summary of EPP protocol research by CornellAugust 11 2011 at 4:13 PM
|Anna (no login)|
if any one interested in Dr. Davis protol, read this. i am making my RE use this next cycle and he accepted.
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 (1, 2, 3, 4).
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 (5, 6). Consequently, early in the subsequent follicular phase, some antral follicles may be more sensitive to exogenous gonadotropin stimulation (7).
Fanchin et al. (8, 9) 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 (10). Recently, since the inception of our study, Fanchin et al. (11) 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:  four or fewer oocytes retrieved in previous stimulation;  basal follicular-stimulating hormone levels >12 mIU/mL (follicular female range, 314.4 mIU/mL); or  low E2 level on the day of hCG administration (
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 (1, 2, 3, 4, 13, 14). 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 (3,30010,000 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 3536 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 ÷2 test was used to compare cycle cancellation rates. A P value
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
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 (÷2 = 5.4, P
TABLE 1. Stimulation parameters for completed cycles.
Cycle parameter Prior cycle (n = 66) E2 patch cycle (n = 66) P value
Cancellation rate (%)a 33.3% 13.6%
Ampules of gonadotropins 53.0 ± 21.3 70.5 ± 16.8
Days of stimulation 10.8 ± 2.4 11.0 ± 1.5 NS
Ampules of gonadotropins/day 5.5 ± 1.4 6.9 ± 1.2
E2 day of hCG (pg/mL) 873.0 ± 603.2 931.3 ± 562.3 NS
Oocytes retrieved 6.4 ± 4.3 8.3 ± 5.3
Mature oocytes 5.2 ± 3.4 6.8 ± 4.4
Two pronucleib 2.4 ± 2.5 4.5 ± 3.2
Mean fertilization rate 64.7% 68.5% NS
Embryo grade 2.3 ± 0.5 2.2 ± 1.1 NS
Embryos transferred 2.5 ± 1.7 3.1 ± 1.7
Note: Values are means ± SD. NS = not significant.
Dragisic. Luteal E2 patch in poor responders. Fertil Steril 2005.
a ÷2 = 5.4, P
b Embryo grade on a scale of 15, with 1 being the highest.
Using this approach, patients had a significantly lower cancellation rate (P
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 (15). When the adjusted P value was applied (P
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. (9, 10, 11) 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 (16, 17).
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
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.
- thanks! - jnoels on Aug 11, 4:45 PM
- This is the protocol I used for my BFP (pg ment) - JulesM on Aug 11, 6:01 PM
- JulesM - Anna on Aug 11, 6:17 PM
- Thanks Anna - JulesM on Aug 11, 6:28 PM
- If you want to move on to DE that's a perfectly great option - Mrs. A on Aug 12, 3:53 PM
- Re: summary of EPP protocol research by Cornell - bigboy on Aug 11, 6:34 PM
- Great Protocol.... - DeeinNYC on Aug 11, 8:44 PM
- deeinnYC - anna on Aug 11, 10:19 PM
- Re: deeinnYC - DeeinNYC on Aug 12, 4:43 AM
- Thank you for posting this - Cee on Aug 12, 2:30 PM
- Just a caution.. - BabyDance on Aug 12, 6:57 PM