Endometrial receptivity: the age-related decline in pregnancy rates and the effect of ovarian function.

OBJECTIVE: To assess the effect of age and ovarian function on endometrial receptivity. DESIGN: Retrospective comparison between standard IVF and ovum donation in younger and older patients (< 40 and > or = 40 years of age, respectively). PATIENTS: In standard IVF, there were 325 transfer cycles in older patients and 1,103 transfer cycles in younger ones. In ovum donation, there were 236 transfer cycles in older patients and 222 cycles in younger women. Ovum recipients were then redivided into two groups, according to ovarian function: ovarian failure group (219 cycles) and eugonadal group (239 cycles) in patients with retained ovarian function as manifested by regular menstrual cycles and normal gonadotropins. RESULTS: In standard IVF, clinical pregnancy rates (PRs) were significantly lower in older patients (12.9% versus 23.8%, respectively). In ovum donation, clinical PRs were also significantly lower in older patients (21.2% versus 29.3%, respectively). A significantly higher clinical PR (31.1%) was noted in patients with ovarian failure, compared with both eugonadal patients undergoing ovum donation (19.7%) and standard IVF patients (21.3%). CONCLUSIONS: The decrease in endometrial receptivity with age is responsible for the higher rate of implantation failure in older women. Patients with nonfunctioning ovaries do better than eugonadal patients in ovum donation programs.

Avoidance of cancellation of potential hyperstimulation cycles by conversion to in vitro fertilization-embryo transfer.

OBJECTIVE: The study was undertaken to minimize the rate of ovarian hyperstimulation and to avoid cancellation of human treatment cycles in women treated with human menopausal gonadotropin (hMG) for induction of ovulation. SETTING: Patients were treated in the fertility clinic and in vitro fertilization unit of our institution, which is a government, university-affiliated hospital. PATIENTS: Ninety anovulatory patients were treated with hMG. Of these, 12 were at high risk for ovarian hyperstimulation. The criteria for potential ovarian hyperstimulation syndrome were rising excessive 17 beta-estradiol levels of greater than 1,500 pg/mL in the presence of multiple follicles with a mean diameter greater than 15 mm. These patients were transferred for continuation of treatment to our in vitro fertilization-embryo transfer (IVF-ET) unit. INTERVENTIONS: The patients underwent ova retrieval by the ultrasonically guided transvaginal approach. RESULTS: Of the 12 patients, 5 conceived (41.6%). Two patients had a mild ovarian hyperstimulation syndrome, and 1 had a moderate syndrome and was hospitalized for observation for 48 hours. CONCLUSION: In view of the results, we suggest that IVF-ET should be considered in cases in which ovarian hyperstimulation syndrome is imminent, rather than withhold human chorionic gonadotropin and cancelling the treatment cycle.

Pregnancy and birth after transfer of embryos that developed from single-nucleated zygotes obtained by injection of round spermatids into oocytes.

OBJECTIVE: To use injection of spermatids into oocytes as a mode of infertility treatment in cases in which spermatozoa are not available. DESIGN: Prospective clinical evaluation and case report. SETTING: In Vitro Fertilization Unit, Herzliya Medical Centers, Herzliya-on-Sea, Israel. PATIENT(S): Thirteen couples with male factor infertility in which the male partner lacked spermatozoa in the ejaculate or testicular biopsy samples. INTERVENTION(S): Round spermatid injection and elongated spermatid injection into oocytes. MAIN OUTCOME MEASURE(S): Evaluation of the rate of two-pronucleated and single-nucleated zygote development. RESULT(S): The rate of two-pronucleated zygote development after round spermatid injection and elongated spermatid injection was relatively low (27% and 36%, respectively). Single-nucleated zygotes develop more frequently after round spermatid injection and elongated spermatid injection (35% and 17%, respectively) than after intracytoplasmic sperm injection with mature spermatozoa. A normal pregnancy and childbirth resulted from the transfer of 4 cleaving embryos, each of which developed from a single-nucleated zygote in a round spermatid injection treatment cycle with ejaculated spermatids. CONCLUSION(S): Embryos derived from single-nucleated zygotes after spermatid conception can be viable and give rise to an ongoing clinical pregnancy and childbirth.

High initial values of beta-subunits of human chorionic gonadotropin in ovum donation pregnancies indicate better implantation.

Fifty-five patients were treated by ovum donation, and a control group of 165 patients underwent IVF. The number of pregnancies obtained were 28 and 25, respectively. The initial beta-hCG values, as well as the PRs and implantation rates, in the ovum donation series were significantly higher than those of the IVF series. The clinical significance and potential application of these observations are discussed.

Uterine preparation with estrogen for oocyte donation: assessing the effect of treatment duration on pregnancy rates.

OBJECTIVE: To assess the effect of the duration of uterine preparation with E2 on pregnancy rates (PRs) in oocyte donation. DESIGN: A retrospective study. SETTING: IVF-ET Unit, oocyte donation program. PATIENTS: Four hundred eleven patients undergoing 865 ET cycles after oocyte donation. Uterine preparation consisted of 6 mg/d E2 valerate. The duration of treatment varied according to the availability of the oocytes for donation. Progesterone, 100 mg/d, was added upon oocyte retrieval. Patients were divided into seven groups according to the duration of uterine preparation with E2, in 5-day ranks. MAIN OUTCOME MEASURES: Pregnancy rates per ET according to the duration of uterine preparation. RESULTS: No differences were noted in the mean age, number of oocytes received, fertilization rates, or number of embryos transferred when comparing all groups. Pregnancy rates ranged from 19% to 27% for E2 treatment of 5 to 35 days. CONCLUSION: Endometrial preparation in anonymous oocyte donation programs is achieved with continuous administration of E2 until oocytes become available. Our results show that this treatment may be extended for as long as 5 weeks with no significant decrease in PRs.

High progesterone levels adversely affect embryo quality and pregnancy rates in in vitro fertilization and oocyte donation programs.

OBJECTIVE: To assess the effect of P levels on oocyte and embryo quality and pregnancy rates (PRs) in IVF and oocyte donation. DESIGN: Retrospective analysis of PRs in ovum donors and their recipients with regard to P levels on day of hCG administration. SETTING: In Vitro Fertilization Units, oocyte donation programs. PATIENTS: In vitro fertilization patients who agreed to donate oocytes were treated by hMG alone (53 cycles) or in combination with a GnRH analog (122 cycles). INTERVENTIONS: Uterine preparation in oocyte recipients consisted of 6 mg/d E2 valerate. Progesterone (100 mg/d) was added when oocytes became available. Hormonal treatment was continued until 12 weeks of gestation. RESULTS: Using a series of Fisher's Exact Tests, a critical threshold for P was identified at 1.9 ng/mL (conversion factor to SI units, 3.185). With elevated P levels (> 1.9 ng/mL), lower PRs were noted for the donors (7.1% versus 17%), as well for the recipients (8.3% versus 26.7%). CONCLUSIONS: Exposure to elevated P levels resulted in lower PRs for the donors and significantly lower PRs in the recipients. Because the endometria in the recipients were prepared uniformly, we conclude that this is the result of detrimental effects of P on oocyte or embryo quality.

Estrone-3-glucuronide chemiluminescence immunoassay: an alternative method for monitoring induction of ovulation with human menopausal gonadotropin in an in vitro fertilization program.

A simple, rapid, and sensitive solid-phase immunoassay procedure for the determination of estrone-3-glucuronide (E1-3-G), which uses chemiluminescence as the end point in unextracted morning urine, is described. Thirty-one patients undergoing induction of ovulation in an in vitro fertilization (IVF) unit participated in the study. From day 3 of the menstrual cycle until the day of hCG administration, morning blood samples and morning urine specimens were collected for the determination of serum 17 beta-estradiol (E2) and urine E1-3-G, respectively. A good correlation was noted between E2 measured by radioimmunoassay (RIA) and the E1-3-G measured by chemiluminescence immunoassay (CIA), from day 5 up to the day of hCG administration (0.6 less than r less than 0.85, P less than 0.001). It is evident from this study that the CIA measurement of E1-3-G in morning urine is an accurate and rapid (2.5 hours) method and is convenient for monitoring induction of ovulation with human menopausal gonadotropins.

The performance of primary and secondary unexplained infertility in an in vitro fertilization-embryo transfer program.

The term "unexplained infertility" is applied to a couple in whom after an elaborate workup no apparent reason for infertility is found. Between August 1985 and May 1987, 435 patients underwent 720 treatment cycles in an in vitro fertilization-embryo transfer (IVF-ET) unit. Eighty-three of the patients had unexplained infertility as their indication for IVF-ET. Fifty-two (group A) had primary unexplained infertility and 31 (group B) had secondary unexplained infertility. Group A underwent 87 and group B underwent 50 treatment cycles. Forty-six ET were performed in group A and 34 in group B. Clinical pregnancies were achieved in 20 patients of group A (11.5% per treatment cycle) and 13 of group B (26.0%), for a combined rate of 16.8% per cycle. Patients with tubal infertility treated in the program had a pregnancy rate of 18.8% per treatment cycle. The performance of the secondary unexplained infertility group is significantly better than that of the primary unexplained infertility group. However, the overall results with patients with unexplained infertility are similar to those patients treated for tubal infertility.

[Initial results of a cryopreservation program for human ova and embryos]. / Erste Ergebnisse eines Kryokonservierungsprogrammes menschlicher Eizellen und Embryonen.

A human egg and embryo freezing program for non fertilized eggs and spare embryos was established recently in our ib vitro fertilization clinic. The first results are reported. Two cryoprotectants, glycerol and dimethylsulfoxid (DMSO) were used in an automatic computerized freezing program. DMSO gave us better results in terms of a 55% survival of all blastomeres (from 6 normal and 5 pathologic 2- to 16-cell embryos) after thawing. Some of the thawed embryos continued cleavage in vitro. Four embryo replacements were performed with the 6 normal embryos, but none of them resulted in pregnancy. The rapid technique using glycerol gave us less good results in terms of blastomere survival (34%); however, from 3 embryo replacements one "biochemical pregnancy" was obtained from a thawed four-cell embryo. At first attempts to freeze and thaw unfertilized eggs, DMSO seemed also to give better results. The presented cryopreservation techniques which are modifications of those published by Trounson et al. and Zeilmaker et al. need further improvement although the first results are encouraging.

Use of lasers in assisted fertilization and hatching.

The erbium-yttrium-aluminium-garnet (Er:YAG) laser has been applied to micromanipulation in humans. It was used in the fertilization process for both subzonal insemination (SUZI) and for partial zona dissection (PZD). Laser-assisted micromanipulation achieved significantly higher fertilization rates (34.8%) when compared to mechanical SUZI (16.1%), but use of the laser did not improve the PZD results (laser 14.8% versus mechanical 14%). The Er:YAG laser was used to assist hatching. In the mouse it significantly improved the hatching rate (80 versus 29.3%) 110 h after administration of human chorionic gonadotrophin. This technique was applied in two different centres to patients with previous in vitro fertilization (IVF) failures. the implantation rate per embryo (14.4% laser-assisted hatching versus 6% control group) and the pregnancy rate per transfer (40 versus 16.2%) were improved.

[Assisted hatching and micro-fertilization]. / Eclosion et microfécondation assistées.

Erbium-YAG laser has been applied for micromanipulation in human beings. In a first series of attempts it was used in the fertilization process for subzonal insemination (SUZI): laser assisted micromanipulation achieved significant higher fertilization rates (34.8%) when compared to mechanical SUZI (16.1%), and for partial zona dissection (PZD): in this case laser did not improve the results (laser 14.8% vs mechanical 14%). Erbium-YAG laser was used to assist hatching. In the mouse it significantly improved the hatching rate (80% vs 29.3%) 110 hours post hCG. This technique was applied in two different centres to patients with previous IVF failures. The implantation rate per embryo (14.4% laser assisted hatching vs 6% control group) and the pregnancy rate per transfer (40% vs 16.2%) were improved.

Does glucose affect fertilization, development and pregnancy rates of human in-vitro fertilized oocytes?

The study was conducted to examine whether the presence of glucose in the incubation medium affects fertilization, development and implantation rates of human oocytes of patients who were attending our in-vitro fertilization programme. Harvested oocytes were transferred into one of four different media: human tubal fluid (HTF), P1, M3 and IVF-Universal (IVF-Med). Three of these contained glucose; the fourth (P1), contained no glucose or phosphate ions. In an independent preliminary study, some of the oocytes of each patient were incubated in IVF-Med, which lacks phosphate ions, but not glucose. Comparisons of fertilization rates between media pairs showed differences among all pairs except HTF and M3. When comparing the four study groups, no difference was noticed in embryo development or embryo quality 48 h post-ovum retrieval. A higher development rate was demonstrated in embryos incubated in M3 medium, in comparison with the P1 and IVF-Med embryos after incubation for 72 h. No difference in pregnancy rate was found after embryo transfers of preimplantation embryos which were incubated in one of the following media: HTF, M3 and IVF-Med (seven out of 22, 18 of 54 and 32 of 69 treatment cycles respectively). A lower incidence of pregnancies occurred following transfers of embryos which were incubated in P1 medium (seven pregnancies out of 37 cycles). We suggest that the presence of glucose in the incubation medium enhances implantation potential of in-vitro-developing preimplantation embryos.

Oocyte donation in Israel: a study of 1001 initiated treatment cycles.

There are numerous studies concerning pregnancy rates in oocyte donation, yet only a handful report the obstetric outcome in such pregnancies. The purpose of this study was to assess factors that influence pregnancy rates, to determine the incidence of complications, and to evaluate obstetric outcome in pregnancies resulting from oocyte donation. This study included 423 oocyte recipients who underwent 1001 oocyte donation cycles at the Oocyte Donation Programme, In-Vitro Fertilization (IVF)-Embryo Transfer Unit, Herzlia Medical Center, Israel. Donors were all healthy women < 34 years old who underwent IVF themselves. In 873 cycles, fertilization occurred and embryo transfer was performed, resulting in 194 clinical pregnancies. Pregnancy rates (PR) significantly declined with the increase in number of previous attempts, and with increasing age of recipient (36.8%/embryo transfer in patients < or = 30 compared to 17.8% in patients > 40 years old). A significant increment in PR was noted with the increasing number of embryos transferred. The overall PR was 22.2%/embryo transfer. However, in young amenorrhoeic patients with normal karyotypes undergoing their first cycle, PR was 52.2%; the 'take home baby' rate was 38.3% per patient undergoing embryo transfer and 17.8% per embryo transfer cycle. A significant increase in the incidence of pregnancy-induced hypertension and a higher proportion of abortions were noted in older patients. A significantly higher incidence of prematurity and low birthweight was observed in multiple pregnancies.

Metabolic aspects of a hypoxia test for placental sufficiency.

A hypoxia test for placental sufficiency was performed on 24 healthy pregnant women nearing term and 23 high-risk pregnant women in advanced stages of gestation. Hypoxia was induced by inhalation of a breathing mixture containing 7% oxygen through a semi-open system which permitted partial rebreathing, thus preventing hypocapnia. The changes in fetal heart rate (FHR) resulting from maternal hypoxia were recorded continuously by external or internal monitoring. The changes observed in FHR were more marked in high-risk cases. Maternal blood gases were tested before and after 10 min of hypoxia in 10 normal and 10 high-risk patients. In no case was maternal acidosis observed. All pregnant patients regarded as high-risk because of hypertensive disorders or chronic renal disease manifested metabolic alkalosis. This finding cannot be explained. It is regarded as being responsible for the more severe FHR changes through a negative Bohr effect, which reduces the dynamic exchange of oxygen in the placenta. Metabolic alkalosis does not appear in high-risk pregnant women exposed to milder hypoxia by breathing 12% oxygen. The changes in FHR observed during severe maternal hypoxia, i.e., 7% oxygen, are probably due more to maternal metabolic alkalosis than to placental insufficiency. Consequently, the "severe hypoxia test" cannot be used as a test for placental insufficiency.

Relationship between anticomplement in seminal plasma and complement in follicular fluid associated with outcome in an in vitro fertilization program.

PURPOSE: The study was conducted to evaluate levels of anticomplement in seminal plasma and levels of complement in follicular fluid, in correlation with fertilization and pregnancy rate after in vitro fertilization and intracytoplasmic sperm injection programs. MATERIALS AND METHODS: Anticomplement levels were determined in 70 couples undergoing in vitro fertilization therapy. In 15 of these couples, complement levels were measured. Anticomplement and complement levels were also determined in an additional 21 couples (apart from the 70 couples) undergoing intracytoplasmic sperm injection treatment. RESULTS: A correlation was found between fertilization rate and anticomplement levels in the seminal plasma (r = 0.4, P < 0.01) after standard in vitro fertilization. No correlation was found in the intracytoplasmic sperm injection group, or observed between complement levels and any parameter examined in both groups. Pregnancy occurred only in those couples with an anticomplement:complement ratio below 0.49. CONCLUSIONS: Determination of anticomplement and complement levels may contribute to the assessment of a successful outcome of in vitro fertilization/intracytoplasmic sperm injection.

The optimal number of embryos to be transferred in shared oocyte donation: walking the thin line between low pregnancy rates and multiple pregnancies.

There has been growing concern about the number of multiple gestations resulting from assisted reproductive technologies. For in-vitro fertilization (IVF), there are guidelines concerning the number of embryos to be transferred. In oocyte donation, however, there is a paucity of studies addressing this issue and common practice is extrapolated from standard IVF procedures. This may not be correct since endometrial receptivity has been shown to be altered in oocyte donation. Thus the purpose of this study was to assess the optimal number of embryos to be transferred in oocyte donation. The study population included 254 patients with ovarian failure who underwent a total of 601 embryo transfers in a single shared oocyte donation programme. Pregnancy rates (PRs), multiple pregnancies, triplet pregnancy rates, and implantation rates were evaluated according to the number of embryos transferred. A significant linear increase in PRs was noted with the increasing number of embryos transferred up to five (11.1% for one embryo, 36.7% for five embryos). Multiple pregnancies increased significantly from 15.8% for two embryos transferred, to 44.4% for five embryos. The rate of triplet pregnancies also increased from 2.7% for three embryos transferred, to 8.3% for five embryos. Optimization of the number of embryos to be transferred is discussed.

The development of an efficient ambulatory in vitro fertilization (IVF) and embryo transfer (ET) program using ultrasonically guided oocyte retrieval.

Until recently most of the current in vitro fertilization and embryo transfer (IVF-ET) programs used laparoscopy for oocyte retrieval and included hospitalization in the treatment. The establishment of a successful ambulatory IVF program that uses ultrasonically guided oocyte aspiration, is described. Between August 1985 and February 1987, 384 percutaneous transvesical ultrasonically and transvaginally guided follicle aspirations were performed on 414 patients, following ovarian stimulation with hMG and hCG. Ninety two clinical pregnancies were confirmed by ultrasound. The clinical pregnancy rate was 26.8% when based on the number of embryo transfers. There were 16 multiple pregnancies (17.4%), 18 miscarriages (19.5%), and two tubal pregnancies (2.1%). The most important factors contributing toward the success of this program were rigid adherence to clinical and laboratory protocols, and the maintenance of a strict quality control. The ambulatory management was very well accepted by the patients, who during the entire period of ovarian stimulation had minimal disruption of their routine activities.