Protocol In Poor Responders Research Articles

A luteal estradiol stimulation protocol improves embryo number and quality for poor-responders undergoing ART

Poor response to ovarian hyperstimulation is a complication in 5–18% of all IVF cycles. Through a search of the literature, we could find no published manuscript which evaluated a luteal estradiol protocol in poor responders. Two published manuscripts have evaluated the luteal estradiol protocol in normal responders. We therefore undertook a retrospective paired analysis evaluating patients at our center who had been treated with a luteal estradiol protocol and a standard poor-responder protocol.

Ultrashort gonadotropin-releasing hormone agonist combined with flexible multidose gonadotropin-releasing hormone antagonist for poor responders in in vitro fertilization/embryo transfer programs

To evaluate the appropriate controlled ovarian hyperstimulation (COH) protocol in poor responders, we compared the stimulation characteristics of 21 cycles, which included the ultrashort gonadotropin-releasing hormone (GnRH) agonist combined with the flexible multidose GnRH antagonist, to the patients' previous failed in vitro fertilization attempts. The use of an ultrashort GnRH-agonist/GnRH-antagonist COH protocol resulted in a statistically significantly greater number of follicles larger than 14 mm on the day of hCG administration, a higher number of oocytes retrieved and embryos transferred, and a reasonable clinical pregnancy rate (14.3%).

Novel follicular-phase gonadotropin-releasing hormone antagonist stimulation protocol for in vitro fertilization in the poor responder

Poor responders continue to be vexing in infertility therapy. By using GnRH antagonists before ovarian stimulation, we demonstrate an improvement in oocyte, embryo, and zygote yield in patients with a prior poor response.

P-31: Luteal phase recombinant FSH as a novel stimulation protocal in the IVF poor responder

It has been shown that FSH first begins to rise in serum 12 days after ovulation suggesting that recruitment of follicles for the next cycle does not start on day one, but potentially during the luteal phase that immediately precedes the next menses. We report preliminary experience with a novel luteal phase IVF stimulation protocol in poor responders to test the hypothesis that exposure to gonadotropins in the preceding luteal phase increases oocyte yield.

GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial

This is the first published report of a prospective, randomized, controlled trial comparing a fixed, multi-dose GnRH antagonist protocol with a long GnRH agonist protocol in poor responders undergoing IVF. Sixty-six poor responders were randomized into two groups: the study group received 0.25 mg of cetrorelix daily starting on day 6 of stimulation; the control group received 600 microg of buserelin acetate daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a fixed dose of recombinant FSH (300 IU daily) for stimulation. There were no significant differences in the cycle cancellation rates, duration of stimulation, consumption of gonadotrophins, and mean numbers of mature follicles, oocytes and embryos obtained. The implantation rates were similar, but the number of embryos transferred was significantly higher for the antagonist group (2.32 +/- 0.58 versus 1.50 +/- 0.83; P = 0.01). The pregnancy rates were also higher in the antagonist group, but the difference was not statistically significant. A fixed multi-dose GnRH antagonist protocol is feasible for patients who are poor responders on a long agonist protocol; however, our study failed to demonstrate an overall improvement in ovarian responsiveness. Clinical outcomes may be improved by developing more flexible antagonist regimens, an approach that requires further evaluation.

Outcome of preimplantation genetic diagnosis in frozen-thawed embryos

Cryopreservation of embryos is widely applied in ART. And it is also useful for efficient preimplantation genetic diagnosis (PGD) in cases with supernumerary embryos or with collected embryos through several cycles in poor responders. The aim of this study is to evaluate the feasibility of FISH or PCR in the blastomeres biopsied from frozen-thawed embryos and the outcome of PGD, and to determine whether frozen- thawing process affect the embryo development after blastomere biopsy. Retrospective clinical study. In 86 patients, 319 PGD cycles were performed between Jan. 2000 and Dec. 2003. Patients were divided into 2 groups: thawed PGD group − PGD cycle was performed in frozen-thawed embryos (33 patients, 40 cycles, age = 34.2±4.7yrs. (mean±SD)), fresh PGD group − PGD cycle was performed in fresh embryos (patients=53, cycles=279, mean age = 31.8±4.3yrs.). In 20 cycles, supernumerary embryos were frozen and thawed, and in 19 cycles, embryos were collected through several cycles in poor responders and then thawed altogether. PGD was performed for translocation carriers or aneuploidy screening and some single gene diseases were included. Ovarian stimulation was done using GnRH agonist/FSH long protocol or clomifen citrate/GnRH antagonist protocol in poor responders. Oocytes were inseminated by ICSI and the fertilized embryos were cryopreserved at PN stage or cleaving embryo stage. In thawed embryo transfer cycles, estradiol was administrated from day 2 of menstrual cycle and progesterone injection was started from 1 day before 2PN thawing. The cryopreserved embryos were thawed and blastomeres were biopsied in survived embryos developed to 6–10 cell stage. PGD was performed by using FISH or PCR and the embryos were replaced 3 days after PN thawing. The survival rate of the thawed embryos, the rate of successful diagnosis for FISH or PCR, embryo development and pregnancy rate were compared between thawed and fresh PGD cycles. The survival rate of thawed embryos was 71.2±29.8% (mean±SD). The FISH or PCR analysis was successful in 88.1±22.0 % in thawed PGD group and 95.2±10.3% in fresh PGD group (P>0.05). The proportion of transferable embryos in thawed PGD group was similar to fresh PGD group (21.6±19.7% vs. 27.4±18.8%; P>0.05). The rate of embryos developed cleavage after biopsy was also similar in both groups (62.0±26.5% vs. 66.4±26.1%; P>0.05). The clinical pregnancy rate per transfer was 11.4 % (4/35) in thawed PGD group and 21.3% (57/267) in fresh PGD group. Although it was not statistically significant, the pregnancy rate tends to be lower in thawed PGD group. Our data suggest that blastomere biopsy and analysis with FISH or PCR is feasible in frozen-thawed embryos if the embryos survive well. The embryo development was not affected by biopsy in thawed embryos, but the pregnancy rate was lower in thawed PGD cycles. Therefore PGD in thawed embryos could be applied usefully in cycles with supernumerary embryos or collected cyropreserved embryos, and optimization of freezing-thawing condition might be important.

GnRH flare improves pregnancy rates only in a subset of poor responders

Objective: GnRH agonist given early in the menstrual cycle (flare) causes an endogenous discharge of FSH and LH, and has been used in conjunction with ovarian stimulation by gonadotropins for IVF patients. However, there is an ongoing controversy in the literature regarding whether the flare protocol improves pregnancy rates in poor responders. The current study was designed to assess the role of flare protocol in poor responders during IVF cycles.Design: Retrospective analysis.Materials/Methods: Seventy-three cycles using flare protocol from the beginning of 1999 to July of 2001 were retrospectively compared with previous IVF cycles in the same patients using GnRHa long-term down-regulation protocol, and with128 IVF cycles in age-matched poor ovarian responders (peak E2 less than 1000 pg/ml and/or less than five mature follicles with diameter >15 mm on the day of hCG administration) during the same time period. Student t- test was used to analyze parametrical data and Chi-squared test to compare fertilization and pregnancy rates.Results: When compared between IVF cycles using flare and down regulation protocols in the same patients, flare protocol produced higher peak E2 levels (1647 747 vs 720 258, p <0.05) and a larger number of mature follicles (5.8 2.2 vs 4.0 1.0, p <0.05). Pregnancy rates were significantly improved after using flare protocol (30% vs 0%, p <0.01). When compared between flare protocol and age-matched poor ovarian responders using down regulation protocol, the later produced lower peak E2 levels (877 312, p <0.05) and fewer mature follicles (3.8 2.2, p <0.01), but comparable pregnancy rates (36.7%, p >0.05).Conclusions: This study demonstrates that flare protocol can improve ovarian responses in poor responders, and increase pregnancy rates in poor responders who failed to conceive in IVF cycles using down regulation protocol. This study suggests that down regulation protocol may compromise treatment outcome in a subset of poor responders.Supported by: N/A. Objective: GnRH agonist given early in the menstrual cycle (flare) causes an endogenous discharge of FSH and LH, and has been used in conjunction with ovarian stimulation by gonadotropins for IVF patients. However, there is an ongoing controversy in the literature regarding whether the flare protocol improves pregnancy rates in poor responders. The current study was designed to assess the role of flare protocol in poor responders during IVF cycles. Design: Retrospective analysis. Materials/Methods: Seventy-three cycles using flare protocol from the beginning of 1999 to July of 2001 were retrospectively compared with previous IVF cycles in the same patients using GnRHa long-term down-regulation protocol, and with128 IVF cycles in age-matched poor ovarian responders (peak E2 less than 1000 pg/ml and/or less than five mature follicles with diameter >15 mm on the day of hCG administration) during the same time period. Student t- test was used to analyze parametrical data and Chi-squared test to compare fertilization and pregnancy rates. Results: When compared between IVF cycles using flare and down regulation protocols in the same patients, flare protocol produced higher peak E2 levels (1647 747 vs 720 258, p <0.05) and a larger number of mature follicles (5.8 2.2 vs 4.0 1.0, p <0.05). Pregnancy rates were significantly improved after using flare protocol (30% vs 0%, p <0.01). When compared between flare protocol and age-matched poor ovarian responders using down regulation protocol, the later produced lower peak E2 levels (877 312, p <0.05) and fewer mature follicles (3.8 2.2, p <0.01), but comparable pregnancy rates (36.7%, p >0.05). Conclusions: This study demonstrates that flare protocol can improve ovarian responses in poor responders, and increase pregnancy rates in poor responders who failed to conceive in IVF cycles using down regulation protocol. This study suggests that down regulation protocol may compromise treatment outcome in a subset of poor responders. Supported by: N/A.

Midluteal use of GnRH antagonist with microdose protocol in poor responders undergoing ICSI: effects on the follicular dynamics.

Midluteal use of GnRH antagonist with microdose protocol in poor responders undergoing ICSI: effects on the follicular dynamics.

Gonadotropin stimulation following GnRH-a priming for poor responders in in vitro fertilization–embryo transfer programs

The effect of gonadotropin-releasing hormone agonist (GnRH-a) administration before gonadotropin super-ovulation on the stimulation characteristics of poor responder patients was assessed in an in vitro fertilization (IVF) program.Thirty consecutive patients who had exhibited low ovarian response (fewer than four retrieved oocytes) in at least two previous IVF cycles (control cycles, n = 60), were eligible for the study. GnRH-a (nafarelin) was administered daily for 7–10 days from the mid-luteal phase of the previous cycle until the first day of menstruation. Menotropin treatment was commenced on cycle day 3 (with no additional GnRH-a) (study cycles, n = 39).A significantly higher number of oocytes was retrieved (p < 0.0002) and a higher number of embryos transferred (p < 0.003) in the study cycles than in the control cycles. No cases of premature luteinizing hormone surge were recorded. Pregnancy rates per embryo transfer and per cycle were 10.4% and 7.7% for the study cycles and 2.8% and 1.6% for the control cycles, respectively.GnRH-a, administered prior to gonadotropin treatment, should be an additional option of ovulation induction protocol for poor responders in IVF programs.

Cessation of gonadotropin-releasing hormone analogue (GnRH-a) upon down-regulation versus conventional long GnRH-a protocol in poor responders undergoing in vitro fertilization

Objective: To determine whether a controlled ovarian hyperstimulation (COH) regimen that involves GnRH agonist (GnRH-a) discontinuation before administration of gonadotropins would benefit poor responders. Design: A prospective, randomized controlled trial. Setting: Hospital-based IVF Unit. Patient(s): Sixty-three patients with previous poor response to COH and/or high basal FSH level (≥9 mIU/mL) undergoing 78 IVF-ET cycles. Intervention(s): In both groups, administration of GnRH-a was started in the midluteal phase. Whereas in the study group (40 cycles), it ended before administration of gonadotropins, in controls (38 cycles) GnRH-a treatment was continued throughout the follicular phase. Main Outcome Measure(s): Ovarian stimulation patterns and IVF outcome. Result(s): A significantly higher cancellation rate was noted in the study group than in the controls (22.5% versus 5%, respectively). The new and control regimens resulted in similar stimulation characteristics and clinical pregnancy rates (11% versus 10.3%, respectively). In 13 patients with a basal FSH level that was not persistently high, the new regimen resulted in a significantly higher number of retrieved oocytes compared with the standard protocol (7.6 ± 1.03 versus 4.0 ± 0.68, respectively). Conclusion(s): Whereas for most low responders, the new COH regimen offers no further advantage, future prospective studies may demonstrate whether it can confer a benefit for a subset of patients with a basal FSH level that is not persistently high.

Limited success using the “flare” protocol in poor responders in cycles with low basal follicle-stimulating hormone levels during in vitro fertilization

Objective: To assess an alternate protocol for stimulating poor responders. Design: Prospective clinical study. Setting: University-affiliated infertility clinic. Patient(s): Eighty poor responders. Intervention(s): Stimulation was withheld until patients fulfilled the following criteria: basal FSH ≤ 12 mIU/mL (conversion factor to SI unit, 1.00) with concurrent E 2 level ≤ 100 pg/ mL (conversion factor to SI unit, 3.671), and P level ≤ 1.0 ng/mL (conversion factor to SI unit, 3.467). They then started leuprolide acetate on cycle day 2 and a high dose of gonadotropins on cycle day 3. Main Outcome Measure(s): Stimulation response and pregnancy rates (PRs). Result(s): Nineteen cycles (23.8%) were canceled because of poor ovarian response. The mean E 2 level on day of hCG was 2,578 ± 1,339 pg/mL (9,464 ± 4,915 pmol/L) (range, 789 to 5934 pg/mL [2,896 to 21,784 pmol/l]). The number of oocytes retrieved was 10 ± 6.6 (range, 1 to 37). Nine patients did not have ET (failed fertilization [n = 5], no cleavage of preembryos [n = 3], freeze all [n = 1]). The number of pre-embryos transferred was 3.9 ± 1.6 (range, 1 to 8). The clinical pregnancy rate was 7 of 61 (11.5%) per retrieval, and 7 of 52 (13.4%) per transfer with an implantation rate of 7 of 201 (3.5%). Three patients miscarried with an ongoing PR of 4 of 61 (6.5%) per retrieval and 4 of 52 (7.6%) per transfer. Conclusion(s): Poor responders undergoing controlled ovarian hyperstimulation with the “flare” protocol in cycles with low basal FSH will often show adequate ovarian response and reach oocyte retrieval and ET. The PRs, however, remain low.

Comparison of a blocking vs. a flare-up protocol in poor responders with a normal and abnormal clomiphene citrate challenge test

This study aimed to standardize the clomiphene citrate test (CC-t) in our laboratory while comparing two different protocols of controlled ovarian stimulation in poor responders.One hundred and forty-four patients scheduled for assisted reproductive techniques were submitted to the CC-t within 3 months before starting stimulation; 133 underwent controlled ovarian stimulation with a blocking protocol. Poor responders in the first cycle (n = 30) were subsequently treated with a flare-up protocol. Although it was not statistically significant, more patients reached oocyte retrieval with the flare-up protocol. In the completed cycles, more gonadotropin ampules (55 ± 15 vs. 34 ± 13; p < 0.001) and more stimulation days (12.6 ± 1 vs. 11.6 ± 1.2; p < 0.005) were needed in the blocking than in the flare-up protocol. No difference was observed in peak 17ß-estradiol levels, preovulatory follicles, oocytes retrieved or pregnancy rate between the two protocols.According to the threshold values, established on CC-t of patients who obtained a clinical pregnancy (n = 44), the incidence of abnormal results was 10%. All but one patient with abnormal CC-t were poor responders during the first stimulation cycle. The flare-up protocol did not improve the ovarian response in these patients.