拮抗剂方案黄体支持中添加GnRH-a对新鲜周期临床结局的影响

目的:比较拮抗剂方案中添加促性腺激素释放激素激动剂(GnRH-a)进行黄体支持对新鲜移植周期临床结局的影响,探讨更合适的黄体支持方案。方法:回顾性分析2018年1月至2021年12月在本院行体外受精或卵胞浆内单精子注射-胚胎移植(IVF/ICSI-ET)助孕治疗,采用拮抗剂方案行新鲜周期移植的不孕症患者共674个周期的临床资料。根据黄体期是否添加GnRH-a进行黄体支持分为对照组和观察组,对照组给予常规的黄体支持,共348个周期;观察组在常规黄体支持的基础上,于取卵后多剂量间断给予GnRH-a 0.1 mg,共326个周期。比较分析两组患者的一般资料、促排卵情况及临床结局。结果:两组患者间的年龄、不孕年限、体质量指数(BMI)、基础卵泡刺激素(bFSH)、促性腺激素(Gn)天数及总量、绒促性素(HCG)日黄体生成素(LH)、雌二醇(E2)及孕酮(P)、获卵数、MII卵数、优质胚胎数、正常受精率、中重度卵巢过度刺激综合征(OHSS)发生率、流产率、活产率、多胎率、妊娠期并发症发生率、子代的出生体质量、早产率及出生缺陷率等比较差异均无统计学意义(P>0.05);观察组的着床率及临床妊娠率显著高于对照组(P<0.05)。多因素Logistic回归分析显示,年龄、移植胚胎数是临床妊娠率的影响因素(OR 0.958,95%CI 0.917～1.000;OR 1.857,95%CI 1.173～2.942)。结论:拮抗剂方案新鲜移植周期中,在常规黄体支持基础上,多剂量间断给予短效GnRH-a进行黄体支持可提高患者的着床率及临床妊娠率,可能成为拮抗剂方案新鲜周期移植后较合适的黄体支持方案。     

改良长方案在初次拮抗剂方案助孕治疗失败患者中的应用

目的:比较改良长方案和拮抗剂方案在初次拮抗剂方案失败患者中的临床结局。方法:回顾分析初次拮抗剂方案失败行再次IVF/ICSI助孕治疗的169例患者,其中130例采用改良长方案治疗(研究组),39例采用拮抗剂方案治疗(对照组)。结果:两组患者的一般情况无明显差异(P0.05)。研究组的注射HCG日E2值、Gn用药时间和Gn剂量均显著高于对照组(P0.05),注射HCG日LH值显著低于对照组(P0.05)。研究组的临床妊娠率、种植率及活产率分别为55.2%、36.4%和46.4%,均显著高于对照组(27.3%、22.0%和21.2%)(P0.05)。结论:初次拮抗剂方案失败行再次助孕治疗的患者中,改良长方案可能通过改善子宫内膜的容受性,获得了较拮抗剂方案更好的妊娠结局。     

黄体期使用促性腺激素释放激素激动剂的效果评价

由于控制性超促排卵(COH)过程中超剂量雌、孕激素的生成以及垂体降调节药物的使用,经常出现黄体功能不全,需要常规进行黄体支持,常见的黄体支持方案包括使用人绒毛膜促性激素(hCG)及补充雌孕激素等。在近些年,多项研究表明促性腺激素释放激素激动剂(GnRH-a)在黄体支持中有很多积极方面,可以改善临床结局。其主要机制尚不清楚,可能与刺激黄体分泌雌、孕激素,提高子宫内膜容受性,提高胚胎发育潜能,促进滋养细胞分泌hCG相关。GnRHa进行黄体支持的机制及用法用量还有待进一步探究。     

不同预处理促性腺激素拮抗剂方案在超促排卵中应用的临床分析

目的:探讨如何在体外受精-胚胎移植(IVF-ET)周期中更有效地运用拮抗剂方案。方法:回顾性分析319个使用拮抗剂方案进行IVF-ET无输卵管积液、无内膜息肉及无子宫解剖结构异常的新鲜移植周期。根据拮抗剂治疗前使用短效激动剂(n=125,A组)、口服避孕药(达英-35)(n=113,B组)和未处理组(n=81,C组)分组,比较各组患者的年龄、促性腺激素(Gn)使用天数和剂量、注射hCG日LH和E2水平、获卵数、优质胚胎率、临床妊娠率等。同时以261个促性腺激素激动剂长方案移植周期为对照组(D组)作进一步对比。结果:C组年龄(32.9±4.8岁)较其它组年龄明显偏大,P<0.05;A和B组Gn使用剂量大于C组,其中A组明显增多(P<0.01);A和B组hCG注射日LH水平均较C组明显低,其中A组LH值最低(P<0.01);A组获卵数最多(P<0.05);B组子宫内膜最薄(P<0.01)。3组的受精率、优质胚胎率均无统计学差异(P>0.05)。A组、B组和C组临床妊娠率分别为:32.8%、17.7%和37.0%,B组临床妊娠率显著低于A、C组(P<0.01)。C组、D组间临床妊娠率比较无统计学差异(37.0%vs 40.2%,P>0.05);C组Gn使用的时间和剂量均比D组明显减少(P<0.05)。结论:在IVF-ET中GnRH拮抗剂治疗前使用达必佳预处理未能提高妊娠率,使用过达因-35避孕的患者妊娠率明显下降,而未使用任何药物的患者接受GnRH拮抗剂超促排卵方案,能获得比较好的临床结局。     

第三代促性腺激素释放激素拮抗剂:西曲瑞克

促性腺激素释放激素(GnRH)类似物包括GnRH激动剂(GnRHa)和GnRH拮抗剂(GnRHA),两者的分子结构是对GnRH不同位点氨基酸的改变,决定了两者的作用机制不同.GnRHA的研究进展缓慢,继第一、二代GnRHA后,现第三代GnRHA用于临床Ⅲ期实验,西曲瑞克(cetrorelix)作为第三代GnRHA有其独特的药物动力学和稳定性,也有不良反应和禁忌证,在临床广泛应用于激素依赖性疾病,如子宫内膜异位症、子宫肌瘤、妇科恶性肿瘤、性早熟等,应用范围与GnRHa类似,但与之比较又有自身的特点和优点.     

第三代促性腺激素释放激素拮抗剂：西曲瑞克

促性腺激素释放激素(GnRH)类似物包括GnRH激动剂(GnRHa)和GnRH拮抗剂(GnRHA),两者的分子结构是对GnRH不同位点氨基酸的改变,决定了两者的作用机制不同。GnRHA的研究进展缓慢,继第一、二代GnRHA后,现第三代GnRHA用于临床Ⅲ期实验,西曲瑞克(cetrorelix)作为第三代GnRHA有其独特的药物动力学和稳定性,也有不良反应和禁忌证,在临床广泛应用于激素依赖性疾病,如子宫内膜异位症、子宫肌瘤、妇科恶性肿瘤、性早熟等,应用范围与GnRHa类似,但与之比较又有自身的特点和优点。     

激动剂方案和拮抗剂方案对波塞冬组1人群的疗效分析

目的:评估促性腺激素释放激素激动剂(GnRH-a)方案和促性腺激素释放激素拮抗剂(GnRH-ant)方案在波塞冬(POSEIDON)组1人群中的疗效。方法:回顾性分析2019年1月至2020年12月在南通大学附属医院生殖医学中心行辅助生殖助孕的POSEIDON组1患者399例。采用1∶1倾向性评分匹配(PSM)筛选具有相似基线特征的队列,比较GnRH-a方案组和GnRH-ant方案组患者的基线资料、临床及实验室指标和临床结局。结果:(1)100例行GnRH-a方案的患者和100例行GnRH-ant方案的患者形成匹配。(2)GnRH-a方案组的促性腺激素(Gn)使用总量和Gn总使用时间均高于GnRH-ant方案组(P<0.001,P=0.048),绒促性素(HCG)注射日的激素水平(黄体生成素、雌二醇、孕酮)均低于GnRH-ant方案组(P<0.001,P=0.011,P<0.001),两组间卵泡数差异无统计学意义(P>0.05);GnRH-a方案组获卵数、成熟卵子数、正常受精数、优质胚胎数和可利用胚胎数均低于GnRH-ant方案组(P<0.01)。(3)G...     

辅助生殖促排卵药物治疗专家共识

辅助生殖技术(ART)的重要内容之一是促排卵治疗,其应用改善了临床妊娠率,但多胎妊娠、卵巢过度刺激综合征(OHSS)等并发症发生几率较高。促排卵最常用药物为克罗米芬(CC),芳香化酶抑制剂、促性腺激素(Gn)类和促性腺激素释放激素类似物(Gn RHa),包括激动剂(Gn RH-a)和拮抗剂(Gn RH-A)近年来的应用也逐渐增加。各种药物有不同的适应证、禁忌证和用药方案,另外还可使用其他促排卵辅助药物,如口服避孕药(OC)、二甲双胍、多巴胺受体激动剂等,这些促排卵治疗效果可通过常用的疗效评估指标及计算方法来统计。中华医学会生殖医学分会部分专家结合近年来国内、外相关领域研究进展及临床应用,对促排卵药物在ART中的应用达成共识,以指导规范的临床应用。     

使用促性腺激素释放激素激动剂过程中妊娠的临床分析

目的 研究在控制性超促排卵(COH)使用促性腺激素释放激素激动剂(GnRH-a)过程中妊娠的临床结局。方法 回顾性分析我中心4 988例体外受精或卵母细胞质内单精子显微注射受精与胚胎移植(IVF/ICSI-ET)长方案超促排卵使用GnRH-a过程中妊娠的21例临床资料。结果 在使用GnRH-a过程中21例妊娠,妊娠发生率为0.42%(21/4 988)。其中宫内孕19例,2例足月分娩健康新生儿;8例妊娠中;7例自然流产,自然流产发生率为33.33%(7/21);2例异位妊娠,异位妊娠发生率为9.52%(2/21);2例失访。结论 在COH中使用GnRH-a可导致意外妊娠,GnRH-a对妊娠结果无不良影响、无胎儿致畸作用,且有良好的妊娠结局。     

GnRH-a长方案和GnRH-ant方案在高龄患者IVF-ET中应用效果的比较

目的比较高龄患者应用促性腺激素释放激素激动剂（GnRH-a）长方案和促性腺激素释放激素拮抗剂（GnRH-ant）方案行体外受精-胚胎移植（in vitro fertilization-embryo transfer,IVF-ET）的疗效,探讨适合高龄患者控制性卵巢刺激的方案。方法回顾性分析2007年1月至2010年6月156例高生育年龄（35～40岁）不孕症女性在南方医科大学南方医院生殖医学中心行IVF-ET的临床资料,评估GnRH-a长方案和GnRH-ant方案的助孕效果。结果 GnRH-a长方案组和GnRH-ant方案组患者的促性腺激素（Gn）应用总量及hCG日孕激素（P）水平比较,差异无统计学意义（P〉0.05）;但两组在Gn应用时间、hCG日雌二醇（E2）水平、hCG日子宫内膜厚度、获卵数、成熟卵子数、受精数和2PN数比较,差异有统计学意义（P〈0.01）;同时,两组的hCG日黄体生成素（LH）水平比较,差异有统计学意义（P〈0.05）;GnRH-a长方案组的临床妊娠率和着床率显著高于GnRH-ant方案组（P〈0.001）。结论高生育年龄患者IVF-ET中应用GnRH-a长方案的助孕结局优于GnRH-ant方案。     

Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study

This study was designed to evaluate the effect of luteal-phase administration of single-dose gonadotrophin-releasing hormone (GnRH) agonist on pregnancy, implantation and live birth rates in patients who received GnRH antagonist for pituitary suppression. The study population consisted of 164 patients who underwent intracytoplasmic sperm injection (ICSI) after ovulation induction by gonadotrophins and GnRH antagonist for the prevention of a premature LH surge. For luteal-phase support, all the cases received intravaginal 600 mg micronized progesterone. In this prospective study, patients were randomly assigned to two groups. In one group, patients received an additional single dose of GnRH agonist (0.5 mg leuprolide acetate) subcutaneously on day 6 after ICSI, whereas the patients in the other group did not. Although the number of embryos transferred and the grade of the embryos were similar in the two groups, the patients in the luteal-phase agonist group had significantly higher rates of implantation and clinical pregnancy rates (P < 0.05). When the two groups were compared, there were also statistically significant differences in multiple pregnancy and live birth rates (P < 0.05). Administration of single-dose GnRH agonist as a luteal-phase support in ovarian stimulation-GnRH antagonist cycles in addition to standard luteal support seems to be effective in all cycle outcome parameters.     

Luteal phase oestradiol administration in ovarian stimulation cycles with GnRH antagonist is comparable to the GnRH agonist (long) protocol

Purpose: The purpose of the study was to compare the effectiveness of GnRH antagonist with luteal phase estradiol administration to GnRH agonist cycles, long protocol. Methods: 55 IVF-ICSI patients received oestradiol in the luteal phase of the cycle, before a cycle with GnRH antagonist. Fifty-five patients submitted to IVF-ICSI with the use of agonist were allocated, age matched, as a control group (historical control). The primary outcome was the number of retrieved oocytes. Results: Patients were similar in terms of clinical characteristics. No differences were found in the number of oocytes retrieved (study group, 8.1 ± 4.7; control group, 7.4 ± 4.5) or in oocyte quality. Conclusions: We clearly demonstrated that the effectiveness of GnRH antagonist when combined with luteal phase estradiol is comparable to GnRH agonist cycles. Capsule Oestradiol associated to GnRH antagonist may increase the rates of oocytes causing reproductive results to be comparable to the results with the use of agonists.     

Live births after management of severe OHSS by GnRH antagonist administration in the luteal phase

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian stimulation protocols. Currently, no curative therapy exists and the main preventive option is cycle cancellation. Gonadotrophin-releasing hormone (GnRH) antagonist administration in the luteal phase was recently proposed as a new approach for the management of patients with established severe OHSS. Three polycystic ovarian syndrome patients undergoing IVF treatment developed severe OHSS, diagnosed 6 days after oocyte retrieval. On day 6, the patients underwent blastocyst transfer and received GnRH antagonist for 4 days, combined with luteal phase support using exogenous oestradiol and progesterone. Two patients had successful pregnancies that resulted in births of healthy infants, while one patient had a biochemical pregnancy. In all patients, established severe OHSS regressed to a moderate form of the syndrome, no pregnancy-induced life-threatening OHSS was observed, while a short monitoring period was required at an outpatient level, avoiding the need for patient hospitalization. This is the first report in the literature on GnRH antagonist administration in the luteal phase, combined with embryo transfer and exogenous oestradiol and progesterone supplementation. This novel treatment was effective in the regression of established severe OHSS, and resulted in the birth of healthy infants.     

Scheduling GnRH antagonist cycles by a short course of oral estradiol administration during early follicular phase: a comparative study with non-scheduled cycles

Abstract

This hypothesis generating study investigated whether GnRH antagonist cycles can be scheduled by a short course of oral estradiol administration during the follicular phase without impairing treatment outcome. Thirty-five women who underwent follicular phase estrogen scheduling (ES) of GnRH antagonist cycles were retrospectively matched for age and number of prior failed cycles with 35 women who underwent unscheduled GnRH antagonist cycles. ES group was given 6?mg/day estradiol orally from cycle day 2 until (including) one day before the scheduled start of stimulation. Gonadotropins were started on cycle days 2–3 in the control group. Flexible GnRH antagonist protocol was employed in both groups. ES group received estradiol for a median of 5 days. Total gonadotropin consumption was similar but one more GnRH antagonist injection was required in the ES group. Endometrial thickness on the day of hCG injection was increased in the ES group (12 versus 10?mm, p?<?0.01). Number of oocytes, metaphase II oocytes and transferred embryos were similar. Embryo implantation rates were 44.8% versus 34.4% (p?=?0.3), and clinical pregnancy rates were 48.6% versus 37.1%, (p?=?0.33) in the ES and control groups, respectively. All women in the ES group had oocyte retrieval and embryo transfer within the desired period.     

Luteal phase characteristics following GnRH antagonist or agonist treatment - a comparative study

Due to inherent differences between gonadotrophin-releasing hormone (GnRH) antagonists and agonists, their late effect on ovarian steroidal production during the luteal phase of IVF cycles may differ. The aim of this study was to characterize and compare the luteal phase hormonal profile after the use of GnRH antagonists or agonists in ovarian stimulation protocols for IVF, in non-conception cycles, to avoid the effect of human chorionic gonadotrophin (HCG) during the luteal phase in conception cycles. Seventy-eight normo-ovulatory patients <35 years old, undergoing IVF due to male or tubal infertility were randomly allocated either to a GnRH antagonist (study group) or GnRH agonist treatment (control group). Similar standard luteal support was given to all patients, using vaginal micronized progesterone. In non-conception cycles, no statistically significant differences were found comparing luteal phase. oestradiol or progesterone levels in the study and control groups. No statistically significant differences were found comparing the hormonal profile dynamics, the mid-luteal (HCG day +8) oestradiol/progesterone ratio and the percentage of mid-luteal oestradiol decline between the study and control groups. In conclusion, similar characteristics and dynamics of luteal phase oestradiol and progesterone were demonstrated comparing ovarian stimulation for IVF using GnRH agonist or antagonists, under similar luteal support.     

Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial

Aim.?To compare donor and recipient outcome after inducing the final oocyte maturation with hCG or GnRH agonist in GnRH-antagonist treated oocyte donation (OD) cycles.

Methods.?Two-hundred fifty-seven oocyte donors were enrolled to participate in a clinical trial in a private fertility centre. After stimulation with 225 IU rFSH and Cetrorelix 0.25 mg/day, 212 oocyte donors were randomised with sealed envelopes for triggering with recombinant hCG (Ovitrelle 250 μgr, n = 106) or a GnRH agonist (triptorelin 0.2 mg, n = 106).

Results.?The number of retrieved COCs (12 ± 6.3 vs 11.4 ± 6.4), mature oocytes (8 ± 4.6 vs 7.5 ± 4.1), the proportion of mature oocytes (67.2 ± 20.4% vs 67.1 ± 20.9%) and fertilisation rates (67.8 ± 23.5% vs 71.1 ± 22.1%) were comparable. Clinical, ongoing pregnancy and live birth rates were not statistically different in the corresponding recipient groups. Nine cases of mild and one case of severe OHSS occurred in hCG group, whereas no cases were detected in GnRH agonist group.

Conclusions.?The findings of our RCT suggest that donor and recipient outcome are comparable in OD cycles triggered with hCG or a GnRH agonist. Furthermore, the risk of OHSS seems to be reduced considerably, therefore the combination of a GnRH antagonist protocol with GnRH agonist triggering constitutes a safe treatment option for egg-donors.     

IVF/ICSI outcomes between cycles with luteal estradiol (E2) pre-treatment before GnRH antagonist protocol and standard long GnRH agonist protocol: a prospective and randomized study

Objective

To study if luteal E₂ pre-treatment before GnRH antagonist protocol improves IVF/ICSI outcomes compared with standard long GnRH agonist protocol.

Design

A prospective, randomized and controlled study.

Setting

ART center of a state public hospital

Patient(s)

Two hundred twenty infertile women underwent IVF/ICSI treatments.

Intervention(s)

Participants received oral Estradiol Valerate 4 mg/day preceding the IVF cycle from day 21 until day 2 of next cycle before GnRH antagonist protocol (E₂ pre-treatment group n?=?109) or received standard long GnRH agonist protocol as control group (n?=?111).

Main outcome measure(s)

Number of oocytes collected, MII oocytes, fertilization, implantation, live birth and early pregnancy rate, and hormone profiles.

Result(s)

E₂ pre-treatment exerted a significant suppressive effect on FSH but not LH secretion compared with basal FSH and LH levels. In E₂ pre-treatment group serum LH level was significantly higher during COH and serum P was also significantly higher on the day of HCG injection compared with control group. Five patients from E₂ pre-treatment group had elevated LH at all time (≥10 IU/L) and also a concomitantly high P (>1 ng/mL). Two of the five women achieved pregnancy but had early pregnancy loss. Overall, IVF/ICSI outcomes such as implantation, clinical pregnancy and live birth rates were similar between E₂ pre-treatment and control groups.

Conclusion(s)

Luteal E₂ pre-treatment before GnRH antagonist protocol significantly increases serum LH level and incidence rate of premature LH but no significant effect is observed on implantation, clinical pregnancy, live birth and early pregnancy loss rates compared with long GnRH agonist protocol. However, more studies in large numbers of cycles are needed to confirm that increased serum LH level by E₂ pre-treatment during COH has no negative effect on the IVF/ICSI outcomes.     

Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders

All IVF-ICSI cycles carried out between October 2009 and October 2012 using GnRH agonist (GnRHa) ovulation trigger (n = 62) followed by a single dose of HCG plus progesterone and oestradiol in the luteal phase because of anticipated ovarian hypertsimulation were retrospectively compared with historic control cycles using HCG trigger (n = 29) and standard luteal phase support. Women's mean age, body mass index, anti-Müllerian hormone, FSH, LH, starting and total stimulation dose, number of follicles, oocytes, embryos, fertilization, implantation, polycystic ovary syndrome, ICSI, live birth and ongoing pregnancy rates per embryo transfer were similar (GnRHa 40.7% versus HCG 35.0%). For each started cycle, GnRHa resulted in 11.4% higher (statistically non-significant) live birth and ongoing pregnancy rate (OR 1.73, CI 0.64 to 4.69), with a similar difference for double-embryo transfers (OR 1.62, CI 0.44 to 6.38) and less need for freezing all embryos (9.7% versus 27.6%; P = 0.04). Incidence of mild-to-moderate OHSS was 16.2% with GnRHa trigger and 31.0% with HCG trigger) and no severe OHSS in the former. The addition of single low-dose HCG in the luteal phase after GnRHa trigger for suspected high-responders reduced the incidence of OHSS with good clinical outcomes, compared with HCG trigger.