拮抗剂方案中hCG的临床应用

促性腺激素释放激素拮抗剂(GnRH-A)在控制性超促排卵(COH)中被用于防止早现的内源性促黄体激素(LH)峰,与GnRH激动剂(GnRH-a)相比较,GnRH-A具有以下优点:没有低雌激素副作用、没有点火效应、起效快且作用可逆。2011年最新的循证医学证据显示,GnRH-A方案联合GnRH-a促发卵子最终成熟在获得了与GnRH-a方案类似的临床妊娠率的同时,可以显著降低卵巢过度刺激综合征(OHSS)的发病率,该方案值得进一步推广和优化。但由于GnRH-A导致体内LH水平显著低于生理水平,可能影响部分患者的卵泡发育,以及GnRH-a应用后对LH活性的抑制可能对黄体功能产生不利影响,LH活性的补充成为近来研究的热点。hCG可以结合体内的LH受体,且半衰期更长、亲和力更高,其效能是LH的6倍左右,hCG在拮抗剂方案中的应用值得进一步研究。     

卵泡刺激素与高纯度尿促性腺激素联合方案在体外受精中有效性的评价

在控制性促排卵(controlled ovarian stimulation,COS)中,促卵泡生成素(FSH)联合高纯度尿促性腺激素(HP-hMG)促排卵的理论基础是基于促黄体生成素(LH)具有协同FSH促进卵泡发育和卵子成熟的作用。COS通常采用促性腺激素释放激素激动剂(GnRH-a)或促性腺激素释放激素抑制剂(GnRH-A)抑制早发内源性LH峰,致内源性LH水平降低,尤其在卵泡发育中晚期随着颗粒细胞上LH受体增加,对生理性LH的需求也增加。因此,理论上COS中FSH促排卵同时配伍一定量的LH活性制剂(如:HP-hMG,商品名为贺美奇)可能有利于改善COS结局。但目前FSH联合hMG应用的报道并不多,从目前有限的数据显示FSH联合hMG的多样化配伍方案均可获得满意的临床结果,关键是需要针对每个个体制定个体化的COS方案。     

国产曲普瑞林在体外受精-胚胎移植中垂体降调节效果的观察

<正>1984年Porter等[1]首次报道促性腺激素释放激素类似物(gonadotropin releasing hormone agonist,GnRH-a)用于体外受精-胚胎移植控制性促超排卵以来,GnRH-a与促性腺激素(Gn)联合促超排卵已广泛用于IVF-ET,尤以长方案应用最多。GnRH-a能有效地抑制内源性促黄体生成素(LH)峰出现,避免自发性排卵而获得较好的卵子质量与数量。但目前     

控制性卵巢刺激方案中扳机与取卵时机

<正>在控制性卵巢刺激(COS)方案中,一般使用促性腺激素释放激素激动剂(GnRH-a)进行垂体降调节或者促性腺激素释放激素拮抗剂(GnRH-ant)直接抑制LH峰,因此需要在卵泡发育成熟时使用外源性绒促性素(h CG)以模拟内源LH峰的作用(俗称扳机)[1],     

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。     

垂体降调节在控制性超排卵中的应用

不同剂型、不同剂量的促性腺激素释放激素激动剂(GnRH-a)在人类辅助生育技术中广泛应用。但多大剂量GnRH-a既能使垂体-卵巢轴有效降调节,抑制内源性LH峰出现,又不会使垂体-卵巢轴过度抑制而影响卵子的质量及妊娠率已成为人们探索的热门问题,本文就国内外在垂体降调节中的GnRH-a应用剂量等相关研究进展作一论述。     

卵巢慢反应患者控制性超促排卵相关因素分析:一项多中心回顾性研究

目的探讨控制性超促排卵(COH)过程中发生卵巢慢反应可能的相关因素。方法回顾性分析2014年1月—2016年1月期间于兰州大学第一医院、新疆佳音医院、青海省人民医院、银川市妇幼保健院、广西玉林市妇幼保健院进行促性腺激素释放激素激动剂(GnRH-a)长方案体外受精-胚胎移植(IVF-ET)的144例卵巢慢反应患者的临床资料,与132例卵巢正常反应患者(正常对照组)进行对比。结果与正常对照组相比,慢反应组患者体质量指数(BMI)、促甲状腺激素(TSH)较高,降调节及促排卵时间较长,促性腺激素(Gn)使用后7d平均卵泡直径偏小,雌二醇(E_2)、黄体生成素(LH)低,hCG注射日E_2低,IVF双原核(2PN)卵裂率较高,临床妊娠率低,差异均有统计学意义(P0.05)。患者年龄、不孕年限、基础卵泡刺激素(FSH)、LH、催乳素(PRL)、E_2、基础卵泡数、hCG注射日孕酮(P)、获卵率、胚胎质量、胚胎种植率、流产率、宫外孕率、继续妊娠率及取消移植率组间均无统计学差异(P0.05)。结论卵巢慢反应可能与患者BMI过高、甲状腺功能降低及GnRH-a过度抑制相关,较长的Gn天数仍可使慢反应患者获得较好的妊娠结局。     

适当延后促排卯启动时间有利于IVF-ET结局

目的:探讨不同促排卵(COH)启动时间对IVF-ET结局的影响.方法:回顾性分析845个IVF-ET周期结局.分别比较过度抑制组(A组)及非过度抑制组(B组)中d 3-5启动(亚组1)和d 6-8启动(亚组2)的临床结局.同时比较GnRH-a降调后常规d3 COH启动病例(C组)中,出现垂体过度抑制与未出现过度抑制组的临床结局.结果:C组中垂体过度抑制者与非过度抑制者相比,Gn用量、Gn刺激天数增加,获卵数、优质胚胎数、胚胎种植率、持续妊娠率低(P＜0.05).hCG注射日E2、LH下降(P＜0.01).而A组与B组的比较中均得出同样的结论:d 6-8启动比d 3-5启动获得更多的直径＞14mm的卵泡数及获卵教,Gn用量及Gn使用天数减少,hCG注射日有更高的E2和LH水平(P均＜0.05),但是2种启动时间相比获得的优质胚胎数、胚胎种植率及持续妊娠率均无统计学差异(P均＞0.05).结论:延迟COH启动时间可减少卵巢刺激时间、Gn用量,可增加＞14 mm卵泡数及获卵数,且不影响优质胚胎数、胚胎种植率及持续妊娠率.     

促性腺激素释放激素激动剂触发排卵的临床观察

目的:探讨促性腺激素释放激素激动剂(GnRH-a)触发排卵的疗效。方法:对应用氯米芬(CC)、来曲唑(LE)和/或人绝经期促性腺激素(hMG)促排卵治疗的不孕患者,卵泡成熟时给与GnRH-a(A组)或人绒毛膜促性腺激素(hCG)(B组)触发排卵,卵巢过度刺激综合征(OHSS)高危周期则给予GnRH-a,观察比较其临床结局。结果:共分析了81例患者132个促排卵周期,A、B组周期数分别为75和57,组间周期排卵率、多胎率、流产率相似(P>0.05)。周期临床妊娠率、OHSS发生率A组高于B组(P<0.05),无重度OHSS发生。结论:GnRH-a触发排卵临床妊娠率高,可有效预防重度OHSS的发生。     

控制性超促排卵过程中血清LH低于正常时添加rLH或hMG的效果比较

目的:比较控制性超促排卵(COH)过程中血清促黄体生成素(LH)低于正常时添加基因重组LH(rLH)或人绝经期尿促性腺激素(hMG)的效果。方法:选取因输卵管因素不孕行常规IVF-ET患者85例,全部采用长方案超促排卵,均给予基因重组促卵泡激素(rFSH)进行超促排卵,超促排卵第6日时如血清LH≥1.2 mIU/ml,继续用rFSH,作为对照组(rFSH组,n=37);如血清LH<1.2 mIU/ml,则随机纳入到hMG组(rFSH+hMG,n=30)或rLH组(rFSH+rLH,n=18)。结果:3组间在促性腺激素(Gn)用量、COH天数、获卵数、双原核率、优质胚胎率、临床妊娠率方面均无统计学差异。hMG组的rFSH用量显著低于rLH组(P<0.01)。结论:在黄体期降调节长方案超促排卵第6日,如血清LH<1.2 mIU/ml时,添加hMG或rLH,可获得与对照组(rFSH组)相似的临床结果。与添加rLH组相比,添加hMG组降低了rFSH用量,减少了患者的费用。     

Short-term use of gonadotropin-releasing hormone agonist (Leuprolide) for in vitro fertilization

A common problem encountered by in vitro fertilization (IVF) programs is the premature occurrence of the spontaneous lutenizing hormone (LH) surge during ovarian stimulation cycles. Administration of gonadotropin-releasing hormone agonists (GnRH-a) for 2 to 3 weeks produces a state of hypogonadotropic hypogonadism, thus allowing ovarian stimulation to proceed uncomplicated by a spontaneous LH surge. We have elected to treat seven patients with GnRH-a in a short-term protocol, with GnRH-a initiated on cycle day 3 along with exogenous gonadotropins. In this series, we found that the spontaneous LH surge was abolished, while ovarian responsiveness seemed to be improved. These results suggest that the initial surge of gonadotropins elicited by GnRH-a administration may enhance ovarian stimulation and that spontaneous LH surge is blocked when GnRH-a and exogenous gonadotropins are initiated concomitantly.     

Variations of luteinizing hormone serum concentrations after exogenous human chorionic gonadotropin administration during ovarian hyperstimulation

Changes in luteinizing hormone (LH), estradiol, and progesterone (P) serum levels before and after preovulatory administration of human chorionic gonadotropin (hCG) were assayed in 30 patients stimulated with clomiphene citrate (CC) and human menopausal gonadotropin (hMG) and compared with LH variations in 43 patients submitted to pharmacological hypophysectomy with a gonadotropin-releasing hormone agonist (GnRH-a) and stimulation with hMG. In CC + hMG-treated patients, an endogenous LH surge occurred systematically 4.25 +/- 2.75 hours after hCG injection. Multiparametric analysis indicated an inverse correlation between the delay in the initial rise of the LH surge and the increase in P levels during the 6 hours after hCG administration. Gonadotropin-releasing hormone agonist + hMG treatment did not lead to an LH surge after hCG but to a significant fall in LH levels. Thus, exogenous hCG, administered before ovulation, induces an endogenous LH surge if pituitary function is not blocked by a GnRH-a, probably through an increase in P secretion.     

A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization.

OBJECTIVE: To compare the effects of gonadotropin-releasing hormone agonist (GnRH-a) initiation either preceding or concurrent with controlled ovarian hyperstimulation (COH) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). DESIGN: Fifty-five patients were prospectively randomized to receive either GnRH-a on cycle day 21 before COH until ovarian suppression was achieved (group I) or GnRH-a concurrently with COH commencing on cycle day 3 (group II). MAIN OUTCOME MEASURES: Serum gonadotropin and ovarian steroid hormone levels, as well as fertilization, spontaneous abortion, and live birth rates. RESULTS: Twenty-six patients in group I and 29 patients in group II underwent COH for IVF-ET. Patients in group II had significantly higher serum luteinizing hormone, progesterone, and testosterone levels during stimulation with human menopausal gonadotropins (hMG) before oocyte retrieval (P < 0.05). Despite similar fertilization, biochemical, and clinical pregnancy rates, the spontaneous abortion rate was higher in group II (5/6) compared with group I (1/7) (P < 0.05). Thus, the live birth rate/retrieval for group I was 6 of 24 (25%) as compared with that of group II, which was 1 of 26 (3.8%) (P < 0.05). CONCLUSIONS: The initiation of GnRH-a in the follicular phase concurrently with hMG is associated with evidence of premature luteinization, hyperandrogenemia, and poorer pregnancy outcome compared with luteal phase administration of GnRH-a before hMG for IVF-ET.     

GnRH analogs: depot versus short formulations

Gonadotropin releasing hormone agonists (GnRH-a) are widely used in controlled ovarian hyperstimulation (COH) for assisted reproduction (ART). Two different formulations are now available: short formulations and depot formulation. Some authors have suggested that depot GnRH-a induce a too high pituitary suppression and have put forward protocols using reduced GnRH-a doses. A reduced dose of daily triptorelin is enough for pituitary suppression during ovarian stimulation but provides no significant improvement in IVF cycle outcome when compared with depot formulation in normally responding women. However, it seems to improve ovarian response and overall results in poor responding patients. Low doses of short GnRH-a allow shorter treatment, requiring lower amounts of gonadotropins. This possibility should be considered in view of its economic advantage.     

Leuprolide acetate-prepared in vitro fertilization-gamete intrafallopian transfer cycles: efficacy versus controls and cost analysis.

OBJECTIVE: To evaluate the effect of gonadotropin-releasing hormone agonist (GnRH-a) when given through stimulation with gonadotropins versus stopping it as stimulation was initiated versus a control group unprepared in this manner. Also, to construct a cost analysis for this type of therapy in an in vitro fertilization-gamete intrafallopian transfer program (IVF-GIFT). DESIGN: Prospective, consecutive, randomized, with a control group. SETTING: An out-patient IVF-GIFT program. PATIENTS: One hundred new patients entering an IVF-GIFT program. INTERVENTIONS: In vitro fertilization or GIFT cycles with or without preparation (pituitary suppression) by GnRH-a administration in which suppression was continued or halted as gonadotropins were begun. MAIN OUTCOME MEASURES: Cancellation rates, ampules, and days of gonadotropin use, costs, estradiol (E2) level, egg numbers and quality, and pregnancy rates. RESULTS: Stopping GnRH-a (leuprolide acetate) therapy as stimulation was begun did not lessen the suppressive effect in reduction of spontaneous luteinizing hormone surge as seen with continued use of agonist. In contrast, the control group had a 30.3% cancellation rate before ovum retrieval. The E2 and egg data among the groups were similar, but as expected, agonist use led to the need for more and longer duration of gonadotropin stimulation. Pregnancy rates were not different by group. Costs were approximately even by the third initiated cycle.     

A study of the controlled ovarian hyperstimulation using GnRH agonist and pure FSH in in vitro fertilization-embryo transfer and gamete intrafallopian transfer program

The present study was undertaken to examine controlled ovarian hyperstimulation (COH) during an IVF-ET/GIFT program with GnRH agonist (GnRH-a) and pure FSH and with the conventional method. Pituitary desensitization was induced with a subcutaneous injection of GnRH agonist (leuprolide acetate) in 20 patients undergoing COH for oocyte recovery. These 20 patients had previously dropped out of our IVF-ET/GIFT program because of a low estradiol response or premature LH surge. Comparisons were made among the menstrual cycles of 20 drop-out patients, the same patients' cycles after GnRH-a and pure FSH administration (GnRH-a group), and the cycles of 20 non-drop-out patients (control group). After treatment with GnRH-a and pure FSH, Estradiol levels were increased (GnRH-a cycles:previous cycles, 1,520 +/- 416 pg/ml:416 +/- 209.1 pg/ml), while the premature LH surge was decreased (GnRH-a cycles:previous cycles, 2:12). Moreover, the number of follicles at the day of hCG injection was increased (GnRH-a group: control group, 4.6 +/- 1.3:3.4 +/- 1.5). However, the fertilization rates for the GnRH-a group and the control group did not differ markedly, though the pregnancy rate was increased slightly in the former (GnRH-a group:control group, 25%:15%). In conclusion, it was seen that COH using GnRH-a and pure FSH contributed to a better ovarian response and suppression of LH surge in patients who had previously dropped out of the IVF-ET/GIFT program using conventional ovarian stimulation.     

Pituitary function before, during, and after chronic gonadotropin-releasing hormone agonist therapy.

OBJECTIVE: To examine possible adverse effects on pituitary function of long-term administration of gonadotropin-releasing hormone agonist (GnRH-a). DESIGN: Prospective analysis of blood sampling before, during, and after GnRH-a therapy. SETTING: Tertiary institutional outpatient care. PATIENTS: Twelve normally ovulatory women with a diagnosis of endometriosis. INTERVENTIONS: Six-month suppression with GnRH-a. MAIN OUTCOME MEASURES: Serum levels of follicle-stimulating hormone, luteinizing hormone, free thyroxin index, cortisol (F), growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). RESULTS: Basal and stimulated values of gonadotropins, PRL, F, TSH, and GH were normal and unchanged by 6 months of GnRH-a after resumption of menses. CONCLUSIONS: Utilizing dynamic pituitary function tests, we were unable to demonstrate an adverse effect of long-term GnRH-a therapy on pituitary function.     

Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques

OBJECTIVE: To assess the efficacy of various controlled ovarian hyperstimulation (COH) regimens in the prior poor-responder patient preparing for assisted reproductive techniques. DESIGN: English-language literature review. PATIENT(s): Candidates for assisted reproductive techniques who had been defined as having a prior suboptimal response to standard COH regimens. INTERVENTION(s): A variety of regimes are reviewed, including increased gonadotropin doses, change of gonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist (GnRH-a) initiation, early follicular phase (flare) GnRH-a initiation, low-dose luteal phase (ultrashort) GnRH-a initiation, progestin pretreatment, and microdose flare GnRH-a initiation. MAIN OUTCOME MEASURE(s): Maximal serum E(2) levels, follicular development, dose, and duration of gonadotropin therapy, cycle cancellation rates, oocytes retrieved, embryos transferred, and clinical and ongoing pregnancy rates. RESULT(s): A lack of uniformity in definition of the poor responder and of prospective randomized trials make data interpretation somewhat difficult. Of the varied strategies proposed, those that seem to be more uniformly beneficial are microdose GnRH-a flare and late luteal phase initiation of a short course of low-dose GnRH-a discontinued before COH. CONCLUSION(s): No single regimen will benefit all poor responders. General acceptance of uniform definitions and performance of large-scale prospective randomized trials are critical. Development of a reliable precycle screen will allow effective differentiation among normal responders, poor responders, and those who will not conceive with their own oocytes.     

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。