Comparison between follicular stimulation and luteal stimulation protocols with clomiphene and HMG in women with poor ovarian response

This retrospective study is to compare the follicular mild stimulation and luteal simulation protocols for poor responders undergoing in vitro fertilization (IVF). A total of 131 women were diagnosed as poor responders. Thirty-three women started ovarian stimulation in early-luteal phase and 98 women started in early follicular phase with 100?mg/d clomiphene citrate and 75–150?IU/d HMG. There were more oocytes retrieved (2.8?±?2.0 versus 2.0?±?1.2, p?0.05), more available embryos (1.8?±?1.4 versus 1.3?±?1.1, p?0.05) and top-quality embryos (0.9?±?0.9 versus 0.4?±?0.6, p?0.05), and reduced cycle cancellation rate (12.1% versus 30.6%, p?0.05) in luteal group than in follicular group. The clinical pregnancy (17.7%, 20.0% and 41.2%) and live-birth rates (10.78%, 20.0% and 29.4%) after transferring embryos obtained from luteal, follicular and mixed stages were comparable (p?>?0.05). For poor responders, luteal phase stimulation could be an option because of increasing the chance to obtain competent embryos and reducing the cycle cancellation rate.     

Comparison of outcomes and direct cost between minimal stimulation and conventional protocols on ovarian stimulation in in vitro fertilization

AIM: To determine whether minimal stimulation with clomiphene and gonadotropin provides outcomes and direct costs comparable with those of a conventional GnRHa-gonadotropin stimulation protocol for infertile patients undergoing in vitro fertilization. METHODS: A non-randomized clinical trial was conducted from 1 July 1996 to 31 March 2003 at the Infertility and Assisted Reproductive Unit, Ramathibodi Hospital, Faculty of Medicine, Mahidol University, Thailand. A total of 192 patients were recruited of whom 96 cases underwent ovarian stimulated cycles with minimal stimulation protocol, and 96 controls underwent ovarian stimulated cycles with GnRHa-gonadotropin protocol, with cases and controls matched for age and infertility cause. RESULTS: The median patient age was 35 years. Endometriosis was the most frequent infertility cause (28.1%). The conventional GnRHa-gonadotropin protocol could give more oocyte numbers than the minimal stimulation protocol (7.3 +/- 4.9 vs 4.5 +/- 3.3 oocytes). The fertilization rate and cleavage rate were similar (73.4 +/- 31.9 and 84.9 +/- 32.6 in minimal stimulation protocol, 69.3 +/- 29.6 and 88.4 +/- 28.0 in GnRHa-gonadotropin protocol, respectively). The pregnancy rate per oocyte retrieval cycle in the GnRHa-gonadotropin protocol was similar to the minimal stimulation protocol. (13.1%vs 13.0%, P = 1.000). However, the cost per pregnancy of minimal stimulation protocol was less than that of GnRHa-gonadotropin protocol. (6021.95 US dollars for minimal stimulation protocol per pregnancy, 10,785.65 US dollars for GnRHa-gonadotropin protocol per pregnancy, P < 0.000). CONCLUSION: Minimal stimulation was less effective than conventional GnRHa-gonadotropin on the ovarian stimulation. However, the total costs of minimal stimulation were cheaper than the conventional GnRHa-gonadotropin protocol. The decreased costs of minimal stimulation justifies further evaluation of its role in the treatment of infertility in selected cases.     

3种控制性促排卵方案治疗卵巢反应不良效果的比较

目的:探讨3种控制性促排卵方案治疗卵巢反应不良年轻患者的效果。方法:回顾分析2009年6月至2011年7月在中山大学附属第一医院生殖中心行辅助生育治疗、年龄30～40岁、出现2次及以上卵巢反应不良周期患者的所有周期共240个,选取其中标准GnRH激动剂长、短及拮抗剂方案共220个周期。在220个周期中GnRH激动剂长方案86个周期为长方案组、短方案83个周期为短方案组、拮抗剂方案51个周期为拮抗剂方案组。比较3组病例的临床资料、实验室资料和妊娠结局,评估不同促排卵方案治疗卵巢反应不良的结果。结果:短方案组基础FSH高于长方案组(P=0.039),但Gn总量少于长方案组(P=0.000),两组胚胎质量及妊娠结局的差异无统计学意义。短方案组基础FSH与拮抗剂方案组的差异无统计学意义,虽然Gn使用量高于拮抗剂方案组(P=0.000),但获卵数亦高于拮抗剂方案组(P=0.001),且周期取消率低于拮抗剂方案组(P=0.013)。3组其他临床资料(年龄、不孕年限等)、受精数、受精率、可利用胚胎率、胚胎种植率及妊娠结局等差异均无统计学意义(P>0.05)。比较添加生长激素对长、短方案获卵数的影响,差异无统计学意义(P>0.05)。结论:GnRHa短方案用于小于40岁的卵巢反应不良患者的促排卵效果较优。     

Minimal ovarian stimulation is an alternative to conventional protocols for older women according to Poseidon’s stratification: a retrospective multicenter cohort study

ObjectiveTo investigate whether minimal ovarian stimulation (mOS) is as effective as conventional ovarian stimulation (cOS) for older women belonging to different groups according to the Poseidon criteria.Material and methodsObservational retrospective multicentre cohort including women from Poseidon’s groups 2 and 4 that underwent in vitro fertilization (IVF). We performed a mixed-effects logistic regression model, adding as a random effect the patients and the stimulation cycle considering the dependence of data. Survival curves were employed as a measure of the cumulative live birth rate (CLBR). The primary outcomes were live birth rate per embryo transfer and CLBR per consecutive embryo transfer and oocyte consumed until a live birth was achieved.ResultsA total of 2002 patients underwent 3056 embryo transfers (mOS = 497 and cOS = 2559). The live birth rates per embryo transfer in mOS and cOS showed no significant difference in both Poseidon’s groups. Likewise, the logistic regression showed similar live birth rates between the two protocols in Poseidon’s groups 2 (OR 1.165, 95% CI 0.77–1.77; p = 0.710) and 4 (OR 1.264 95% CI 0.59–2.70; p = 0.387). However, the survival curves showed higher CLBR per oocyte in women that received mOS (Poseidon group 2: p < 0.001 and Poseidon group 4: p = 0.039).ConclusionsMinimal ovarian stimulation is a good alternative to COS as a first-line treatment for patients belonging to Poseidon’s groups 2 and 4. The number of oocytes needed to achieve a live birth seems inferior in mOS strategy than cOS.     

The prognostic importance of the number of oocytes retrieved and estradiol levels in poor and normal responders in in vitro fertilization (IVF) treatment

A low response to ovarian stimulation in in vitro fertilization poses a unique therapeutic challenge. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as a modality for treatment of this condition. In this study, we analyzed the results of 880 in vitro fertilization treatment cycles with respect to modality of ovarian stimulation, degree of hormonal response, and number of oocytes retrieved. In patients with estradiol (E ₂ )levels less than 501 pg/ml on the day of human chorionic gonadotropin administration, 27% pregnancy rate was achieved with clomiphene citrate (CC) combined with human menopausal gonadotropin (hMG), compared to 15.1% (P <0.005) with hMG alone and 20.8% (NS) with GnRHa and hMG. Pregnancy rates were not lower in these patients compared to patients with higher estradiol levels in the different stimulation protocols, but pregnancy rates were significantly lower in cycles during which three or fewer oocytes were retrieved, compared to those in which four or more oocytes were retrieved (10.8 vs 23.8%; P <0.0005). In low-retrieval cycles pregnancy rates actually decreased with increasing levels of estradiol. Our results indicate that the number of oocytes retrieved is a better prognostic parameter than E ₂ levels in predicting the outcome of in vitro fertilization treatment and that GnRHa in the long protocol do not seem to be superior to CC combined with hMG for the treatment of poor responders.     

卵巢低反应患者高孕激素状态下促排卵的有效性研究

目的:探讨高孕激素状态下促排卵对卵巢低反应患者LH水平的影响及促排卵效果。方法:将100例存在卵巢低反应的患者随机分为观察组、对照组,每组各50例。观察组采用醋酸甲羟孕酮联合注射用尿促性素促排卵,对照组采用超短方案。分析观察组促排卵过程中LH水平的变化,比较两组患者的获卵数、成熟卵数、优质胚胎数及行冻融胚胎移植(FET)后的妊娠率等。结果:观察组在促排卵过程中未监测到LH峰;两组的获卵数、成熟卵数、受精数等比较,差异均无统计学意义(P0.05),两组行FET后的妊娠率、胚胎种植率比较,差异无统计学意义(P0.05)。结论:高孕激素状态下促排卵能有效抑制LH峰,对于卵巢低反应者能达到较好的促排卵效果,可作为一种备选方法。     

Effects of luteal estradiol pre-treatment on the outcome of IVF in poor ovarian responders

Background: In view of the discrepancies about the luteal estradiol treatment before stimulation protocols having some potential advantages compared with the standard protocols in poor ovarian responders undergoing IVF, a meta-analysis of the published data was performed to compare the efficacy of the luteal estradiol pre-treatment protocols in IVF poor response patients. Methods: We searched for all published articles. The searches yielded 32 articles, from which seven studies met the inclusion criteria. We performed this meta-analysis involving 450 IVF patients in luteal estradiol pre-treatment protocol group and 606 patients in standard protocol group. Results: The luteal estradiol protocol resulted in a significantly higher duration of stimulation compared with the standard protocol. In addition, the number of oocytes retrieved and mature oocytes retrieved were significantly higher in the luteal estradiol protocols than those in the standard protocols. The cycle cancellation rate (CCR) in the luteal estradiol protocols was lower than the standard protocols. Moreover, no significant difference was found in the clinical pregnancy rate (CPR). Conclusions: The addition of the estradiol in the luteal phase preceding IVF in poor responders improved IVF cycle outcomes, including increasing the number of oocytes retrieved and mature oocytes retrieved and decreasing the CCR.     

短方案和微刺激方案在卵巢低反应助孕患者中的应用研究

目的探讨卵巢低反应助孕患者在进行体外受精-胚胎移植（IVF-ET）治疗中微刺激方案和短方案的应用价值。方法将2009年1月至2010年12月首次在江西省妇幼保健院生殖中心接受IVF/ICSI-ET治疗并预测卵巢低反应的121例患者分为微刺激方案（57例,微刺激组）和短方案（64例,短方案）组。比较两组的周期取消率、hCG注射日子宫内膜厚度、血LH、E2、P水平,以及平均获卵数、MⅡ卵率、着床率和临床妊娠率。结果微刺激组的周期取消率高于短方案组,差异有统计学意义（P〈0.05）。微刺激组Gn天数低于短方案组,微刺激组hCG日LH值高于短方案组,差异均有统计学意义（P〈0.01）。微刺激组hCG日P值高于短方案组,但差异无统计学意义（P〉0.05）。微刺激组hCG日E2值、子宫内膜厚度和获卵数均低于短方案组,差异有统计学意义（P〈0.05）。微刺激组MⅡ卵率和临床妊娠率低于短方案组,着床率高于短方案组,但差异均无统计学意义（P〉0.05）。结论微刺激方案是卵巢低反应患者较理想的促排卵方案。     

Freeze-all embryo strategy in poor ovarian responders undergoing ovarian stimulation for in vitro fertilization

This retrospective study determined the efficacy of the ‘freeze-all’ embryo strategy in poor ovarian responders undergoing ovarian stimulation for in vitro fertilization (IVF). A total of 559 poor responders who met Bologna criteria between January 2012 and December 2014 were included in this study: 256 in the fresh embryo transfer group and 303 in the freeze-all group. Vitrification and warming of day 3 embryos were performed using the Cryotop method. The poor responders treated with fresh embryo transfer and those treated with freeze-all strategy showed similar live birth rates per cycle (12.1% vs. 16.2%, p?=?.172) and per transfer (15.9% vs. 20.9%, p?=?.182). Multivariate logistic regression analysis showed that maternal age at retrieval (odds ratio, 0.919; 95% confidence interval, 0.865–0.977; p?=?.006) and number of good-quality embryos transferred (odds ratio, 1.953; 95% confidence interval, 1.346–2.835; p?相似文献   

高剂量来曲唑在卵巢低反应患者微刺激方案中的临床观察#br#

Objective?To explore the clinical application value of high-dose letrozole in poor ovarian response(POR) patients during mild ovarian stimulation protocols receiving IVF/ICSI. Methods?A retrospective analysis was performed on 102 patients with POR treated with letrozole mild ovarian stimulation in IVF/ICSI at our reproductive Center from January 2016 to December 2018. The high-dose letrozole group (7.5 mg/d×5 d) was the high-dose group (n=50), and the conventional letrozole group (5 mg/d×5 d) was the conventional dose group (n=52). Results?The age and basal FSH of the high-dose group were higher than those of the conventional dose group (P<0.05), and the number of sinus follicles (AFC) in the high-dose group was significantly lower than that in the conventional dose group (P<0.05). The time of use of gonadotropin (Gn) in high dose group was shorter than that in conventional dose group (P<0.05), the daily serum E2 level of human chorionic gonadotropin (hCG) was significantly decreased (P<0.05), the egg number was lower than that in conventional dose group, but the egg MⅡrate was significantly higher than that in conventional dose group (P<0.05). The clinical pregnancy rate and live birth rate per fresh transplant cycle increased in the high-dose group [55.56% vs 50%; 55.56% vs 37.5%], but the difference was not statistically significant compared with the conventional dose group (P>0.05). Conclusion?For POR patients receiving ART, high-dose letrozole with mild ovarian stimulation protocol can improve the clinical pregnancy outcome of POR patients to some extent without obvious adverse reactions, especially for POR patients with poor ovarian reserve, which may benefit from improving oocyte quality and high MII rate suggesting improved follicle quality.     

Effect of estrogen priming through luteal phase and stimulation phase in poor responders in in-vitro fertilization

Purpose  

To verify whether a novel protocol administering E₂ during the luteal phase of the preceding cycle and during ovarian stimulation in GnRH antagonist cycle could enhance follicular response and hence improve outcomes in poor responders.     

The need to step up the gonadotropin dosage in the stimulation phase of IVF treatment predicts a poor outcome

Purpose It is a common practice to increase the gonadotropin dose during ovarian stimulation when the estradiol (E₂) rise is found to be inadequate. The prognostic impact of the use of this step-up regimen on the outcome of the affected in vitro fertilization (IVF) cycle is the subject of this study. Methods This is a retrospective analysis of IVF cycles in a series of consecutive patients who required an increase in the gonadotropin dosage during the stimulation phase because of inadequate E₂ rise. Controls consisted of patients in whom the dose was not increased. After 4 days of stimulation, the gonadotropin dosage was increased if E₂ levels failed to rise by 70% every 2 days. Outcome was defined in terms of maximum E₂ level, number of follicles at aspiration, number of oocytes obtained, fertility rate, and pregnancy rate and was compared in study and control patients. Pregnancy was defined by sonographic demonstration of cardiovascular activity. Results One hundred forty-five patients were analyzed. A stepup regimen was used in 35 patients (24.1%). Patients who required the step-up dosing had significantly lower peak E₂ levels (1373 vs 1828 pg/ml; P < 0.005), fewer follicles measuring greater than 16 mm (7.2 vs 9.7; P < 0.003), and fewer oocytes recovered (8.3 vs 11.2; P < 0.009). The fertilization rate (67.6 vs 64.2%) was not significantly different. The pregnancy rate (8.5 vs 32.7%; P < 0.004) was significantly lower in the group requiring the stepup regimen. Conclusions The utilization of a step-up regimen during an IVF treatment cycle is a predictor of a poor outcome for the specific IVF cycle. As this information is available before retrieval, consideration of cycle cancellation may be appropriate.     

Different ovarian stimulation protocols for women with diminished ovarian reserve

Purpose To review the available treatments for women with significantly diminished ovarian reserve and assess the efficacy of different ovarian stimulation protocols. Methods Literature research performed among studies that have been published in the Pubmed, in the Scopus Search Machine and in Cohrane database of systematic reviews. Results A lack of clear, uniform definition of the poor responders and a lack of large-scale randomized studies make data interpretation very difficult for precise conclusions. Optimistic data have been presented by the use of high doses of gonadotropins, flare up Gn RH-a protocol (standard or microdose), stop protocols, luteal onset of Gn RH-a and the short protocol. Natural cycle or a modified natural cycle seems to be an appropriate strategy. Low dose hCG in the first days of ovarian stimulation has promising results. Molecular biology tools (mutations, single nucleotide polymorphisms (SNPs)) have been also considered to assist the management of this group of patients. Conclusions The ideal stimulation for these patients with diminished ovarian reserve remains a great challenge for the clinician, within the limits of our pharmaceutical quiver. Stimulation protocols commonly used for women with significantly diminished ovarian reserve.     

Day 3 embryo transfer may have better pregnancy outcomes in younger than 35-year-old patients with poor ovarian response

Objective

To explore the pregnancy outcomes of embryo transfer with D2 or D3 embryos in patients with poor ovarian response.

Methods

The pregnancy outcomes of 620 patients who had poor ovarian response and underwent the first in vitro fertilization-embryo transfer (IVF-ET) were retrospectively analyzed. Of the 620 cycles, all available fresh D2 embryos were used in 365 cycles (day 2 embryo transfer) and all available fresh D3 embryos were used in 255 cycles (day 3 embryo transfer) without superfluous embryos for freezing.

Results

There was a significant difference in clinical pregnancy rate between day 2 (32.73 %) and day 3 (50.83 %) embryo transfer in younger than 35-year-old patients, but no significant differences in implantation rate, live birth rate and spontaneous abortion rate (P > 0.05). There were similar pregnancy outcomes between day 2 and 3 embryo transfer in 35-year and older patients.

Conclusion

D3 embryo transfer may have better pregnancy outcomes in younger than 35-year-old patients with poor ovarian response.     

A comparison of dual triggering (by administration of GnRH agonist plus HCG) versus HCG alone in poor ovarian responders in ART outcomes

Background

The use of dual triggering in high and normal responders accompanied with better IVF cycles outcomes. Also, it has been suggested that dual triggering in poor responders can accompanied with better results.

A randomized trial of microdose leuprolide acetate protocol versus luteal phase ganirelix protocol in predicted poor responders

We performed a randomized trial to compare IVF outcomes in 54 poor responder patients undergoing a microdose leuprolide acetate (LA) protocol or a GnRH antagonist protocol incorporating a luteal phase E(2) patch and GnRH antagonist in the preceding menstrual cycle. Cancellation rates, number of oocytes retrieved, clinical pregnancy rates (PR), and ongoing PRs were similar between the two groups.     

Growth hormone co-treatment on controlled ovarian stimulation in normal ovarian response women can improve embryo quality

To investigate the clinical efficacy of growth hormone (GH) in normal response patients with poor embryo quality in previous in vitro fertilization cycles. A total of 1562 infertile women were enrolled in this matched case–control study: 781 women were treated with GH (study group), whereas 781 matched patients were treated without GH (control group). GH was administered by a daily subcutaneous injection of 2 or 4?IU started from either D2 of the previous cycle (6?weeks GH pretreatment) or the initial day of controlled ovarian stimulation (2?weeks GH pretreatment) until hCG trigger. The study group was further divided into four subgroups: 2?IU-6 weeks GH pretreatment, 4?IU-6 weeks GH pretreatment, 2?IU-2 weeks GH pretreatment, and 2?IU-4 weeks GH pretreatment. Patients receiving GH showed significantly lower Gn dosage. The total number of oocytes retrieved, embryos formed, endometrial thickness on hCG day were significantly higher with GH. 2PN rate and high-quality embryo rate were lower in the GH group. However, GH increased clinical pregnancy rate with significant difference. 4?IU-6 weeks GH pretreatment showed lowest duration of Gn and highest clinical pregnancy rate compared with other three groups. Number of transferred embryos was confounding factor both in univariate and multivariate analysis. Our study showed that co-treatment with GH in patients with normal ovarian response could increase pregnancy rate.     

The clinical analysis of poor ovarian response in in-vitro-fertilization embryo-transfer among Chinese couples

Purpose To explore the prevalence, predictor of clinical pregnancy and possible aetiology of poor ovarian response (POR) in in vitro fertilization–embryo transfer (IVF–ET) in Chinese. Methods A total of 4,600 retrieval oocyte cycles were finished between July 1, 2004 and April 30, 2006. Poor ovarian responses were observed in 426 patients of 472 cycles undergoing IVF, which were selected on the same retrieve oocyte day as the control group. The outcome of IVF–ET and the common markers of ovarian reserve were compared. Results The patients had previous ovarian surgery in 64 cycles of 472 poor ovarian response cycles. The group with poor ovarian response has significant differences in comparison with the control group in age (36.6 ± 4.2 vs 33.3 ± 4.04), ovarian surgeries (13.6 vs 2.8%), dose of gonadotrophin (58.5 ± 15.8 vs 40.6 ± 17.0), fertilization rate (71.5 vs 86%) and pregnancy rate (14.8 vs 36.7%). In the group with poor ovarian responses, clinical pregnancy rate declined significantly in women aged >40 years than in those aged ≤40 years (2.8 vs 18.5%, P < 0.001). The age, basal serum follicle stimulating hormone (FSH), basal serum luteinizing hormone (LH), basal oestradiol (E2) concentrations, FSH to LH ratio and the antral follicle count (AFC) are the common markers of ovarian reserve in our center. We found that there were significant differences in age, basal FSH, FSH-to-LH ratio and the antral follicle count. But no statistical significant differences were observed in basal oestradiol concentration and basal serum LH when comparing the two groups. Binary logistic regression analysis was used to study the relation among age, FSH, LH, E2, AFC and clinical pregnancy, and the age (odds ratio, 0.863; 95% confidence interval, 0.805–0.925; p = 0.000) was the only variable selected. Conclusion Our data show that the prevalence of poor ovarian response in Chinese is 11.9%. Previous ovarian surgery is associated with poor ovarian responses. The pregnancy rate of women with poor ovarian response is low in IVF–ET, especially the decline in clinical pregnancy rate of women aged >40 years became accelerated. Correct identification of those who are at risk for POR prior to stimulation is helpful in tailoring the best stimulation protocol to individual patients. Chronological age significantly improved the prediction of clinical pregnancy of poor ovarian responders.