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 <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.

Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol.

STUDY QUESTION: Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol? SUMMARY ANSWER: Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH. WHAT IS KNOWN ALREADY: Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women with an indication for COS prior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE: In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were prognostic for high ovarian response, and serum estradiol at stimulation Day 1 was associated with low ovarian response. The area under the receiver operating characteristic (ROC) curve (AUC) for the model for a high ovarian response was 0.82. Sensitivity and specificity were 0.82 and 0.73; positive and negative predictive values were 0.40 and 0.95, respectively. The AUC for the model for a low ovarian response was 0.80. Sensitivity and specificity were 0.77 and 0.73, respectively; positive and negative predictive values were 0.29 and 0.96, respectively. In Xpect, 19.1% of patients were high ovarian responders and 16.1% were low ovarian responders. The slope of the calibration line was 0.81 and 1.35 for high and low ovarian responses, respectively, both not statistically different from 1.0. In summary, common prognostic factors for high and low ovarian responses were female age, AFC and basal serum FSH and LH. Simple multivariable models are presented that are able to predict both a too low or too high ovarian response in patients treated with a GnRH antagonist protocol and daily rFSH. LIMITATIONS, REASONS FOR CAUTION: Anti-Müllerian hormone was not included in the prediction modelling. WIDER IMPLICATIONS OF THE FINDINGS: The findings will help with the identification of patients at risk of a too high or too low ovarian response and individualization of COS treatment. STUDY FUNDING/COMPETING INTERESTS: Financial support for this study and the editorial work was provided by Merck, Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA. F.J.B. received a grant from CVZ to his institution; P.J.M.V. and H.W. are employees of MSD, and B.M.J.L.M. was an employee of MSD at the time of development of this manuscript. TRIAL REGISTRATION NUMBERS: NCT 00696800 and NCT00778999.

Comparative incidence of ovarian hyperstimulation syndrome following ovarian stimulation with corifollitropin alfa or recombinant FSH.

Corifollitropin alfa is a novel recombinant gonadotrophin with sustained follicle-stimulating activity. A single injection can replace seven daily injections of recombinant follicle-stimulating hormone (rFSH) during the first week of ovarian stimulation. All cases of ovarian hyperstimulation syndrome (OHSS) with corifollitropin alfa intervention in a gonadotrophin-releasing hormone antagonist protocol have been assessed in three large trials: Engage, Ensure and Trust. Overall, 1705 patients received corifollitropin alfa and 5.6% experienced mild, moderate or severe OHSS. In the randomized controlled trials, Engage and Ensure, the pooled incidence of OHSS with corifollitropin alfa was 6.9% (71/1023 patients) compared with 6.0% (53/880 patients) in the rFSH group. Adjusted for trial, the odds ratio for OHSS was 1.18 (95% CI 0.81-1.71) indicating that the risk of OHSS for corifollitropin alfa was similar to that for rFSH. The incidence of mild, moderate and severe OHSS was 3.0%, 2.2% and 1.8%, respectively, with corifollitropin alfa, with 1.9% requiring hospitalization, and 3.5%, 1.3% and 1.3%, respectively, in the rFSH arms, with 0.9% requiring hospitalization. Despite a higher ovarian response with corifollitropin alfa compared with rFSH for the first 7days of ovarian stimulation, the incidence of OHSS was similar. Corifollitropin alfa is a new agent used in ovarian stimulation treatment for IVF fertilization. One injection of corifollitropin alfa can replace seven injections of recombinant FSH (rFSH). In three studies of corifollitropin alfa treatment, we assessed all cases of ovarian hyperstimulation syndrome (OHSS), a potentially serious complication of ovarian stimulation treatment. Overall, 5.6% of the patients (95/1701) experienced OHSS. Two of the trials compared corifollitropin alfa versus rFSH. Because OHSS is relatively rare, we pooled the results of these trials to give a more reliable estimate of the incidence of OHSS. In the pooled analysis, 6.9% (71/1023) of patients receiving corifollitropin alfa had signs or symptoms of OHSS, compared with 6.0% in the rFSH group (53/880). The risk of OHSS with corifollitropin alfa treatment was similar to the risk of OHSS in patients who received rFSH: the incidence of mild, moderate and severe OHSS was 3.0%, 2.2% and 1.8%, respectively, in patients in the corifollitropin alfa treatment groups, with 1.9% requiring hospitalisation, and 3.5%, 1.3% and 1.3%, respectively, in patients in the rFSH treatment groups, with 0.9% requiring hospitalization. Although the ovaries respond more to corifollitropin alfa than to rFSH for the first 7days of ovarian stimulation, neither treatment regimen was significantly more likely to cause OHSS.

Corifollitropin alfa doses based on body weight: clinical overview of drug exposure and ovarian response.

Corifollitropin alfa is a new recombinant gonadotrophin with a different pharmacokinetic profile but similar pharmacodynamic properties to conventional recombinant FSH. A single dose of corifollitropin alfa sustains multiple follicular development during the first 7 days of ovarian stimulation. This review is based on results of phase II and III trials testing the selected dose of 150 µg corifollitropin alfa in subjects >60 kg and 100 µg in subjects ≤60 kg. Exposure to corifollitropin alfa is inversely related to bodyweight. The selected doses of 100 and 150 µg in subjects weighing ≤60 and >60 kg, respectively, provide, on average, equal drug exposure producing similar ovarian responses in terms of the number of growing follicles, serum oestradiol, inhibin B and number of oocytes retrieved. Clinicians treating IVF patients with corifollitropin alfa should alter their treatment paradigm as a lower or higher dose than recommended according to body weight does not affect the ovarian response, which depends mainly on the ovarian reserve. After decades of daily dosing with FSH preparations, corifollitropin alfa allows a simpler IVF treatment regime with fewer injections. Successful use of corifollitropin alfa requires assessment of patient suitability and dosing before the start of stimulation.

Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF.

A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150 µg corifollitropin alfa versus daily 200 IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ≥11 mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (Cl) 0.5-1.8; P < 0.01) and on the day of HCG injection (difference, 2.1; 95% Cl 1.4-2.8; P < 0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar.

Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF.

A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150µg corifollitropin alfa versus daily 200IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ⩾11mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (CI) 0.5-1.8; P<0.01) and on the day of HCG injection (difference, 2.1; 95% CI 1.4-2.8; P<0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar. A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. The objective of this study was to compare the pharmacokinetics and pharmacodynamics of corifollitropin alfa versus daily rFSH. A total of 1509 patients were randomized in a double-blind, controlled trial to either a single injection of 150µg corifollitropin alfa or to daily injections of 200IU rFSH for the first 7 days of ovarian stimulation. Serum levels of FSH immunoreactivity were analysed (pharmacokinetic analysis), together with the number and size of growing follicles and serum inhibin B and oestradiol concentrations as biomarkers of the ovarian response (pharmacodynamic analysis). Serum FSH immunoreactivity levels were higher up to stimulation day 5 for corifollitropin alfa compared with the daily rFSH regimen but were similar from day 8 onwards, when patients started rFSH if the criteria for human chorionic gonadotrophin were not yet reached. Corifollitropin alfa treatment resulted in a similar growth rate of follicles though a slightly higher number of follicles were recruited compared with daily rFSH. It is concluded that the pharmacokinetics of corifollitropin alfa and rFSH are quite different but their induced pharmacodynamic effects at the dosages used are similar.

Obstetrical and neonatal outcome after controlled ovarian stimulation for IVF using the GnRH antagonist ganirelix.

BACKGROUND: To establish long-term safety, follow-up data on pregnancy, birth and neonatal outcome were collected during clinical development trials with ganirelix (Orgalutran) in women undergoing controlled ovarian stimulation for conventional IVF or ICSI. METHODS: Results of an analysis of the pooled data of all follow-up data of the phase 2 and 3 programme for the development of ganirelix are presented. Obstetrical data on 340 ongoing pregnancies ( vertical line16 gestational weeks) after ganirelix treatment and 134 pregnancies after GnRH agonist treatment in a long protocol are shown. Furthermore, the neonatal outcome of 432 children [258 (75.9%) singletons, 72 (21.2%) twins and 10 (2.9%) triplets] born in the ganirelix group is presented and compared with 184 children [91 (67.9%) singletons, 36 (26.9%) twins and seven (5.2%) triplets] in the agonist group. RESULTS: There were no differences between the two groups in pregnancy loss after 16 weeks gestation. Incidence and nature of complications during pregnancy and delivery did not differ between the two groups. The overall mean gestational age was approximately 38.0 weeks, ranging from an average of 39 weeks for singletons to 34 weeks for triplets. No major differences were observed in neonatal characteristics of infants in the ganirelix and agonist groups, who had an overall mean birth weight of on average 3200 g for singletons, 2300 g for twins and 1800-1900 g for triplets. Congenital malformations were observed in 32 of 424 (7.5%) fetuses vertical line26 gestational weeks in the ganirelix group and in 10 of 181 (5.5%) in the agonist group. When applying a broad definition of major malformation (a major congenital malformation is a condition that causes functional impairment or requires surgical intervention) the rates were 4.5 versus 3.3 (odds ratio 1.37, 95% confidence interval 0.54-3.48) for the ganirelix and agonist group respectively. CONCLUSIONS: Reviewing the presented data and the literature on obstetric and neonatal outcome after conventional IVF or ICSI, we conclude that a controlled ovarian stimulation protocol including the novel GnRH antagonist ganirelix has been shown to be safe for pregnant women and their newborn babies.

The gonadotrophin-releasing hormone antagonist ganirelix--history and introductory data.

The gonadotrophin-releasing hormone antagonist ganirelix has recently become available to clinicians. Its indication, prevention of premature luteinizing hormone surges in assisted reproduction programmes, has been investigated extensively in numerous studies. This article summarizes the major results from pharmacokinetics studies, a double-blind dose-finding trial and three large-scale phase III randomized clinical trials, comparing ganirelix and the most commonly used gonadotrophin-releasing hormone agonists, buserelin,leuprolide and triptorelin, in a long protocol. It is concluded that controlled ovarian hyperstimulation with ganirelix offers significant advantages in terms of convenience of treatment as reflected in a considerably reduced treatment period.Safety and tolerance as well as overall clinical outcome are good.