Follicular and endocrine dose responses according to anti-Müllerian hormone levels in IVF patients treated with a novel human recombinant FSH (FE 999049)

Objective: To study the association between serum anti-Mullerian hormone (AMH) levels and follicular development and endocrine responses induced by increasing doses (5.2-12.1 mu g/day) of a novel recombinant human FSH (rhFSH, FE 999049) in patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in a GnRH antagonist protocol. Design: Secondary analysis of a randomized controlled trial with stratified randomization according to AMH (lower stratum: 5.0-14.9 pmol/l; higher stratum: 15.0-44.9 pmol/l). Patients: Infertile women of good prognosis (n = 265). Measurements: Follicular development and endocrine parameters during controlled ovarian stimulation (COS) with rhFSH. Results: Serum FSH levels increased with increasing rhFSH doses and steady-state levels for each dose were similar in both AMH strata. In the whole study population, significant (P = 12 mm, and serum levels of oestradiol, inhibin B, inhibin A and progesterone at end of stimulation. In comparison with the higher AMH stratum, patients in the lower AMH stratum had significantly different slopes of the dose-response curves for these hormones, and no clear dose-related increase was observed for the number of follicles in these patients. Conclusions: Dose-response relationships between rhFSH and follicular development and endocrine parameters are significantly different for IVF/ICSI patients with lower and higher serum AMH levels at start of COS

Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial

Objective To compare the efficacy and safety of follitropin delta, a new human recombinant FSH with individualized dosing based on serum antimüllerian hormone (AMH) and body weight, with conventional follitropin alfa dosing for ovarian stimulation in women undergoing IVF. Design Randomized, multicenter, assessor-blinded, noninferiority trial (ESTHER-1). Setting Reproductive medicine clinics. Patient(s) A total of 1,329 women (aged 18â40 years). Intervention(s) Follitropin delta (AMH <15 pmol/L: 12 μg/d; AMH â¥15 pmol/L: 0.10â0.19 μg/kg/d; maximum 12 μg/d), or follitropin alfa (150 IU/d for 5 days, potential subsequent dose adjustments; maximum 450 IU/d). Main Outcomes Measure(s) Ongoing pregnancy and ongoing implantation rates; noninferiority margins â8.0%. Result(s) Ongoing pregnancy (30.7% vs. 31.6%; difference â0.9% [95% confidence interval (CI) â5.9% to 4.1%]), ongoing implantation (35.2% vs. 35.8%; â0.6% [95% CI â6.1% to 4.8%]), and live birth (29.8% vs. 30.7%; â0.9% [95% CI â5.8% to 4.0%]) rates were similar for individualized follitropin delta and conventional follitropin alfa. Individualized follitropin delta resulted in more women with target response (8â14 oocytes) (43.3% vs. 38.4%), fewer poor responses (fewer than four oocytes in patients with AMH <15 pmol/L) (11.8% vs. 17.9%), fewer excessive responses (â¥15 or â¥20 oocytes in patients with AMH â¥15 pmol/L) (27.9% vs. 35.1% and 10.1% vs. 15.6%, respectively), and fewer measures taken to prevent ovarian hyperstimulation syndrome (2.3% vs. 4.5%), despite similar oocyte yield (10.0 ± 5.6 vs. 10.4 ± 6.5) and similar blastocyst numbers (3.3 ± 2.8 vs. 3.5 ± 3.2), and less gonadotropin use (90.0 ± 25.3 vs. 103.7 ± 33.6 μg). Conclusion(s) Optimizing ovarian response in IVF by individualized dosing according to pretreatment patient characteristics results in similar efficacy and improved safety compared with conventional ovarian stimulation. Clinical Trial Registration Number NCT01956110

Ganirelix and the prevention of premature luteinizing hormone surges

Ganirelix is a gonadotropin-releasing hormone (GnRH) antagonist with high antagonistic activity that blocks the GnRH receptor by competitive binding. A daily dose of 0.25 mg of ganirelix was sel5ected after a phase II study because it was the minimal, effective daily dose to prevent premature luteinizing hormone surges and this dose yielded the highest ongoing pregnancy rate per started cycle. After subcutaneous administration, ganirelix is rapidly absorbed, reaching peak levels within 1–2 hours (tmax), and has a high absolute bioavailability (>90%). Prospective, comparative studies have demonstrated the advantages of GnRH antagonists over long GnRH agonist treatment in assisted reproduction, including the immediate reversibility of drug effects, a requirement for less follicle-stimulating hormone, a shortened duration of stimulation, a reduced incidence of ovarian hyperstimulation syndrome, and reduced patient burden. Combined analyses concluded that in the general in vitro fertilization population, there is a trend for a slightly lower ongoing pregnancy rate and a lower risk of ovarian hyperstimulation syndrome that is largely eliminated when considering triggering with GnRH agonist instead of human chorionic gonadotropin. Regardless of all the research, it is still not fully elucidated why the long GnRH agonist protocol has a trend for higher pregnancy rates after fresh transfer of the same number of good-quality embryos

Anti-Mullerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta

OBJECTIVE: The stability of anti-Müllerian hormone (AMH) across and between menstrual cycles has been the subject of debate. The objective of this analysis was to study the inter- and intracycle variability in repeated measurements and assess the impact on an individualized gonadotropin dosing algorithm and predicted oocyte yield. DESIGN: Retrospective analysis of repeat AMH measures from a randomized controlled trial. PATIENTS: A total of 1326 women aged 18-40 years. MEASUREMENTS: Serum AMH levels at screening and at cycle day 2-3 in up to three ovarian stimulation cycles. AMH variability and its impact on gonadotropin dose and the predicted number of oocytes. RESULTS: Repeat serum AMH measurements were strongly correlated within individual women (correlation coefficient 0.92). AMH exhibited limited within-subject variation (coefficient of variation 23%), a small time-related decline (mean 6% decrease/y), but no systematic variation across the menstrual cycle. Irrespective of whether the AMH screening value or the AMH at the initiation of ovarian stimulation was used, for women with an AMH level <15 pmol/L, 93% would receive the same gonadotropin dose and attain an identical number of oocytes in 97% of cases. For women with an AMH level ≥15 pmol/L, 80% would receive an individualized dose within ±1.5 μg and 90% would attain ±1 oocyte. CONCLUSION: AMH variability had limited impact on individualized gonadotropin dosing, with 95% of women predicted to obtain an oocyte yield that does not vary beyond 1 oocyte count, irrespective of whether a random or early follicular AMH measurement was used to determine the individualized gonadotropin dose

Anti‐Müllerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta

Objective: The stability of anti‐Müllerian hormone (AMH) across and between menstrual cycles has been the subject of debate. The objective of this analysis was to study the inter‐ and intracycle variability in repeated measurements and assess the impact on an individualized gonadotropin dosing algorithm and predicted oocyte yield. Design: Retrospective analysis of repeat AMH measures from a randomized controlled trial. Patients: A total of 1326 women aged 18‐40 years. Measurements: Serum AMH levels at screening and at cycle day 2‐3 in up to three ovarian stimulation cycles. AMH variability and its impact on gonadotropin dose and the predicted number of oocytes. Results: Repeat serum AMH measurements were strongly correlated within individual women (correlation coefficient 0.92). AMH exhibited limited within‐subject variation (coefficient of variation 23%), a small time‐related decline (mean 6% decrease/y), but no systematic variation across the menstrual cycle. Irrespective of whether the AMH screening value or the AMH at the initiation of ovarian stimulation was used, for women with an AMH level &lt;15 pmol/L, 93% would receive the same gonadotropin dose and attain an identical number of oocytes in 97% of cases. For women with an AMH level ≥15 pmol/L, 80% would receive an individualized dose within ±1.5 μg and 90% would attain ±1 oocyte. Conclusion: AMH variability had limited impact on individualized gonadotropin dosing, with 95% of women predicted to obtain an oocyte yield that does not vary beyond 1 oocyte count, irrespective of whether a random or early follicular AMH measurement was used to determine the individualized gonadotropin dose