Highly Purified Human Menopausal Gonadotropin Research Articles

Comparison of highly purified human menopausal gonadotropin and recombinant follicle stimulating hormone use in patients undergoing in vitro fertilization with progestin-primed ovarian stimulation protocol: a single center retrospective analysis.

Recently, progesterone has been used to prevent LH surge instead of GnRH analogues during ART treatments, which is known as progesterone-primed ovarian stimulation (PPOS) protocol. During ART treatment, highly purified human menopausal gonadotropin (HP-hMG) and recombinant follicle stimulating hormone (rFSH) are two of the agents used for stimulation of antral follicles. The aim of this study is to compare the efficacy and success of HP-hMG and rFSH agents in the ovarian stimulation step of the PPOS protocol, which has not been previously reported in the literature. This retrospective study was conducted at a university hospital with patients who underwent IVF treatment using PPOS protocols in between January 2019 and July 2021. For ovarian stimulation, rFSH was used in group I and HP-hMG was used in group II. Mature oocyte ratio was the primary outcome, and live birth rate was the secondary outcome. Mann-Whitney and Chi-square tests were used for statistical analysis. All p values below 0.05 were considered significant. Total numbers of follicles, oocytes, MII, and 2PN numbers obtained were similar between the two groups. The fertilization rates were 66.7% in the rFSH group and 64.3% in the HP-hMG group (p > 0.05). The pregnancy rates were 53.5% and 46.7% in the rFSH and HP-hMG groups, respectively. There was no statistically significant difference between pregnancy, abortus, and live birth rates. In this study, it is demonstrated that stimulation of oocytes with either rFSH or hMG in the PPOS protocol, which has been added to IVF treatment protocols in recent years, had no statistical difference regarding mature oocyte numbers and live birth rates between the two groups. These results are consistent with the previous literature which compared rFSH and hMG in GnRH agonist and antagonist protocols.

P-675 Tolerability characterization of a highly purified human menopausal gonadotrophin (HP-hMG) in a pre-filled injection pen, a CLARA Trial Analysis

Abstract Abstract withdrawn by the authors

P-677 Demonstration of non-inferiority of highly purified human menopausal gonadotrophin (HP-hMG) in a pre-filled injection pen to an approved HP-hMG powder formulation: CLARA trial results

Abstract Abstract withdrawn by the authors

Effects of different gonadotropin preparations in GnRH antagonist protocol for patients with polycystic ovary syndrome during IVF/ICSI: a retrospective cohort study.

To compare the effects of recombinant FSH alfa (rFSH-alfa), rFSH-beta, highly purified human menopausal gonadotropin (HP-hMG) and urinary FSH (uFSH) in women with polycystic ovarian syndrome who have undertaken the GnRH antagonist protocol during IVF/ICSI treatment. A single-center retrospective cohort study including women with PCOS who received the GnRH antagonist protocol from January 2019 to July 2022 was conducted. Patients were divided into rFSH-alfa group, HP-hMG group, uFSH group, and rFSH-beta group, and the number of oocytes retrieved, clinical pregnancy rate of the fresh cycle (primary outcomes), embryo quality, and severe OHSS rate (secondary outcomes) were compared. No statistical differences were found among the four groups in fresh cycle clinical pregnancy rate (p=0.426), nor in the subgroup analyses. The HP-hMG group had a smaller number of oocytes retrieved and a higher high-quality D3 embryo rate than the three FSH groups (p<0.05). No statistical differences were found among the four groups in the severe OHSS rate (p=0.083). For women with PCOS undergoing the GnRH antagonist protocol, the clinical pregnancy rates of fresh IVF/ICSI-ET cycle are similar for all four types of Gn. With a lower risk of OHSS and a similar number of high-quality and available embryos, HP-hMG may have an advantage in the PCOS population.

Highly Purified Human Menopausal Gonadotropin (HP-hMG) Versus Recombinant Follicle-Stimulating Hormone (rFSH) for Controlled Ovarian Stimulation in USPredicted High-Responder Patients: A Cost-Comparison Analysis.

Infertility imposes considerable clinical and economic burden, and the high costs of fertility care are a major barrier to payers. This study assessed the cost differences of highly purified human menopausal gonadotropin (HP-hMG) versus recombinant follicle stimulating hormone (rFSH) for controlled ovarian stimulation (COS) protocols in predicted high-responders from the US payer perspective. A discrete event simulation model was built to perform a cost-comparison analysis of HP-hMG versus rFSH in a cohort of predicted high-responders undergoing up to three embryo transfer cycles, informed by efficacy data from the MEGASET-HR trial. The model considered an event-based treatment pathway and transition probabilities were derived from MEGASET-HR. A variable time horizon was employed, and deterministic and probabilistic sensitivity analyses conducted. Subjects undergoing COS with HP-hMG and rFSH demonstrated comparable live birth rates following three in vitro fertilization (IVF) cycles, with 161 live births with HP-hMG and 152 live births with rFSH, per 310 high-responders. The total cost saving per live birth in subjects receiving HP-hMG versus rFSH was US$3024. These cost savings were largely driven by the need for fewer embryo transfers to achieve similar efficacy outcomes and a reduced rate of ovarian hyperstimulation syndrome. Following deterministic sensitivity analysis, HP-hMG remained cost saving in all baseline parameter variations. No parameters led to rFSH providing cost savings when compared with HP-hMG. Comparable clinical outcomes can be achieved at a lower cost when using HP-hMG versus rFSH based COS protocols in a cohort of predicted high-responders. Such cost savings may reduce the economic burden infertility currently presents to US healthcare providers and those seeking fertility care.

P-658 Clinical outcomes from ART in predicted hyperresponders: in-vitro maturation of oocytes versus conventional ovarian stimulation

Abstract Study question Do ongoing pregnancy rates (OPR) differ in predicted hyperresponders undergoing ART after in-vitro maturation of oocytes (IVM) compared with conventional ovarian stimulation (COS)? Summary answer One cycle of IVM is non-inferior to one cycle of COS in women with serum AMH levels &amp;gt;10ng/mL. What is known already Women with high antral follicle count (AFC) and elevated serum AMH levels, indicating an increased functional ovarian reserve, are prone to hyperresponse during ART treatment. To avoid iatrogenic complications of COS, IVM has been proposed as a mild-approach alternative treatment in predicted hyperresponders, including women with polycystic ovary syndrome (PCOS) who are eligible for ART. To date, inferior pregnancy rates from IVM compared to COS have hampered the uptake of IVM by ART clinics. However, it is unclear whether the efficiency gap between IVM and COS may differ depending on the extent of AMH elevation. Study design, size, duration This study is a retrospective cohort analysis of clinical and laboratory data from the first completed highly purified human menopausal gonadotropin (HP-hMG) primed, non-hCG triggered IVM or COS (FSH or HP-hMG stimulation in a GnRH antagonist protocol) cycle with ICSI in predicted hyperresponders ≤36 years of age at a tertiary referral university hospital. A total of 1707 cycles were included between January 2016 and June 2022. Participants/materials, setting, methods Predicted hyperresponse was defined as a serum AMH level &amp;gt;3.25ng/mL (Elecsys® AMH, Roche Diagnostics). The primary outcome was cumulative ongoing pregnancy rate (OPR) assessed 10-11 weeks after embryo transfer. The predefined non-inferiority limit was -10.0%. The analysis was adjusted for AMH strata. Time-to-pregnancy (TTP), defined by the time interval between egg retrieval and date of successful embryo transfer, was a secondary outcome. Statistical analysis was performed using a multivariable regression model controlling for potential confounders. Main results and the role of chance Data from 463 IVM cycles were compared with those from 1244 COS cycles. Women in the IVM group more often had a diagnosis of Rotterdam PCOS (434/463, 93.7%) compared to those undergoing COS (522/1193, 43.8%), were significantly younger (29.5 years vs 30.5 years, p ≤ 0.001), had a higher BMI (25.7kg/m² vs 25.1kg/m², p ≤ 0.01) and higher AMH (11.6ng/mL vs 5.3ng/mL, p ≤ 0.001). Although IVM cycles yielded more cumulus oocyte complexes (COCs) (25.8 COC vs 15.0 COC, p ≤ 0.001), both groups had similar numbers of mature oocytes (MII) (11.9 MII vs 10.6 MII, p = 0.9). In the entire cohort, non-adjusted cumulative OPR from IVM was significantly lower (198/463, 42.8%) compared to COS (794/1244, 63.8%), p ≤ 0.001. When analysing OPR across different serum AMH strata, cumulative OPR in both groups converged with increasing serum AMH, and OPR from IVM was non-inferior compared to COS from serum AMH levels &amp;gt;10ng/mL onwards (113/221, 51.1% [IVM]; 29/48, 60.4% [COS]). Time-To-Pregnancy was shorter in the IVM group compared to COS (11.3 weeks vs 21.0 weeks, p ≤ 0.001). Multivariable regression analysis adjusting for ART type, age, BMI, oocyte number and PCOS phenotype showed that the number of COCs was the only parameter associated with OPR in predicted hyperresponders with a serum AMH &amp;gt;10ng/mL. Limitations, reasons for caution These data should be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. Patients enrolled in a clinical IVM program received one-to-one care, in contrast with COS patients who received standard care, which may have influenced TTP. Wider implications of the findings Among subfertile women who are eligible for ART, IVM and COS resulted in comparable reproductive outcomes in a subset of women with a serum AMH &amp;gt;10ng/mL. These findings should be corroborated by an RCT comparing both treatments in selected patients with elevated AMH. Trial registration number Not applicable

P-617 Cost-effectiveness analysis of In Vitro Fertilization (IVF) antagonist protocols utilizing highly purified human menopausal gonadotropin (HP-hMG) and three different recombinant FSH (rFSH) preparations

Abstract Study question Is there a mixed ovarian stimulation antagonist protocol for IVF that obtains more good quality blastocysts with less cost? Summary answer Mixed protocol of HP-hMG and follitropin delta obtains a significantly more good quality blastocysts with significantly lower cost per embryo obtained. What is known already FSH and LH are used for controlled ovarian stimulation (COS) to increase the number of oocytes produced in IVF. Determination of a stimulation protocol and FSH dosage is generally established by the physician based on the patient’s age, body weight and ovarian reserve profile. Mixed protocols (concomitant HP-hMG and rFSH) for ovarian stimulation have been used to obtain better quality oocytes and embryos and thus, higher pregnancy rates compared to the use of rFSH alone. However, to date no data exist comparing cost-effectiveness of mixed protocols using different rFSH preparations. Study design, size, duration This is a cost-effectiveness analysis of the retrospective cohort study encompassing COS for IVF with 3 different mixed protocols performed between January 2018 and September 2019 in 2 fertility clinics. The 267 subjects evaluated were between 18 and 42 years of age and were divided into 3 groups of 89 subjects each according to the rFSH used: group A follitropin alfa; group B follitropin beta and group D follitropin delta. Participants/materials, setting, methods HP-hMG was used in all three groups while different rFSH was prescribed. All three groups used an antagonist protocol. IVF or intra-cytoplasmatic sperm injection (ICSI) was used as clinically indicated. Resulting embryos were cultured until day 5 or 6. The dose of gonadotropins used, the number of mature oocytes (MII), the number of utilizable blastocysts and the FSH/blastocyst ratio were evaluated. For cost-effectiveness analysis we used prices accepted by the provincial healthcare system in Quebec. Main results and the role of chance The mean age of subjects was 34.62 years (± 3.74) and weight 71.65 kg (± 14.61). No significant differences were observed in age or weight among groups. Since follitropin delta is administered in micrograms, the comparison between rFSH preparations was performed using dose equivalence between (10 µg follitropin delta) and (150 IU follitropin alpha and beta). Statistically significant differences were observed among groups in mean total dose of FSH (IU) (A = 4269 IU vs. B = 3947 IU vs. D = 3713 IU, p = 0.01), and number of days of stimulation (A = 11.6 vs. B = 10.6 vs. D = 11.4, p &amp;lt; 0.01). Group D used less gonadotropins despite a longer stimulation. No statistically significant differences were observed in the number of MII oocytes. However, the number of good quality utilizable blastocysts was significantly higher in group D (4.8) than in group A (3.9) or B (3.6). The FSH/blastocyst ratio was significantly lower in group D (370) than in the other groups (A = 541, B = 653). The total price per cycle was similar (A= $4,028 vs. B= $3,649 D= $3,740), however the price per embryo obtained was significantly lower in group D ($779) than in the other groups (A= $1,033, B= $1,014). Limitations, reasons for caution The limitation of this cost-effectiveness analysis is the retrospective nature of the study. Wider implications of the findings Our analysis demonstrates that the price per cycle was similar between the groups, however the price per embryo obtained was significantly lower in group D compared to the other groups. This gives follitropin delta an advantage in terms of cost-effectiveness. Trial registration number NA

Consecutive versus concomitant follicle-stimulating hormone and highly purified human menopausal gonadotropin: A milder response but better quality

ObjectiveThis study investigated the impact of two stimulation protocols using highly purified human menopausal gonadotropin (HP-hMG) on the endocrine profile, follicular fluid soluble Fas levels, and outcomes of intracytoplasmic sperm injection (ICSI) cycles.MethodsThis prospective clinical trial included 100 normal-responder women undergoing ovarian stimulation for ICSI; 55 patients received concomitant follicle-stimulating hormone (FSH) plus HP-hMG from the start of stimulation, while 45 patients received FSH followed by HP-hMG during mid/late follicular stimulation. The primary outcome was the number of top-quality embryos. The secondary outcomes were the number and percentage of metaphase II (MII) oocytes and the clinical pregnancy rate.ResultsThe number of MII oocytes was significantly higher in the concomitant protocol (median, 13.0; interquartile range [IQR], 8.5–18.0 vs. 9.0 [8.0–13.0] in the consecutive protocol; p=0.009); however, the percentage of MII oocytes and the fertilization rate were significantly higher in the consecutive protocol (median, 90.91; IQR, 80.0–100.0 vs. 83.33 [75.0–93.8]; p=0.034 and median, 86.67; IQR, 76.9–100.0 vs. 77.78 [66.7–89.9]; p=0.028, respectively). No significant between-group differences were found in top-quality embryos (p=0.693) or the clinical pregnancy rate (65.9% vs. 61.8% in the consecutive vs. concomitant protocol, respectively). The median follicular fluid soluble Fas antigen level was significantly higher in the concomitant protocol (9,731.0 pg/mL; IQR, 6,004.5–10,807.6 vs. 6,350.2 pg/mL; IQR, 4,382.4–9,418.4; p=0.021).ConclusionPersonalized controlled ovarian stimulation using HP-hMG during the late follicular phase led to a significantly lower response, but did not affect the quality of ICSI.

Added value of anti-Müllerian hormone serum concentration in assisted reproduction clinical practice using highly purified human menopausal gonadotropin (HP-hMG)

IntroductionThe individual response to controlled ovarian stimulation (COS) depends on several factors, including the initial dose of gonadotropin. In repeated in vitro fertilization (IVF) cycles, the initial dose of gonadotropin is mainly established on the basis of the previous attempts’ outcomes. Conversely, in naive patients, the ovarian response should be estimated using other criteria, such as the serum concentration of anti-Müllerian hormone (AMH). However, in clinical practice, the initial gonadotropin dose is not systematically adapted to the AMH level, despite the known relationship between AMH and ovarian reserve. Material and MethodsFrench non-interventional, longitudinal, prospective, multicentre, cohort study that included infertile women who underwent COS with highly purified human menopausal gonadotropin (HP-hMG 600 IU/mL) during their first IVF/intracytoplasmic sperm injection (ICSI) cycle. Data were collected prospectively during routine follow-up visits from COS initiation to 10–11 weeks after embryo transfer. ResultsData from 235 of the 297 enrolled women were used for the study. Serum AMH level was negatively correlated with the initial and total HP-hMG doses (p<0.001), and positively correlated with the number of retrieved oocytes (p<0.007). Embryos were obtained for 94.0% of women, and fresh embryo transfer was performed in 72.8% of them. The clinical pregnancy rate was 28.5% after the first embryo transfer. ConclusionSelecting the appropriate starting dose of gonadotropin is crucial to optimize the IVF/ICSI procedure. For the first attempt, the serum AMH level is a good biomarker to individualize treatment.

First pre-filled pen device with highly purified human menopausal gonadotropin (HP-hMG, Menopur) in liquid is shown to be bioequivalent to powder for reconstitution.

Objective: To determine whether serum human follicle-stimulating hormone (FSH) levels after single subcutaneous dosing of highly purified human menopausal gonadotropins (HP-hMG) in a liquid formulation and a powder formulation are bioequivalent. Materials and methods: This was a randomized, two-way, crossover, single-dose, bioequivalence trial comparing Menopur liquid injected by pre-filled pen, with Menopur powder injected by conventional syringe and needle. The primary endpoints were AUCt and Cmax of baseline-adjusted FSH. Pituitary-suppressed, healthy women were administered single subcutaneous injections of 450 IU Menopur liquid (600 IU/0.96 mL) and 450 IU Menopur powder (by 2 subcutaneous injections of 225 IU in 1 mL) in a randomized order. The pharmacokinetic parameters of FSH and human chorionic gonadotropin (hCG) were assessed by non-compartmental methods with adjustment for endogenous pre-dose levels. Results: In total, 76 women were randomized, and 56 completed the trial. The mean FSH and hCG serum concentration-time profiles were comparable between the two HP-hMG formulations. The geometric mean ratios and 90% confidence intervals of FSH for HP-hMG liquid versus HP-hMG powder were 1.12 (1.0562 – 1.1889) for AUCt and 1.17 (1.0946 – 1.2490) for Cmax, showing that the two formulations were bioequivalent. The incidence and severity of adverse events were similar between the two preparations, and both preparations were well tolerated. Conclusion: The 90% CIs for the geometric mean ratios of serum FSH AUCt and Cmax were both within 0.8000 – 1.2500, thus the two formulations are bioequivalent.

COST COMPARISON OF HIGHLY PURIFIED HUMAN MENOPAUSAL GONADOTROPIN (HP-HMG) VERSUS RECOMBINANT FOLLICLE-STIMULATING HORMONE (RFSH) FOR CONTROLLED OVARIAN STIMULATION IN US HIGH-RESPONDER PATIENTS BASED ON THE MEGASET-HR TRIAL

Assess the cost difference between treatment groups [highly purified human menopausal gonadotropin (HP-hMG) and recombinant follicle stimulating hormone (rFSH)] after three cycles (one fresh and two frozen transfers).

O-113 Effectiveness and treatment cost of assisted reproduction technology for women stimulated by gonadotropin in France: A cohort study using the National Health Database

Abstract Study question How effective is Assisted Reproduction Technology (ART) in terms of cumulative live birth rate (CLBR) in France, depending on the gonadotropin used? Summary answer Among 214,539 stimulations, originator follitropin-alfa was associated with significantly higher CLBR when compared to Highly Purified-Human Menopausal Gonadotropin (HP-HMG) and biosimilars. What is known already Deciding which type of gonadotropin to prescribe for a woman undergoing controlled ovarian stimulation (COS) remains difficult. The effectiveness of different gonadotropins is one factor to consider. However, studies comparing r-hFSH-alfa, its biosimilars and HP-HMG are scarce and are mostly based on a single ART treatment cycle and fresh embryo transfers. Some clinical trials have shown similar pregnancy, pregnancy loss, and live birth rates after fresh embryo transfer (ET) between HP-HMG and r-hFSH. However, because more oocytes are retrieved with r-hFSH when compared to HP-HMG, it is logical to hypothesize that the CLBR is higher with r-hFSH. Study design, size, duration A non-interventional study based on the French National Health System (SNDS) database was designed to assess the CLBR and treatment costs from the national payer perspective of four gonadotropin groups (originator follitropin-alfa (r-hFSH-alfa), its biosimilars, HP-HMG and r-hFSH-beta) used for COS cycles leading to oocyte pick-up (OPU) between 01/01/2013 and 31/12/2017 with a follow-up period up to 31/12/2018. The study compared CLBR, with originator r-hFSH-alfa as the reference. Participants/materials, setting, methods Women with COS cycles resulting in OPU with one of the specified gonadotropins were included. Data were extracted from billing and reimbursement records of outpatient healthcare consumption and national hospital discharge databases using a unique, anonymized patient number. CLBR was estimated using an Andersen–Gill model, adjusted for clinical baseline, stimulation and ET variables. Costs were reported as secondary outcomes. Main results and the role of chance 135,752 women (mean age 34.1), underwent 214,539 stimulations leading to OPU and contributed one (61.5%), two (24.8%), three (9.4%) or four (3.2%) COS cycles. COS cycles were stimulated with either Originator r-hFSH-alfa (46%), HP-HMG (29%), r-hFSH-beta (21%) or r-hFSH-alfa biosimilars (4%). Over the study period, CLBR reached 20.5%; 21.9% with originator r-hFSH-alfa, 17.9% with HP-HMG, 21.3% with r-hFSH-beta and 18.4% with r-hFSH-alfa biosimilars. After adjusting for age, pre-treatment, GnRH analog, ovulation triggering, luteal phase support, previous COS, fresh or frozen ET and type of center, as possible cofounding variables, the adjusted hazard ratio (HR) for CLBR (delivery [originator r-hFSH-alfa as reference]) was 0.88 (95% CI 0.86 to 0.95, p &amp;lt; 0.0001) with HP-HMG; 0.98 (95% CI 0.95 to 1.00, p = 0.1020) with r-hFSH-beta, and 0.84 (95% CI 0.79 to 0.90, p &amp;lt; 0.0001) with r-hFSH-alfa biosimilars. Although the mean acquisition cost of r-hFSH-alfa during the study was 33% higher than HP-HMG and 20% higher than r-hFSH-alfa biosimilars, the global ART management costs were only 4% higher than HP-HMG, 3% higher than r-hFSH-beta, and similar to r-hFSH-alfa biosimilars. Limitations, reasons for caution Patients were included only from oocyte pick-up, due to missing data in the SNDS database, meaning that it was not possible to estimate the proportion of cancelled cycles. Furthermore, as r-hFSH-alfa biosimilars were only available since 2015, results for biosimilars should be interpreted with caution. Wider implications of the findings This population-wide French study confirms other Real-World and meta-analysis evidence that CLBR is higher with originator r-hFSH-alfa than with HP-HMG or r-hFSH-alfa biosimilars, respectively, and are relevant for healthcare professionals to support gonadotropin treatment decision making. To further support this, the cost analysis should be completed by a cost-effectiveness analysis. Trial registration number Not applicable

Individualized ovarian stimulation for in vitro fertilization: a multicenter, open label, exploratory study with a mixed protocol of follitropin delta and highly purified human menopausal gonadotropin

To evaluate the safety profile and the number of usable blastocysts on day 5 and on day 6 after treatment with an individualized dosing regimen of a follitropin delta and highly purified human menopausal gonadotropin (HP-hMG) for controlled ovarian stimulation. Multicenter, open label, exploratory study. Reproductive medicine clinics. A total of 110 patients (aged 18-40 years). Follitropin delta coadministered with HP-hMG, with follitropin delta dose fixed according to an established algorithm and HP-hMG dose at 75 IU when the follitropin delta starting dosage was <12 μg; 150 IU when follitropin delta dosage was 12 μg and weight <100 kg, and 225 IU when follitropin delta dosage was 12 μg and weight ≥100 kg (dosage adjustments confined to HP-hMG only). Mean number of good-quality blastocysts obtained at day 5 and day 6 as well as the proportion of women with ovarian hyperstimulation syndrome (OHSS). A cohort study was compared with the follitropin delta group from the Evidence-based Stimulation Trial with Human Recombinant Follicle-Stimulating Hormone in Europe and Rest of World 1 (ESTHER-1) study. Even when stratified by age, a statistically significantly higher mean in the number of oocytes retrieved and number of good-quality blastocysts was observed in this study compared with the ESTHER-1 trial in which follitropin delta was used alone. The rate of patients triggered with a gonadotropin-releasing hormone agonist was statistically significantly higher in our Menopur and Rekovelle Combined Study (MARCS) cohort (43%) when compared with the rates reported in the follitropin delta cohort in the ESTHER-1 study (2.3%). Incidence of any grade of OHSS was 9.3% in the present study compared to 2.6% in follitropin delta group from ESTHER-1 trial. No cases of moderate or severe OHSS were observed in our study compared with 1.4% in the follitropin delta group of ESTHER-1. Optimizing the ovarian response during invitro fertilization employing a mixed protocol of individualized dosing of follitropin delta and HP-hMG resulted in a statistically significant number of usable blastocysts on days 5 and 6 with an increased risk of mild OHSS, which did not require medical intervention or hospitalization. NCT03483545.

DIFFERENTIAL OVARIAN RESPONSE TO GONADOTROPIN PREPARATIONS DESPITE SIMILAR OVARIAN RESERVE: MENOPUR IN GNRH (GONADOTROPIN RELEASING HORMONE) ANTAGONIST SINGLE EMBRYO TRANSFER - HIGH RESPONDER (MEGASET-HR) TRIAL ANALYSIS

Assess possible interactions between treatment group [highly-purified human menopausal gonadotropin (HP-hMG) or recombinant follicle stimulation hormone (r-FSH)] and ovarian reserve as indicated by baseline levels of anti-Müllerian Hormone (AMH) on the number of oocytes retrieved. Post-hoc analysis of a randomized, open-label, assessor-blind, non-inferiority trial conducted at 31 U.S. trials sites. 620 ovulatory women aged 21-35y with BMI 18-30 kg/m2 and serum anti-Müllerian hormone (AMH) ≥5 ng/mL were randomized 1:1 to a 150 IU start dose of HP-hMG (N=311) or rFSH (N=309) in a GnRH antagonist cycle with dose adjustments based upon response from day 6 onward. Human chorionic gonadotropin (hCG) was used to trigger oocyte maturation (GnRH agonist if at high risk of ovarian hyperstimulation syndrome [OHSS]). Central laboratory serum hormone measurements were measured at baseline and stimulation days: 6, day of/after trigger. Fresh transfer of a single blastocyst was performed in hCG-triggered cycles; all embryos were frozen if the risk of OHSS was high. Live births resulting from all fresh and any frozen transfers occurring within 6 months of randomization were collected. A normal regression model was used to explore interactions between treatment group and baseline AMH on the number of oocytes retrieved. Demographics across treatment arms were similar (mean patient age: 30 years for both; HP-hMG, rFSH mean [SD] BMI: 24.4 [3.3], 24.3 [3.4] kg/m2; AMH: 7.8 [3.6], 7.5 [2.4] ng/mL; antral follicle count: 30.5 [15.5], 31.0 [12.2]). The average number of oocytes per patient in the rFSH arm (22.2 [11.54]) was significantly higher than in the HP-hMG arm (15.1 [10.12]) as were serum estradiol levels at stimulation days 6 and trigger and OHSS rates, described previously.1 Cumulative live birth rates were similar between treatment groups at 51.5% and 50.6% in rFSH and HP-hMG arms respectively. A positive effect of baseline AMH levels on the number of oocytes retrieved was identified and differed statistically by treatment group (p value=0.032); subjects with higher baseline level of AMH had a larger ovarian response to rFSH versus HP-hMG. For every 1.6 ng/ml (11.1 pmol/L) increase in baseline AMH, rFSH stimulation results in one extra oocyte versus HP-hMG in predicted high-responders. Increasing baseline AMH was associated with higher oocyte yields but no difference in cumulative live birth rates in rFSH vs HP-hMG treated patients, with an accompanying increase in OHSS rates also observed in the rFSH arm. This unexpectedly exaggerated ovarian response, which is positively correlated with increasing ovarian reserve based upon the well-established biomarker AMH, highlights a key distinction between the gonadotropin preparations evaluated, creating opportunities for further optimization of stimulation.

Comparison of Highly Purified HMG versus Recombinant FSH with Antagonist Protocol in Poor Responder Patients

Background:Luteinizing hormone (LH) supplementation may have beneficial effect on the maturity and fertilizability of oocytes in poor ovarian reserve (POR) and may influence the progesterone level, thus increasing the pregnancy rate. However, previous studies on the effect of LH activity supplementation on poor responders have shown conflicting results. This study aimed to compare the clinical effectiveness of two different forms of gonadotropin (highly purified human menopausal gonadotropin (HP-HMG) vs. recombinant human follicle-stimulating hormone (r-hFSH)-only) in Indonesian population.Methods: Women diagnosed with poor ovarian response who received gonadotropin-releasing hormone (GnRH) antagonist protocol with either HP-HMG or r-hFSH-only were investigated. Women who underwent freeze all cycles, mini stimulation, and natural stimulation were excluded. Multiple logistic regression was performed to assess the effect of follicle-stimulating hormone (FSH) + human chorionic gonadotropin (HCG)-driven LH activity combination in HP-HMG to pregnancy event adjusting for progesterone level, demographic variables, and clinical characteristic variables.Results: A total of 101 subjects in the HP-HMG treatment group and 89 subjects in r-hFSH-only treatment group were involved in the study. There was no significant difference of clinical pregnancy rate between HP-HMG group and r-hFSH-only group (adjusted OR: 0.94, 95% CI: 0.39–2.25; p-value: 0.890).Conclusion: Compared to r-hFSH-only group, combination of FSH + HCG-driven LH activity in HP-HMG group had similar effectiveness in poor responders undergoing in vitro fertilization (IVF) using the antagonist protocol.

Assisted Reproductive Technologies Across a Heterogeneous Patient Population

With individualised treatment becoming an increasingly relevant topic in reproductive medicine, this symposium discussed how new and existing evidence can support a more patient-centric approach to fertility treatment. Co-Chair Prof Filicori opened the symposium by welcoming delegates and taking a moment to reflect on some of the key milestones in fertility treatment over the past few decades, including approaches that are currently being used to facilitate an individualised approach to controlled ovarian stimulation (OS). Prof Baker continued the theme of individualisation by discussing how the use of different data sources, such as randomised controlled trials (RCT), observational studies, and prediction models, could help guide personalised care. Dr Raine-Fenning presented results from the recent MEGASET-HR trial, which compared the efficacy of highly purified human menopausal gonadotrophin (HP-hMG) versus recombinant follicle-stimulating hormone (rFSH)α in patients predicted to be high responders based on their anti-Müllerian hormone (AMH) levels. The results of this study build on the existing evidence for human chorionic gonadotrophin (hCG)-driven luteinising hormone (LH) activity (HP-hMG) and provide exciting and practical insights on tailoring treatment in this subgroup of patients at risk of ovarian hyperstimulation. Dr Wijngaard-Boom then presented new data from the follitropin delta ESTHER clinical trial programme as well as real-world experience from her own clinic in Rotterdam. The real-world data presented showed that individualised follitropin delta dosing based on the approved algorithm delivers a predictable ovarian response, which is consistent with the results from the ESTHER registration trials, thereby offering positive reassurance about the role of follitropin delta in a clinical setting. The symposium was closed by Co-Chair Prof Laven, who concluded that the approaches discussed during the symposium demonstrate how treatment can be individualised based on a patient’s characteristics, and that, if they are not already, fertility experts should be looking to individualise the treatment for each of their own patients.

Clinical outcomes following long GnRHa ovarian stimulation with highly purified human menopausal gonadotropin plus rFSH or rFSH in patients undergoing in vitro fertilization-embryo transfer: a multi-center randomized controlled trial.

This clinical trial aimed to compare the clinical efficacy of highly purified human menopausal gonadotropin (HP-HMG) plus recombinant human follicle-stimulating hormone (rFSH) versus rFSH alone on controlled ovarian stimulation (COS) in vitro fertilization-embryo transfer (IVF-ET). A total of 610 women underwent long gonadotropin-releasing hormone (GnRH) agonist protocol for IVF treatment. The subjects were randomized into 2 groups: HP-HMG + rFSH group (n=305) and rFSH group (n=305). The main outcome was the progesterone (P) level on the day of HCG injection. There was no significant difference in terms of the demographic and baseline characters between the two groups. In rFSH group, the P level on the day of HCG trigger were significantly higher than that of HP-HMG+rFSH group (4.3±2.2 vs. 3.8±1.7 nmol/L, P<0.001). The fertilization rate in rFSH group was significantly lower than that of HP-HMG + rFSH group (69.2% vs. 73.9%, P<0.001). Simultaneously, the percentage of cycles with fresh embryo transfer in rFSH group was also significantly lower than that of HP-HMG + rFSH group (49.6% vs. 57.5%, P=0.007). However, there was no difference in terms of cleavage rate, implantation rate, clinical pregnancy rate and ovarian hyperstimulation syndrome (OHSS) rate between two groups. The use of combined HP-HMG with FSH may be superior to rFSH alone in stimulating the ovary in normal responders undergoing IVF treatment. Furthermore, the further prospective studies with large sample are still needed to confirm the study.

Association between the number of oocytes retrieved and cumulative live birth rate in IVF treatment: menopur in GnRH antagonist single embryo transfer - high responder (MEGASET-HR) trial outcomes

Although retrieval of high numbers of oocytes (>15) is linked with increased OHSS incidence, agonist trigger and freeze-only approaches nearly eliminate the severe form of the syndrome. Physicians therefore strategically pursue high oocyte yields and the prospect of high cumulative live birth rates, translated as increased efficiency at lower cost to patients. Although published data consistently shows no benefit of high response in fresh transfer cycles, the impact on cumulative live birth rates remains unclear. We evaluated this question on data obtained from the recently concluded randomized controlled MEGASET-HR trial. Analysis of the association between pregnancy outcomes and oocyte number resulting from stimulation with highly-purified human menopausal gonadotropin (HP-hMG) or recombinant follicle stimulating hormone (rFSH) in fresh and frozen cycles. This multicenter, randomized, assessor-blind, non-inferiority study included ovulatory women aged 21-35 years with body mass index 18-30 kg/m2 and serum AMH ≥ 5 ng/mL who were randomized 1:1 to a 150 IU starting dose of HP-hMG (n=311) or rFSH (n=309). Human chorionic gonadotropin was used to trigger oocyte maturation. Oocytes were fertilized by intracytoplasmic sperm injection and fresh single blastocyst transfer was performed; resultant ongoing pregnancy (detectable fetal heartbeat 8-9 weeks after fresh transfer) was the primary endpoint. Those with excessive ovarian response were required to have all embryos frozen after agonist trigger. Live birth outcomes for all fresh and frozen transfers occurring within 6 months of randomization were collected. Data presented are mean ± standard deviation unless otherwise indicated. Patient demographics were similar between HP-hMG and rFSH arms, respectively: age (30.0±3.1, 30.4±3.0 years), BMI (24.4±3.3, 24.3±3.4 kg/m2), AMH (7.8±3.6, 7.5±2.4 ng/mL), antral follicle count (30.5±15.5, 31.0±12.2). The average number of oocytes per patient in the rFSH arm (22.2±11.54) was approximately 7 higher than in the hMG arm (15.1±10.12), a striking difference in ovarian response that was however, accompanied by statistically significant increases in rates of OHSS (21.4% vs 9.7%; p<0.05) and pregnancy loss (25.5% vs 14.5%; p<0.05). Despite increased numbers of transfers in rFSH treated patients, the cumulative live birth rate was similar between groups (51.5% vs. 50.6%, p>0.05). Consistent with published data, fresh transfer ongoing pregnancy rates were lower in patients with ≥15 compared to ≤14 oocytes retrieved for both rFSH and HP-hMG. Interestingly, cumulative live birth rates also peaked and plateaued beyond 11-14 retrieved oocytes. Supernumerary oocytes did not confer a cumulative live birth rate benefit to patients predicted to be high-responders; moreover, they may have contributed to the increase in observed adverse events. Retrieval of high numbers of oocytes (>15) had a negative impact on the ongoing pregnancy rate in fresh transfer cycles with only a marginal benefit to cumulative live birth rates. Taken together the data suggest that optimal fresh and cumulative efficacy and safety outcomes can be achieved through retrieval of 8-14 oocytes through proper selection of gonadotropin type and dose.

Required amount of rFSH, HP-hMG and HP-FSH to reach a live birth: a systematic review and meta-analysis

STUDY QUESTIONIn women undergoing IVF or ICSI cycles, do recombinant gonadotrophins differ from urinary-derived highly purified human menopausal gonadotropin (HP-hMG) or highly purified follicle-stimulating hormone (HP-FSH) in the total amount of gonadotrophins required to reach a live birth?SUMMARY ANSWERThe difference between recombinant and urinary-derived HP-hMG or HP-FSH in the required amount to reach a live birth in IVF/ICSI cycles appears small.WHAT IS KNOWN ALREADYAt present, gynecologists can choose between recombinant FSH (rFSH), urinary-derived HP-hMG and HP-FSH. These products are equally effective and safe, but it is unknown how these gonadotrophins compare in terms of IU required to reach a live birth.STUDY DESIGN, SIZE AND DURATIONWe conducted a search in Medline, Embase and CINAHL up to July 2018. We included randomized controlled trials (RCTs) that compared rFSH with HP-hMG or HP-FSH for ovarian stimulation in couples scheduled for IVF or ICSI treatment. From each randomized trial, we extracted the outcome data and information on participants, methods, interventions and funding.PARTICIPANTS/MATERIALS, SETTING AND METHODSWomen undergoing ovarian stimulation with rFSH, HP-hMG or HP-FSH were included. We extracted data for the mean amount of gonadotrophins with SD, clinical pregnancy rate, live birth rate and cumulative live birth rate per woman from the included RCTs. We summarized these outcomes by calculating the individual and pooled mean difference (MD) or relative risk (RR) with 95% CI. We used the Review Manager software to perform the meta-analyses. We applied a random effect model to pool the data. We estimated the total amount of gonadotrophins used per extra live birth by STATA 14.2 and R software.MAIN RESULTS AND THE ROLE OF CHANCEA total of 28 studies with 7553 women were included in this review, of which 24 studies provided information on the total amount of gonadotrophins per woman who started an IVF/ICSI cycle. The total amount of gonadotrophins varied significantly between studies. The MDs in total amount were −37 IU (seven studies; N = 3220; 95% CI, −115 to 41; I2 = 68%) for rFSH versus HP-hMG and −31 IU (17 studies; N = 3629; 95% CI, −290 to 228; I2 = 97%) for rFSH versus HP-FSH. For rFSH versus HP-hMG, the RR for clinical pregnancy, live birth and cumulative live birth were 0.90 (95% CI, 0.81–1.00), 0.88 (95% CI, 0.78–0.99) and 0.91 (95% CI, 0.80–1.04), respectively. For rFSH versus HP-FSH, the RR for clinical pregnancy and live birth were 1.03 (95% CI, 0.94–1.13) and 1.03 (95% CI, 0.90–1.18), respectively; the data on cumulative live birth rate were lacking. The estimated difference in mean gonadotrophin amount per extra live birth was 789 IU (95% CI, −9.5 to 1570) for rFSH versus HP-hMG and −365 IU (95% CI, −2675 to 1945) for rFSH versus HP-FSH.LIMITATIONS, REASONS FOR CAUTIONThere was severe heterogeneity in the total amount of gonadotrophins between studies. A small fraction of women did not start gonadotrophin treatment; this was usually not accounted for in the provided mean amount of gonadotrophins per study and might have affected the averaged total amount of gonadotrophins but is unlikely to have affected the differences in the amount between rFSH and HP-hMG or HP-FSH.WIDER IMPLICATIONS OF THE FINDINGSThe differences in the required amount to reach a live birth between rFSH, HP-hMG and HP-FSH appear to be small. Decision-making should be based on convenience, availability, actual costs and patient preferences.STUDY FUNDING/COMPETING INTERESTSThe authors declare no conflict of interest. No external funding was either sought or obtained for this study.REGISTRATION NUMBERProspero CRD42016038238

Gonadotrophins for ovulation induction in women with polycystic ovary syndrome.

Gonadotrophins for ovulation induction in women with polycystic ovary syndrome.