Joan-Carles Arce

Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients

OBJECTIVE To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol. DESIGN Secondary analysis of data prospectively collected in a randomized, assessor-blind trial comparing two different gonadotropin preparations with respect to ongoing pregnancy rate. SETTING Twenty-five centers in seven countries. PATIENT(S) 749 women, aged 21 to 34 years, with primary diagnosis of infertility being unexplained infertility or mild male factor infertility and with serum follicle-stimulating hormone (FSH) level 1-12 IU/L and antral follicle count (AFC) ≥10. INTERVENTION(S) Controlled ovarian stimulation with highly purified human menopausal gonadotropin (hphMG) or recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer and potential subsequent 1-year cryopreserved blastocyst replacement in natural cycles. MAIN OUTCOME MEASURE(S) Relationships between AMH at start of stimulation and ovarian response and treatment outcome. RESULT(S) Serum AMH concentration was strongly correlated with oocyte yield: AMH accounted for 85%, FSH for 14%, and inhibin B and AFC for <1% each of the explained variation in oocyte yield. Also, AMH showed a high accuracy for the prediction of poor (≤3 oocytes) and high response (≥15 oocytes), which was statistically significantly better than basal FSH, AFC, or inhibin B. AMH was statistically significantly positively associated with ongoing pregnancy rate in the fresh cycle as well as with the 1-year cumulative ongoing pregnancy and live-birth rates. CONCLUSION(S) There is a positive relationship between AMH and oocyte yield in GnRH antagonist cycles, and AMH is the best predictor for identifying patients with poor and high ovarian response. The positive association between AMH and cumulative live-birth rates after fresh and cryopreserved cycles reflects the availability of more oocytes/blastocysts, not higher quality. CLINICAL TRIAL REGISTRATION NUMBER NCT00884221.

The value of anti-Müllerian hormone measurement in the long GnRH agonist protocol: association with ovarian response and gonadotrophin-dose adjustments

BACKGROUND This study evaluated the predictive value of serum and follicular fluid (FF) concentrations of anti-Müllerian hormone (AMH) with respect to treatment outcome variables in an IVF cycle. METHODS A retrospective analysis was performed with data from 731 normogonadotrophic women undergoing controlled ovarian stimulation after stimulation with highly purified menotrophin (HP-hMG) or rFSH following a long GnRH agonist protocol. RESULTS In both treatment groups, the serum AMH concentration at the start of the stimulation was significantly (P < 0.001) positively correlated with the serum levels of estradiol (HP-hMG: r = 0.45; rFSH: r = 0.55), androstenedione (HP-hMG: r = 0.50; rFSH: 0.49) and total testosterone (HP-hMG: r = 0.40; rFSH: r = 0.36) at the end of the stimulation as well as the number of oocytes retrieved (HP-hMG: r = 0.48; rFSH: r = 0.62), the AMH concentration in FF (HP-hMG: r = 0.55; rFSH: 0.61) and the serum progesterone concentration (HP-hMG: r = 0.39; rFSH: r = 0.50) at oocyte retrieval. For both treatments, serum AMH at the start of the stimulation was a good predictor of the need to increase or decrease the gonadotrophin dose on stimulation day 6 and of ovarian response below (<7 oocytes) or above (>15 oocytes) the target. No significant relationships were observed between serum AMH and embryo quality or ongoing pregnancy. CONCLUSION The serum AMH concentration at the start of the stimulation in IVF patients down-regulated with GnRH agonist in the long protocol revealed a positive relationship with ovarian response to gonadotrophins in terms of oocytes retrieved and accompanying endocrine response. AMH is a good predictor of the need for gonadotrophin-dose adjustment on stimulation day 6 for patients with a fixed starting dose, but a poor predictor of embryo quality and pregnancy chances in individual patients.

Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone–stratified, dose–response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection

OBJECTIVE To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrations. DESIGN Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0-14.9 pmol/L [0.7-<2.1 ng/mL]; high: 15.0-44.9 pmol/L [2.1-6.3 ng/mL]) trial. SETTING Seven infertility centers in four countries. PATIENT(S) Two hundred sixty-five women aged ≤37 years. INTERVENTION(S) Controlled ovarian stimulation with either 5.2, 6.9, 8.6, 10.3, or 12.1 μg of rhFSH, or 11 μg (150 IU) of follitropin alfa in a GnRH antagonist cycle. MAIN OUTCOME MEASURE(S) Number of oocytes retrieved. RESULT(S) The number of oocytes retrieved increased in an rhFSH dose-dependent manner, from 5.2 ± 3.3 oocytes with 5.2 μg/d to 12.2 ± 5.9 with 12.1 μg/d. The slopes of the rhFSH dose-response curves differed significantly between the two AMH strata, demonstrating that a 10% increase in dose resulted in 0.5 (95% confidence interval 0.2-0.7) and 1.0 (95% confidence interval 0.7-1.3) more oocytes in the low and high AMH stratum, respectively. Fertilization rate and blastocyst/oocyte ratio decreased significantly with increasing rhFSH doses in both AMH strata. No linear relationship was observed between rhFSH dose and number of blastocysts overall or by AMH strata. Five cases of ovarian hyperstimulation syndrome were reported for the three highest rhFSH doses and in the high AMH stratum. CONCLUSION(S) Increasing rhFSH doses results in a linear increase in number of oocytes retrieved in an AMH-dependent manner. The availability of blastocysts is less influenced by the rhFSH dose and AMH level. CLINICAL TRIAL REGISTRATION NUMBER NCT01426386.

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 (βHCG), 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 βHCG 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.

The non-ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, double-blind, placebo-controlled trial

BACKGROUND Ovarian hyperstimulation syndrome (OHSS) seems to be induced by the ovarian release of vascular endothelial growth factor (VEGF), which increases vascular permeability. Dopamine agonists inhibit VEGF receptor phosphorylation and thereby decrease vascular permeability. METHODS A randomized, double-blind, placebo-controlled, multicentre study assessing three oral doses (50, 100, 200 µg/day) of the non-ergot derived dopamine agonist quinagolide started on the day of human chorionic gonadotrophin (hCG) and continued for 17–21 days without dose-titration in comparison to placebo in preventing moderate/severe early OHSS (onset ≤9 days after hCG administration) in 182 IVF patients with ≥20 but less than 30 follicles ≥10 mm. RESULTS The incidence of moderate/severe early OHSS was 23% (12/53) in the placebo group and 12% (6/51), 13% (7/52) and 4% (1/26) in the quinagolide 50, 100 and 200 µg/day groups, respectively. The moderate/severe early OHSS rate was significantly lower with all quinagolide groups combined compared with placebo [P = 0.019; OR = 0.28 (0.09–0.81)]. The incidence of ultrasound evidence of ascites among patients with no clinical pregnancy was significantly reduced from 31% (8/26) with placebo to 11% (8/70) with all quinagolide groups combined [P = 0.033; OR = 0.29 (0.10–0.88)], although there was no difference for those with clinical pregnancy. Quinagolide did not have a detrimental effect on pregnancy or live birth rates. The incidence of gastrointestinal and central nervous system adverse events increased with increasing doses of quinagolide. CONCLUSIONS Quinagolide appears to prevent moderate/severe early OHSS while not affecting treatment outcome. The effect is more marked in patients who did not achieve a clinical pregnancy. Quinagolide administered in high doses without dose-titration is associated with poor tolerability. ClinicalTrials.gov Identifier: NCT00329693.

Comparison of antimüllerian hormone levels and antral follicle count as predictor of ovarian response to controlled ovarian stimulation in good-prognosis patients at individual fertility clinics in two multicenter trials

OBJECTIVE To compare antimüllerian hormone (AMH) and antral follicle count (AFC) as predictors of ovarian response to controlled ovarian stimulation at individual fertility clinics. DESIGN Retrospective analysis of individual study center data in two multicenter trials. Centers that provided >10 patients were included in the analysis. SETTING A total of 19 (n = 519 patients) and 18 study centers (n = 686 patients) participating in a long GnRH agonist trial (MERIT) and a GnRH antagonist trial (MEGASET), respectively. PATIENT(S) Infertile women of good prognosis. INTERVENTION(S) Long GnRH agonist or GnRH antagonist cycles. MAIN OUTCOME MEASURE(S) Correlation between AMH and AFC, and oocyte yield by each study center for each trial. RESULTS(S) Antimüllerian hormone was more strongly correlated with oocyte yield than AFC: r = 0.56 vs. r = 0.28 in the GnRH agonist cohort, and r = 0.55 vs. r = 0.33 in the GnRH antagonist cohort. The correlation was numerically higher for AMH than for AFC at a significantly higher proportion of study centers: 17 (89%) and 15 (83%) centers in the long GnRH agonist and GnRH antagonist trial, respectively. Assessment of the relative capacity of AMH and AFC for predicting oocyte yield demonstrated that AMH dominated the model: AMH, R(2) = 0.29 and 0.23; AFC: R(2) = 0.07 and 0.07; AMH + AFC: R(2) = 0.30 and 0.23 for long GnRH agonist and GnRH antagonist trials, respectively. CONCLUSIONS(S) Antimüllerian hormone was a stronger predictor of ovarian response to gonadotropin therapy than AFC at the study center level in both randomized trials utilizing GnRH agonist and GnRH antagonist protocols. Antral follicle count provided no added predictive value beyond AMH.

The effect of barusiban, a selective oxytocin antagonist, in threatened preterm labor at late gestational age: a randomized, double-blind, placebo-controlled trial

OBJECTIVE The objective of the study was to compare barusiban with placebo in threatened preterm labor. STUDY DESIGN This was a randomized, double-blind, placebo-controlled, multicenter study. One hundred sixty-three women at 34-35 weeks plus 6 days, and with 6 or more contractions of 30 seconds duration during 30 minutes, cervical length 15 mm or less, and cervical dilatation > 1 and < 4 cm were randomized to a single intravenous bolus of barusiban (0.3, 1, 3, or 10 mg) or placebo. The primary endpoint was percentage of women who did not deliver within 48 hours. RESULTS None of the barusiban doses reduced the number of uterine contractions compared with placebo. There was no significant difference in the percentage of women who did not deliver within 48 hours (72% placebo and 65-88% barusiban groups; P = .21-.84). Barusiban was not associated with an adverse safety profile in the woman, fetus, neonate, or infant. CONCLUSION An intravenous bolus of barusiban was no more effective than placebo in stopping preterm labor in pregnant women at late gestational age.

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

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 ≥17 mm, or 2–3 follicles ≥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.

A differential cytokine expression profile is induced by highly purified human menopausal gonadotropin and recombinant follicle-stimulating hormone in a pre- and postovulatory mouse follicle culture model

OBJECTIVE To compare the differential effects of highly purified (HP) hMG or recombinant FSH (rFSH) on cytokine expression before and after ovulation in an in vitro mouse ovarian follicle model. DESIGN A prospective laboratory in vitro study. SETTING A university-based reproductive biology laboratory. MATERIAL(S): Mechanically isolated mouse preantral follicles from 14-day-old prepubertal mouse ovaries (F1 hybrids: C57BL/6JxCBA/ca). INTERVENTION(S) Randomly distributed mouse early preantral follicles were exposed to two hyperstimulation conditions with either HP-hMG or rFSH. An ovulatory stimulus was given using hCG/epidermal growth factor. Conditioned media from the two culture conditions were collected on the days before and after in vitro ovulation. Conditioned media were compared for their relative cytokine profile content as measured by a cytokine antibody array analysis. MAIN OUTCOME MEASURE(S) Relative concentrations of 62 cytokines in conditioned media before and after ovulation. RESULT(S) Statistically significant increase in the production of a number of cytokines was found after HP-hMG stimulation compared with rFSH: 14 and 24 pre- and post-rhCG, respectively. Cytokines with the largest significant difference (more than 5 times) before and after ovulation included thymus-expressed cytokine (TECK), sTNFRI, and SDF-1alpha. The cytokines that are most strongly related to oocyte and embryo quality and implantation and that have been related to oocyte yield and maturation were significantly higher with HP-hMG. CONCLUSION(S) The significant differences in follicular cytokine production induced by HP-HMG and rFSH before and after in vitro ovulation might explain the difference in treatment outcome.

Late preterm birth is associated with short‐term morbidity but not with adverse neurodevelopmental and physical outcomes at 1 year

We compared the neonatal and infant outcomes at one year (Bayley mental and psychomotor development index, and physical growth) of babies who were (n = 63) or were not (n = 100) delivered prior to 37 weeks in women admitted in threatened late preterm labor (34–35+6 weeks) with a cervix ≤15 mm. The women were part of a clinical trial to investigate the tocolytic effect of the oxytocin antagonist barusiban. Babies born late preterm (34–36+6 weeks) had a significantly increased risk of short‐term morbidity (hepatobiliary disorders, respiratory disorders, metabolic disorders, nervous system disorders, infection; p < 0.05 for each) compared with those born at term, but there were no significant differences in the neurodevelopmental and physical outcomes at one year (p > 0.05 for both one‐year outcomes).