Randomized, controlled, open-label, non-inferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa.

In this randomized, controlled, open-label, phase IV study, ovarian response after a follitropin alfa starting dose determined by the CONSORT calculator was compared with a standard dose (150 IU). Normo-ovulatory women (aged 18-34 years) eligible for assisted reproductive techniques were recruited (23 centres: nine European countries and Chile); 200 women were randomized (CONSORT [n = 96]; standard dosing [n = 104]). Significantly lower mean daily (121.5 versus 167.4 IU; P < 0.001) and total (1288.5 versus 1810.0 IU; P < 0.001) doses of follitropin alfa were administered in the CONSORT group. Clinical pregnancy rates were CONSORT (36.0%) and standard dosing (35.5%); estimated difference (confidence interval 0.6%; -13.5 to 14.6). Ovarian hyperstimulation syndrome occurred in 6.3% and 12.5% of patients in the CONSORT and standard-dosing groups, respectively. The primary efficacy analysis found a significantly lower mean [SD] number of oocytes retrieved in the CONSORT (10.0 [5.6]; P = 0.037) versus standard-dosing group (11.8 [5.3]). Although the CONSORT calculator was statistically inferior to standard dosing in the number of oocytes retrieved, clinical pregnancy rates (fresh embryo transfers) were similar in both groups, and incidence of ovarian hyperstimulation syndrome was lower in the CONSORT group.

Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study.

The CONSORT dosing algorithm individualizes recombinant human FSH (r-hFSH) doses for assisted reproduction technologies, assigning 37.5 IU increments according to patient characteristics: basal FSH, body mass index, age and antral follicle count. A prospective, uncontrolled, international, 18-centre, pilot study of normo-ovulatory women aged 18-34 years inclusive undergoing a long agonist treatment protocol was performed. Follitropin alfa filled-by-mass (GONAL-f®) dose was assigned by the algorithm and was intended to be altered only for risk of ovarian hyperstimulation syndrome (OHSS). Primary end-point was number of oocytes retrieved. Dose groups containing ≥5 patients were analysed: 75 IU (n = 48), 112.5 IU in = 45), 150 IU (n = 34), 187.5 IU (n = 24), 225 IU (n = 10). Cancellations due to inadequate response were higher than expected in the 75 IU group (12/48). Overall, a median of 9.0 oocytes were retrieved (8.5, 8.0, 10.0, 12.0 and 8.0 in the 75, 112.5, 150, 187.5 and 225 IU groups respectively). Clinical pregnancy rates/cycle started were 31.3, 31.1, 35.3, 50.0 and 20.0%, respectively (overall, 34.2%). Two patients had severe OHSS. Use of the CONSORT algorithm achieved an adequate oocyte yield and good pregnancy rates in this preliminary study. Adjustment of the algorithm could reduce cancellation rates.

[Teratozoospermia, myth or reality? A 10-years retrospective study on 101404 consecutive sperm samples]. / Tératozoospermie: mythe ou réalité? Étude d'une cohorte de 101 404 examens de sperme.

OBJECTIVES: Several studies have reported a time-related decline in semen quality. In this context, 101,404 spermograms-spermocytograms performed in a single andrology laboratory from January 2000 to December 2009 were investigated retrospectively. Variations of sperm parameters were analyzed over the years. PATIENTS AND METHODS: For each semen sample, age at semen collection, duration of sexual abstinence, volume of seminal fluid, pH, concentration of spermatozoa, percentages of overall motile and progressive motile sperm, percentage of morphologically abnormal spermatozoa (according to David's classification) and amplitude of lateral head displacement (ALH) were analyzed. For each parameter, the mean value per year was determined. To examine trends over time the statistical tests used were analyses of variance and correlation studies. RESULTS: Data showed an increasing age of patients from 36.5 years in 2000 to 37.2 years in 2009. The semen concentration was 63.5 millions/mL in 2000 and 63.6 millions/mL in 2009 with a slight fall from 2001 to 2008. The vitality continuously increased from 67.8% in 2000 to 73.5% in 2009 as well as the overall motility (from 37.7% to 39.2%) and the progressive motility (from 34.6% to 36.2%). The percentage of morphologically abnormal spermatozoa continuously increased from 64.5% to 84.2% (r=0.43, P<0.001). DISCUSSION AND CONCLUSION: Contrary to a variety of works, our very large study of semen analysis did not show a real decline in semen WHO parameters during a 10-year period, except for the percentage of morphologically abnormal spermatozoa, which dramatically increased over the years.

Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study.

The CONSORT dosing algorithm individualizes recombinant human FSH (r-hFSH) doses for assisted reproduction technologies, assigning 37.5 IU increments according to patient characteristics: basal FSH, body mass index, age and antral follicle count. A prospective, uncontrolled, international, 18-centre, pilot study of normo-ovulatory women aged 18-34 years inclusive undergoing a long agonist treatment protocol was performed. Follitropin alpha filled-by-mass (GONAL-f) dose was assigned by the algorithm and was intended to be altered only for risk of ovarian hyperstimulation syndrome (OHSS). Primary end-point was number of oocytes retrieved. Dose groups containing >or=5 patients were analysed: 75 IU (n = 48), 112.5 IU (n = 45), 150 IU (n = 34), 187.5 IU (n = 24), 225 IU (n = 10). Cancellations due to inadequate response were higher than expected in the 75 IU group (12/48). Overall, a median of 9.0 oocytes were retrieved (8.5, 8.0, 10.0, 12.0 and 8.0 in the 75, 112.5, 150, 187.5 and 225 IU groups respectively). Clinical pregnancy rates/cycle started were 31.3, 31.1, 35.3, 50.0 and 20.0%, respectively (overall, 34.2%). Two patients had severe OHSS. Use of the CONSORT algorithm achieved an adequate oocyte yield and good pregnancy rates in this preliminary study. Adjustment of the algorithm could reduce cancellation rates.

Parenting and the psychological development of a representative sample of triplets conceived by assisted reproduction.

BACKGROUND: The aim of the study was to examine the quality of parenting and the psychological development of three-year-old children in IVF/ICSI families with triplets. METHODS: Comparisons were carried out between a representative sample of 10 families with triplets and matched groups of 15 families with twins and 30 families with singletons. The families were recruited from Follow-Up, a national organization in France that was established to study children conceived by assisted reproduction. Standardized measures of the mother's psychological well-being (parenting stress, depression and quality of marriage) and standardized measures of the child's psychological development (emotional/behavioural problems and general development) were completed by the mother. RESULTS: Mothers with a multiple birth were found to experience greater difficulties in parenting than mothers of singletons, with no differences between mothers of triplets and mothers of twins. Regarding the children, there were no differences in emotional or behavioural problems between triplets, twins and singletons. However, there were indications of mild delay among triplets and twins in some aspects of language development in comparison with the singleton children. CONCLUSIONS: The birth of triplets or twins does appear to cause difficulties for parents in the early years, however, the children themselves do not seem to experience markedly raised levels of psychological or developmental problems.

Treatment with the GnRH antagonist ganirelix prevents premature LH rises and luteinization in stimulated intrauterine insemination: results of a double-blind, placebo-controlled, multicentre trial.

BACKGROUND: This study was designed to assess whether the use of ganirelix in women undergoing stimulated IUI could prevent the occurrence of premature LH rises and luteinization (LH+progesterone rises). METHODS: Women of infertile couples, diagnosed with unexplained or male factor infertility, were randomized to receive either ganirelix (n=103) or placebo (n=100) in a double-blind design. All women were treated with an individualized, low-dose rFSH regimen started on day 2-3 of cycle. Ganirelix (0.25 mg/day) was started if one or more follicles>or=14 mm were visualized. Ovulation was triggered by HCG injection when at least one follicle>or=18 mm was observed and a single IUI was performed 34-42 h later. The primary efficacy outcome was the incidence of premature LH rises (+/-progesterone rise). RESULTS: In the ganirelix group, four subjects had a premature LH rise (value>or=10 IU/l), one LH rise prior to the start of ganirelix and three LH rises during ganirelix treatment, whereas in the placebo group 28 subjects had a premature LH rise, six subjects prior to the start of placebo and 22 subjects during placebo treatment. The incidence of LH rises was significantly lower in ganirelix cycles compared to placebo cycles (3.9 versus 28.0%; P=0.003 for ITT analysis). When excluding subjects with an LH value>or=10 IU/l before the start of ganirelix/placebo the incidence of LH rises was also significantly lower in ganirelix cycles compared to placebo cycles (2.9 versus 23.4%; P=0.003 for ITT analysis). Premature luteinization (LH rise with concomitant progesterone rise>or=1 ng/ml) was observed in one subject in the ganirelix group and in 17 subjects in the placebo group of which three subjects had a premature spontaneous ovulation. Ongoing pregnancy rates per attempt were 12.6 and 12.0% for the ganirelix and placebo groups respectively. CONCLUSIONS: Treatment with ganirelix effectively prevents premature LH rises, luteinization in subjects undergoing stimulated IUI. Low-dose rFSH regimen combined with a GnRH antagonist may be an alternative treatment option for subjects with previous proven luteinization or in subjects who would otherwise require insemination when staff are not working.

[Suspension of ART coverage: results of a survey in France]. / Arrêt de prise en charge en AMP: résultat d'une enquête en France.

The objective of the study was to investigate the criteria of patient selection and ART cycle cancellation in public and private fertility centers in France. A specific questionnaire was sent to 105 fertility centers. 81 centers have answered. Age was used as the main selection criteria. Others factors to consider are the number of previous IVF attempts, ovarian response and FSH levels. Less than 10 percent of centers investigate antral follicle count.

[Oocyte donation: parents's secrets and lies]. / Don d'ovocytes: secrets et mensonges.

BACKGROUND: Since 1994, oocyte donation in France must be organized anonymously, in compliance with the bioethics law. The donation is free and any publicity to enrol donors is forbidden. In this system, the recipients are encouraged to incite a donor to visit the recipient's fertility unit. These donors are called "symbolic" donors, since they allow the recipient to be entitred to receive oocytes from another anonymous donor. According to the law, this procedure can be performed both anonymously and non-anonymously. OBJECTIVES: We wanted to study the implication of the anonymous system, focusing on the secret of the child's conception and on the relationship between the recipient family and the "symbolic" donor. MATERIAL AND METHODS: We contacted all the patients (n=83) who had children with oocyte donation in our center between 1988 and 1998. These patients participated in an interview conducted with a standardized questionnaire. RESULTS: Fourteen (17.8%) of the couples were lost to follow-up and three declined to participate. Five recipient couples preferred a non-anonymous donation. In all, 70% of the couples had not yet told their child about the donation. They had mentioned the IVF but not the donation despite of the fact that 50% of symbolic donors came from the family of the recipients, 34% from their friends, or 6% from their professional environment; 10% were not related to the recipients. Long after the child's birth, 25% of the recipients had no contact with the symbolic donor but 41% had selected her as the child's godmother and 15% of symbolic donors were the first to be informed of the birth of the child. After the donation, a gift was offered to the "symbolic" donor by 57% of couples, 33% did not know how to thank them (retribution is forbidden by law) and 10% of couples mentioned that their donor refused any gift. Concerning the donor whose oocytes were used, 63% of recipients did not want to know anything about her. 20% would have liked to have medical information and 13% would like to have all kind of information about her. Only 2% of recipients would have liked to know her identity and 2% would have liked to meet her. CONCLUSION: In agreement with earlier reports in the literature, the majority (70%) of the parents did not inform their child about the oocyte donation even though the symbolic donor was in contact with the child (being his aunt or his godmother for example). The French system has created a double debt: one related to the real donor and another related to the symbolic donor. In the long run, the parents have found a way to humanize this technique: they have given a symbolic place of godmother to the volunteer donor.

Detectable levels of interleukin-18 in uterine luminal secretions at oocyte retrieval predict failure of the embryo transfer.

BACKGROUND: Most implantation failures after successful in vitro fertilization-embryo transfer (IVF-ET) result from inadequate uterine receptivity. There is currently no way to predict this receptivity. METHODS: We investigated whether the detection of interleukin-(IL)18 by ELISA in uterine luminal secretions might predict implantation failure. Secretions of 133 patients enrolled in our IVF-ET program were sampled by uterine flushing immediately before oocyte retrieval. We assessed the following outcomes: pregnancy rate, multiple pregnancy rate, and implantation rate per embryo transferred. RESULTS: Interleukin-18 was detected in the flushing fluid of 38 patients (28.6%). Although the two groups were comparable for all other characteristics (age, etiology, ovarian reserve, number of embryos transferred, quality of embryos), all outcome variables differed significantly. The pregnancy rate was 37.9% in the IL-18 - ve group and 15% in the IL-18 + ve group, the multiple pregnancy rate 27.7% and 0%, and the implantation rate per embryo transferred 19.4% and 6.7% (all comparisons, P=0.02). Only embryos meeting good quality criteria were transferred to 65 patients: 50 IL-18 - ve and 15 IL-18 + ve. The pregnancy rate was 51% for the IL-18 - ve group and 20% for the IL-18 + ve group, the multiple pregnancy rate 36% and 0.0%, respectively, and the implantation rate 29% and 8.3% (P = 0.02). CONCLUSION: This non-invasive and simple method predicted inadequate uterine receptivity, independent of embryo quality.

[Onset and maintenance of the luteal phase with GnRH agonists or hCG in cycles under GnRH antagonists]. / Déclenchement par agonistes de la GnRH ou hCG et soutien de la phase lutéale dans les cycles sous antagonistes de la GnRH.

Corpus luteum function seems to be impaired in IVF cycles with COH (Controlled Ovarian Hyperstimulation) and GnRH antagonist. Support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment. GnRH antagonists do not have any impact on the luteal phase of IVF/ICSI cycles when hormonal support is given. A new treatment option for patients undergoing ovarian stimulation is the gonadotrophin-releasing hormone (GnRH) antagonist protocol, with the possibility to trigger a mid-cycle LH surge using a single bolus of GnRH agonist, reducing the risk of developing ovarian hyperstimulation syndrome (OHSS) in high responders. In IVF cycle with COH and GnRH antagonist, support of corpus luteum function is essential, whatever molecule to trigger LH surge (hCG, r-hLH, GnRH agonist). Adequate luteal support (progesterone and estrogens) compensates for luteolysis and assures good clinical outcome.

Safety and efficacy of a 3 mg dose of the GnRH antagonist cetrorelix in preventing premature LH surges: report of two large multicentre, multinational, phase IIIb clinical experiences.

Gonadotrophin-releasing hormone antagonists are effective and safe in preventing premature LH surges, a leading cause of cycle cancellation or failure during assisted conception. Two studies assessed two administration regimens for cetrorelix (as Cetrotide): the multiple-dose (MD, 0.25 mg/day, n = 1066) and single-dose (SD, 3 mg, n = 541) protocols. Patient outcomes were very similar: >90% reached criteria for human chorionic gonadotrophin (HCG) administration and underwent oocyte retrieval; embryo transfer was performed in 83-84%; failure to retrieve oocytes was rare (0.8%); on average, 11 follicles > or =10 mm in diameter were seen on the day of HCG administration. The SD protocol was associated with higher numbers of oocytes retrieved and available for insemination, although the numbers of embryos obtained or transferred were comparable. A total of 251 and 121 pregnancies were reported in the MD and SD groups respectively. Pregnancy rates per embryo transfer were 27 and 28% respectively. Severe ovarian hyperstimulation syndrome (OHSS) occurred in <1% of cycles. Twelve per cent of patients reported local reactions to injections in the MD group, compared with 8% in the SD group; none was serious or led to discontinuation. Seventy-three per cent of patients in the SD group received only one injection. These two studies therefore show that the single-dose cetrorelix protocol offers equal efficacy and safety to the MD regimen, while having the advantage of requiring only one injection in most patients.

Single dose application of cetrorelix in combination with clomiphene for friendly IVF: results of a feasibility study.

A prospective randomized feasibility study was carried out on 10 patients undergoing IVF treatment using a single-dose LHRH antagonist protocol (cetrorelix, Cetrotide) with clomiphene citrate in combination with either human menopausal gonadotrophin (HMG) (n = 5) or recombinant human FSH (rFSH) (n = 5). Both treatment-groups, HMG and rFSH, were comparable with regard to age (33.2 +/- 2.6 versus 34.4 +/- 4.0 years) BMI (23.2 +/- 2.6 versus 22.7 +/- 1.6) and cause of infertility. They yielded comparable results concerning gonadotrophin dose (19.8 +/- 8.7 versus 17.0 +/- 8.9), stimulation days (6.5 +/- 2.0 versus 5.8 +/- 1.9) and live births (one versus two). No premature LH surge (LH >10 IU/ml and progesterone >1 ng/ml) occurred. The overall baby take-home rate was 30%. In a small number of patients, cetrorelix could be shown to effectively prevent premature LH surges in stimulation protocols combining clomiphene with gonadotrophins with an excellent baby take-home rate per started cycle of 30%.