Luteal phase progesterone and oestradiol after ovarian stimulation: relation to response and prediction of pregnancy.

Research has focused on optimizing luteal phase support and endometrial receptivity in ovarian stimulation cycles. In this study, serial endocrine measurements were taken in 600 patients after a gonadotrophin-releasing hormone antagonist stimulation protocol. On the day of blastocyst transfer, serum progesterone and oestradiol were similar irrespective of a subsequent positive or negative pregnancy test (median 99 ng/ml versus 103 ng/ml for progesterone, respectively) or a subsequent live birth or pregnancy loss. Serum progesterone was significantly correlated to each ovarian response parameter (total number of follicles, number of oocytes retrieved and oestradiol concentration; r = 0.45, 0.57 and 0.54 respectively, all P < 0.0001). These correlations were consistent irrespective of clinical outcome. On the day of the pregnancy test, these correlations had vanished except in the live birth subgroup showing a weaker correlation (r = 0.22, 0.27 and 0.32 respectively, all P < 0.005). The lowest HCG and progesterone levels associated with live birth were 59.3 IU/l and 12.3 ng/ml, respectively. Fourteen out of 92 patients (15.2%) with pregnancy loss had normal HCG but low progesterone levels (above and below their respective 5th percentile), and miscarried before the end of the 7th week, when the luteal-placental shift occurs.

Association between blastocyst morphology and outcome of single-blastocyst transfer.

The aim of this study was to assess the ability of three individual blastocyst morphology parameters - expansion and hatching (EH) stage, inner cell mass (ICM) grade and trophectoderm grade - to predict outcome of a cycle with single-blastocyst transfer. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 intracytoplasmic sperm injection patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist cycle with compulsory single-blastocyst transfer on day 5 were included. In the simple logistic regression analysis, all three blastocyst morphology parameters were statistically significantly (P<0.005 for each) associated with positive human chorionic gonadotrophin, clinical and ongoing pregnancy rates and live birth rates, while only the ICM grade was significantly (P=0.033) associated with early pregnancy loss rate. Blastocyst EH stage was the only significant predictor of live birth (P=0.002) in the multiple logistic regression. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the EH stage. Transfer of a blastocyst with ICM grade A may reduce the risk of early pregnancy loss. Choosing the embryo(s) with the best implantation potential is essential for securing each couple the highest chance of achieving pregnancy after assisted reproduction. The selection of embryo(s) for transfer at the blastocyst stage is based on morphology parameters of expansion and hatching stage, inner cell mass grade and trophectoderm grade. The aim of this study was to assess the relative impact of each parameter in predicting the probability of a successful outcome. The study was a secondary analysis of data prospectively collected in a large multicentre trial. A total of 618 patients who underwent single-blastocyst transfer on day 5 were included. Statistical analysis showed that all three blastocyst morphology parameters were significantly associated with positive human chorionic gonadotrophin (ßHCG), clinical and ongoing pregnancy rates and live birth rates. Only the inner cell mass grade was significantly associated with early pregnancy loss between the positive ßHCG test and confirmation of ongoing pregnancy 10-11weeks after transfer. The expansion and hatching stage was the only significant predictor of live birth in the multiple logistic regression analysis. In conclusion, although all three blastocyst morphology parameters were related to treatment outcome of fresh single-blastocyst cycles, selection of high-quality blastocysts for transfer should consider first the expansion and hatching stage. Transfer of a blastocyst with inner cell mass grade A may reduce the risk of early pregnancy loss.

Predicting the FSH threshold dose in women with WHO Group II anovulatory infertility failing to ovulate or conceive on clomiphene citrate.

UNLABELLED: BACKGROUND The objective of this investigation was to establish independent predictors of follicle-stimulating hormone (FSH) threshold dose in anovulatory women undergoing ovulation induction with FSH preparations. METHODS: One hundred and fifty-one patients with WHO Group II anovulatory infertility failing to ovulate or conceive on clomiphene citrate underwent ovarian stimulation with FSH-only preparations following a low-dose step-up protocol. The individual FSH threshold dose was defined as the FSH dose when meeting the human chorionic gonadotrophin criteria (one follicle > or =17 mm, or 2-3 follicles > or =15 mm). The influence of demographics, physical characteristics, obstetric and infertility and menstrual cycle history, ovarian ultrasonography, endocrine parameters and type of gonadotrophin preparation on the FSH threshold dose was assessed through multiple regression analysis. RESULTS: In the univariate analysis, age, body mass index (BMI), failure to ovulate with clomiphene citrate, menstrual cycle history (amenorrhea, oligomenorrhea or anovulatory cycles of 21-35 days), mean ovarian volume, LH/FSH ratio, testosterone and free androgen index were significant (P < 0.05) predictors of FSH threshold dose. In the multivariate analysis, menstrual cycle history, mean ovarian volume and BMI remained significant (P < 0.001). CONCLUSIONS: The individual FSH threshold dose for ovulation induction in anovulatory women can be predicted based on three variables easily determined in clinical practice: menstrual cycle history, mean ovarian volume and BMI. A FSH dosage nomogram was constructed based on these parameters.

Highly purified FSH is as efficacious as recombinant FSH for ovulation induction in women with WHO Group II anovulatory infertility: a randomized controlled non-inferiority trial.

BACKGROUND: The objective of this study was to demonstrate non-inferiority of a highly purified urinary follicle stimulating hormone (HP-FSH) preparation compared with a recombinant (rFSH) preparation with respect to ovulation rate (primary end-point). METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-FSH (n=73) or rFSH (n=78) using a low-dose step-up protocol. The non-inferiority limit was prespecified at -20%. RESULTS: The ovulation rate was 85.2% (51/62) with HP-FSH and 90.9% (60/66) with rFSH (per-protocol population), and non-inferiority was demonstrated [95% confidence interval: -16.9; 5.6]. No differences were noted between groups in number of follicles>or=12 mm, >or=15 mm or >or=18 mm, mono-follicular development, pregnancy rates, endometrial thickness, number of ovarian stimulation syndrome cases or frequency of injection site reactions/pain. The singleton live birth rate was 15% in both groups (11/73 with HP-FSH and 12/78 with rFSH). CONCLUSIONS: This urinary HP-FSH preparation is non-inferior compared with a rFSH preparation with respect to ovulation rate in anovulatory WHO Group II women failing to ovulate or conceive on clomiphene citrate.

Influence of ovarian stimulation with HP-hMG or recombinant FSH on embryo quality parameters in patients undergoing IVF.

BACKGROUND: There are limited data on the impact of different gonadotrophin preparations on embryo quality. METHODS: This evaluation was part of a randomized, assessor-blind, multinational trial, conducted in 731 women undergoing IVF after stimulation with highly purified human menopausal gonadotropin (HP-hMG; MENOPUR) (n = 363) or recombinant FSH (rFSH; GONAL-F) (n = 368). Ongoing pregnancy was the primary end-point [HP-hMG 27% and rFSH 22%; odds ratio (OR) (95% confidence interval, CI) 1.25 (0.89-1.75)]. All 7535 oocytes retrieved were evaluated daily until day 3 (embryo transfer) in a blinded manner both by local site embryologists and a central panel of three embryologists. RESULTS: The proportion of top-quality embryos per oocyte retrieved was higher with HP-hMG (11.3%) compared with rFSH (9.0%) (P = 0.044) in the local assessment, but comparable in the central assessment (9.5 and 8.0%, respectively). Significant differences in favour of HP-hMG were observed for number of blastomeres and degree of fragmentation, while uniformity of blastomere sizes, localization of fragments, frequency of multinucleation and homogeneous cytoplasm were comparable between HP-hMG and rFSH. The live birth, ongoing pregnancy and ongoing implantation rates for top-quality embryos were higher with HP-hMG than rFSH [48 versus 32% (P = 0.038), 48 versus 32% (P = 0.038), 41 versus 27% (P = 0.032)]. Both the proportion of embryos with at least 50% surviving blastomeres after cryopreservation and embryos resuming mitosis were more frequent with HP-hMG compared with rFSH. CONCLUSIONS: Composition of gonadotrophin preparations used during ovarian stimulation has an impact on some embryo quality parameters. The capacity to implant of the top-quality embryos derived from stimulation with HP-hMG appears to be improved, although the mechanism needs to be elucidated.

Interobserver agreement and intraobserver reproducibility of embryo quality assessments.

BACKGROUND: The objective of this investigation was to determine the inter- and intraobserver agreement when assessing embryo quality. METHODS: This investigation included 4002 cleaved embryos from 7535 oocytes retrieved in 688 patients undergoing IVF cycles in a multicentre trial. Embryos were evaluated locally at the inverted microscope at 28, 44 and 68 h (+/-1 h) post-insemination. Digital images of the embryos were assessed centrally by three blinded embryologists. To assess reproducibility, 215 randomly selected cleaved embryos from 33 patients were re-evaluated by the three central embryologists. RESULTS: The interobserver agreement among the central embryologists (using the same method of evaluation; 2D images) was good for classification of top-quality embryos (kappa 0.71-0.73), excellent for classification of normally developed embryos (kappa 0.83-0.86) and good-excellent for classification of transferable embryos (kappa 0.78-0.82). The interobserver agreement between local and consolidated central assessment (different methods of evaluation, inverted microscopy versus 2D images) was good for all three embryo classifications (kappa 0.64-0.79). The intraobserver reproducibility for all three overall embryo classifications was excellent for the consolidated central assessment (kappa 0.80-0.91). CONCLUSION: Embryo quality can be determined with a good degree of interobserver agreement independently of the method of evaluation. Embryologists classify embryos with excellent intraobserver reproducibility.

Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO Group II anovulatory infertility: a randomized controlled study.

BACKGROUND: The contribution of the LH activity in menotrophin preparations for ovulation induction has been investigated in small trials conducted versus FSH preparations. The objective of this study was to demonstrate non-inferiority of highly purified urinary menotrophin (HP-HMG) versus recombinant FSH (rFSH) with respect to the primary outcome measure, ovulation rate. METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-HMG (n=91) or rFSH (n=93) using a low-dose step-up protocol. RESULTS: The ovulation rate was 85.7% with HP-HMG and 85.5% with rFSH (per-protocol population), and non-inferiority was demonstrated. Significantly fewer intermediate-sized follicles were observed in the HP-HMG group (P<0.05). The singleton live birth rate was comparable between the two groups. The frequency of ovarian hyperstimulation syndrome and/or cancellation due to excessive response was 2.2% with HP-HMG and 9.8% with rFSH (P=0.058). CONCLUSIONS: Stimulation with HP-HMG is associated with ovulation rates at least as good as a rFSH in anovulatory WHO Group II women. LH activity modifies follicular development so that fewer intermediate-sized follicles develop. This could have a positive impact on the safety of ovulation induction protocols.