From October 1992 to December 1994, 2732 cycles of treatment by intracytoplasmic sperm injection ... more From October 1992 to December 1994, 2732 cycles of treatment by intracytoplasmic sperm injection (ICSI) were carried out in couples mainly with severe male-factor infertility. The overall fertilization rate in these 2732 cycles was 71% of intact oocytes. However, in 76 (72 couples) of these cycles, none of the injected oocytes became fertilized, so the total fertilization failure rate was 3% (76/2732 cycles). Details of these 76 cycles were analysed. The results show that total fertilization failure after ICSI may be explained by different factors related to (i) semen characteristics (only immotile or round-headed spermatozoa for ICSI) or (ii) the oocytes (number, abnormal morphology, damage after ICSI). Of 26 couples, 22 achieved fertilization in their subsequent ICSI cycles. In conclusion, total fertilization failure after ICSI for the treatment of severe male-factor infertility was mainly caused by the poor viability of the spermatozoa used for injection; it was also associated with a low number and poor quality of oocytes. Repeated ICSI treatment may be useful or necessary in couples with total fertilization failure.
The present retrospective cohort study was conducted to investigate whether serum anti-Müllerian ... more The present retrospective cohort study was conducted to investigate whether serum anti-Müllerian hormone (AMH) levels, determined by either the Immunotech (IOT) or the second generation (Gen II) assay, can predict follicular recruitment in women with PCOS undergoing ovulation induction with clomiphene citrate (CC). Patients received 50mg CC daily for ovulation induction followed by natural intercourse or intrauterine insemination. Overall, 84 women had their serum AMH levels tested before treatment [42 patients with Immunotech (IOT), and 42 patients with the Gen II-assay]. The primary outcome was to determine dominant follicle (>10mm) recruitment in relation to AMH levels. Thirty three (79%) patients in the IOT and 34 (81%) patients in the Gen II assay group developed a dominant follicle within 15 days after initiation of CC. Circulating AMH levels did not differ between women with or without dominant follicular recruitment in the both groups. By using either the AMH IOT or the Gen II assay, serum AMH levels were not predictive of the development of a dominant follicle. In conclusion, serum AMH levels measured by IOT or Gen II assay, has limited value to predict PCOS patients who will develop a dominant follicle following ovulation induction with CC.
Crude RNA preparations from uteri of oestradiol-treated rats induced the implantation of delayed ... more Crude RNA preparations from uteri of oestradiol-treated rats induced the implantation of delayed blastocysts when injected into the parametrium of ovariectomized pregnant rats. Treatment of donor animals with labelled oestradiol showed that this effect could not be due to contamination of the RNA extracts by oestradiol. RNase digestion of these extracts suppressed their capacity to induce implantation. Purified poly (A)-rich RNA from oestrogen-treated uteri failed to elicit implantation although it was capable of increasing epithelial height when repeatedly injected into uterine horns of ovariectomized rats. These results suggest that uterine RNA synthesis might somehow mediate the effects of oestrogen in causing implantation and that RNAs other than messenger RNA might be involved.
This retrospective study determined the efficacy of ovarian stimulation for IVF/intracytoplasmic ... more This retrospective study determined the efficacy of ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) in poor ovarian responders fulfilling the Bologna criteria for poor ovarian response and identified predictors of live birth rates. Overall, 485 patients undergoing 823 ovarian stimulation cycles for IVF/ICSI with maximum gonadotrophin dose (≥ 300 IU) between January 2009 and December 2011 were included. Patients were considered eligible, irrespective of the treatment protocol, if they were classified as poor responders based on the recently developed definition for poor ovarian response by the European Society of Human Reproduction and Embryology, the Bologna criteria. Live birth rates did not significantly differ between women aged <40 and women aged ≥ 40 years either per cycle (7.1 versus 5.2%, OR 1.38, 95% CI 0.77-2.46) or per patient (11.6 versus 8.8%, OR 1.36, 95% CI 0.75-2.46). In logistic regression analysis, the number of oocytes retrieved was the only variable significantly associated with live births (OR 1.92, 95% CI 1.03-3.55 for >3 versus 1-3 oocytes). Bologna poor responders demonstrate very low live birth rates, irrespective of age and treatment protocol used. An increase in the number of oocytes retrieved is an independent variable related to live birth rates.
Estradiol growth rate (EGR) during active follicular development was calculated for 89 stimulated... more Estradiol growth rate (EGR) during active follicular development was calculated for 89 stimulated in vitro fertilization cycles by exponential curve fit (r = 0.83). Cycles could be divided into four groups with very low, low, moderate, and high EGR values. Cases without oocyte fertilization and/or embryo replacement did not occur in the moderate EGR range, which also corresponded to a significantly better ratio of replaceable embryos versus oocytes recovered. This group was also endowed with a pregnancy rate amounting to 28.5% per laparoscopy and per replacement, i.e., about three times higher than in the three other groups. Very low or high EGR entailed significantly higher percentages of missed oocyte recovery and/or fertilization failure. The frequency of occurrence of a spontaneous luteinizing hormone peak was negatively correlated with EGR. The data indicate that a better outcome of in vitro fertilization may be expected when the estrogen rise starts early in the cycle and adopts a moderate growth rate (0.3 to 0.4).
What is the impact on pregnancy rates when intrauterine insemination (IUI) is performed 1 or 2 da... more What is the impact on pregnancy rates when intrauterine insemination (IUI) is performed 1 or 2 days after the spontaneous LH rise? IUI 1 day after the spontaneous LH rise results in significantly higher clinical pregnancy rates compared with IUI performed 2 days after the LH rise. IUI is scheduled within a limited time interval during which successful conception can be expected. Data about the optimal timing of IUI are based on inseminations following ovarian stimulation. There is no available evidence regarding the correct timing of IUI in a natural menstrual cycle following the occurrence of a spontaneous LH rise. A prospective RCT, including patients undergoing IUI with donor sperm in a natural menstrual cycle. IUI cycles (n = 435) were randomized between October 2010 and April 2013, of which 23 were excluded owing to protocol deviation and 412 received the allocated intervention. Serial serum LH concentrations were analysed in samples taken between 07:00 and 09:00 h to detect an LH rise from Day 11 of the cycle onwards. The subjects were randomized to receive insemination either 1 or 2 days after the observed LH rise. In the final analysis, there were 213 cycles in the group receiving IUI 1 day after the LH rise and 199 cycles in the group receiving IUI 2 days after the LH rise. Significantly higher clinical pregnancy rates per IUI cycle were observed in patients undergoing IUI 1 day after the LH rise when compared with patients undergoing IUI 2 days after the LH rise [19.7 (42/213) versus 11.1% (22/199), P = 0.02]. In view of the timing of sampling for LH, the inseminations were performed at 27 h (±2 h) and 51 h (±2 h) after detection of the LH rise. The risk ratio of achieving a clinical pregnancy if IUI was scheduled 1 day after the LH rise compared with 2 days was 1.78 [95% confidence interval (CI), 1.11-2.88]. This points towards a gain of one additional clinical pregnancy for every 12 cycles performed 1 day instead of 2 days after the LH rise. When analysing the results per patient, including only women who underwent their first treatment cycle of insemination, the outcome was in line with the per cycle analysis, demonstrating an 8% difference in pregnancy rate in favour of the early group (20.5 versus 12.2%), however, this difference was not significant. Optimal monitoring for the occurrence of the LH rise involves several daily LH measurements, which is not always amenable to everyday clinical practice, however, daily sampling was sufficient to detect a significant difference in pregnancy rate. The strict inclusion of a highly selected population of patients who underwent IUI in a natural cycle may have been a limitation. IUI in a natural menstrual cycle confers lower success rates compared with IUI following ovarian stimulation and is not suitable for patients with ovulatory dysfunction. Furthermore, a similar study in a larger number of women is required to confirm the result in terms of pregnancy rate per patient. This is the first RCT to show that timing of IUI in a natural menstrual cycle is important and that IUI should be performed 1 day after the LH rise, rather than 2 days post-LH rise. Daily monitoring of the rise in LH, as performed in our study, can be adopted to achieve a higher pregnancy rate per IUI cycle. No funding was received for this study. All authors declare to have no conflict of interest with regard to this trial. The trial was registered at clinicaltrials.gov (NCT01622023).
The successive stages leading to fertilization in mammals are reviewed in this article. Methods o... more The successive stages leading to fertilization in mammals are reviewed in this article. Methods of human sperm preparation for IVF are described and the "ideal" delay between oocyte pick-up and insemination time is discussed, as well as methods to reduce the incidence of polyspermy. Different culture media and their supplementation are mentioned, as well as a semi-quantitative embryonic scoring system, defined by the IVF team of the Saint-Pierre Hospital in Brussels. Finally the optimal transfer time, and the handling of embryos at replacement are discussed.
Four-hundred-and-ninety-one oocytes were collected from 142 successive patients attending for in-... more Four-hundred-and-ninety-one oocytes were collected from 142 successive patients attending for in-vitro fertilization. The systematic observation of pronuclei between 14 and 18 h after insemination revealed 27 cases of tripronucleate eggs among 391 fertilized eggs (6.9%), which corresponds to rates generally reported in the literature. The following parameters were analysed in relation to the incidence of these eggs: aetiology of infertility, follicular response to hormonal stimulation, type of ovulatory stimulus, sperm count and motility and the incidence of fertilization. Only fertilization rates and concentration of motile spermatozoa in the insemination medium were found to be correlated with tripronucleate eggs, confirming that the condition is predominantly due to polyspermy. Comparisons with data from animals, and measures aimed at preventing polyspermy are suggested.
After ovarian stimulation with clomiphene citrate combined with human menopausal gonadotropin for... more After ovarian stimulation with clomiphene citrate combined with human menopausal gonadotropin for in vitro fertilization, the appearance of a spontaneous luteinizing hormone (LH) surge before fulfillment of the minimal criteria of follicular maturity (at least one follicle greater than 19 mm and serum estradiol [E2] greater than 400 pg/ml/follicle greater than 17 mm) is associated with reduced pregnancy rates. In these cases, follicles are smaller and serum E2 values are lower at the time of the LH surge. Oocyte recovery rate is reduced, embryonic anucleate fragments are more frequently observed, and the level of luteal progesterone on day 4 after oocyte retrieval is lower. Hyperandrogenic patients are more prone to display such premature spontaneous LH surge. We concluded that in case of an untimely LH rise, laparoscopy for oocyte retrieval should be cancelled.
Thirty-eight single and 10 multiple pregnancies obtained after in-vitro fertilization were compar... more Thirty-eight single and 10 multiple pregnancies obtained after in-vitro fertilization were compared. In the group of multiple gestations, maternal age was lower and the amounts of ovulatory drugs given were significantly smaller than in relation to single pregnancies. All multiple pregnancies arose from triple embryo transfers and the embryos from this group exhibited significantly higher vitality scores. In both groups, plasma levels of oestradiol and progesterone followed the same pattern until day 8 after oocyte retrieval. Following implantation, the secretion of these hormones increased more rapidly in multiple pregnancies pointing at greater luteal activity in this group. HCG levels became significantly higher in multiple gestation on day 25 after oocyte collection. Echographic examination showed that, compared to normal pregnancy, growth in both groups of IVF conceptuses was initially retarded but caught up with normal evolution at approximately 30 days after egg retrieval. The need for adjusting the number of embryos transferred not only to expected success rates but also to the risk of high rank multiples is emphasized.
The rationale and results of using epididymal and testicular spermatozoa with intracytoplasmic sp... more The rationale and results of using epididymal and testicular spermatozoa with intracytoplasmic sperm injection (ICSI) for zoospermic patients are reviewed. A total of 128 consecutive ICSI/MESA cycles and a total of 120 consecutive ICSI/TESE cycles were performed up to December 1994. The two-pronuclei fertilization rate per intact oocyte (observed after the injection) was 58% and 60%, respectively, when epididymal and testicular spermatozoa were used. The embryo transfer rate was similar for the two procedures (91% after ICSI/MESA and 90% after ICSI/TESE). Fifty women became pregnant (positive HCG) when epididymal spermatozoa were used (39% per cycle and 40% per embryo transfer). These results are comparable to those obtained when ejaculated spermatozoa are used.
From October 1992 to December 1994, 2732 cycles of treatment by intracytoplasmic sperm injection ... more From October 1992 to December 1994, 2732 cycles of treatment by intracytoplasmic sperm injection (ICSI) were carried out in couples mainly with severe male-factor infertility. The overall fertilization rate in these 2732 cycles was 71% of intact oocytes. However, in 76 (72 couples) of these cycles, none of the injected oocytes became fertilized, so the total fertilization failure rate was 3% (76/2732 cycles). Details of these 76 cycles were analysed. The results show that total fertilization failure after ICSI may be explained by different factors related to (i) semen characteristics (only immotile or round-headed spermatozoa for ICSI) or (ii) the oocytes (number, abnormal morphology, damage after ICSI). Of 26 couples, 22 achieved fertilization in their subsequent ICSI cycles. In conclusion, total fertilization failure after ICSI for the treatment of severe male-factor infertility was mainly caused by the poor viability of the spermatozoa used for injection; it was also associated with a low number and poor quality of oocytes. Repeated ICSI treatment may be useful or necessary in couples with total fertilization failure.
The present retrospective cohort study was conducted to investigate whether serum anti-Müllerian ... more The present retrospective cohort study was conducted to investigate whether serum anti-Müllerian hormone (AMH) levels, determined by either the Immunotech (IOT) or the second generation (Gen II) assay, can predict follicular recruitment in women with PCOS undergoing ovulation induction with clomiphene citrate (CC). Patients received 50mg CC daily for ovulation induction followed by natural intercourse or intrauterine insemination. Overall, 84 women had their serum AMH levels tested before treatment [42 patients with Immunotech (IOT), and 42 patients with the Gen II-assay]. The primary outcome was to determine dominant follicle (>10mm) recruitment in relation to AMH levels. Thirty three (79%) patients in the IOT and 34 (81%) patients in the Gen II assay group developed a dominant follicle within 15 days after initiation of CC. Circulating AMH levels did not differ between women with or without dominant follicular recruitment in the both groups. By using either the AMH IOT or the Gen II assay, serum AMH levels were not predictive of the development of a dominant follicle. In conclusion, serum AMH levels measured by IOT or Gen II assay, has limited value to predict PCOS patients who will develop a dominant follicle following ovulation induction with CC.
Crude RNA preparations from uteri of oestradiol-treated rats induced the implantation of delayed ... more Crude RNA preparations from uteri of oestradiol-treated rats induced the implantation of delayed blastocysts when injected into the parametrium of ovariectomized pregnant rats. Treatment of donor animals with labelled oestradiol showed that this effect could not be due to contamination of the RNA extracts by oestradiol. RNase digestion of these extracts suppressed their capacity to induce implantation. Purified poly (A)-rich RNA from oestrogen-treated uteri failed to elicit implantation although it was capable of increasing epithelial height when repeatedly injected into uterine horns of ovariectomized rats. These results suggest that uterine RNA synthesis might somehow mediate the effects of oestrogen in causing implantation and that RNAs other than messenger RNA might be involved.
This retrospective study determined the efficacy of ovarian stimulation for IVF/intracytoplasmic ... more This retrospective study determined the efficacy of ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) in poor ovarian responders fulfilling the Bologna criteria for poor ovarian response and identified predictors of live birth rates. Overall, 485 patients undergoing 823 ovarian stimulation cycles for IVF/ICSI with maximum gonadotrophin dose (≥ 300 IU) between January 2009 and December 2011 were included. Patients were considered eligible, irrespective of the treatment protocol, if they were classified as poor responders based on the recently developed definition for poor ovarian response by the European Society of Human Reproduction and Embryology, the Bologna criteria. Live birth rates did not significantly differ between women aged <40 and women aged ≥ 40 years either per cycle (7.1 versus 5.2%, OR 1.38, 95% CI 0.77-2.46) or per patient (11.6 versus 8.8%, OR 1.36, 95% CI 0.75-2.46). In logistic regression analysis, the number of oocytes retrieved was the only variable significantly associated with live births (OR 1.92, 95% CI 1.03-3.55 for >3 versus 1-3 oocytes). Bologna poor responders demonstrate very low live birth rates, irrespective of age and treatment protocol used. An increase in the number of oocytes retrieved is an independent variable related to live birth rates.
Estradiol growth rate (EGR) during active follicular development was calculated for 89 stimulated... more Estradiol growth rate (EGR) during active follicular development was calculated for 89 stimulated in vitro fertilization cycles by exponential curve fit (r = 0.83). Cycles could be divided into four groups with very low, low, moderate, and high EGR values. Cases without oocyte fertilization and/or embryo replacement did not occur in the moderate EGR range, which also corresponded to a significantly better ratio of replaceable embryos versus oocytes recovered. This group was also endowed with a pregnancy rate amounting to 28.5% per laparoscopy and per replacement, i.e., about three times higher than in the three other groups. Very low or high EGR entailed significantly higher percentages of missed oocyte recovery and/or fertilization failure. The frequency of occurrence of a spontaneous luteinizing hormone peak was negatively correlated with EGR. The data indicate that a better outcome of in vitro fertilization may be expected when the estrogen rise starts early in the cycle and adopts a moderate growth rate (0.3 to 0.4).
What is the impact on pregnancy rates when intrauterine insemination (IUI) is performed 1 or 2 da... more What is the impact on pregnancy rates when intrauterine insemination (IUI) is performed 1 or 2 days after the spontaneous LH rise? IUI 1 day after the spontaneous LH rise results in significantly higher clinical pregnancy rates compared with IUI performed 2 days after the LH rise. IUI is scheduled within a limited time interval during which successful conception can be expected. Data about the optimal timing of IUI are based on inseminations following ovarian stimulation. There is no available evidence regarding the correct timing of IUI in a natural menstrual cycle following the occurrence of a spontaneous LH rise. A prospective RCT, including patients undergoing IUI with donor sperm in a natural menstrual cycle. IUI cycles (n = 435) were randomized between October 2010 and April 2013, of which 23 were excluded owing to protocol deviation and 412 received the allocated intervention. Serial serum LH concentrations were analysed in samples taken between 07:00 and 09:00 h to detect an LH rise from Day 11 of the cycle onwards. The subjects were randomized to receive insemination either 1 or 2 days after the observed LH rise. In the final analysis, there were 213 cycles in the group receiving IUI 1 day after the LH rise and 199 cycles in the group receiving IUI 2 days after the LH rise. Significantly higher clinical pregnancy rates per IUI cycle were observed in patients undergoing IUI 1 day after the LH rise when compared with patients undergoing IUI 2 days after the LH rise [19.7 (42/213) versus 11.1% (22/199), P = 0.02]. In view of the timing of sampling for LH, the inseminations were performed at 27 h (±2 h) and 51 h (±2 h) after detection of the LH rise. The risk ratio of achieving a clinical pregnancy if IUI was scheduled 1 day after the LH rise compared with 2 days was 1.78 [95% confidence interval (CI), 1.11-2.88]. This points towards a gain of one additional clinical pregnancy for every 12 cycles performed 1 day instead of 2 days after the LH rise. When analysing the results per patient, including only women who underwent their first treatment cycle of insemination, the outcome was in line with the per cycle analysis, demonstrating an 8% difference in pregnancy rate in favour of the early group (20.5 versus 12.2%), however, this difference was not significant. Optimal monitoring for the occurrence of the LH rise involves several daily LH measurements, which is not always amenable to everyday clinical practice, however, daily sampling was sufficient to detect a significant difference in pregnancy rate. The strict inclusion of a highly selected population of patients who underwent IUI in a natural cycle may have been a limitation. IUI in a natural menstrual cycle confers lower success rates compared with IUI following ovarian stimulation and is not suitable for patients with ovulatory dysfunction. Furthermore, a similar study in a larger number of women is required to confirm the result in terms of pregnancy rate per patient. This is the first RCT to show that timing of IUI in a natural menstrual cycle is important and that IUI should be performed 1 day after the LH rise, rather than 2 days post-LH rise. Daily monitoring of the rise in LH, as performed in our study, can be adopted to achieve a higher pregnancy rate per IUI cycle. No funding was received for this study. All authors declare to have no conflict of interest with regard to this trial. The trial was registered at clinicaltrials.gov (NCT01622023).
The successive stages leading to fertilization in mammals are reviewed in this article. Methods o... more The successive stages leading to fertilization in mammals are reviewed in this article. Methods of human sperm preparation for IVF are described and the "ideal" delay between oocyte pick-up and insemination time is discussed, as well as methods to reduce the incidence of polyspermy. Different culture media and their supplementation are mentioned, as well as a semi-quantitative embryonic scoring system, defined by the IVF team of the Saint-Pierre Hospital in Brussels. Finally the optimal transfer time, and the handling of embryos at replacement are discussed.
Four-hundred-and-ninety-one oocytes were collected from 142 successive patients attending for in-... more Four-hundred-and-ninety-one oocytes were collected from 142 successive patients attending for in-vitro fertilization. The systematic observation of pronuclei between 14 and 18 h after insemination revealed 27 cases of tripronucleate eggs among 391 fertilized eggs (6.9%), which corresponds to rates generally reported in the literature. The following parameters were analysed in relation to the incidence of these eggs: aetiology of infertility, follicular response to hormonal stimulation, type of ovulatory stimulus, sperm count and motility and the incidence of fertilization. Only fertilization rates and concentration of motile spermatozoa in the insemination medium were found to be correlated with tripronucleate eggs, confirming that the condition is predominantly due to polyspermy. Comparisons with data from animals, and measures aimed at preventing polyspermy are suggested.
After ovarian stimulation with clomiphene citrate combined with human menopausal gonadotropin for... more After ovarian stimulation with clomiphene citrate combined with human menopausal gonadotropin for in vitro fertilization, the appearance of a spontaneous luteinizing hormone (LH) surge before fulfillment of the minimal criteria of follicular maturity (at least one follicle greater than 19 mm and serum estradiol [E2] greater than 400 pg/ml/follicle greater than 17 mm) is associated with reduced pregnancy rates. In these cases, follicles are smaller and serum E2 values are lower at the time of the LH surge. Oocyte recovery rate is reduced, embryonic anucleate fragments are more frequently observed, and the level of luteal progesterone on day 4 after oocyte retrieval is lower. Hyperandrogenic patients are more prone to display such premature spontaneous LH surge. We concluded that in case of an untimely LH rise, laparoscopy for oocyte retrieval should be cancelled.
Thirty-eight single and 10 multiple pregnancies obtained after in-vitro fertilization were compar... more Thirty-eight single and 10 multiple pregnancies obtained after in-vitro fertilization were compared. In the group of multiple gestations, maternal age was lower and the amounts of ovulatory drugs given were significantly smaller than in relation to single pregnancies. All multiple pregnancies arose from triple embryo transfers and the embryos from this group exhibited significantly higher vitality scores. In both groups, plasma levels of oestradiol and progesterone followed the same pattern until day 8 after oocyte retrieval. Following implantation, the secretion of these hormones increased more rapidly in multiple pregnancies pointing at greater luteal activity in this group. HCG levels became significantly higher in multiple gestation on day 25 after oocyte collection. Echographic examination showed that, compared to normal pregnancy, growth in both groups of IVF conceptuses was initially retarded but caught up with normal evolution at approximately 30 days after egg retrieval. The need for adjusting the number of embryos transferred not only to expected success rates but also to the risk of high rank multiples is emphasized.
The rationale and results of using epididymal and testicular spermatozoa with intracytoplasmic sp... more The rationale and results of using epididymal and testicular spermatozoa with intracytoplasmic sperm injection (ICSI) for zoospermic patients are reviewed. A total of 128 consecutive ICSI/MESA cycles and a total of 120 consecutive ICSI/TESE cycles were performed up to December 1994. The two-pronuclei fertilization rate per intact oocyte (observed after the injection) was 58% and 60%, respectively, when epididymal and testicular spermatozoa were used. The embryo transfer rate was similar for the two procedures (91% after ICSI/MESA and 90% after ICSI/TESE). Fifty women became pregnant (positive HCG) when epididymal spermatozoa were used (39% per cycle and 40% per embryo transfer). These results are comparable to those obtained when ejaculated spermatozoa are used.
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