Hung-Ching Liu

Withholding gonadotropin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome

OBJECTIVEnTo evaluate the outcomes of IVF and the incidence of ovarian hyperstimulation syndrome (OHSS) after discontinuing gonadotropin therapy in patients at risk of developing OHSS by delaying hCG administration until a drop in serum E2 levels was observed.nnnDESIGNnRetrospective study.nnnSETTINGnIVF program at a university center.nnnINTERVENTIONSnGonadotropin administration was withheld in 22 patients (group 1) when their serum E2 level was > or = 3,000 pg/mL (conversion factor to SI unit, 3.671). Patients continued GnRH analogue injections daily, and hCG was administered when serum E2 levels dropped to < or = 3,000 pg/mL. Outcomes were compared with 26 patients (group 2) in whom embryo transfer was canceled and all embryos cryopreserved for transfer during a subsequent unstimulated cycle.nnnMAIN OUTCOME MEASURESnOutcomes of IVF and incidence of OHSS were compared in both groups of patients. In group 1, follicular and hormonal parameters before and after the coasting interval were compared in pregnant versus nonpregnant patients. In addition, serum hormonal profiles were evaluated daily during the coasting period to determine the effects of gonadotropin withdrawal.nnnRESULTSnAlthough the mean number of oocytes retrieved was significantly higher in group 2, fertilization rates, miscarriage rates, delivery rates/stimulation cycle, and the incidence of OHSS did not differ significantly between the two groups.nnnCONCLUSIONnWithholding gonadotropin administration is an effective alternative to prevent the development of severe OHSS in a high-risk population. Although the risk of cancellation cannot be completely eliminated, this strategy can provide a high pregnancy rate without the need to repeat multiple frozen-thawed cycles.

Assisted hatching facilitates earlier implantation.

OBJECTIVEnTo examine whether opening of the zona pellucida (i.e., assisted hatching) accelerates implantation.nnnDESIGNnIn a controlled, randomized trial, patients were assigned to control and assisted hatching groups.nnnSETTINGnAll patients studied were of the Center for Reproductive Medicine at Cornell University Medical College.nnnINTERVENTIONnAll patients underwent stimulation with gonadotropins after luteal phase GnRH down regulation. Assisted hatching with zona drilling using acidic Tyrodes solution was performed on the assigned embryos.nnnMAIN OUTCOME MEASURESnLuteal E2, P, and hCG on days +5, +6, +7, +8, +9, +11, +13, and +15 were measured. The implantation time, peak midluteal E2 and intervals between these two values were studied.nnnRESULTSnImplantation occurred significantly earlier in the assisted hatching group. The interval between implantation and peak midluteal E2 was also significantly shorter in the assisted hatching group than in the controls. However, there was no significant difference in the day of the peak midluteal E2 between the assisted hatching and control groups.nnnCONCLUSIONnAssisted hatching may enhance embryo implantation not only by mechanically facilitating the hatching process but also by allowing earlier embryo-endometrium contact. Such early contact may enhance embryonic development potential and may optimize synchronization between embryo and endometrium, resulting in improved implantation efficiency.

Midfollicular anticardiolipin and antiphosphatidylserine antibody titers do not correlate with in vitro fertilization outcome

OBJECTIVEnTo determine the prevalence of anticardiolipin and antiphophatidylserine antibodies in an IVF population and to correlate their presence and specific isotype with IVF cycle outcome.nnnDESIGNnRetrospective clinical study using stored midfollicular sera for determination of antibody status.nnnSETTINGnUniversity hospital infertility clinic.nnnPATIENT(S)nWomen who underwent IVF treatment in 1991.nnnINTERVENTION(S)nMidfollicular sera were used to assess antibody status during the time of stimulation for IVF.nnnMAIN OUTCOME MEASURE(S)nAnticardiolipin and antiphosphatidylserine antibody titers and biochemical or sonographic documentation of IVF cycle outcome.nnnRESULT(S)nThe overall prevalence of anticardiolipin and antiphosphatidylserine antibodies in IVF patients was 7.0% and 11.2%, respectively. There was no statistically significant difference in the prevalence of these antibodies in the groups of patients with a biochemical pregnancy (0 for anticardiolipin and 2.8% for antiphosphatidylserine), spontaneous miscarriage (11.4% for anticardiolipin and 20% for antiphosphatidylserine), ongoing pregnancy (7.3% for anticardiolipin and 11.6% for antiphosphatidylserine), and patients who failed to conceive (7.2% for anticardiolipin and 10.8% for antiphosphatidylserine). There was no correlation between outcome and the antibody isotype expressed.nnnCONCLUSION(S)nAnticardiolipin and antiphosphatidylserine antibodies are poorly predictive of the IVF cycle outcome. Routine testing of IVF patients for the presence of these antibodies is of limited clinical utility.

Expression of Inhibin/Activin Subunits and Their Receptors and Binding Proteins in Human Preimplantation Embryos

Purpose:Our purpose was to study the role of inhibin/activin during embryogenesis.Methods:Transcripts of inhibin/activin subunits (α, βA, βB), activin receptors (types I and II), and follistatin were detected by a reverse transcriptase–polymerase chain reaction in human reproductive cells and preembryos cultured alone or co-cultured with human endometrial cells.Results:Transcripts of α, βA, βBsubunits were all detected in granulosa luteal cells, but only βAunits were detected in endometrial stromal and decidualized cells. In human preimplantation embryos, none of these subunits were detected in embryos from the four-cell to the morula stage and only βAsubunits were detectable in blastocyst embryos. Activin receptors were detectable in all of the studied embryos and cells. Transcripts of βA, activin receptors, and follistatin were differentially expressed in human preimplantation embryos cultured in vitro and their expressions were significantly enhanced with the presence of endometrial stromal cells.Conclusions:Our data suggest that there is a possible endometrium–embryo interaction via endometrial activins and preimplantation embryo receptors and that the embryonic expressions of these activins, their receptors, and binding proteins are dependent on embryonic stage.

An Analysis of the Effect of Age on Implantation Rates

AbstractPurpose: To evaluate implantation rate as a function of age.nMethods: A total of 1621 consecutive cycles of IVF wereevaluated for implantation as a function of age at The NewYork Hospital/Cornell Medical Center.nResults: An overall implantation rate of 23.3% (1328/5691)was found. The implantation rate as a function of agedecreased in a nonlinear fashion. Implantation remainedconstant until the age of 35 and then decreased in a significantly,linear fashion by 2.77% per year (P < 0.001, R2 =0.975). A formula to predict implantation rates for a givenage was developed: Implantation rate = −119.352 + (9.985× Age − (0.164 × Age2)).nConclusions: We have demonstrated that implantation ratesremain constant until the age of 35 at which time a lineardecrease of 2.77% per year is observed.

The embryo toxicity of hydrosalpinx fluid is only apparent at high concentrations: an in vitro model that simulates in vivo events

OBJECTIVEnTo simulate the in vivo model in studying the effect of hydrosalpinx fluid on embryonic development.nnnDESIGNnControlled prospective study.nnnSETTINGnAcademic research center.nnnPATIENT(S)nFive hundred eighty-seven two-cell murine embryos.nnnINTERVENTION(S)nEmbryos were grown under two sets of conditions. Half were cultured using 10% fetal calf serum in RPM1 medium in varying concentrations of hydrosalpinx fluid (0, 1%, 10%, 50%, 75%, and 100%). To more closely mimic the in vivo environment, the other half were grown in an endometrial coculture system with the same media and hydrosalpinx fluid concentrations.nnnMAIN OUTCOME MEASURE(S)nEmbryonic development.nnnRESULT(S)nFor each stage of embryogenesis, diminished development was noted with increasing concentrations of hydrosalpinx fluid. In the group of embryos grown without endometrial coculture, only at a minimum concentration of 50% hydrosalpinx fluid was diminished development noted for the blastocyst, hatching, and outgrowth stages. When an endometrial coculture system was used, development was not inhibited until exposure to a minimum of 75% hydrosalpinx fluid. Embryogenesis was enhanced when an endometrial coculture system was used for each concentration of hydrosalpinx fluid.nnnCONCLUSION(S)nWhen a model is used that more accurately mimics the in vivo conditions of IVF-ET in a patient with hydrosalpinges, it appears that high concentrations of hydrosalpinx fluid are required to signiticantly impede embryogenesis. The endometrium appears to help detoxify hydrosalpinx fluid.

Human preembryo development on autologous endometrial coculture versus conventional medium

OBJECTIVEnTo evaluate the effect of autologous endometrial coculture versus conventional medium on preembryo development.nnnDESIGNnControlled systematic clinical study.nnnSETTINGnUniversity-based IVF center.nnnPATIENT(S)nWomen with a history of failed IVF-ET with poor preembryo quality.nnnINTERVENTION(S)nPatients underwent a luteal phase endometrial biopsy. The tissue then was digested enzymatically, and the stromal and glandular cells were separated by differential sedimentation rates. These cells were cultured to confluence, released, and then cryopreserved until the patients IVF-ET cycle. All normally fertilized oocytes then were allocated systematically to growth on autologous endometrial coculture or conventional medium until transfer on day 3.nnnMAIN OUTCOME MEASURE(S)nPreembryo blastomere numbers and cytoplasmic fragmentation rates were measured.nnnRESULT(S)nForty-two women underwent 44 cycles of IVF-ET. In the morning on day 3, the mean (+/-SD) number of blastomeres and cytoplasmic fragments per preembryo on coculture compared with conventional medium was 5.9+/-1.5 versus 5.5+/-1.4 and 21%+/-13% versus 24%+/-11. At transfer the mean (+/-SD) number of blastomeres per preembryo on coculture was 7.4+/-1.3 versus 6.7+/-1.9 on conventional medium.nnnCONCLUSION(S)nThere was a significant improvement in the mean (+/-SD) number of blastomeres per preembryo and decrease in the fragmentation rate for preembryos on autologous endometrial coculture compared with noncocultured preembryos from the same patient.

Human endometrial stromal cells improve embryo quality by enhancing the expression of insulin-like growth factors and their receptors in cocultured human preimplantation embryos.

OBJECTIVEnTo demonstrate the mechanism by which human endometrial stromal cells improve embryo quality in coculture.nnnDESIGNnRandomized study.nnnSETTINGnAcademic research center.nnnPATIENT(S)nPatients undergoing IVF-ET.nnnINTERVENTION(S)nDonated human embryos were cultured randomly either alone (group A) or with human endometrial stromal cells (group B), and the embryonic expression of insulin-like growth factors (IGFs) and their receptors was detected by reverse transcriptase polymerase chain reaction after culture.nnnMAIN OUTCOME MEASURE(S)nThe embryo frequency distribution of groups A and B before and after culture and the embryonic transcripts of the IGF family genes of the two study groups after culture were compared.nnnRESULT(S)nThe embryo frequency distribution of the day 3 embryonic stages in groups A and B was not different. However, after culture, a statistically significant difference in blastocyst formation was observed between groups A and B. A significant increase in the expression of IGF-1, IGF-2, the IGF-1 receptor, and the insulin-receptor also was noted. Among the embryos that reached the blastocyst stage, the expression of IGF-1 and the IGF-1 receptor also was significantly different in the two study groups.nnnCONCLUSION(S)nHuman endometrial stromal cells enhanced the expression of IGFs and their receptors in cocultured human embryos, which may be essential for improving embryo quality.

Characteristics of consecutive in vitro fertilization cycles among patients treated with follicle-stimulating hormone (FSH) and human menopausal gonadotropin versus FSH alone

OBJECTIVEnTo compare the endocrine responses of patients who first received hMG plus FSH, then were treated in a subsequent cycle with FSH alone.nnnDESIGNnRetrospective study.nnnSETTINGnAn academic research environment.nnnPATIENT(S)nNinety-six women with pituitary down-regulation who underwent two sequential IVF treatments, the first with combined hMG and FSH and the second with FSH alone.nnnMAIN OUTCOME MEASURE(S)nDuration of stimulation, serum estradiol level on the day of hCG administration, amount of gonadotropin used, number of oocytes retrieved, number of oocytes fertilized, and selected preembryo morphologic features.nnnRESULT(S)nNo difference in the mean duration of stimulation was observed between the treatment cycles among patients who received hMG and FSH (11.9 days) followed by FSH alone (11.7 days). The mean number of oocytes retrieved, the mean number of oocytes fertilized, the percentage of preembryo fragmentation, and the preembryo cell number at transfer did not differ significantly between the stimulation protocols. The cumulative amount of gonadotropin used during stimulation was slightly greater in the cycles stimulated with FSH alone, but this difference was not significant (29.4 ampules of hMG plus FSH versus 31.8 ampules of FSH alone). Serum estradiol levels measured on the day of hCG administration during stimulation with hMG and FSH (1,382 pg/mL) were higher than those measured during stimulation with FSH alone (1,149 pg/mL).nnnCONCLUSION(S)nFollicular response and preembryo quality were not significantly different when patients were treated first with hMG and FSH and then with FSH alone in a subsequent cycle. Similarities in ovarian response and preembryo characteristics, as well as differences in estradiol patterns seen in each stimulation setting, should be anticipated when patients receive these protocols.

Autologous Endometrial Co-culture in Patients with Repeated Failures of Implantation After In Vitro Fertilization–Embryo Transfer

Purpose:Our purpose was to evaluate the effect of co-culture on preembryo development and clinical outcome.Methods:Enrolled patients underwent a luteal-phase endometrial biopsy. The tissue was then enzymatically digested (collagenase) and the stromal and glandular cells were separated by differential sedimentation rates. These cells were cultured to confluence, released, and then cryopreserved until the patients in vitro fertilization (IVF)–embryo transfer (ET) cycle. All normally fertilized oocytes were then placed on the co-cultured cells until transfer on day 3. Preembryo development on co-culture was compared to that in the patients noncocultured previous cycle. Implantation and clinical pregnancy rates were compared to those in a control group of patients undergoing IVF during the study period who were matched for age, stimulation protocol, number of oocytes retrieved, and preembryos transferred.Results:Twenty-nine women underwent 31 cycles of IVF-ET. On day 3 the overall mean number of blastomeres per preembryo on co-culture compared to that in the patients previous cycle was 6.3 ± 1.8 vs. 5.6 ± 1.2 (P = 0.04). The average percentage of cytoplasmic fragments on co-culture compared to the previous cycle was 16 ± 9% vs. 19 ± 9% (P = 0.32). At transfer, after preembryo selection, the mean number of blastomeres per preembryo on co-culture compared to that in the patients previous cycle was 6.8 ± 1.6 vs. 6.6 ± 1.3 (P = 0.5). The implantation and clinical pregnancy rates between co-culture and the matched control group were 15% (14/93) vs. 13% (16/124) (P = 0.79) and 29% (9/31) vs. 25% (10/40) (P = 0.45).Conclusions:There was a significant improvement in the average number of blastomeres per preembryo on co-culture compared to that in the patients previous noncoculture cycle. The overall implantation and clinical pregnancy rates between co-culture and a matched control group were not significantly different.