Reprod Genet 2000;17: SAS/STAT Software, version 8.2. Cary (NC): SAS Institute Inc., FERTILITY & STERILITY 115