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• W2040887320 abstract "To examine whether day 3 LH level or FSH-LH ratio predict IVF outcome, we studied patients with a favorable prognosis a priori undergoing controlled ovarian hyperstimulation (COH) with GnRH agonist (agonist group; n = 131) or antagonist (antagonist group; n = 137). Although LH level could not predict IVF outcome, patients undergoing COH using the GnRH antagonist or agonist protocols with FSH-LH ratios >2 or >3, respectively, achieved significantly lower pregnancy rates (11.1% vs. 27.7% and 8.3% vs. 31.9%, respectively). To examine whether day 3 LH level or FSH-LH ratio predict IVF outcome, we studied patients with a favorable prognosis a priori undergoing controlled ovarian hyperstimulation (COH) with GnRH agonist (agonist group; n = 131) or antagonist (antagonist group; n = 137). Although LH level could not predict IVF outcome, patients undergoing COH using the GnRH antagonist or agonist protocols with FSH-LH ratios >2 or >3, respectively, achieved significantly lower pregnancy rates (11.1% vs. 27.7% and 8.3% vs. 31.9%, respectively). Controlled ovarian hyperstimulation (COH) is considered to be a key factor in the success of in vitro fertilization-embryo transfer (IVF-ET). Although individualization and careful tailoring of the COH protocol are mandatory for IVF success, currently there is no accurate test to predict ovarian response except for a patient's response to previous COH (1Penzias A.S. Improving results with assisted reproductive technologies: individualized patient-tailored strategies for ovulation induction.Reprod Biomed Online. 2004; 9: 43-46Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 2Muasher S.J. Abdallah R.T. Hubayter Z.R. Optimal stimulation protocols for in vitro fertilization.Fertil Steril. 2006; 86: 267-273Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Day 3 FSH and LH levels are universally measured during the routine assessment of patients' ovarian reserve, with no definitive evidence for their predictive value (3Broekmans1 F.J. Kwee J. Hendriks1 D.J. Mol B.W. Lambalk C.B. A systematic review of tests predicting ovarian reserve and IVF outcome.Hum Reprod Update. 2006; 12: 685-718Crossref PubMed Scopus (921) Google Scholar). Moreover, only a few studies have evaluated the predictive role of day 3 serum LH levels, and with conflicting results. Mukherjee et al. (4Mukherjee T. Copperman A.B. Lapinski R. Sandler B. Bustillo M. Grunfeld L. An elevated day three follicle-stimulating hormone:luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation.Fertil Steril. 1996; 65: 588-593PubMed Scopus (87) Google Scholar) suggested that day 3 LH value <3 IU/L and FSH:LH ratio >3.6 are predictive of a poor response to the long GnRH agonist suppressive COH protocol. Moreover, although Shrim et al. (5Shrim A. Elizur S.E. Seidman D.S. Rabinovici J. Wiser A. Dor J. Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response.Reprod Biomed Online. 2006; 12: 418-422Abstract Full Text PDF PubMed Scopus (40) Google Scholar) and Barroso et al. (6Barroso G. Oehninger S. Monzo A. Kolm P. Gibbons W.E. Muasher S.J. High FSH:LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome.J Assist Reprod Genet. 2001; 18: 499-505Crossref PubMed Scopus (35) Google Scholar) confirmed the association between FSH-LH ratio >3 and reduced clinical pregnancy rates, neither Barroso et al. (6Barroso G. Oehninger S. Monzo A. Kolm P. Gibbons W.E. Muasher S.J. High FSH:LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome.J Assist Reprod Genet. 2001; 18: 499-505Crossref PubMed Scopus (35) Google Scholar) nor Noci et al. (7Noci I. Maggi M. Fuzzi B. Biagiotti R. Ricci F. Marchionni M. Effects of low day 3 luteinizing hormone levels on in vitro fertilization treatment outcome.Gynecol Endocrinol. 2000; 14: 321-326Crossref PubMed Scopus (15) Google Scholar) could find any difference in ovarian response among patients with serum LH <3 IU/L or >3 IU/L. Of note, although all of these studies included patients who underwent the short flare-up or the long suppressive GnRH agonist COH protocols, the only study evaluating patients undergoing the GnRH antagonist COH protocol found lower baseline levels of FSH and E2, but not LH, to correlate with improved ovarian response and pregnancy rates (8Jurema M.W. Bracero N.J. Garcia J.E. Fine tuning cycle day 3 hormonal assessment of ovarian reserve improves in vitro fertilization outcome in gonadotropin-releasing hormone antagonist cycles.Fertil Steril. 2003; 80: 1156-1161Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Prompted by these findings, we sought to examine the predictive role of day 3 serum LH level or FSH:LH ratio on IVF cycle outcome, in patients undergoing COH protocols using GnRH agonists versus GnRH antagonists. These findings may help to clarify the proper approach to GnRH analogues in COH and to aid fertility specialists and their patients in the decision-making process. We reviewed the computerized files of all consecutive women admitted to our IVF unit during an 8-year period who reached the ovum pick-up (OPU) stage. The elimination of bias in this selection, for the purposes of this study, was achieved by including only patients with a favorable prognosis a priori, that is, women ≤35 years old, with day 3 FSH level <15 IU/L, undergoing up to their third IVF cycle attempt. Other exclusion criteria were use of donor oocytes or transfer of frozen-thawed embryos and use of other than a midluteal long GnRH agonist suppressive protocol (agonist group) or the flexible multidose GnRH antagonist protocol (antagonist group). The selection of type of analogue used was the decision of the treating physician and largely dependent on the fashion at that time. Data on patients' age, day 3 FSH and LH levels, and infertility treatment–related variables were collected from the files. Ovarian stimulation characteristics, number of oocytes retrieved, and number of embryos transfered per cycle were recorded. Results are presented as mean ± SD. Differences in variables were statistically analyzed with nonparametric Wilcoxon signed rank test, Student t test, and chi-squared test, as appropriate. A P value of less than .05 was considered to be significant. Two hundred sixty-eight IVF cycles were evaluated, 131 in the agonist group and 137 in the antagonist. Pregnancy was achieved in 74 patients (pregnancy rate 27.6% per cycle), 39 in the agonist group (pregnancy rate 29.8% per cycle) and 35 in the antagonist group (pregnancy rate 25.5% per cycle). As expected (9Ludwig M. Katalinic A. Diedrich K. Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol. Meta-analysis.Arch Gynecol Obstet. 2001; 265: 175-182Crossref PubMed Scopus (144) Google Scholar, 10Al-Inany H. Aboulghar M. GnRH antagonist in assisted reproduction: a Cochrane review.Hum Reprod. 2002; 17: 874-885Crossref PubMed Scopus (315) Google Scholar), the agonist group used significantly more gonadotropin ampules (36 ± 13 vs. 28 ± 14, respectively; P<.04) and required longer stimulation (10.4 ± 2.1 vs. 9.8 ± 2.0 days, respectively; P<.04), although there were no differences between the groups in patients' age, peak E2 and progesterone levels, number of oocytes retrieved, or embryos transfered. We analyzed patients according to their different day 3 FSH:LH ratio (subgroup I ≤3; subgroup II >3). Although in the antagonist group no differences were observed between the subgroups in stimulation characteristics or pregnancy rates (26.2% vs. 14.3%, for subgroups I and II, respectively; P=.4), in the agonist group patients in subgroup I (FSH:LH ratio ≤3) achieved a higher pregnancy rate compared with subgroup II (FSH:LH ratio >3) (31.9% vs. 8.3%, respectively; P<.01), with no differences between the other COH characteristics. When using a different cutoff for day 3 FSH:LH ratio (subgroup IA ≤2; subgroup IIA >2), although in the agonist group no differences in the COH characteristics or pregnancy rates (33.3% vs. 18.8%, for subgroups IA and IIA, respectively; P=.08) were observed between the subgroups, in the antagonist group patients in subgroup IA (FSH:LH ratio ≤2) achieved higher E2 levels (1,826 ± 1,127 pg/mL vs. 1,296 ± 650 pg/mL, respectively; P<.05) on the day of hCG administration, with a significantly higher pregnancy rate compared with subgroup IIA (27.7% vs. 11.1%, respectively; P<.05). Patients were also divided into subgroups according to their day 3 LH level (subgroup A ≤3 IU/L; subgroup B >3 IU/L). In the antagonist group, patients in subgroup A (LH ≤3 IU/L) achieved lower E2 levels on the day of hCG administration compared with subgroup B (LH >3 IU/L) (1,367 ± 907 pg/mL vs. 1,843 ± 1,112 pg/mL, respectively; P<.04). Furthermore, in both the GnRH agonist and the GnRH antagonist groups, no in-between subgroup differences were observed in the other COH variables or pregnancy rates (Table 1).Table 1COH characteristics according to different day 3 LH and FSH:LH subgroups.Day 3 LH levelDay 3 FSH:LH ratio≤3 IU/L>3 IU/LP value≤3>3P valueAgonist groupPatient age (yrs)30.1 ± 2.528.8 ± 3.4ns29.0 ± 3.430.4 ± 1.5nsLength of stimulation (days)10.4 ± 1.910.4 ± 2.2ns10.3 ± 2.210.8 ± 1.8nsNumber of Gn ampules used33 ± 1131 ± 14ns31 ± 1334 ± 13nsE2 levels on day of hCG (pg/mL)1714 ± 7702010 ± 962ns1933 ± 9471966 ± 687nsProgesterone levels on day of hCG (ng/mL)0.6 ± 0.40.8 ± 0.5ns0.7 ± 0.50.8 ± 0.4nsNumber of oocytes retrieved9.7 ± 5.211.3 ± 6.6ns10.8 ± 6.311.7 ± 6.7nsNumber of embryos transfered1.7 ± 0.41.9 ± 0.6ns1.8 ± 0.61.8 ± 0.4nsPregnancy rate18.8% (6/32)33.3% (33/99)ns31.9% (38/119)8.3% (1/12)<.01≤3 IU/L>3 IU/LP value≤2>2P valueAntagonist groupPatient age (yrs)28.6 ± 3.428.5 ± 3.2ns28.4 ± 3.229.4 ± 2.9nsLength of stimulation (days)10.2 ± 2.49.8 ± 1.9ns9.8 ± 1.910.2 ± 2.6nsNumber of Gn ampules used28 ± 828 ± 15ns28 ± 1529 ± 9nsE2 levels on day of hCG (pg/mL)1367 ± 9071843 ± 1112.041826 ± 11271296 ± 650<.05Progesterone levels on day of hCG (ng/mL)0.7 ± 0.40.9 ± 1.0ns0.9 ± 1.00.7 ± 0.4 nsNumber of oocytes retrieved11.3 ± 7.213.6 ± 7.8ns13.4 ± 7.711.5 ± 8.0nsNumber of embryos transfered1.8 ± 0.72.0 ± 0.4ns2.0 ± 0.41.8 ± 0.7nsPregnancy rate24% (6/25)25.9% (29/112)ns27.7% (33/119)11.1% (2/18)<.05Note: Gn = gonadotropin. Open table in a new tab Note: Gn = gonadotropin. In the present study of patients undergoing COH for IVF, with a favorable prognosis a priori, day 3 FSH:LH ratio, but not LH level, was found to predict treatment outcome. Moreover, although day 3 FSH:LH ratio of ≤3 was associated with a higher pregnancy rate in patients undergoing the long GnRH agonist suppressive protocol, in patients undergoing the flexible multidose GnRH antagonist protocol a day 3 FSH:LH ratio of ≤2 predicts a better outcome. The observed lack of association between low baseline LH levels and poor IVF outcome is in agreement with studies consisting of patients undergoing either the long GnRH agonist suppressive (6Barroso G. Oehninger S. Monzo A. Kolm P. Gibbons W.E. Muasher S.J. High FSH:LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome.J Assist Reprod Genet. 2001; 18: 499-505Crossref PubMed Scopus (35) Google Scholar, 7Noci I. Maggi M. Fuzzi B. Biagiotti R. Ricci F. Marchionni M. Effects of low day 3 luteinizing hormone levels on in vitro fertilization treatment outcome.Gynecol Endocrinol. 2000; 14: 321-326Crossref PubMed Scopus (15) Google Scholar, 11Kassab A. Sabatini L. Lieberman G. Tozer A. Zosmer A. Davis C. et al.Does measuring early basal serum follicular luteinising hormone assist in predicting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcome?.Reprod Biol Endocrinol. 2007; 5: 32Crossref PubMed Scopus (3) Google Scholar) or the GnRH antagonist (8Jurema M.W. Bracero N.J. Garcia J.E. Fine tuning cycle day 3 hormonal assessment of ovarian reserve improves in vitro fertilization outcome in gonadotropin-releasing hormone antagonist cycles.Fertil Steril. 2003; 80: 1156-1161Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar) COH protocol. Moreover, although the results of the present study confirm earlier reports (4Mukherjee T. Copperman A.B. Lapinski R. Sandler B. Bustillo M. Grunfeld L. An elevated day three follicle-stimulating hormone:luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation.Fertil Steril. 1996; 65: 588-593PubMed Scopus (87) Google Scholar, 5Shrim A. Elizur S.E. Seidman D.S. Rabinovici J. Wiser A. Dor J. Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response.Reprod Biomed Online. 2006; 12: 418-422Abstract Full Text PDF PubMed Scopus (40) Google Scholar, 6Barroso G. Oehninger S. Monzo A. Kolm P. Gibbons W.E. Muasher S.J. High FSH:LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome.J Assist Reprod Genet. 2001; 18: 499-505Crossref PubMed Scopus (35) Google Scholar) on the role of FSH:LH ratio >3 in the prediction of poor IVF outcome in patients undergoing the long GnRH agonist protocol, we report, for the first time, that in patients undergoing the GnRH antagonist COH protocol an FSH:LH ratio >2 is associated with poor IVF outcome. Studies comparing GnRH agonist long protocol with GnRH antagonist protocol have yielded conflicting results for pregnancy rate, with a tendency toward a better outcome for GnRH agonists (9Ludwig M. Katalinic A. Diedrich K. Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol. Meta-analysis.Arch Gynecol Obstet. 2001; 265: 175-182Crossref PubMed Scopus (144) Google Scholar, 10Al-Inany H. Aboulghar M. GnRH antagonist in assisted reproduction: a Cochrane review.Hum Reprod. 2002; 17: 874-885Crossref PubMed Scopus (315) Google Scholar, 12Orvieto R. Rabinson J. Meltzer S. Homburg R. Anteby E. Zohav E. GnRH agonist versus GnRH antagonist in ovarian stimulation: is the emperor naked?.Clin Exp Obstet Gynecol. 2006; 33: 197-199PubMed Google Scholar). The lower pregnancy rate observed during the GnRH antagonist cycles was related to their use in cycles with an unfavorable prognosis a priori, or to “centers' inexperience” (13Fauser B.C. Devroey P. Why is the clinical acceptance of gonadotropin-releasing hormone antagonist cotreatment during ovarian hyperstimulation for in vitro fertilization so slow?.Fertil Steril. 2005; 83: 1607-1611Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 14Griesinger G. Felberbaum R. Diedrich K. GnRH antagonists in ovarian stimulation: a treatment regimen of clinicians' second choice? Data from the German National IVF Registry.Hum Reprod. 2005; 20: 2373-2375Crossref PubMed Scopus (65) Google Scholar). Our recent attempts to examine whether physicians' experience may influence IVF outcome in patients undergoing GnRH antagonist COH protocols, revealed that only patients with a body mass index >25 kg/m2 (15Rabinson J. Meltcer S. Zohav E. Gemer O. Anteby E.Y. Orvieto R. GnRH agonist versus GnRH antagonist in ovarian stimulation: the influence of body mass index on in vitro fertilization outcome.Fertil Steril. 2008; 89: 472-490Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) and those achieving, on day of hCG administration, an E2-follicle ratio <100 pg/mL (16Orvieto R, Rabinson J, Meltcer S, Gemer O, Anteby EY, Zohav E. Does physicians' experience influence IVF success in patients undergoing controlled ovarian stimulation with GnRH-antagonists? Fertil Steril Published online May 11, 2007.Google Scholar) had pregnancy rates similar to those of the agonist group. Otherwise, the agonist group was the preferred protocol. The two-cell theory suggests that both FSH and LH are needed for normal follicular growth and maturation. Moreover, from experimental and clinical evidence it seems that there is a ”threshold” for LH requirements during folliculogenesis (17Hillier S.G. Controlled ovarian stimulation in women.J Reprod Fertil. 2000; 120: 201-210Crossref PubMed Google Scholar), that together with the intricate auto- and paracrine actions of intraovarian regulators influence follicular development (18Taymor M.L. The regulation of follicle growth: some clinical implications in reproductive endocrinology.Fertil Steril. 1996; 65: 235-247PubMed Google Scholar, 19Noci I. Biagiotti R. Maggi M. Ricci F. Cinotti A. Scarselli G. Low day 3 luteinizing hormone values are predictive of reduced response to ovarian stimulation.Hum Reprod. 1998; 13: 531-534Crossref PubMed Scopus (37) Google Scholar). A classic study of patients with hypogonadotropic hypogonadism has already demonstrated that although an LH-depleted environment yielded oocytes with reduced fertilization potential and lower serum and follicular E2 concentration, LH supplementation could resume follicular development, promoted E2 secretion, enhanced the effect of FSH on follicular growth, and permitted successful luteinization of follicles when exposed to hCG (20European Recombinant Human LH Study Group (1998) Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study.J Clin Endocrinol Metab. 1998; 83: 1507-1514Crossref PubMed Scopus (247) Google Scholar). The observed relatively lower LH in the presence of normal FSH concentration could simply be a marker of an impaired balance between ovarian steroid concentration, peptide production, and pituitary secretion, with the consequent reduced activity of these intraovarian regulators accounting for the observed decrease in pregnancy rate. In the present study, after excluding cycles and patients with an unfavorable prognosis, we found day 3 FSH:LH ratio to have a role in predicting IVF outcome and to probably contribute to the appropriate selection of the optimal COH protocol. Further large prospective studies are needed to elucidate the role of day 3 FSH:LH ratio in the various COH protocols. Moreover, it would be interesting to examine whether the subgroup of patients with high FSH:LH ratio would benefit from LH supplementation during COH—an unresolved issue which is subject to a recent extensive debate (2Muasher S.J. Abdallah R.T. Hubayter Z.R. Optimal stimulation protocols for in vitro fertilization.Fertil Steril. 2006; 86: 267-273Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 21Penarrubia J. Fabregues F. Creus M. Manau D. Casamitjana R. Guimera M. et al.LH serum levels during ovarian stimulation as predictors of ovarian response and assisted reproduction outcome in down-regulated women stimulated with recombinant FSH.Hum Reprod. 2003; 18: 2689-2697Crossref PubMed Scopus (47) Google Scholar, 22Kolibianakis E.M. Kalogeropoulou L. Griesinger G. Papanikolaou E.G. Papadimas J. Bontis J. et al.Among patients treated with FSH and GnRH analogues for in vitro fertilization, is the addition of recombinant LH associated with the probability of live birth? A systematic review and meta-analysis.Hum Reprod Update. 2007; 13: 445-452Crossref PubMed Scopus (92) Google Scholar)." @default.
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• W2040887320 title "Does day 3 luteinizing-hormone level predict IVF success in patients undergoing controlled ovarian stimulation with GnRH analogues?" @default.
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