A luteal estradiol protocol for expected poor-responders improves embryo number and quality

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A luteal estradiol protocol for expected poorresponders improves embryo number and quality John L. Frattarelli, M.D.,a Micah J. Hill, D.O.,b Grant D. E. McWilliams, D.O.,b Kathleen A. Miller, B.S.,a Paul A. Bergh, M.D.,a and Richard T. Scott, Jr., M.D., H.C.L.D.a a Reproductive Medicine Associates of New Jersey, Morristown, New Jersey; and b Tripler Army Medical Center, Honolulu, Hawaii

Objective: To compare embryo and oocyte data between a standard protocol and a luteal phase estradiol protocol. Design: Retrospective paired cohort analysis. Setting: Private in vitro fertilization (IVF) center. Patient(s): 60 poor-responder patients undergoing 120 IVF cycles. Intervention(s): Addition of luteal estradiol to the standard IVF protocol. Main Outcome Measure(s): Number of embryos with R7 cells on day 3 of development. Result(s): The luteal phase estradiol protocol showed a statistically significantly greater number of embryos with R7 cells, oocytes retrieved, mature oocytes, and embryos than did the standard protocol. There was no difference between the two protocols with respect to basal antral follicle count, days of stimulation, number of follicles R14 mm on day of surge, or endometrial thickness on day of surge. A trend toward improved pregnancy outcomes was found with the luteal estradiol protocol. Conclusion(s): Giving estradiol in the luteal phase preceding IVF hyperstimulation increases the number and the quality of embryos achieved in patients deemed to have a poor response to IVF. Ultimately, this may translate into improved pregnancy outcomes in these patients. (Fertil Steril 2008;89:1118–22. 2008 by American Society for Reproductive Medicine.) Key Words: Poor responders, IVF outcome, luteal phase, estradiol, embryo morphology, oocytes, pregnancy, ovarian responsiveness, follicular pool

Poor response to ovarian hyperstimulation is a complication in 5% to 18% of all in vitro fertilization (IVF) cycles (1–4). Poor responders have significantly worse IVF outcomes than normal responders, with successful pregnancy rates as low as 2% to 4% (5). There are multiple clinical and laboratory parameters used to define poor ovarian response. A number of criteria have been proposed and evaluated which may be used to prognosticate ovarian responsiveness to exogenous gonadotropin stimulation, the quality of the oocytes, and the subsequent implantation and pregnancy rates. These parameters and criteria include few oocytes or follicles (one to six follicles or oocytes), low peak estradiol levels (13–15 mIU/mL), patient age over 38 years, and fewer basal antral follicles (1, 3, 6–16). A novel strategy for treating poor responders is to give estradiol in the luteal phase preceding the IVF hyperstimulation (17–20). Follicle-stimulating hormone in the luteal phase may selectively stimulate larger follicles and subsequently lead to a size discrepancy in the developing follicles. This

Received February 12, 2007; revised and accepted May 11, 2007. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U. S. government. Reprint requests: John L. Frattarelli, M.D., Reproductive Medicine Associates of New Jersey, 100 Franklin Square Drive, Suite 200, Somerset, NJ 08873 (FAX: 732-537-0134; E-mail: [email protected]).


size discrepancy may ultimately allow fewer follicles to be responsive to gonadotropin stimulation. When given luteal phase estradiol and a gonadotropin-releasing hormone (GnRH) antagonist, poor responders to previous hyperstimulation cycles have been shown to result in improved fertilization rates and higher number of embryos (17). Fanchin et al. (19) reported that luteal phase estradiol resulted in a greater number of follicles R16 mm, more mature oocytes, and more available embryos when compared with a control population. Our study investigated the effect of exogenously administered estradiol in the preceding luteal phase on IVF parameters in patients proven or suspected to be poor responders. Although Dragisic et al. (17) evaluated the combination of estradiol and a GnRH antagonist given in the preceding luteal phase to poor responders, a thorough search of the literature did not reveal any publications that had evaluated a luteal estradiol protocol in poor responders. Two published studies have evaluated the luteal estradiol protocol in normal responders (18, 19). Therefore, we undertook a retrospective, paired analysis to evaluate patients at our center who had been treated with a luteal estradiol protocol and a standard poor-responder protocol.

MATERIALS AND METHODS This retrospective paired study was designed to evaluate a fairly new, rarely used protocol (the luteal estradiol protocol) in patients thought to be poor responders to IVF. In

Fertility and Sterility Vol. 89, No. 5, May 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.

0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.05.025

a review of our electronic database, we found 60 patients who were treated with both a traditional protocol for poor responders and the luteal estradiol protocol in consecutive cycles. Because these women had been treated with both protocols with the first treatment cycle being unsuccessful, pregnancy outcome rates are not the best outcome measure. For this study, the main outcome measure was number of embryos with R7 cells on day 3. Other outcome measures included basal antral follicle number, number of follicles R14 mm on day of human chorionic gonadotropin (hCG) administration, peak estradiol level (defined as the level of estradiol on the day of hCG administration), ampules of gonadotropins administered, days of stimulation, endometrial response to stimulation, number of oocytes retrieved, and number of embryos. Pregnancy outcomes (pregnancy, loss, and live-birth rates) for the latter cycle were evaluated and compared. Patients The records were evaluated of all patients from January 1, 2004, to July 31, 2006, undergoing a fresh IVF cycle, with or without intracytoplasmic sperm injection (ICSI), who had a luteal estradiol protocol stimulation at Reproductive Medicine Associates of New Jersey. Sixty patients were identified for analysis who had both a luteal estradiol protocol and either a microdose flare protocol or GnRH antagonist protocol in consecutive cycles. Only patients who had the same protocol (microdose flare, n ¼ 15; or GnRH antagonist, n ¼ 45) with each cycle (luteal estradiol and standard) were included. Only patients who had fertilization occur in the same manner (conventional IVF, n ¼ 34; or ICSI, n ¼26) each cycle were included. All patients were treated with these protocols secondary to the diagnosis of IVF poor responder based on patient evaluation or prior response. All IVF patients meeting these criteria were included regardless of original diagnosis or patient age. No egg recipient or cryopreserved-thawed embryo cycles were included. Study Design This is a retrospective, paired-cohort analysis of 60 couples who underwent 120 fresh IVF cycles at the Reproductive Medicine Associates of New Jersey. To analyze the effect of luteal estradiol stimulation outcome parameters, only patients who underwent a luteal estradiol protocol and a microdose flare or GnRH antagonist protocol in consecutive cycles (regardless of order) were included. Transvaginal ultrasound to assess basal antral follicle number was performed on menstrual cycle day 3 (the start of gonadotropin administration). Institutional review board approval was obtained from the Western Institutional Review Board of Olympia, Washington. Patient Treatment Protocols Patients underwent controlled ovarian hyperstimulation generally using a ‘‘step-down’’ protocol, with an initiating dose of 375–450 IU/day of recombinant FSH or a combination of recombinant FSH and low-dose hCG administered at Fertility and Sterility

10–50 IU/day. The two methods of controlled ovarian hyperstimulation used either a microdose flare GnRH agonist down-regulation or intra-cycle GnRH antagonist administration. If microdose flare GnRH agonist down-regulation was used, it was initiated on menstrual cycle day 3 using leuprolide acetate (Lupron; TAP Pharmaceuticals, Deerfield, IL) at a daily dose of 0.05 mg given subcutaneously and continued until the day of hCG administration. For antagonist cycles, a GnRH antagonist was administered when the lead follicle reached 14–15 mm in greatest diameter at a dose of 250 mg in 0.5 mL/day until the day of hCG injection. For luteal estradiol protocols, oral micronized 17b-estradiol (Estrace; Mead Johnson, Evansville, IN) 2 mg twice a day orally was started on luteal day 21 and continued through the first 3 days of gonadotropin stimulation (again, gonadotropins were started on menstrual cycle day 3). When the largest two or three follicles reached 18 mm, a single 10,000 IU intramuscular dose of hCG (Pregnyl, Organon Inc., West Orange, NJ; or Novarel, Ferring Pharmaceuticals Inc., Tarrytown, NY) or its recombinant equivalent (Ovidrel 500 mg, Serono Laboratories, Rockland, MD) was administered. Transvaginal follicular aspiration took place 35 to 36 hours later. Embryo Transfer Technique Embryo transfers were all performed 3 to 5 days after oocyte retrieval. Patients were instructed to have a full bladder, which would provide an acoustic window for visualization of the uterus, in preparation for the ultrasound-guided embryo transfer. Each patient was placed in the dorsal lithotomy position without anesthesia or sedation. Each embryo transfer was performed with an Embryon Genesis Catheter System (Rocket Medical PLC, Hingham, MA), and the ultrasonographer performed the abdominal ultrasound using a 5 MHz probe (GE Logiq 400 Pro Series, General Electric Company, Pewaukee, WI). Statistical Analysis For normally distributed data, a paired t-test was used to compare the mean values between the two different stimulation protocols. For data that were not normally distributed, a Wilcoxon signed rank-sum test was used to compare the mean values between the two stimulation protocols. Differences in outcome rates were analyzed using a chi-square or twotailed Fisher’s exact test. An alpha error of .05 was considered statistically significant for all comparisons. Relative risk and 95% confidence intervals are displayed where appropriate. All data are reported as means with their associated standard deviations. RESULTS Sixty patients deemed poor responders for IVF underwent 120 IVF cycles. Fifteen patients were treated with a microdose flare protocol and 45 patients were treated with a GnRH antagonist protocol. Sixteen patients had a luteal estradiol protocol as their first protocol with a subsequent cycle 1119

without luteal estradiol. Forty-four patients had a standard protocol followed by a luteal estradiol protocol. Table 1 displays the demographics and stimulation variables for the patient population. The mean patient age was 37.9  3.8 years, and the mean partner age was 39.5  5.0 years. Both the patient’s age and partner’s age were statistically significantly greater in the luteal phase estradiol protocol arm as the patients served as their own historic controls and the majority of the luteal estradiol protocols occurred in the later cycles. There was no difference between the two protocols with respect to basal antral follicle count, days of stimulation, number of follicles R14 mm on day of surge, endometrial thickness on day of surge, or amount of low-dose hCG administered; the number of embryos transferred was similar in each cycle (Table 1). However, the luteal phase estradiol protocol required more total gonadotropins (P
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