P–594 Ovarian stimulation with luteinizing hormone supplementation: the impact of timing on ovarian response and ICSI outcomes

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
A Iaconell ◽  
A Setti ◽  
D Braga ◽  
E Borge
Keyword(s):  
Luteinizing Hormone ◽  
Sample Size ◽  
Ovarian Stimulation ◽  
Gnrh Antagonist ◽  
Implantation Rate ◽  
Ovarian Response ◽  
Follicular Phase ◽  
Blastocyst Development ◽  
Normal Response ◽  
Icsi Outcomes

Abstract Study question Is there an impact of recombinant luteinizing-hormone (rLH) administration timing during controlled ovarian stimulation (COS) on ovarian response and intracytoplasmic sperm injection (ICSI) cycles outcomes? Summary answer rLH supplementation in patients with poor ovarian response (POR) improves laboratorial and clinical outcomes when started in the mid-follicular phase, in GnRH antagonist ICSI cycles. What is known already Meta-analyses demonstrated that the use of rLH combined with rFSH for COS may lead to more ongoing pregnancies than rFSH alone. However, there is limited evidence that the timing of rLH addition to rFSH may impact the ovarian response or the outcomes of ICSI, based on a limited casuistic, which demonstrated improved ovarian response, embryo quality and pregnancy rate with LH supplementation from GnRH antagonist administration day, in estimated POR patients. The objective of the present study was to further investigate this hypothesis in a larger population, and in subpopulations of patients stratified by age and response to COS. Study design, size, duration This historical cohort study included data obtained via chart review of 1278 ICSI cycles performed in 1278 patients between 2015 and 2018, in a private university-affiliated in vitro fertilization center. Post hoc power analysis was calculated, given α of 5%, sample size of 1278, and effect size for implantation rate. The achieved power was superior to 99%. Participants/materials, setting, methods Two groups were formed according to timing of LH administration: Group LH-start (n = 323), in which LH was started on day–1; and Group LH-mid (n = 955), in which LH was started with GnRH antagonist. Then, data were stratified according to female age (<35 years-old, n = 283, and ≥35 years-old, n = 995) and response to COS (poor response (POR): ≤4 retrieved oocytes, n = 423, and normal response: >5 retrieved oocytes, n = 855). Ovarian response and ICSI outcomes were compared among the groups. Main results and the role of chance In POR patients, significantly higher fertilization rate (68.3% ± 2.5 vs. 78.6% ± 3.7, p = 0.023), blastocyst development rate (22.5% ± 7.2 vs. 44.7% ± 6.2, p = 0.022) and implantation rate (17.6% ± 59.1 vs. 20.2% ± 43.2, p < 0.001) were observed in Group LH-mid, even though the amount of LH used in these patients was not significant different from that used in Group LH-mid from patients with normal response to COS (1062.35 IU ± 54.33 vs. 925.81 IU ± 414.41, p: 0.431, respectively). For the general group and in patients aged ≥ 35 years, higher blastocyst development rates were observed in Group LH-mid compared to Group LH-start (33.0% ± 31.9 vs. 40.8% ± 32.6, p = 0.012, and 28.8% ± 30.4 vs 38.5% ± 32.3, p = 0.006, respectively). In patients aged < 35 years and in those with normal response to COS, similar outcomes were obtained irrespective of timing of LH administration. Limitations, reasons for caution The limitations included the retrospective design and limited sample size in subpopulations. In addition, the reduced clinical outcomes related to POR patients may hamper the true estimation of the differences between the stimulation groups in terms of pregnancy and miscarriage rates. Wider implications of the findings: In POR patients, mid-follicular phase LH supplementation starting with 150 IU daily doses, may rescue the ongoing cycle by compensating an initial slow response, and balancing the deprivation of endogenous LH in GnRH antagonist cycles, with no need of expending more gonadotropin compared to patients with normal response to COS. Trial registration number Not applicable

scholarly journals Improving Implantation Rate in 2nd ICSI Cycle through Ovarian Stimulation with FSH and LH in GNRH Antagonist Regimen

2021 ◽  
Vol 43 (10) ◽  
pp. 749-758
Author(s):  
Amanda Souza Setti ◽  
Daniela Paes de Almeida Ferreira Braga ◽  
Assumpto Iaconelli ◽  
Edson Borges
Keyword(s):  
Luteinizing Hormone ◽  
Ovarian Stimulation ◽  
Implantation Rate ◽  
Miscarriage Rate ◽  
Retrospective Case ◽  
High Quality ◽  
Oocyte Yield ◽  
Icsi Cycle ◽  
Icsi Outcomes ◽  
Estradiol Levels

Abstract Objective To investigate whether patients with a previous recombinant follicle stimulating hormone (rFSH)-stimulated cycle would have improved outcomes with rFSH + recombinant luteinizing hormone (rLH) stimulation in the following cycle. Methods For the present retrospective case-control study, 228 cycles performed in 114 patients undergoing intracytoplasmic sperm injection (ICSI) between 2015 and 2018 in an in vitro fertilization (IVF) center were evaluated. Controlled ovarian stimulation (COS) was achieved with rFSH (Gonal-f, Serono, Geneva, Switzerland) in the first ICSI cycle (rFSH group), and with rFSH and rLH (Pergoveris, Merck Serono S.p.A, Bari, Italy) in the second cycle (rFSH + rLH group). The ICSI outcomes were compared among the groups. Results Higher estradiol levels, oocyte yield, day-3 high-quality embryos rate and implantation rate, and a lower miscarriage rate were observed in the rFSH + rLH group compared with the rFSH group. In patients < 35 years old, the implantation rate was higher in the rFSH + rLH group compared with the rFSH group. In patients ≥ 35 years old, higher estradiol levels, oocyte yield, day-3 high-quality embryos rate, and implantation rate were observed in the rFSH + rLH group. In patients with ≤ 4 retrieved oocytes, oocyte yield, mature oocytes rate, normal cleavage speed, implantation rate, and miscarriage rate were improved in the rFSH + rLH group. In patients with ≥ 5 retrieved oocytes, higher estradiol levels, oocyte yield, and implantation rate were observed in the rFSH + rLH group. Conclusion Ovarian stimulation with luteinizing hormone (LH) supplementation results in higher implantation rates, independent of maternal age and response to COS when compared with previous cycles stimulated with rFSH only. Improvements were also observed for ICSI outcomes and miscarriage after stratification by age and retrieved oocytes.

scholarly journals A Luteinizing Hormone-based Protocol Versus Traditional Flexible Gonadotropin-Releasing Hormone Antagonist Protocol in Women with Normal Ovarian Response: Study Protocol for a non-Inferiority Trial

2021 ◽  
Author(s):  
Ya-su Lv ◽  
Yuan Li ◽  
Shan Liu
Keyword(s):  
Luteinizing Hormone ◽  
Pregnancy Rate ◽  
Ovarian Stimulation ◽  
Gnrh Antagonist ◽  
Ovarian Response ◽  
Gonadotropin Releasing Hormone ◽  
Ongoing Pregnancy ◽  
Ongoing Pregnancy Rate ◽  
Gnrh Antagonist Protocol ◽  
Antagonist Protocol

Abstract BackgroundUse of gonadotropin-releasing hormone (GnRH) antagonists during the late follicular phase can prevent premature luteinizing hormone (LH) surge. Many patients demonstrate an insufficient endogenous LH concentration during ovarian stimulation. Previous studies have demonstrated that ultra-low LH concentration influences pregnancy outcomes. However, affected patients cannot be distinguished prior to ovarian stimulation using baseline characteristics alone. With traditional fixed or flexible GnRH antagonist protocols, antagonist administration may further reduce LH activity. Previously, we proved that LH can be used as an indicator for the timing and dosage of antagonist. Patients with a persistently low LH concentration during ovarian stimulation may not require antagonists, whereas antagonist administration can affect reproductive outcomes. To further explore this hypothesis, we designed a randomized clinical trial to compare the LH-based flexible GnRH antagonist protocol with traditional flexible GnRH antagonist protocol in women with normal ovarian response. MethodsThis study was a multicenter, parallel, prospective, randomized, non-inferiority study. The primary efficacy endpoint was cumulative ongoing pregnancy rate per cycle. The study aimed to prove the non-inferiority of cumulative ongoing pregnancy rate per cycle with a LH-based flexible GnRH antagonist protocol versus traditional flexible GnRH antagonist protocol. Secondary endpoints were the high-quality embryo rate, clinical pregnancy rate, and cancellation rate. Differences in cost-effectiveness and adverse events were evaluated. The cumulative ongoing pregnancy rate per cycle in women with normal ovarian response was 70%. Considering that a non-inferiority threshold should retain 80% of the clinical effect of a control treatment, a minimal clinical difference of 14% (one-sided: α, 2.5%; β, 20%) and a total of 338 patients were needed. Anticipating a 10% dropout rate, the total number of patients required was 372.DiscussionThis is the first randomized controlled trial to compare the efficacy of a LH-based treatment regimen with a traditional flexible GnRH antagonist protocol during ovarian stimulation. We hypothesized no significant difference in cumulative ongoing pregnancy rate per cycle between the two protocols. Moreover, patients with insufficient endogenous LH during ovarian stimulation may benefit from LH-based GnRH antagonist protocols. The results will provide new information on when to introduce antagonists and the appropriate dosage of antagonist.Trial registration: ClinicalTrials.gov, ChiCTR1800018077. Registered on 29 August, 2018.

P–687 Impact of medroxyprogesterone acetate (MPA) as pituitary suppression on oocyte quality and clinical outcomes in egg donation recipients

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
I Ortega ◽  
P Alamá ◽  
M Cruz ◽  
J Giles ◽  
J A García-Velasco
Keyword(s):  
Oral Administration ◽  
Ovarian Stimulation ◽  
Gnrh Antagonist ◽  
Oocyte Quality ◽  
Follicular Phase ◽  
Egg Donation ◽  
Ovum Donation ◽  
Gnrh Analogues ◽  
Group 2 ◽  
Group 1

Abstract Study question To compare the impact on oocyte quality and reproductive outcomes in patients who received oocytes from donors stimulated with MPA versus GnRH antagonist protocol. Summary answer Compared to GnRH antagonist, MPA does not exert a major effect on oocyte quality and yields similar reproductive outcomes in egg donation recipients. What is known already Conventional ovarian stimulation (OS) protocols have classically used GnRH analogues, both agonists and antagonists, to avoid premature follicular luteinization. The oral administration of MPA or micronized progesterone during the follicular phase of OS has emerged as an attractive alternative to conventional protocols in the prevention of early luteinization. Compared to progesterone, MPA is characterized by a moderate-strong progestanic action, lower androgenic properties and does not interfere with the measurement of endogenous progesterone. In our group, administration of MPA during the follicular phase of OS has been included in the routine clinical practice of our donor program since late 2019. Study design, size, duration Multicentre, retrospective, observational, cohort study carried out in eleven private university-affiliated IVF centers. The present study included a total of 14,282 fresh ovum donation cycles performed from October 2017 to March 2020. Oocyte donors were recruited and stimulated under either MPA (n = 4,665) or GnRHa (n = 9,617) to suppress the pituitary during the follicular phase of OS, and GnRH agonist was administered to trigger final oocyte maturation in all the participants. Participants/materials, setting, methods Recipients were divided according to the protocol used for premature luteinization prevention during the follicular phase of the ovum donation matched-cycle: Group 1, recipients who received oocytes from donors treated with 10 mg/day of MPA (ProgeveraÒ); Group 2, recipients who received oocytes from GnRH antagonist (FyremadelÒ) down-regulated donor cycles. All the procedures were approved by an Institutional Review Board (1910-VLC–091-JG) and complied with Spanish law on assisted reproductive technologies (14/2006). Main results and the role of chance Regarding donoŕs baseline characteristics, age and antral follicle count were significantly different between groups, but not clinical differences. The length of ovarian stimulation was similar in both groups (10.7 days [95% Confidence Interval (CI) 10.5–10–8] vs 10.5 days [95% CI 10.0–11.00]). Despite slightly higher mean total dose of FSH administered in Group 1 compared to Group 2 (1.841 IU [95% CI 1.813–1.868] vs 1.739 IU [95% CI 1.723–1.754]), there were no differences in the total dose of hMG administered between both groups (967 IU [95% CI 901–1.034] vs 971 IU [95% CI 944–998]). With regard to IVF data, both the number of retrieved oocytes (22.9 [95% CI 22.4–23.4] vs 24.1 [95% CI 23.8–24.3]), and mature oocytes (18.7 [95% CI 18.3–19.1] vs 19.3 [95% CI 19.1–19.6]), were slightly lower in Group 1 compared to Group 2, whereas fertilization rate was significantly higher in Group 1 compared to Group 2 (82.1% [95% CI 81.7–82.6] vs 80.8% [95% CI 80.6–81.2]),. Regarding the clinical outcomes, no differences were observed in either implantation rate (58.7% [95% CI 56.7–60.7] vs 59.3% [95% CI 57.3–61.3]) or clinical pregnancy rate (59.5% vs 59.8%, P = 0.04) between both groups. Limitations, reasons for caution As a consequence of being a retrospective study, only association, and not causation, can be inferred from the results. A further limitation is that donors are healthy young women and do not perfectly match other populations, as infertile patients who may be older, low or high responders to OS. Wider implications of the findings: MPA emerges as an effective oral alternative to GnRH analogues for preventing premature luteinizing hormone surges in donors undergoing OS in ovum donation program. Compared with GnRH antagonists, MPA has advantages of being an oral administration route and providing easy access, yielding similar clinical results. Trial registration number 1910-VLC–091-JG

scholarly journals Progestin primed ovarian stimulation using corifollitropin alfa in PCOS women effectively prevents LH surge and reduces injection burden compared to GnRH antagonist protocol

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ting-Chi Huang ◽  
Mei-Zen Huang ◽  
Kok-Min Seow ◽  
Ih-Jane Yang ◽  
Song-Po Pan ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Gnrh Agonist ◽  
Ovarian Stimulation ◽  
Gnrh Antagonist ◽  
Polycystic Ovary ◽  
Implantation Rate ◽  
Live Birth Rate ◽  
Lh Surge ◽  
Corifollitropin Alfa ◽  
Premature Lh Surge

AbstractUtilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 μg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

scholarly journals Whether poor responses have worse perinatal prognosis (retrospective analysis of assisted reproductive technologies cycle)

2018 ◽  
Vol 22 (3) ◽  
pp. 503-508
Author(s):  
G.V. Strelko
Keyword(s):  
Gestational Diabetes ◽  
Ovarian Stimulation ◽  
Preterm Labor ◽  
Perinatal Outcomes ◽  
Ovarian Response ◽  
Control Group ◽  
Poor Responders ◽  
Poor Ovarian Response ◽  
Normal Response ◽  
Significant Difference

The prevalence of poor ovarian response is 5.6–35.1% in women undergoing controlled ovarian stimulation in ART cycles. The frequency of delivery of poor responders after ART is on average from 9.9% to 23.8%. In clinical practice, the vast majority of poor responders are older women, which may have an effect on perinatal outcomes, respectively. Although numerous studies have reported that the fertility rate after ART in women of this age group is quite low, data on perinatal outcomes in this group of women is limited. Therefore, the aim of our study was to retrospectively analyze and compare perinatal outcomes in women with poor ovarian response to stimulation compared to control group (normal response to stimulation) in assisted reproductive technology programs. 278 women with infertility with a reduced response to stimulation (poor responders), who were the main group, were screened. Indications for the inclusion of women in the main group were the presence of at least two of the following criteria for a poor ovarian response according to the 2011 Bologna criteria and 93 infertile patients with a normal ovarian response to stimulation of the control group. Subsequently, retrospective study of perinatal effects such as preterm labor, low birth weight, gestational diabetes, preeclampsia in 50 women with infertility with reduced response to stimulation and 37 controls with normal response to stimulation in which pregnancy was diagnosed was performed. Variational-statistical processing of the results of the study was performed using the program “Statistica 6.0”. The study demonstrated a significantly lower pregnancy rate in poor responders compared with women from the control group — 50 (17.9%) vs. 37 (39.8%), respectively. Perinatal outcome were similar only to the statistically significant difference in the percentage of spontaneous abortions before 12 weeks of gestation — 9 (18%) vs. 4 (10.8%), respectively, in groups with no significant difference in the preterm labor frequency — 10 (20.8%) and 6 (18.1%) of the low weight of the child at birth — 9 (18.7%) versus 5 (15.1%), respectively, in poor responders patients and in women with normal ovarian response. The frequency of complications such as gestational diabetes and high blood pressure were not significantly different in both clinical groups — 3 (6.25%) versus 2 (6.1%) and 5 (10.4%) versus 3 (9.1%) respectively. Thus, he poor responders in ART programs have a significantly lower pregnancy rate and a higher incidence of pregnancy loss up to 12 weeks compared with women who had a normal response to ovarian stimulation without a significant difference in the rates of various complications of pregnancy and perinatal outcomes. Wide randomized multicentric trials are needed to find out the causal relationships with regard to the effect on pregnancy, miscarriage, perinatal effects of controlled ovarian stimulation regimens, embryotransfers in fresh or cryo cycles etc.

Randomised controlled trial on the effect of clomiphene citrate and gonadotropin dose on ovarian response markers and IVF outcomes in poor responders

2020 ◽  
Author(s):  
R Moffat ◽  
C Hansali ◽  
A Schoetzau ◽  
A Ahler ◽  
U Gobrecht ◽  
...  
Keyword(s):  
Ovarian Stimulation ◽  
Primary Outcome ◽  
Clomiphene Citrate ◽  
Ovarian Response ◽  
Serum Levels ◽  
Follicular Phase ◽  
Poor Responders ◽  
Starting Dose ◽  
Early Follicular Phase ◽  
Randomised Controlled

Abstract STUDY QUESTION Does the gonadotropin (GN) starting dose and the addition of clomiphene citrate (CC) during the early follicular phase influence oocyte yield in poor responders undergoing ovarian stimulation for IVF treatment? SUMMARY ANSWER The number of retrieved oocytes was similar regardless of the starting dose of GN (150 versus 450 IU) with or without the addition of CC (100 mg from Day 3 to 7 versus placebo). WHAT IS KNOWN ALREADY ART in poor responders is a challenge for patients and clinicians. So far, randomised controlled studies addressing interventions have shown that neither the GN dose nor the addition of oral medication has any significant effect on the clinical outcome of ART in poor responders. There is limited knowledge about the effect of GN starting dose in combination with CC during the early follicular phase of ovarian stimulation on ovarian response markers and ART outcome. STUDY DESIGN, SIZE, DURATION This single-centre randomised double-blinded clinical trial was conducted from August 2013 until November 2017. Using the Bologna criteria, 220 of 2288 patients (9.6%) were identified as poor responders and 114 eligible participants underwent ovarian stimulation in a GnRH-antagonist protocol for ART. PARTICIPANTS/MATERIALS, SETTING, METHODS The participants were equally randomised to one of four treatment arms: Group A (n = 28) received 100 mg CC (Day 3–7) and a starting dose of 450 IU HMG, Group B (n = 29) received 100 mg CC and a starting dose of 150 IU HMG, Group C (n = 30) received placebo and a starting dose of 450 IU HMG and Group D (n = 27) received placebo and a starting dose of 150 IU HMG. Serum levels of FSH, LH, estradiol and progesterone were measured on Day 1 and 5 and on the day of ovulation induction. Available embryos were cultured up to the blastocyst stage and were always transferred in the same cycle. The primary outcome was the number of oocytes collected after ovarian stimulation. Other outcome measures were response to ovarian stimulation, embryo development and obstetrical outcome. MAIN RESULTS AND THE ROLE OF CHANCE All study participants (n = 114) fulfilled at least two of the Bologna criteria for poor responders. Median age of the study population was 38.5 years. There were 109 patients who underwent oocyte retrieval. The number of oocytes retrieved was similar among the groups (±SD; 95% confidence intervals); A: 2.85 (±0.48; 2.04–3.98), B: 4.32 (±0.59; 3.31–5.64); C: 3.33 (±0.52; 2.45–4.54); D: 3.22 (±0.51; 2.36–4.41); P overall = 0.246. However, ovarian stimulation with 150 IU plus CC resulted in a higher number of blastocysts compared to ovarian stimulation with 450 IU plus CC (±SD; 95% confidence intervals); A: 0.83 (±0.15; 0.58–1.2), B: 1.77 (±0.21; 1.42–2.22); P overall = 0.006. Mean FSH serum levels were lower in the groups with a starting dose of 150 IU. Adding CC did not affect mean serum FSH levels. There were no differences in estradiol concentrations among the groups. Endometrial thickness was lower in the groups receiving CC. The overall live birth rate (LBR) was 12.3%, and the cumulative LBR was 14.7%. LIMITATIONS, REASONS FOR CAUTION The trial was powered to detect differences in neither the number of blastocysts nor the LBR, which would be the preferable primary outcome of interventional trials in ART. WIDER IMPLICATIONS OF THE FINDINGS We found that ovarian stimulation with 150 IU gonadotrophin in combination with 100 mg CC produced more blastocysts. The effect of adding CC to GN on LBR in poor responders remains to be proven in randomised trials. High GN doses (450 IU) resulted in high FSH serum levels but increased neither the estradiol levels nor the number of retrieved oocytes, implying that granulosa cell function is not improved by high FSH serum levels. Lower starting doses of GN lead to a reduction of costs of medication. The small but significant difference in blastocyst formation and the lower FSH levels in the treatment groups receiving less GN may be an indication of better oocyte quality with higher developmental competence. STUDY FUNDING/COMPETING INTEREST(S) The costs for the HMG used for ovarian stimulation were provided by IBSA Switzerland. The study was also supported by the Repronatal Foundation, Basel, Switzerland. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER NCT01577472 TRIAL REGISTRATION DATE 13 April 2012 DATE OF FIRST PATIENT’S ENROLMENT August 2013

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