A multi-centre phase 3 study comparing efficacy and safety of Bemfola(®) versus Gonal-f(®) in women undergoing ovarian stimulation for IVF.

Bemfola (follitropin alfa) (Finox AG, Switzerland), a new recombinant FSH, has a comparable pharmacological profile to that of Gonal-f (Merck Serono, Germany), the current standard for ovarian stimulation. A randomized, multi-centre, Phase 3 study in women undergoing IVF or intracytoplasmic sperm injection (n = 372) showed Bemfola yielding similar efficacy and safety profiles to Gonal-f. Women aged 20-38 years of age were randomized 2:1 to receive a single, daily, subcutaneous 150 IU dose of either Bemfola or Gonal-f. This study tested equivalence in the number of retrieved oocytes using a pre-determined clinical equivalence margin of ±2.9 oocytes. Compared with Gonal-f, Bemfola treatment resulted in a statistically equivalent number of retrieved oocytes (Bemfola 10.8 ± 5.11 versus Gonal-f 10.6 ± 6.06, mean difference: 0.27 oocytes, 95% confidence interval: -1.34, 1.32) as well as a similar clinical pregnancy rate per embryo transfer in first and second cycles (Bemfola: 40.2% and 38.5%, respectively; Gonal-f: 48.2% and 27.8%, respectively). No difference in severe ovarian hyperstimulation syndrome was observed between treatment groups (Bemfola: 0.8%; Gonal-f: 0.8%). This study demonstrates similar clinical efficacy and safety profiles between Bemfola and Gonal-f, and suggests that Bemfola can be an appropriate alternative in ovarian stimulation protocols.

Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study.

BACKGROUND: The aim of this study was to assess the non-inferiority of an oral contraceptive (OC)-pretreated cetrorelix regimen and a buserelin regimen in IVF/ICSI patients treated with r-hFSH in terms of total number of oocytes retrieved. METHODS: Multicentre, randomized study. One hundred and eighty two patients were randomized to receive cetrorelix with OC pretreatment (n = 91) or to receive buserelin (n = 91). The cetrorelix group started with daily OCs on cycle day 5 and continued for 21-28 days. Cetrorelix (0.25 mg) was given daily from stimulation day 6 up to and including the day of r-hCG administration. The buserelin group started with buserelin (500 microg/day) for at least 10 days until down-regulation was achieved, after which the dose was reduced to daily 200 microg up to and including the day of r-hCG administration. r-hFSH was started in both groups on a Friday, in the cetrorelix group 5 days after the last OC pill intake. Both regimens were followed by a standard IVF or ICSI procedure. The primary efficacy endpoint was the number of oocytes retrieved per patient. RESULTS: Number of oocytes, cancellation rates, r-hFSH requirements, number of oocyte retrievals during the weekend or public holiday and number of pregnancies were similar in both groups. Both treatment regimens were well tolerated. CONCLUSIONS: Cetrorelix pretreated with OCs resulted in similar number of oocytes retrieved compared with a long buserelin protocol. Both regimens were well tolerated and allowed scheduling of the oocyte retrieval, with only small number of retrievals falling on a weekend or public holiday.

Ovarian function during and after treatment with the new progestagen Org 30659.

OBJECTIVE: To evaluate ovarian function during 21 days of oral administration of different doses of Org 30659, a novel selective progestagenic steroid. DESIGN: Randomized, double-blind, dose-finding study. SETTINGS: Three centers in Austria, Sweden, and the United Kingdom. PARTICIPANTS: Eighty-one healthy women 19-40 years of age with regular ovulatory cycles. INTERVENTION: Daily oral administration of 0.060, 0.120, 0.180, or 0.240 mg of Org 30659, or 0.075 mg desogestrel (reference group), for 21 days. MAIN OUTCOME MEASURE(S): Once-daily measurements of follicular diameter and 17-beta estradiol, progesterone, FSH, and LH levels. RESULT(S): Daily treatment with Org 30659 for 21 days caused dose-dependent suppression of ovarian activity. No ovulation was observed in any study group. On average, ovulation returned 16.5 to 22.1 days after treatment. The effects of desogestrel, 0.075 mg, were similar to those of 0.060 and 0.120 mg of Org 30659. All doses were well tolerated, as shown by the type of side effects that occurred, the absence of an effect on physical and laboratory findings, and the low rate of study discontinuation. CONCLUSION(S): Daily oral administration of 0.060-0.240 mg of Org 30659 suppresses ovarian function to a level sufficient to inhibit ovulation. This effect is dose-dependent, and the suppressive effect is readily reversible at all doses tested. Org 30659 can thus be safely administered orally for 21 days to healthy female volunteers in a dosage of 0.060 mg/d to 0.240 mg/d.

Premature ovarian failure: etiology and prospects.

A search of past and current articles on ovarian physiology and premature ovarian failure (POF) using MEDLINE was performed in order to present an overview of clinical manifestations, necessary laboratory investigations, possible etiologies and treatments for POF. POF is defined as gonadal failure before the age of 40 years. Initially, POF was thought to be permanent, but it is now believed that spontaneous remissions and even pregnancies are possible in affected women. In most cases, the etiology of POF remains elusive, but several rare specific causes have been identified. Although the etiology of POF is heterogenic, the treatment principles are the same. Hormone replacement therapy (HRT) is still the cornerstone of treatment. The only proven method of obtaining a pregnancy in patients with POF is fertilization of a donor oocyte. Cryopreservation of oocytes has worked well in animals but awaits refinement before it can be applied routinely to humans with prodromal POF, or to patients before chemotherapy or irradiation in order to save their oocytes for future fertilization. New alternatives to traditional HRT and methods of fertility preservation are under development, but understanding of the basic pathophysiology of POF is necessary for the development and use of innovative treatments.

Number and size of antral follicles as predictive factors in vitro fertilization and embryo transfer.

PURPOSE: The purpose of the study was to evaluate whether number and size of antral follicles can predict the outcome of in vitro fertilization-embryo transfer. METHODS: A total of 113 patients were prospectively included into this study. After 19 days of down-regulation, number and size of follicles were determined by using recent three-dimensional transvaginal ultrasound technology. Before application of gonadotropin, all follicles had been defined as antral follicles. According to size, antral follicles were categorized into four different groups: group I included antral follicles < 5 mm, group II follicles 5-10 mm; group III 11-20 mm; and group IV > 20 mm. Pregnant and non-pregnant patients were compared in terms of their number of antral follicles of group I-IV. These four groups were then compared regarding implantation rate, number of retrieved oocytes, endometrium thickness, and age. RESULTS: Pregnant patients showed an significant higher number of follicles with the size between 5 and 10 mm (P = 0.04). A significant correlation was found between number of retrieved oocytes and antral follicle size of 5-10 mm (P = 0.0001). Antral follicles with a diameter between 5 and 10 mm decreased significantly with age (P = 0.008). In group III and IV, a significant correlation was found between antral follicle size (P = 0.016) and serum estradiol level after gonadotropin-releasing hormone-agonist down-regulation (P = 0.011). CONCLUSIONS: We demonstrated that patients with a higher number of follicles between 5 and 10 mm showed a significantly higher pregnancy rate, whereas patients with a dominant number of antral follicles > 11 mm have a higher cancellation rate due to ovarian low response.

Vascular endothelial growth factor and its receptors in male fertility.

OBJECTIVE: To determine the concentration of vascular endothelial growth factor in the seminal fluid, the presence of vascular endothelial growth factor receptors Flt-1 and KDR in spermatozoa, and the predictive value of seminal vascular endothelial growth factor on fertilization and the chance of pregnancy in patients undergoing intracytoplasmic sperm injection (ICSI) or IVF. DESIGN: Retrospective analysis. SETTING: Private institute (semen collection, IVF/ICSI) and academic research environment (analysis of seminal fluid and spermatozoa). PATIENT(S): Eighty men whose spermatozoa were subsequently used for IVF or ICSI. INTERVENTION(S): Seminal vascular endothelial growth factor was measured by an EIA. Spermatozoa were analyzed by fluorescence-activated cell sorter analysis and by immunocytochemistry. MAIN OUTCOME MEASURE(S): Oocyte fertilization rate, pregnancy rate, and presence of vascular endothelial growth factor receptors on spermatozoa. RESULT(S): Patients with a seminal concentration of vascular endothelial growth factor of 2-100 ng/mL had a sixfold increased chance of pregnancy. Vascular endothelial growth factor concentration and patient's age remained the only independent prognostic factors for pregnancy. The concentration of vascular endothelial growth factor did not correlate with indices of male factor infertility or with the oocyte fertilization rate. Expression of vascular endothelial growth factor receptors (Flt-1, KDR) on spermatozoa was demonstrated. CONCLUSION(S): The seminal concentration of vascular endothelial growth factor correlates with the chance of pregnancy in patients undergoing IVF or ICSI. Vascular endothelial growth factor receptors Flt-1 and KDR were detected on spermatozoa for the first time.

Recombinant luteinizing hormone in ovarian hyperstimulation after stimulation failure in normogonadotropic women.

The aim of this study was to examine the effect of an additional administration of recombinant luteinizing hormone (r-LH) to a gonadotropin-releasing hormone agonist (GnRHa) long protocol using recombinant follicle-stimulating hormone (r-FSH). In particular we determined whether such a stimulation protocol would be more effective in women (1) who respond poorly to stimulation with GnRHa long protocol using r-FSH only, and (2) whose LH concentrations after down-regulation in the cancelled cycle were low but above the values reported in the literature to be sufficient for folliculogenesis. After GnRHa desensitization 150 IU r-FSH and 75 IU r-LH were administered subcutaneously daily to six normogonadotropic women with low response to ovarian hyperstimulation using a GnRHa long protocol with r-FSH and low LH concentrations after down-regulation in the cancelled cycle. All six women had an oocyte retrieval and an embryo transfer after follicular stimulation. One women conceived but had a miscarriage in the eleventh week of gestation. Our results suggest that women with low response to a GnRHa long protocol with r-FSH, and whose LH concentration after down-regulation in the cancelled cycles were low, benefit from the additional administration of r-LH in a GnRHa long protocol using r-FSH. It seems that due to the additional administration of r-LH the LH concentration in the follicular phase is sufficient to support folliculogenesis.

Non-invasive detection of alterations of the carotid artery in pregnant women with high-frequency ultrasound.

OBJECTIVE: To compare the thickness of the layers of the carotid artery wall in pregnant and fertile non-pregnant women. DESIGN: Prospective cross-sectional study. SUBJECTS: Fifty-one pregnant women at a mean gestational age of 38.9 weeks and 64 fertile non-pregnant women were examined at a University hospital. METHODS: The three layers (adventitia, media, intima) of the superficial wall of the left common carotid artery were identified and measured with high-resolution ultrasound (22.5 MHz). RESULTS: Pregnant women had a thinner intima layer (0.25 +/- 0.07/0.29 +/- 0.08 mm) and a thicker media layer (0.31 +/- 0.08/0.27 +/- 0.09 mm) compared with controls. A statistically significantly higher intima/media ratio was calculated for the pregnant women (1.14 +/- 0.03), compared with the non-pregnant women (0.88 +/- 0.04). CONCLUSION: There are differences in the thickness of the histological layers of the carotid artery wall in pregnant compared with non-pregnant women. This is likely to be due to the effect of different estradiol levels in these two groups.

Axillary metastases of an occult primary carcinoma of the breast-discovered only by 99mTc-tetrofosmin scintigraphy.

Recent reports consider 99mTc-tetrofosmin scintigraphy to be a powerful new diagnostic tool for discriminating malignant from benign breast disease. We report on a woman suffering from histologically confirmed axillary metastases of a primary unknown, occult carcinoma, whose origin was suspected within the breast. All the diagnostic procedures performed to discover any lesion failed or were inconclusive. The primary cancer was clearly visualized, however, in the right breast by means of 99mTc-tetrofosmin scintigraphy. Conclusion. We suggest that 99mTc-tetrofosmin scintigraphy is a powerful method to detect breast cancer, especially when other diagnostic imaging procedures are inconclusive.

Successful treatment of a heterotopic pregnancy by sonographically guided instillation of hyperosmolar glucose.

OBJECTIVE: To describe a new conservative approach in the treatment of heterotopic pregnancy. DESIGN: Case report. SETTING: A university hospital and an outpatient IVF center. INTERVENTION(S): Transvaginal ultrasonography-guided puncture of the ectopic gestational sac and instillation of hyperosmolar glucose. RESULT(S): The ectopic pregnancy resolved without further intervention. The intrauterine pregnancy resulted in a full-term live birth. CONCLUSION(S): Transvaginal injection of hyperosmolar glucose may be an effective conservative treatment for unruptured ectopic pregnancies in cases of heterotopic pregnancy.

Ultrastructural observations in human oocytes and preimplantation embryos after zona opening using an erbium-yttrium-aluminium-garnet (Er:YAG) laser.

For more than 3 years we have performed laser-assisted hatching prior to embryo transfer in patients with recurrent implantation failure using an erbium-yttrium-aluminium-garnet (Er:YAG) laser system that operates in the infrared region of the light spectrum. The laser beam is guided through a quartz fibre and is brought into direct contact with the zona pellucida. This study was undertaken to evaluate the ultrastructural effects of this laser on the zona pellucida and underlying cell membrane of unfertilized human oocytes and pathologically fertilized preimplantation embryos using light and scanning electron microscopy. The Er:YAG laser produces an almost circular zona opening in the shape of a truncated cone tapering off towards the inside, with a mean diameter of 18 mm. The exact diameter of the drilled site depends on the diameter of the fibre tip and the total number of pulses applied. After laser interaction, the zona matrix and the surface of the underlying ooplasm membrane showed no degenerative alterations. We conclude that the Er:YAG laser is an effective microsurgical tool for achieving reproducible, precise zona openings particularly suitable for purposes of assisted hatching because of their characteristic shape.

Prospective randomized study of an ultrashort gonadotrophin-releasing hormone agonist versus a modified suppression protocol for ovarian stimulation in intracytoplasmic sperm injection cycles.

To compare oocyte quality and clinical outcome after an ultrashort or a modified suppression gonadotrophin-releasing hormone agonist (GnRHa) protocol for ovarian stimulation in intracytoplasmic sperm injection (ICSI) cycles, we conducted a prospective randomized study of 60 consecutive couples with severe male infertility admitted for their first in-vitro fertilization (IVF) and ICSI attempt. More cycles were cancelled after the ultrashort protocol (8/30) than after the modified suppression protocol (3/30), although the difference was not significant. There were no cases of severe ovarian hyperstimulation syndrome (OHSS) in the ultrashort group compared to three cases in the suppression group. The percentage of mature metaphase II oocytes recovered in both groups was similar (88 versus 86%), as were the fertilization or cleavage rates after ICSI. In the ultrashort group, a total of 64 embryos was replaced in 22 transfers (mean 2.9 embryos per transfer), resulting in three first trimester abortions and seven deliveries. In the suppression group, 11 deliveries were achieved after transfer of a total of 75 embryos in 27 patients (mean 2.8 embryos per transfer). In conclusion, there was no apparent difference between the two GnRHa protocols in terms of oocyte quality and clinical outcome. However, because of the lower rate of severe OHSS, in our study the ultrashort protocol was more appropriate for ovarian stimulation in ICSI cycles than the modified suppression protocol.

Prediction of ovarian hyperstimulation syndrome by ultrasound volumetric assessment [corrected] of baseline ovarian volume prior to stimulation.

The aim of the study was to find out whether the estimation of the baseline ovarian volume prior to stimulation would be a suitable predictor for the risk of ovarian hyperstimulation syndrome (OHSS). A total of 101 patients underwent in-vitro fertilization (IVF) and embryo transfer. They had a 3-D volumetric assessment of the ovaries and body weight estimations on the first day of hormonal stimulation. A second measurement was performed on the day of ovulation induction with human chorionic gonadotrophin (HCG) together with an oestradiol 17 beta estimation in serum. During the IVF programme 15 women developed OHSS and 86 did not. There was a significant correlation between the baseline ovarian volume and subsequent occurrence of OHSS (P = 0.03). Other significant relationships were found between the occurrence of OHSS and the number of follicles (P = 0.002), the number of oocytes retrieved (P = 0.0001) and the length of the cycle (P = 0.0001). The body weight before and after the stimulation was significantly lower in the group of women who did develop the syndrome (P = 0.011 resp. 0.03). The oestradiol 17 beta concentration on the day of HCG administration in the serum of the patients who had OHSS was significantly higher (P = 0.0001). In conclusion, volumetry of the ovaries could help to detect patients at risk and prevent the occurrence of OHSS by early adjustment of the hormonal dosage. Recent advances in ultrasound technology (3-D ultrasound) enable quick and highly accurate volumetric assessments. Furthermore, our study confirms previous observations that low body weight and long cycles seem to be additional risk factors for the development of OHSS.

The effect of various ovulation induction protocols on pregnancy rates following intracytoplasmic sperm injection.

In the last two years intracytoplasmic sperm injection (ICSI) has become frequently employed as an assisted reproductive technique primarily to treat male factor infertility.' In order to achieve high pregnancy rates, all assisted reproductive technologies including ICSI require sufficient number and quality oocytes. In our practice we use three different ovulation induction regimens (CC/hMG, GnRH-a/hMG, and GnRH-a/FSH) to maximize the number of oocytes available for fertilization. In this present report, we retrospectively com- pared pregnancy rates with ICSI following the use of these protocols.

Assisted reproductive technology in the management of azoospermic men--the Austrian experience.

Experience with intracytoplasmic injection of epididymal (MESA) and testicular spermatozoa (TESE) in Austria is summarized. Data from recent publications in scientific journals and results presented at different meetings were stratified for male factors, sperm retrieval methods, assisted reproductive techniques and conceptions. Four cooperative groups of andrologists and gynaecologists reported on MESA and TESE in Austria. They achieved five deliveries (one twin) and two ongoing pregnancies in 40 couples.

Clinical application of volume estimation based on three-dimensional ultrasonography.

The development of three-dimensional sonography represents a milestone in the history of diagnostic ultrasound. It has become possible to evaluate a region of interest not only in the horizontal and vertical planes but also in a third, i.e. the frontal, plane. Among other possible applications, this technique greatly facilitates volume estimation. The objective of the present study was to evaluate the accuracy and precision of volumetry based on three-dimensional sonography. The results demonstrate a good correlation between estimated volumes and the volumes measured by transvaginal needle-guided follicle aspiration performed under sonographic visualization. Our findings confirm the conclusion of previous studies that three-dimensional sonography is making a valuable contribution to imaging techniques.

Fertilization and pregnancies following intracytoplasmic injection of testicular spermatozoa.

PURPOSE: Intracytoplasmic injection (ICSI) with testicular sperm was performed in 16 couples. All men had ductal obstruction and failed previous attempts of epididymal sperm microaspiration. METHODS: Testis tissue was obtained by excisional biopsies and incubated in HEPES buffered EBSS medium over 24 h at 37 degrees C. Motile sperm (Grade 1 to 2) were recovered in 13 patients and fertilized a total of 62 oozytes. Four pregnancies were achieved. RESULTS: One healthy boy and two girls (twin pregnancy) were born. CONCLUSIONS: The ongoing pregnancies revealed no fetal abnormalities on ultrasound scanning.

[Successful outcome of "intracytoplasmic sperm injection" (ICSI) within the scope of in vitro fertilization]. / Erfolgreiche Etablierung der "Intrazytoplasmatischen Spermien Injektion" (ICSI) im Rahmen der In-vitro-Fertilisation.

Poor function of spermatozoa accounts for half of all human infertility. "Intracytoplasmic sperm injection" (ICSI) is a new micromanipulatory method for the treatment of male infertility. "ICSI" was performed in cases of oligoasthenozoospermia in 12 IVF cycles, obtaining a fertilisation rate of 71.2% of all micromanipulated oocytes. So far four ongoing pregnancies occurred. Thus "Intracytoplasmic sperm Injection" represents a new encouraging technique to conceive, even in cases of severe male infertility.

Air in the uterine cavity after embryo transfer.

OBJECTIVE: To examine the effect on the pregnancy rate (PR) caused by air bubbles loaded into the transfer catheter to bracket the embryo-containing medium. DESIGN: Prospective, randomized study. SETTING: One hundred ninety-six consecutive ETs in the Institute of Sterility Treatment. INTERVENTIONS: Air bubbles were loaded into the transfer catheter concomitantly with the medium in group I (n = 98), whereas in group II (n = 98) no air bubbles were used. RESULTS: The PR of group I equals that of group II. CONCLUSIONS: Bracketing the embryo-containing medium by air bubbles offers several advantages, especially the possibility of tracking the air on the ultrasound monitor to localize the embryos after the ET. For these reasons we recommend using the proven method.