Use of a luteal estradiol patch and a gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation for in vitro fertilization in poor responders
2005; Elsevier BV; Volume: 84; Issue: 4 Linguagem: Inglês
10.1016/j.fertnstert.2005.04.031
ISSN1556-5653
AutoresKatherine G. Dragisic, Owen Davis, Sozos J. Fasouliotis, Zev Rosenwaks,
Tópico(s)Sperm and Testicular Function
ResumoThe administration of a luteal E2 patch/GnRH antagonist protocol before gonadotropins in poor responders may improve ovarian stimulation and result in greater uniformity in follicular development and improved pregnancy rates. The administration of a luteal E2 patch/GnRH antagonist protocol before gonadotropins in poor responders may improve ovarian stimulation and result in greater uniformity in follicular development and improved pregnancy rates. The use of a novel protocol for poor responders incorporating E2 patches and a GnRH antagonist (GnRH-a) in the luteal phase of the preceding menstrual cycle followed by high dose follicular phase gonadotropin stimulation was reviewed. Comparison of patients’ responses to this protocol with previous IVF stimulation revealed a lower cancellation rate, a higher mean number of oocytes retrieved and embryos available for transfer, as well as a satisfactory clinical pregnancy rate (PR).Poor responders present a major challenge in assisted reproduction. Despite the implementation of strategies devised to optimize stimulation, these patients still suffer a high rate of cycle cancellation and implantation failure (1Scott R.T. Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization.Fertil Steril. 1994; 61: 880-885PubMed Scopus (153) Google Scholar, 2Schoolcraft W. Schlenker T. Gee M. Stevens J. Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol.Fertil Steril. 1997; 67: 93-97Abstract Full Text PDF PubMed Scopus (172) Google Scholar, 3Olivennes F. Cunha-Filho J.S. Fanchin R. Bouchard P. Frydman R. The use of GnRH antagonists in ovarian stimulation.Hum Reprod Update. 2002; 8: 279-290Crossref PubMed Scopus (117) Google Scholar, 4Akman M.A. Erden H.F. Tosun S.B. Bayazit N. Aksoy E. Bahceci M. Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders results of a prospective randomized trial.Hum Reprod. 2001; 16: 868-870Crossref PubMed Scopus (158) Google Scholar).Controlled ovarian hyperstimulation (COH) protocols for poor responders are designed to counteract early follicle selection in the luteal phase and to optimize the follicular hormonal milieu and antral follicle responsiveness. In the antecedent luteal phase, select follicles may respond to the low level increase in FSH as a result of both innate sensitivity to FSH and follicular size (5Klein N.A. Battaglia D.E. Fujimoto V.Y. Davis G.S. Bremner W.J. Soules M.R. Reproductive aging accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women.J Clin Endocrinol Metab. 1996; 81: 1038-1045Crossref PubMed Scopus (260) Google Scholar, 6Mais V. Cetel N.S. Muse K.N. Quigley M.E. Reid R.L. Yen S.S. Hormonal dynamics during luteal-follicular transition.J Clin Endocrinol Metab. 1987; 64: 1109-1114Crossref PubMed Scopus (41) Google Scholar). Consequently, early in the subsequent follicular phase, some antral follicles may be more sensitive to exogenous gonadotropin stimulation (7McNatty K.P. Hillier S.G. van den Boogaard A.M. Trimbos-Kemper T.C. Reichert Jr, L.E. van Hall E.V. Follicular development during the luteal phase of the human menstrual cycle.J Clin Endocrinol Metab. 1983; 56: 1022-1031Crossref PubMed Scopus (124) Google Scholar).Fanchin et al. (8Fanchin R. Cunha-Filho J.S. Schonauer L.M. Righini C. de Ziegler D. Frydman R. Luteal estradiol administration strengthens the relationship between day 3 follicle-stimulating hormone and inhibin B levels and ovarian follicular status.Fertil Sertil. 2003; 79: 585-589Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 9Fanchin R. Cunha-Filho J.S. Schonauer L.M. Kadoch I.J. Cohen-Bacri P. Frydman R. Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens.Fertil Steril. 2003; 79: 316-321Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) recently reported that luteal E2 administration resulted in a reduction of both antral follicular sizes and heterogeneity in the early follicular phase, ostensibly due to FSH suppression. Furthermore, they recently added luteal E2 suppression to GnRH-a protocols and reported a reduction in the heterogeneity of antral follicles on day 8 of stimulation and an increase in the number of follicles attaining synchronized maturity (10Fanchin R. Salomon L. Castelo-Branco A. Olivennes F. Frydman N. Frydman R. Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists.Hum Reprod. 2003; 18: 2698-2703Crossref PubMed Scopus (118) Google Scholar). Recently, since the inception of our study, Fanchin et al. (11Fanchin R. Branco A.C. Kadoch I.J. Hosny G. Bagirova M. Frydman R. Premenstrual administration of gonadotropin-releasing hormone antagonist coordinates early antral follicle sizes and sets up the basis for an innovative concept of controlled ovarian hyperstimulation.Fertil Steril. 2004; 81: 1554-1559Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar) described luteal GnRH-a administration as a means to suppress day 2 FSH levels and reduce baseline antral follicular size and heterogeneity.We have developed a novel protocol incorporating both transdermal E2 and a GnRH-a in the preceding luteal phase, followed by follicular phase gonadotropin stimulation with adjunctive GnRH-a. Here we evaluate the ability of this protocol to enhance the follicular response in a group of 68 patients who were deemed poor responders between January 2003 and June 2004. Weill Medical College of Cornell University Institutional Review Board approval was obtained for this retrospective study.Patients were included if they were considered poor responders, as defined by one or more of the following criteria: [1] four or fewer oocytes retrieved in previous stimulation; [2] basal follicular-stimulating hormone levels >12 mIU/mL (follicular female range, 3–14.4 mIU/mL); or [3] low E2 level on the day of hCG administration (<500 pg/mL) in previous stimulation (12Fasouliotis S.J. Laufer N. Sabbagh-Ehrlich S. Lewin A. Hurwitz A. Simon A. Gonadotropin-releasing hormone (GnRH)-antagonist versus GnRH-agonist in ovarian stimulation of poor responders undergoing IVF.J Assist Reprod Genet. 2003; 20: 455-460Crossref PubMed Scopus (44) Google Scholar).Responses on the luteal E2 patch/GnRH-a protocol were compared to the previous IVF cycles. Of those patients who had previously attempted stimulation, 40 had been treated with follicular gonadotropins followed by GnRH-a initiated late in the follicular phase; 18 had attempted cycles with a microdose GnRH-agonist flare protocol; 5 patients had undergone cycles with low-dose leuprolide acetate (Lupron; TAP Pharmaceuticals, North Chicago, IL); and 3 had attempted short flare-up (“coflare”) protocols (1Scott R.T. Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization.Fertil Steril. 1994; 61: 880-885PubMed Scopus (153) Google Scholar, 2Schoolcraft W. Schlenker T. Gee M. Stevens J. Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol.Fertil Steril. 1997; 67: 93-97Abstract Full Text PDF PubMed Scopus (172) Google Scholar, 3Olivennes F. Cunha-Filho J.S. Fanchin R. Bouchard P. Frydman R. The use of GnRH antagonists in ovarian stimulation.Hum Reprod Update. 2002; 8: 279-290Crossref PubMed Scopus (117) Google Scholar, 4Akman M.A. Erden H.F. Tosun S.B. Bayazit N. Aksoy E. Bahceci M. Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders results of a prospective randomized trial.Hum Reprod. 2001; 16: 868-870Crossref PubMed Scopus (158) Google Scholar, 13Albano C. Felderbaum R.E. Smitz J. Reithmüller-Winzen H. Engel J. Diedrich K. et al.Ovarian stimulation with HMG results of a prospective randomized phase III European study comparing the luteinizing hormone (LHRH)-antagonist cetorelix and the LHRH-agonist buserelin.Hum Reprod. 2000; 15: 526-531Crossref PubMed Scopus (301) Google Scholar, 14Spandorfer S. Navarro J. Kump L.M. Liu H.C. Davis O.K. Rosenwaks Z. Co-flare stimulation in the poor responder patient predictive value of the flare response.J Assist Reprod Genet. 2001; 18: 629-633Crossref PubMed Scopus (14) Google Scholar). Twenty (30.3%) of the patients had taken oral contraceptive (OC) pills before starting their previous cycle. Four patients (6.3%) had had a first trimester spontaneous abortion after the prior cycle, two (3.2%) had a biochemical pregnancy, and one (1.5%) had had a term pregnancy and delivered.In this protocol, patients were monitored with a home urinary ovulation predictor kit. On the 10th day after the LH surge, patients applied one 0.1-mg transdermal E2 patch and replaced the patch with a new 0.1-mg patch every other day. On the second day of the transdermal E2 patch, the patients began taking daily ganirelix acetate (Antagon; Organon Pharmaceuticals, West Orange, NJ) 0.25 mg subcutaneously for 3 days. Patients presented to the center on day 2 of their ensuing menses for measurement of FSH, LH, and E2 levels and a baseline ultrasound. Patients then remained on the last E2 patch until the patch fell off or until day of hCG administration. Serum samples were assayed by the commercially available Immulyte 2000 assay method (Diagnostic Products Corporation, Los Angeles, CA).On day 2 of menses patients were started on at least two ampules of FSH (Follistim, Organon Pharmaceuticals, West Orange, NJ or Gonal-F, Serono Pharmaceuticals, Rockland, MA) and at least two ampules of hMG (Repronex, Ferring Pharmaceuticals, Tarrytown, NY or Pergonal, Serono Pharmaceuticals, Rockland, MA) using a step-down protocol. Ganirelix acetate was administered starting on either day 7 of stimulation, when the lead follicles measured 13 mm or the E2 level exceeded 300 pg/mL. Human chorionic gonadotropin was administered (3,300–10,000 IU) once at least two lead follicles had attained or exceeded 16- to 17-mm mean diameter as measured by transvaginal ultrasound.Oocytes were harvested by transvaginal ultrasound-guided follicular puncture 35–36 hours after hCG administration. Conventional oocyte insemination or intracytoplasmic sperm injection (ICSI) was performed as indicated. The highest morphological grade embryos were transferred into the uterine cavity 72 hours after retrieval.Paired t tests were used to compare parameters between cycles, and the χ2 test was used to compare cycle cancellation rates. A P value <.05 was considered statistically significant.Sixty-eight patients who were defined as low responders attempted 80 IVF cycles with the luteal E2 patch/GnRH-a protocol. The mean age was 39.7 ± 3.5 years. In addition to being poor responders, some patients had other etiologies of infertility: 22.1% (15) tubal factor, 33.8% (23) male factor, 13.2% (9) endometriosis, and 5.9% (4) recurrent spontaneous abortion.Of the 68 patients, 66 had attempted previous IVF cycles. Patients had attempted a mean number of 3.0 ± 2.0 IVF cycles with 0.9 ± 1.1 mean cancelled cycles. In 66 (82.5%) luteal E2 patch/GnRH-a protocol cycles patients were started on a protocol of 8 ampules per day (40 cycles, 6 ampules of FSH plus 2 ampules of hMG; in 26 cycles, 4 ampules of FSH plus 4 ampules of hMG).After E2 patch/GnRH-a luteal phase suppression, mean day 2 FSH levels were significantly lower and mean E2 levels were significantly higher compared to random day 3 values (FSH: 2.4 ± 1.4 vs. 11.6 ± 5.8 mIU/mL, P<.005; E2: 110.4 ± 67.0 vs. 37.1 ± 20.2 pg/mL, P<.005). During gonadotropin stimulation, mean E2 levels reached a nadir by day 4 before starting to increase (mean E2 levels on days 2, 4, 6, and 8, respectively: 110.1 ± 65.3, 89.7 ± 46.9, 122.4 ± 76.3, and 255.6 ± 188.7 pg/mL).We compared stimulation parameters for patients who completed the luteal E2 patch/GnRH-a protocol with those of their previous completed stimulation protocols in Table 1. Of these 66 patients, 9 (13.6%) failed to complete the IVF cycle, compared to a 33% cancellation rate for the prior protocol (χ2 = 5.4, P<.05).TABLE 1Stimulation parameters for completed cycles.Cycle parameterPrior cycle (n = 66)E2 patch cycle (n = 66)P valueCancellation rate (%)aχ2 = 5.4, P<.05.33.3%13.6%<.05Ampules of gonadotropins53.0 ± 21.370.5 ± 16.8<.05Days of stimulation10.8 ± 2.411.0 ± 1.5NSAmpules of gonadotropins/day5.5 ± 1.46.9 ± 1.2<.05E2 day of hCG (pg/mL)873.0 ± 603.2931.3 ± 562.3NSOocytes retrieved6.4 ± 4.38.3 ± 5.3<.05Mature oocytes5.2 ± 3.46.8 ± 4.4<.05Two pronucleibEmbryo grade on a scale of 1–5, with 1 being the highest.2.4 ± 2.54.5 ± 3.2<.05Mean fertilization rate64.7%68.5%NSEmbryo grade2.3 ± 0.52.2 ± 1.1NSEmbryos transferred2.5 ± 1.73.1 ± 1.7<.05Note: Values are means ± SD. NS = not significant.Dragisic. Luteal E2 patch in poor responders. Fertil Steril 2005.a χ2 = 5.4, P<.05.b Embryo grade on a scale of 1–5, with 1 being the highest. Open table in a new tab Using this approach, patients had a significantly lower cancellation rate (P<.05) and higher mean number of oocytes retrieved (P<.05) and normally fertilized oocytes (P<.005). Patients also had a significantly higher number of embryos transferred (P<.05).To minimize the chance of a type I error in the multiple comparisons made between completed cycles, we applied the Bonferroni correction to the statistical comparisons (15Bonferroni C.E. Teoria statistica delle classi e calcolo delle probabilityá.Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze. 1936; 8: 3-62Google Scholar). When the adjusted P value was applied (P<.05/n, or P<.01, with n = 5), the number of ampules of gonadotropins administered, and the number of normally fertilized oocytes remained statistically different between cycles (P<.008), but the number of oocytes retrieved (P=.03), mature ooctyes (P=.03), and number of embryos transferred (P=.04) were not.The total and clinical PRs were 36.4% (21 patients) and 30.3% (17 patients), respectively, with an ongoing PR of 26.2% (15 patients) (as defined by pregnancies with confirmed fetal heartbeat at the time of writing of this article). The mean implantation rate was 12.3 ± 0.2.Based on these findings, the luteal E2 patch/GnRH-a protocol appears to be a viable option in the treatment of poor responders and yielded superior results compared to patients’ prior IVF cycles. Our findings support the hypothesis of Fanchin et al. (9Fanchin R. Cunha-Filho J.S. Schonauer L.M. Kadoch I.J. Cohen-Bacri P. Frydman R. Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens.Fertil Steril. 2003; 79: 316-321Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 10Fanchin R. Salomon L. Castelo-Branco A. Olivennes F. Frydman N. Frydman R. Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists.Hum Reprod. 2003; 18: 2698-2703Crossref PubMed Scopus (118) Google Scholar, 11Fanchin R. Branco A.C. Kadoch I.J. Hosny G. Bagirova M. Frydman R. Premenstrual administration of gonadotropin-releasing hormone antagonist coordinates early antral follicle sizes and sets up the basis for an innovative concept of controlled ovarian hyperstimulation.Fertil Steril. 2004; 81: 1554-1559Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar) that greater uniformity in antral follicle size and responsiveness after luteal pretreatment with E2 results in an increased number of follicles synchronously attaining maturity. In poor responders, a resultant increased number of oocytes and embryos are important aspects of a successful cycle given the generally diminished oocyte quality in these patients (16Kligman I. Rosenwaks Z. Differentiating clinical profiles predicting good responders, poor responders, and hyperresponders.Fertil Steril. 2001; 76: 1185-1190Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 17Devreker F. Pogonici E. De Maertelaer V. Revelard P. Van den Bergh M. Englert Y. Selection of good embryos for transfer depends on embryo cohort size implications for the “mild ovarian stimulation” debate.Hum Reprod. 1999; 14: 3002-3008Crossref PubMed Scopus (51) Google Scholar).One limitation of this study, as with most published trials of stimulation protocols for poor responders, is its retrospective nature. Our best yardstick to judge the efficacy of the E2 patch/GnRH-a protocol was the historical control of the patients’ prior cycles. In addition, it is possible that the increased number of ooctyes retrieved may be in part due to the higher mean number of ampules of gonadotropins administered in the E2 patch protocol (70.5 ± 16.8 vs. 53.0 ± 21.3, P<.05). However, in the E2 patch protocol patients were only treated with a mean of one additional ampule per day (6.9 ± 1.2 vs. 5.5 ± 1.4, P<.05), which would appear unlikely to significantly improve outcome. Simply increasing the gonadotropin dose has not generally been shown to improve cycle outcomes in poor responders (18Land J.A. Yarmolinskaya M.I. Dumoulin J.C.M. Evers J.L.H. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome.Fertil Steril. 1996; 65: 961-965Abstract Full Text PDF PubMed Scopus (215) Google Scholar, 19Khalaf Y. El-Toukhy T. Taylor A. Braude P. Increasing the gonadotrophin dose in the course of an in vitro fertilization cycle does not rectify an initial poor response.Eur J Obstet Gynecol Reprod Biol. 2002; 103: 146-149Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 20Karande V. Jones G. Veeck L. Muasher S. High-dose follicle stimulating hormone stimulation at the onset of the menstrual cycle does not improve the in vitro fertilization outcome in low-responder patients.Fertil Steril. 1990; 53: 486-489Crossref PubMed Google Scholar, 21Hofmann G. Toner J. Muasher S. Jones G. High-dose follicle-stimulating hormone (FSH) ovarian stimulation in low-responder patients for in vitro fertilization.J In Vitro Fert Embryo Transfer. 1989; 6: 285-289Crossref PubMed Scopus (83) Google Scholar, 22Surrey E.S. Schoolcraft W.B. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques.Fertil Steril. 2000; 73: 667-676Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). It seems likely that the luteal E2/GnRH-a priming created an optimal milieu for follicle recruitment as an adjunct to high dose gonadotropin therapy.In summary, the use of the E2 patch/GnRH-a protocol appears to improve ovarian responsiveness during COH for IVF and may result in more uniform follicular development, more oocytes retrieved, transfer of higher numbers of embryos, and improved PRs. Ultimately, however, randomized controlled trials will be necessary to determine the best protocol for poor responders. The use of a novel protocol for poor responders incorporating E2 patches and a GnRH antagonist (GnRH-a) in the luteal phase of the preceding menstrual cycle followed by high dose follicular phase gonadotropin stimulation was reviewed. Comparison of patients’ responses to this protocol with previous IVF stimulation revealed a lower cancellation rate, a higher mean number of oocytes retrieved and embryos available for transfer, as well as a satisfactory clinical pregnancy rate (PR). Poor responders present a major challenge in assisted reproduction. Despite the implementation of strategies devised to optimize stimulation, these patients still suffer a high rate of cycle cancellation and implantation failure (1Scott R.T. Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization.Fertil Steril. 1994; 61: 880-885PubMed Scopus (153) Google Scholar, 2Schoolcraft W. Schlenker T. Gee M. Stevens J. Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol.Fertil Steril. 1997; 67: 93-97Abstract Full Text PDF PubMed Scopus (172) Google Scholar, 3Olivennes F. Cunha-Filho J.S. Fanchin R. Bouchard P. Frydman R. The use of GnRH antagonists in ovarian stimulation.Hum Reprod Update. 2002; 8: 279-290Crossref PubMed Scopus (117) Google Scholar, 4Akman M.A. Erden H.F. Tosun S.B. Bayazit N. Aksoy E. Bahceci M. Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders results of a prospective randomized trial.Hum Reprod. 2001; 16: 868-870Crossref PubMed Scopus (158) Google Scholar). Controlled ovarian hyperstimulation (COH) protocols for poor responders are designed to counteract early follicle selection in the luteal phase and to optimize the follicular hormonal milieu and antral follicle responsiveness. In the antecedent luteal phase, select follicles may respond to the low level increase in FSH as a result of both innate sensitivity to FSH and follicular size (5Klein N.A. Battaglia D.E. Fujimoto V.Y. Davis G.S. Bremner W.J. Soules M.R. Reproductive aging accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women.J Clin Endocrinol Metab. 1996; 81: 1038-1045Crossref PubMed Scopus (260) Google Scholar, 6Mais V. Cetel N.S. Muse K.N. Quigley M.E. Reid R.L. Yen S.S. Hormonal dynamics during luteal-follicular transition.J Clin Endocrinol Metab. 1987; 64: 1109-1114Crossref PubMed Scopus (41) Google Scholar). Consequently, early in the subsequent follicular phase, some antral follicles may be more sensitive to exogenous gonadotropin stimulation (7McNatty K.P. Hillier S.G. van den Boogaard A.M. Trimbos-Kemper T.C. Reichert Jr, L.E. van Hall E.V. Follicular development during the luteal phase of the human menstrual cycle.J Clin Endocrinol Metab. 1983; 56: 1022-1031Crossref PubMed Scopus (124) Google Scholar). Fanchin et al. (8Fanchin R. Cunha-Filho J.S. Schonauer L.M. Righini C. de Ziegler D. Frydman R. Luteal estradiol administration strengthens the relationship between day 3 follicle-stimulating hormone and inhibin B levels and ovarian follicular status.Fertil Sertil. 2003; 79: 585-589Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 9Fanchin R. Cunha-Filho J.S. Schonauer L.M. Kadoch I.J. Cohen-Bacri P. Frydman R. Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens.Fertil Steril. 2003; 79: 316-321Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) recently reported that luteal E2 administration resulted in a reduction of both antral follicular sizes and heterogeneity in the early follicular phase, ostensibly due to FSH suppression. Furthermore, they recently added luteal E2 suppression to GnRH-a protocols and reported a reduction in the heterogeneity of antral follicles on day 8 of stimulation and an increase in the number of follicles attaining synchronized maturity (10Fanchin R. Salomon L. Castelo-Branco A. Olivennes F. Frydman N. Frydman R. Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists.Hum Reprod. 2003; 18: 2698-2703Crossref PubMed Scopus (118) Google Scholar). Recently, since the inception of our study, Fanchin et al. (11Fanchin R. Branco A.C. Kadoch I.J. Hosny G. Bagirova M. Frydman R. Premenstrual administration of gonadotropin-releasing hormone antagonist coordinates early antral follicle sizes and sets up the basis for an innovative concept of controlled ovarian hyperstimulation.Fertil Steril. 2004; 81: 1554-1559Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar) described luteal GnRH-a administration as a means to suppress day 2 FSH levels and reduce baseline antral follicular size and heterogeneity. We have developed a novel protocol incorporating both transdermal E2 and a GnRH-a in the preceding luteal phase, followed by follicular phase gonadotropin stimulation with adjunctive GnRH-a. Here we evaluate the ability of this protocol to enhance the follicular response in a group of 68 patients who were deemed poor responders between January 2003 and June 2004. Weill Medical College of Cornell University Institutional Review Board approval was obtained for this retrospective study. Patients were included if they were considered poor responders, as defined by one or more of the following criteria: [1] four or fewer oocytes retrieved in previous stimulation; [2] basal follicular-stimulating hormone levels >12 mIU/mL (follicular female range, 3–14.4 mIU/mL); or [3] low E2 level on the day of hCG administration (<500 pg/mL) in previous stimulation (12Fasouliotis S.J. Laufer N. Sabbagh-Ehrlich S. Lewin A. Hurwitz A. Simon A. Gonadotropin-releasing hormone (GnRH)-antagonist versus GnRH-agonist in ovarian stimulation of poor responders undergoing IVF.J Assist Reprod Genet. 2003; 20: 455-460Crossref PubMed Scopus (44) Google Scholar). Responses on the luteal E2 patch/GnRH-a protocol were compared to the previous IVF cycles. Of those patients who had previously attempted stimulation, 40 had been treated with follicular gonadotropins followed by GnRH-a initiated late in the follicular phase; 18 had attempted cycles with a microdose GnRH-agonist flare protocol; 5 patients had undergone cycles with low-dose leuprolide acetate (Lupron; TAP Pharmaceuticals, North Chicago, IL); and 3 had attempted short flare-up (“coflare”) protocols (1Scott R.T. Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization.Fertil Steril. 1994; 61: 880-885PubMed Scopus (153) Google Scholar, 2Schoolcraft W. Schlenker T. Gee M. Stevens J. Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol.Fertil Steril. 1997; 67: 93-97Abstract Full Text PDF PubMed Scopus (172) Google Scholar, 3Olivennes F. Cunha-Filho J.S. Fanchin R. Bouchard P. Frydman R. The use of GnRH antagonists in ovarian stimulation.Hum Reprod Update. 2002; 8: 279-290Crossref PubMed Scopus (117) Google Scholar, 4Akman M.A. Erden H.F. Tosun S.B. Bayazit N. Aksoy E. Bahceci M. Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders results of a prospective randomized trial.Hum Reprod. 2001; 16: 868-870Crossref PubMed Scopus (158) Google Scholar, 13Albano C. Felderbaum R.E. Smitz J. Reithmüller-Winzen H. Engel J. Diedrich K. et al.Ovarian stimulation with HMG results of a prospective randomized phase III European study comparing the luteinizing hormone (LHRH)-antagonist cetorelix and the LHRH-agonist buserelin.Hum Reprod. 2000; 15: 526-531Crossref PubMed Scopus (301) Google Scholar, 14Spandorfer S. Navarro J. Kump L.M. Liu H.C. Davis O.K. Rosenwaks Z. Co-flare stimulation in the poor responder patient predictive value of the flare response.J Assist Reprod Genet. 2001; 18: 629-633Crossref PubMed Scopus (14) Google Scholar). Twenty (30.3%) of the patients had taken oral contraceptive (OC) pills before starting their previous cycle. Four patients (6.3%) had had a first trimester spontaneous abortion after the prior cycle, two (3.2%) had a biochemical pregnancy, and one (1.5%) had had a term pregnancy and delivered. In this protocol, patients were monitored with a home urinary ovulation predictor kit. On the 10th day after the LH surge, patients applied one 0.1-mg transdermal E2 patch and replaced the patch with a new 0.1-mg patch every other day. On the second day of the transdermal E2 patch, the patients began taking daily ganirelix acetate (Antagon; Organon Pharmaceuticals, West Orange, NJ) 0.25 mg subcutaneously for 3 days. Patients presented to the center on day 2 of their ensuing menses for measurement of FSH, LH, and E2 levels and a baseline ultrasound. Patients then remained on the last E2 patch until the patch fell off or until day of hCG administration. Serum samples were assayed by the commercially available Immulyte 2000 assay method (Diagnostic Products Corporation, Los Angeles, CA). On day 2 of menses patients were started on at least two ampules of FSH (Follistim, Organon Pharmaceuticals, West Orange, NJ or Gonal-F, Serono Pharmaceuticals, Rockland, MA) and at least two ampules of hMG (Repronex, Ferring Pharmaceuticals, Tarrytown, NY or Pergonal, Serono Pharmaceuticals, Rockland, MA) using a step-down protocol. Ganirelix acetate was administered starting on either day 7 of stimulation, when the lead follicles measured 13 mm or the E2 level exceeded 300 pg/mL. Human chorionic gonadotropin was administered (3,300–10,000 IU) once at least two lead follicles had attained or exceeded 16- to 17-mm mean diameter as measured by transvaginal ultrasound. Oocytes were harvested by transvaginal ultrasound-guided follicular puncture 35–36 hours after hCG administration. Conventional oocyte insemination or intracytoplasmic sperm injection (ICSI) was performed as indicated. The highest morphological grade embryos were transferred into the uterine cavity 72 hours after retrieval. Paired t tests were used to compare parameters between cycles, and the χ2 test was used to compare cycle cancellation rates. A P value <.05 was considered statistically significant. Sixty-eight patients who were defined as low responders attempted 80 IVF cycles with the luteal E2 patch/GnRH-a protocol. The mean age was 39.7 ± 3.5 years. In addition to being poor responders, some patients had other etiologies of infertility: 22.1% (15) tubal factor, 33.8% (23) male factor, 13.2% (9) endometriosis, and 5.9% (4) recurrent spontaneous abortion. Of the 68 patients, 66 had attempted previous IVF cycles. Patients had attempted a mean number of 3.0 ± 2.0 IVF cycles with 0.9 ± 1.1 mean cancelled cycles. In 66 (82.5%) luteal E2 patch/GnRH-a protocol cycles patients were started on a protocol of 8 ampules per day (40 cycles, 6 ampules of FSH plus 2 ampules of hMG; in 26 cycles, 4 ampules of FSH plus 4 ampules of hMG). After E2 patch/GnRH-a luteal phase suppression, mean day 2 FSH levels were significantly lower and mean E2 levels were significantly higher compared to random day 3 values (FSH: 2.4 ± 1.4 vs. 11.6 ± 5.8 mIU/mL, P<.005; E2: 110.4 ± 67.0 vs. 37.1 ± 20.2 pg/mL, P<.005). During gonadotropin stimulation, mean E2 levels reached a nadir by day 4 before starting to increase (mean E2 levels on days 2, 4, 6, and 8, respectively: 110.1 ± 65.3, 89.7 ± 46.9, 122.4 ± 76.3, and 255.6 ± 188.7 pg/mL). We compared stimulation parameters for patients who completed the luteal E2 patch/GnRH-a protocol with those of their previous completed stimulation protocols in Table 1. Of these 66 patients, 9 (13.6%) failed to complete the IVF cycle, compared to a 33% cancellation rate for the prior protocol (χ2 = 5.4, P<.05). Note: Values are means ± SD. NS = not significant. Dragisic. Luteal E2 patch in poor responders. Fertil Steril 2005. Using this approach, patients had a significantly lower cancellation rate (P<.05) and higher mean number of oocytes retrieved (P<.05) and normally fertilized oocytes (P<.005). Patients also had a significantly higher number of embryos transferred (P<.05). To minimize the chance of a type I error in the multiple comparisons made between completed cycles, we applied the Bonferroni correction to the statistical comparisons (15Bonferroni C.E. Teoria statistica delle classi e calcolo delle probabilityá.Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze. 1936; 8: 3-62Google Scholar). When the adjusted P value was applied (P<.05/n, or P<.01, with n = 5), the number of ampules of gonadotropins administered, and the number of normally fertilized oocytes remained statistically different between cycles (P<.008), but the number of oocytes retrieved (P=.03), mature ooctyes (P=.03), and number of embryos transferred (P=.04) were not. The total and clinical PRs were 36.4% (21 patients) and 30.3% (17 patients), respectively, with an ongoing PR of 26.2% (15 patients) (as defined by pregnancies with confirmed fetal heartbeat at the time of writing of this article). The mean implantation rate was 12.3 ± 0.2. Based on these findings, the luteal E2 patch/GnRH-a protocol appears to be a viable option in the treatment of poor responders and yielded superior results compared to patients’ prior IVF cycles. Our findings support the hypothesis of Fanchin et al. (9Fanchin R. Cunha-Filho J.S. Schonauer L.M. Kadoch I.J. Cohen-Bacri P. Frydman R. Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens.Fertil Steril. 2003; 79: 316-321Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 10Fanchin R. Salomon L. Castelo-Branco A. Olivennes F. Frydman N. Frydman R. Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists.Hum Reprod. 2003; 18: 2698-2703Crossref PubMed Scopus (118) Google Scholar, 11Fanchin R. Branco A.C. Kadoch I.J. Hosny G. Bagirova M. Frydman R. Premenstrual administration of gonadotropin-releasing hormone antagonist coordinates early antral follicle sizes and sets up the basis for an innovative concept of controlled ovarian hyperstimulation.Fertil Steril. 2004; 81: 1554-1559Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar) that greater uniformity in antral follicle size and responsiveness after luteal pretreatment with E2 results in an increased number of follicles synchronously attaining maturity. In poor responders, a resultant increased number of oocytes and embryos are important aspects of a successful cycle given the generally diminished oocyte quality in these patients (16Kligman I. Rosenwaks Z. Differentiating clinical profiles predicting good responders, poor responders, and hyperresponders.Fertil Steril. 2001; 76: 1185-1190Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 17Devreker F. Pogonici E. De Maertelaer V. Revelard P. Van den Bergh M. Englert Y. Selection of good embryos for transfer depends on embryo cohort size implications for the “mild ovarian stimulation” debate.Hum Reprod. 1999; 14: 3002-3008Crossref PubMed Scopus (51) Google Scholar). One limitation of this study, as with most published trials of stimulation protocols for poor responders, is its retrospective nature. Our best yardstick to judge the efficacy of the E2 patch/GnRH-a protocol was the historical control of the patients’ prior cycles. In addition, it is possible that the increased number of ooctyes retrieved may be in part due to the higher mean number of ampules of gonadotropins administered in the E2 patch protocol (70.5 ± 16.8 vs. 53.0 ± 21.3, P<.05). However, in the E2 patch protocol patients were only treated with a mean of one additional ampule per day (6.9 ± 1.2 vs. 5.5 ± 1.4, P<.05), which would appear unlikely to significantly improve outcome. Simply increasing the gonadotropin dose has not generally been shown to improve cycle outcomes in poor responders (18Land J.A. Yarmolinskaya M.I. Dumoulin J.C.M. Evers J.L.H. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome.Fertil Steril. 1996; 65: 961-965Abstract Full Text PDF PubMed Scopus (215) Google Scholar, 19Khalaf Y. El-Toukhy T. Taylor A. Braude P. Increasing the gonadotrophin dose in the course of an in vitro fertilization cycle does not rectify an initial poor response.Eur J Obstet Gynecol Reprod Biol. 2002; 103: 146-149Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 20Karande V. Jones G. Veeck L. Muasher S. High-dose follicle stimulating hormone stimulation at the onset of the menstrual cycle does not improve the in vitro fertilization outcome in low-responder patients.Fertil Steril. 1990; 53: 486-489Crossref PubMed Google Scholar, 21Hofmann G. Toner J. Muasher S. Jones G. High-dose follicle-stimulating hormone (FSH) ovarian stimulation in low-responder patients for in vitro fertilization.J In Vitro Fert Embryo Transfer. 1989; 6: 285-289Crossref PubMed Scopus (83) Google Scholar, 22Surrey E.S. Schoolcraft W.B. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques.Fertil Steril. 2000; 73: 667-676Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). It seems likely that the luteal E2/GnRH-a priming created an optimal milieu for follicle recruitment as an adjunct to high dose gonadotropin therapy. In summary, the use of the E2 patch/GnRH-a protocol appears to improve ovarian responsiveness during COH for IVF and may result in more uniform follicular development, more oocytes retrieved, transfer of higher numbers of embryos, and improved PRs. Ultimately, however, randomized controlled trials will be necessary to determine the best protocol for poor responders.
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