Controlled ovarian stimulation using a long gonadotropin-releasing hormone antagonist protocol: a proof of concept and feasibility study.

BACKGROUND/AIMS: To evaluate the feasibility of a long protocol of controlled ovarian stimulation prior to in vitro fertilization (IVF) and embryo transfer with a gonadotropin-releasing hormone (GnRH) antagonist used for pituitary and ovarian suppression. METHODS: Thirty patients undergoing IVF/intracytoplasmic sperm injection were randomized into two groups. The control group (n = 16) received a standard flexible GnRH antagonist protocol. Ovarian stimulation consisted of 225 IU/day of recombinant follicle-stimulating hormone for 5 days, followed by 225 IU/day of human menopausal gonadotropin until human chorionic gonadotropin (hCG) administration. The study group (n = 14) received 0.25 mg of GnRH antagonist daily for 7 days, thereafter, upon confirmation of pituitary and ovarian suppression, ovarian stimulation was commenced with the same protocol as used in the control group. Hormone and follicle dynamics, as well as laboratory characteristics and cycle outcome, were compared for both groups. RESULTS: Both groups were comparable in baseline characteristics. Pituitary and ovarian suppression were effectively achieved in 12/14 patients in the study group. The duration of ovarian stimulation and gonadotropin consumption were similar in both groups, as was also the number and size of follicles on hCG day. CONCLUSION: The results of our study confirm the feasibility of a long GnRH antagonist protocol. This regimen could become another option to optimize GnRH antagonist protocols, and should thus be further explored.

Zygote intrafallopian transfer among patients with repeated implantation failure.

OBJECTIVE: To summarize the experience of a single center with laparoscopic zygote intrafallopian transfer (ZIFT) performed exclusively among patients with high-order repeated implantation failure (RIF) following in vitro fertilization-embryo transfer (IVF-ET). METHODS: A retrospective cohort study was performed at the Edith Wolfson Medical Center, a tertiary referral university hospital located in Holon, Israel. A group of 176 patients with 8.15±3.9 previously failed IVF-ET cycles underwent 280 ZIFT procedures between 1995 and 2010. The main outcome measure was the live birth rate per patient treated. RESULTS: In all, there were 274 fresh and 6 frozen ZIFT cycles recorded in the study cohort, resulting in 96 clinical pregnancies per attempt (34.3%) and 72 live births (25.7%). The live birth rate per patient was 39.8%. CONCLUSION: The use of ZIFT remains a powerful tool in the clinical management of selected patients with high-order RIF. This procedure should be kept in mind when all other measures fail among patients with at least 1 unobstructed fallopian tube.

Pregnancies and live births following ICSI with testicular spermatozoa after repeated implantation failure using ejaculated spermatozoa.

The use of testicular spermatozoa for IVF/intracytoplasmic sperm injection (ICSI) is currently indicated exclusively for patients with azoospermia, since a favourable outcome is expected even when very few spermatozoa are present in the ejaculate. Here, a series of four couples with long-standing male factor infertility and multiple failed IVF/ICSI cycles are described. In all couples, the use of ejaculated spermatozoa for ICSI resulted in poor embryo quality and repeated implantation failure. Testicular sperm aspiration was performed in subsequent cycles, and testicular spermatozoa were used for ICSI. Embryo implantation and ongoing pregnancies/deliveries were achieved in all four couples. It is postulated that spermatozoa are subjected to post-testicular damage during sperm transport between the seminiferous tubules and epididymis, with the injection of damaged spermatozoa being the cause for repetitive IVF/ICSI failures. In selected patients, the use of testicular spermatozoa for IVF/ICSI should be considered, even when motile spermatozoa can be identified in the ejaculate.

Blastocyst culture and transfer: lessons from an unselected, difficult IVF population.

Blastocyst-stage transfer has yielded excellent results in good prognosis IVF patients, but its efficacy in the general IVF population has not been clearly demonstrated. The objective of this study was to compare cleavage-stage and blastocyst-stage transfer in a mixed, general IVF population. In a prospective, quasi-randomized study, 152 patients underwent 164 treatment cycles. Patients were allocated to cleavage-stage (group 1; n = 94) or blastocyst-stage (group 2; n = 70) transfer. Main outcome measures included implantation, clinical pregnancy and live birth rates. Implantation (11.2% versus 15.5%), clinical pregnancy (34% versus 21%) and live birth rates per transfer (21.3% versus 13.8%) and per started cycle (21.3% versus 11.4%) were all comparable for groups 1 and 2, respectively. Logistic regression analysis revealed that blastocyst culture and transfer reduced the odds for pregnancy in the general IVF population and defined a good prognosis group for blastocyst transfer. Introducing blastocyst culture and transfer to all IVF patients is not advantageous. Blastocyst transfer should be offered primarily to good prognosis patients, and this group should be specifically defined in each clinical set-up.

Timing intra-Fallopian transfer procedures.

With the gradual decline in the use of zygote intra-Fallopian transfer (ZIFT), current practice is to offer ZIFT almost exclusively to patients with repeated implantation failure (RIF). For practical reasons, the procedure is sometimes deferred by 1 day and embryo intra-Fallopian transfer (EIFT) is performed. The aim of the present study was to compare the reproductive outcome of ZIFT versus EIFT. In a retrospective analysis, 176 patients who failed in 7.65 +/- 3.7 previous IVF cycles underwent 200 ZIFT and 73 EIFT procedures. Implantation and live birth rates were compared for both groups. Patients in both groups were found comparable for demographic and clinical parameters. Similar numbers of oocytes were retrieved and fertilized in both groups, and 5.2 +/- 1.2 zygotes/embryos were transferred. Implantation and live birth rates (10.5 and 26.5% versus 10.9 and 24.7% for ZIFT and EIFT respectively) were comparable. It is concluded that tubal transfer of zygotes and day-2 cleavage stage embryos are equally effective.

Prospective evaluation of two stimulation protocols for low responders who were undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To compare two stimulation protocols designed for low responders undergoing IVF. DESIGN: Randomized, prospective study. SETTING: University hospital IVF unit. PATIENT(S): Sixty low responders who were recruited on the basis of results in previous cycles. INTERVENTION(S): Modified flare protocol in which a high dose of GnRH agonist was administered for the first 4 days, followed by a standard agonist dose, or a modified long protocol in which a standard agonist dose was used until pituitary down-regulation, after which the agonist dose was halved during stimulation. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved. RESULT(S): Twenty-nine cycles were performed with the modified flare protocol and 31 were performed with the modified long protocol. Significantly more oocytes were obtained with the modified long protocol than the modified flare protocol (4.42 +/- 2.6 vs. 3.07 +/- 2.15). The number and quality of embryos available for transfer was similar in both groups. One clinical pregnancy (3.4%) was achieved with the modified flare protocol, and 7 pregnancies (22.5%) were achieved using the modified long protocol. CONCLUSION(S): These preliminary results substantiate the poor prognosis and outcome for low responders undergoing IVF. A modified long "mini-dose" protocol appears to be superior to a modified mega-dose flare protocol in terms of oocyte yield and cycle outcome.

Coarse granulation in the perivitelline space and IVF-ICSI outcome.

PURPOSE: To study the effect of the presence of coarse granules in the perivitelline space (PVS) of oocytes on embryonic development, and on implantation and pregnancy rates in IVF. METHODS: The study population included 24 patients treated during the period 1995-2000. The majority or all of their oocytes exhibited repeatedly coarse granulation in the PVS. Clinical and laboratory cycle characteristics of their 65 IVF-ICSI cycles and the resulting implantation and pregnancy rates were compared to a matched control group of 65 IVF- ICSI cycles without granulation in the PVS. RESULTS: A total of 623 oocytes were retrieved, 418 oocytes fertilized, and 246 embryos were transferred in the study group. No difference was detected between the study and control group with regard to patients' clinical data, IVF cycle characteristics, mean number of oocytes retrieved and fertilized, and mean number of embryos transferred. Only seven pregnancies were achieved in the study group, leading to pregnancy and implantation rates of 10.7 and 5.7%, respectively. Pregnancy and implantation rates were significantly higher in the control group of matched IVF-ICSI cycles without granulation in the PVS (32.5 and 11.5%, respectively). CONCLUSIONS: The presence of coarse granules in the PVS correlates with low implantation and pregnancy rates in IVF-ICSI cycles and might be regarded as a distinct entity, part of the yet poorly defined condition of "egg factor infertility."

Maturation arrest of human oocytes as a cause of infertility: case report.

Maturation arrest of human oocytes may occur at various stages of the cell cycle. A total failure of human oocytes to complete meiosis is rarely observed during assisted conception cycles. We describe here a case series of infertile couples for whom all oocytes repeatedly failed to mature during IVF/ICSI. Eight couples, all presenting with unexplained infertility, underwent controlled ovarian stimulation followed by oocyte retrieval and IVF/ICSI. The oocytes were stripped of cumulus cells prior to the ICSI procedure and their maturity status was defined. In each couple, oocyte maturation was repeatedly arrested at the germinal vesicle (GV) (n = 1), metaphase I (MI) (n = 4) and metaphase II (MII) (n = 3) stage. Oocyte maturation arrest may be the cause of infertility in some couples previously classified as having unexplained infertility. The recognition of oocyte maturation arrest as a specific medical condition may contribute to the characterization of the yet poorly defined entity currently known as 'oocyte factor'. The cellular and genetic mechanisms causing oocyte maturation arrest should be the subject of further investigation.

Prospective evaluation of blastocyst stage transfer vs. zygote intrafallopian tube transfer in patients with repeated implantation failure.

OBJECTIVE: To compare extended culture with blastocyst stage transfer and zygote intrafallopian transfer (ZIFT) in the management of IVF patients with repeated implantation failure. DESIGN: Prospective, nonrandomized study. SETTING: An IVF unit at a university hospital. PATIENT(S): Sixty-four infertile patients with more than three previous failed IVF-ET attempts. INTERVENTION(S): Patients were allocated to undergo either blastocyst stage transfer (Group 1; n = 32) or ZIFT (Group 2; n = 32). MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, and live birth rates. RESULT(S): Patient characteristics and response to stimulation were comparable for both groups. Totals of 84.3% and 97% of the patients underwent blastocyst transfer and ZIFT, respectively. Significantly more embryos were transferred through ZIFT (5.5+/-0.8) as compared with blastocyst transfer (2.3+/-1.4), and there were significantly more cycles with embryo cryopreservation in the ZIFT group as compared to the blastocyst transfer group (15/32 vs. 4/32, respectively). Implantation rate (13.6% vs. 1.4%), clinical pregnancy rate (40.6% vs. 3.1%), and live birth rates (38.7% vs. 0%) were all significantly higher in the ZIFT group as compared to the blastocyst transfer group, respectively. CONCLUSION(S): Zygote intrafallopian transfer is a powerful clinical tool in the management of patients with RIF. In contrast, blastocyst stage transfer fails to improve the outcome in this poor-prognosis group. The pathophysiology of RIF should be the subject of intense investigation to allow the introduction of appropriate therapeutic measures earlier in the course of treatment.