预测控制性超促排卵中卵巢低反应的研究进展

卵巢功能下降,对药物反应不良,不能获得一定数量及质量的卵子,是体外受精（IVF）治疗失败的重要原因。其发生率在9%～24%之间,高龄、卵巢手术史、盆腔粘连、放化疗及吸烟等与卵巢反应不良密切相关。其造成的周期取消率约15%～24%[1]。但是目前国际上尚没有明确的卵巢低反应（poor ovarian response,POR）的定义。     

GnRH拮抗剂在卵巢反应不良患者中的应用

目的探讨促性腺激素释放激素（GnRH）拮抗剂在卵巢反应不良患者中的应用。方法对既往应用体外受精-胚胎移植（IVF-ET）技术治疗过程中发生卵巢反应不良或取消周期的60例不孕患者随机对照分为两组,GnRH拮抗剂组和GnRH激动剂方案组,观察激素水平、获卵数、受精率、妊娠率等。结果拮抗剂组获卵数多于激动剂组（3.36±1.97 vs 2.43±0.92,P=0.038）,两组患者在HCG日LH水平、E2水平和P水平没有明显差异,在〉14mm的卵泡数、妊娠率分别为（3.04±1.33 vs 2.73±0.87,P=0.082）、（24%vs 14.3%,P=0.291）,两组患者均没有出现LH峰值。结论GnRH拮抗剂方案对卵巢反应不良的患者不失为可尝试的治疗方法。     

辅助生殖技术中卵巢低反应影响因素与妊娠结局研究

目的探讨辅助生殖技术（ART）中卵巢对控制性超排卵（COH）低反应的影响因素以及低反应患者的妊娠结局。方法回顾性分析327名首次接受IVF/ICSI-ET治疗的不孕症患者的资料。根据患者COH卵巢反应分为卵巢低反应组（n=137例,获卵数≤5个）和卵巢反应良好组（n=190例,获卵数〉5个）,分析年龄、基础卵泡刺激素（bFSH）、窦卵泡数等对COH的影响。结果①单因素分析显示影响卵巢低反应发生的因素有年龄、基础卵泡刺激素水平、基础FSH/LH值和窦卵泡数;Logistic多因素回归分析显示：年龄与卵巢反应性呈负相关,窦卵泡数与卵巢反应性呈正相关,且相关程度窦卵泡数〉年龄。②卵巢低反应组与卵巢反应良好组的临床妊娠率分别为27.83%和39.16%,两组间临床妊娠率差异有统计学意义（P〈0.05）。结论年龄和窦卵泡数可用于预测卵巢的反应性,其中窦卵泡数为最敏感的指标。卵巢低反应影响妊娠结局。     

辅助生殖技术中卵巢过度刺激综合征 发生发展预测指标的研究

目的 研究辅助生殖技术中卵巢过度刺激综合征发生发展预测指标。方法 回顾分析2016年8月~2017年8月在我院接受辅助生殖技术（ART）治疗的52例卵巢过度刺激综合征（OHSS）（分为早发组25例和晚发组27例）和40例非OHSS患者,比较两组患者妊娠结局等指标,筛查OHSS发生发展预测指标。结果 OHSS组患者妊娠率、不良妊娠率、多胎妊娠率高于非OHSS组,差异有统计学意义（P＜0.05）;早发组年龄、促性腺激素（Gn）用量、HCG注射日中小卵泡评分与晚发组对比差异有统计学意义（P＜0.05）,妊娠率、不良妊娠率组间对比,差异无统计学意义（P＞0.05）;中小卵泡评分变量与OHSS发生时间相关,OHSS持续时间与是否妊娠或多胎妊娠相关。结论 早发的OHSS与卵巢对外源性HCG过度反应相关,HCG注射日中小卵泡评分可预测OHSS的发生。晚发的OHSS与胚胎中内源性HCG相关,OHSS持续时间可以预测判断妊娠情况。     

脱氢表雄酮可以改善卵巢低反应患者的体外受精结局

目的探讨卵巢低反应患者补充脱氢表雄酮（DHEA）后卵巢储备指标及体外受精结局的变化。方法纳入50名前次IVF—ET治疗失败,证明是卵巢低反应,并再次要求IVF—ET治疗的患者。采用前瞻性单因素自身对照研究。入选患者接受DHEA75mg／日,至少治疗3个月后,每个患者采用与前一周期相同的卵巢刺激方案和FSH起始剂量促排卵。比较DHEA治疗前后,月经周期第三天AFC数量、FSH、抑制素B、抗苗勒氏管激素水平等卵巢储备指标;比较前后周期血清雌二醇（E2）峰值、HCG日〉15mm卵泡数量、回收卵母细胞和MII卵母细胞的数量、胚胎的数量和质量等治疗反应指标;比较治疗前后,临床妊娠率、流产率、活产率等体外受精周期结局差异。结果50例患者DHEA治疗前后AFC数量显著增加（P〈0．05）,月经第3天FSH、抑制素B和抗苗勒氏管激素水平无明显改变（P〉0．05）;补充DHEA后,卵巢刺激反应得到了显著改善,E2峰值水平、〉15mm的卵泡数量、获卵数、MII的卵子数量均有显著增加（P〉0．05）,治疗前后受精率相似（分别为67±42％和72±30％,P〉0．05）,可移植胚胎数量显著增加,由平均数量0．85个增至2．0个（P〈0．05）,可移植胚胎的优胚率由26％增至47％,但没有统计学意义（P〉0．05）。由于反应不良取消周期的比例显著降低（P〈0．05）,使用DHEA后周期妊娠率为30％,活产率为20％。50例患者对DHEA耐受良好,无严重不良反应。结论补充DHEA后可以增加胚胎数量,改善胚胎质量,提高临床妊娠率,改善卵巢低反应体外受精结局。其改善结局的机制可能是通过减少2—10mm的窦卵泡闭锁,增加AFC途径实现的。     

抗苗勒管激素对卵巢低反应预测价值的研究

目的探讨抗苗勒氏管激素(AMH)在辅助生殖技术(ART)中对控制性超排卵(COH)卵巢低反应的预测价值。方法利用ELISA法对181例首次接受IVF/ICSI-ET治疗的不孕症患者基础血清AMH蛋白水平(bAMH)进行检测。根据患者COH卵巢反应将患者分为2组:卵巢低反应组20例(获卵数≤5个)和卵巢反应良好组161例(获卵数>5个)。比较bAMH与年龄、获卵数、基础FSH等的相关性。结果①181例不孕症患者bAMH水平与获卵数呈显著正相关(r=0.709,P<0.05);②卵巢低反应组(获卵数≤5个)与反应良好组(获卵数>5个)的bAMH水平比较,差异有统计学意义(P<0.05);③受试者工作特征(ROC)曲线分析显示,bAMH水平的曲线下面积(AUC)为0.949。当bAMH截断值≤3.65ng/ml时,灵敏度为86.3%,特异度为90.0%。结论 AMH与卵巢反应性有关,可以在辅助生殖技术中作为评价预测COH中卵巢低反应的血清学标记物。     

卵巢反应不良患者的流产分析

目的 通过分析卵巢反应不良(POR)患者早期自然流产的情况,研究成功妊娠的POR患者卵巢反应不良与卵母细胞数量及质量的关系.方法 收集2005年1月至2009年4月广州医学院第三附属医院生殖医学中心1371例体外受精-胚胎移植妊娠患者,其中58例发生POR,1313例卵巢反应正常(NOR),对比卵巢反应不良与正常患者一般临床情况和各年龄组的流产率.结果 POR组年龄稍高于NOR组](33.2±3.5)岁比(31.5±3.8)岁,P＜0.05],所需促性腺激素剂量较大,而取卵数、移植胚胎数和可用胚胎数较少(均P＜0.05).两组的不孕年限、原发不孕比例、促排卵天数、受精率、种植率差异均没有统计学意义.POR组的多胎妊娠率低于NOR组(15.5％比34.1％,P＜0.05).POR组流产率为20.7％(12/58),NOR组流产率为12.6％(165/1313),差异无统计学意义(P＞0.05).POR组≤30岁、31～35岁、≥36岁组的流产率分别为13.3％、26.9％、17.6％,与NOR组同年龄组10.7％、13.8％、14.4％相比差异无统计学意义(均P＞0.05).结论 成功妊娠的POR患者流产率较NOR患者无明显升高.成功妊娠的POR患者卵巢反应不良是卵母细胞数量的减少,并不是卵母细胞质量的下降.     

经阴道小卵泡抽吸术联合宫腔内人工授精治疗多囊卵巢综合征的临床观察

目的观察经阴道小卵泡穿刺抽吸术后辅助宫腔内人工授精（IUI）治疗多囊卵巢综合症（PCOS）患者排卵障碍所致不孕的临床疗效,探讨其对PCOS患者内分泌及基础窦卵泡数的影响,并观察其在治疗后促排卵的反应性及妊娠情况。方法对于52例耐克罗米芬（CC）的PCOS患者于月经周期的第5天开始肌注HMG 75IU,连用5天后,行B超检查,经阴道抽吸两侧卵巢内小卵泡,保留1～3个相对较大的卵泡,继续应用HMG注射,当1～3个优势卵泡直径达18mm时,注射HCG诱发排卵,36h后行宫腔内人工授精.观察卵巢体积变化、排卵率、单卵泡排卵率、妊娠率、多胎、OHSS发生和周期取消例数。结果对52例患者进行了92个周期的穿刺治疗,2个穿刺周期后患者睾酮（T）和促黄体生成素/促卵泡激素（LH/FSH）比值均明显降低,与治疗前比较,差异有统计学意义（P〈0.01）,29例卵巢体积明显缩小,35例双卵巢内窦卵泡数降到10个以下,穿刺前后对比,差异有显著性（P〈0.01）。92个穿刺周期中,83个周期排卵,排卵率达90.2%,其中单卵排卵率占68.4%（63/92）,临床妊娠25例,妊娠率48%,无1例患者发生卵巢过度刺激综合征（OHSS）。结论对于CC耐药或对Gn反应不良的PCOS患者采用经阴道小卵泡抽吸术及辅助人工授精助孕的治疗方式可极大提高单卵泡排卵和单胎妊娠率,避免多胎和OHSS的发生。     

彩超在预测FSH正常不孕症患者的超排卵期中卵巢反应的研究

目的：探讨彩超在预测FSH正常不孕症患者的超排卵期中卵巢反应的临床价值。方法：将46例FSH正常不孕症患者根据卵巢反应分为正常反应组(n=34)和低反应组(n=12),治疗结束后比较两组患者的窦卵泡计数、卵巢血流速、阻力指数,获得卵数及优质率。结果：治疗后正常组窦卵泡计数及卵巢基质峰值血流速高于低反应组(P<0.05);治疗后正常反应组获卵数、优质卵及优质率高于低反应组(P<0.05)。结论：经阴道彩超检查对FSH正常不孕症患者卵巢反应性具有良好的预测与评估,值得临床推广。     

不孕不育妇女卵巢储备功能的检测

随着辅助生育技术 (assistedreproductivetechnologies,ART)的广泛应用 ,不孕不育妇女进行昂贵的辅助生育治疗之前对她们的生殖潜能做出评价是很有必要的。而生殖潜能直接取决于卵母细胞的质量和子宫内膜的容受性 ,前者的下降即卵巢储备功能的下降可以影响ART的治疗效果。对其进行预测既可以帮助临床医生筛选患者 ,又可以作为病因诊断 ,解释部分患者不孕不育的原因。卵巢储备是指卵巢储备是指卵巢皮质区卵泡的生长 ?发育 ?形成可受精的卵母细胞的能力。其可以借助超声从卵巢的形态及血液流变学的改变来评价 ,也可以通过各种激素的测定或…     

体外受精-胚胎移植中卵巢低反应的多因素研究

目的探讨IVF-ET中卵巢低反应的预测因素及结局。方法回顾性分析2008年1月～2010年3月在我中心首次接受IVF-ET治疗的不孕症患者372个周期,按照卵巢低反应的判断标准筛选出84个周期为卵巢低反应组,同期获卵数5～20个连续的84个IVF-ET周期为对照组。对两组的妊娠结局及卵巢储备功能的相关因素进行单因素分析,有统计学差异的影响因素再进行Logistic多因素回归分析。结果发生卵巢低反应的相关因素有年龄、不孕年限、bFSH、bFSH/bLH、bE2、AFC;卵巢低反应与AFC呈显著正相关（P〈0.001）,与bFSH/bLH、bE2、bFSH呈明显负相关（P均〈0.01）,与卵巢低反应的密切相关程度依次为AFC〉bFSH/bLH〉bE2〉bFSH。结论 AFC、bFSH/bLH、bE2及bFSH可较好地预测卵巢低反应,其中AFC为最敏感指标。     

卵泡输出率的应用研究

目前卵巢反应性的预测指标包括AMH、抑制素B、年龄、窦卵泡、基础性激素、卵巢敏感性（OSI）、卵泡敏感性（FSI）等,而这些指标在预测卵巢对外源性促性腺激素（Gn）的反应存在一定的局限性。在近年生殖医学预测IVF/ICSI妊娠结局及卵巢反应性的相关研究中,提出卵泡输出率（FORT）是一个客观、较新且热门的指标。控制性超促排卵（COH）个体化治疗方案的制定在治疗各种不孕症的过程中具有重要的意义,可以通过FORT评估每个患者卵巢反应性来制定合适的COH方案,从而改善妊娠结局。本文就FORT在卵巢低反应、多囊卵巢综合征（PCOS）、子宫内膜异位症（EMs）、不明原因不孕症、高龄及肿瘤患者对卵巢反应性及IVF/ICSI妊娠结局的相关性研究进行综述。     

基础睾酮水平与不同卵巢储备患者体外受精周期卵巢反应的关系

目的探讨基础睾酮(testosterone,T)水平与不同卵巢储备能力患者体外受精周期(in vitro fertilization,IVF)卵巢反应的相关性。方法对248例首次行IVF的患者行回顾性分析,先按基础日FSH/LH及FSH值大小分成卵巢储备能力正常组(A组164例)和卵巢储备能力低下组(B组84例)分别进行研究,取总体样本248例患者的T值均数为截点,将A、B组分别分为组1(T<0.5ng/ml)和组2(T≥0.5ng/ml),比较组1和组2间卵巢反应参数均值差异;用Pearson相关性分析分别分析A、B两组中T值与卵巢反应参数的相关性;运用多元回归寻找影响获卵数的独立因素;运用受试者工作(receiver operating curve,ROC)曲线分别评价各指标在A、B组患者中预测卵巢反应的价值。结果 (1)A组:①A1组卵巢反应参数低于A2组,差异有统计学意义。②基础T值与卵巢反应参数明显正相关(P<0.05)。③T值是影响获卵数的独立因素之一,且在该组中对获卵数影响最大(P<0.01)。④根据ROC曲线结果当T值为0.500ng/ml的时候,其诊断卵巢低反应的敏感度为86.5%特异度为76.2%。(2)B组中:①B1组部分卵巢反应参数高于B2组,差异有统计学意义。②基础T值与部分卵巢反应参数负相关(P<0.05)。③T值是影响获卵数的独立因素之一,但影响是负面的。④ROC曲线显示该组中基础窦卵泡数(AFC)较T值对卵巢反应具有更高的预测价值。结论在卵巢储备能力低下的组,血清基础睾酮值与体外受精周期卵巢反应参数正相关,对卵巢低反应具有较强的预测价值;卵巢储备能力尚好的组,血清基础睾酮值与部分卵巢反应参数负相关,不具备明显的预测卵巢反应的价值。     

Ovarian response to standard gonadotrophin stimulation for IVF is decreased not only in older but also in younger women in couples with idiopathic and male subfertility

BACKGROUND: With the occasional reports of unexpectedly poor ovarian response to controlled ovarian hyperstimulation (COH) for IVF in young normally cyclic women in mind, we studied age-related ovarian response to COH in a group of women who underwent standard IVF. METHODS: Ovarian response to COH was defined as the number of follicles > or = 14 mm on the day of hCG administration. Ovarian response to COH was analysed by multiple regression analysis with woman's age and basal FSH concentration as explanatory variables in a prospective cohort of patients with idiopathic and mild male factor subfertility (n = 85), and additionally in a large retrospective cohort of women with unexplained, mild male and tubal subfertility (n = 1155), with age as explanatory variable. RESULTS: Ovarian response to COH was associated significantly with age (P < 0.001) and basal FSH concentration (P = 0.002). However, in women with idiopathic or mild male subfertility, in both cohorts the relationship took the form of an inverted U-shape with both older and--surprisingly--young women having a reduced ovarian response (P < 0.001). Maximum ovarian response was around the age of 28 years. In women with tubal infertility, there was only a linear decline of ovarian response with age. CONCLUSION: It is hypothesized that diminished ovarian response to COH in IVF is the very first sign of ovarian ageing in young women diagnosed with idiopathic and mild male subfertility.     

Predictors of ovarian response: progress towards individualized treatment in ovulation induction and ovarian stimulation

Ovarian stimulation is applied in the clinic to restore mono-ovulatory cycles in anovulatory women (ovulation induction) or to induce the development of multiple dominant follicles for assisted reproduction. Ovarian response is the endocrine and follicular reaction of the ovaries to stimulation. Achieving an appropriate ovarian response to anti-estrogens or exogenous gonadotrophins is central to ovulation induction and ovarian stimulation protocols. However, achieving an adequate response, without cycle cancellation or adverse events related to under- or over-stimulation, is complicated by high intra- and inter-individual variability. To predict each patient's ovarian response to medication for ovarian stimulation and to individualize the starting dose of exogenous gonadotrophin or the need for exogenous luteinizing hormone, various clinical, endocrine, ovarian ultrasonographic and genetic characteristics have been explored. Some of these features have been incorporated into prediction models. In this review, the methodology behind predictive factors and prediction models and their potential clinical applicability across ovulation induction and ovarian stimulation are explored.     

A pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism

A controlled clinical study was designed to investigate the value of human chorionic gonadotrophin (HCG) challenge as a test for functional ovarian hyperandrogenism. Dexamethasone administration was followed by 5000 IU HCG and blood samples for steroid hormone assay were obtained 0, 8, 16, and 24 h thereafter. Study subjects were normal women (n = 13); women with functional ovarian hyperandrogenism, defined by androgen excess, amenorrhoea and an increased 17-hydroxyprogesterone response to nafarelin (n = 6); and normal men (n = 4). The responses of 17-hydroxyprogesterone, androstenedione and testosterone to HCG in women with functional ovarian hyperandrogenism were significantly greater than in normal women. However, the 17-hydroxyprogesterone response to HCG in functional ovarian hyperandrogenism was significantly lower after HCG than after nafarelin. The oestradiol response was also significantly lower after HCG than nafarelin, although oestradiol concentration more than doubled in normal women as well as in women with functional ovarian hyperandrogenism. The responses to HCG confirm that functional ovarian hyperandrogenism abnormalities are luteinizing hormone (LH)-dependent. Therefore, the 17- hydroxyprogesterone response to HCG could represent a useful test for the diagnosis of ovarian hyperandrogenism. The lower 17- hydroxyprogesterone response to HCG than to nafarelin in functional ovarian hyperandrogenism suggests that a follicle-stimulating hormone (FSH)-responsive factor modulates thecal 17-hydroxyprogesterone secretion. The oestradiol response to HCG is consistent with HCG directly stimulating the oestradiol secretion by thecal cells.      

Dynamic assays of inhibin B and oestradiol following buserelin acetate administration as predictors of ovarian response in IVF

The study was designed to examine whether dynamic measurements of inhibin B and oestradiol following single administration of buserelin acetate were correlated with the ovarian response to stimulation in IVF. A total of 37 patients undergoing IVF treatment was studied when the long protocol was started in the early follicular phase. Blood samples were taken twice: on day 2 of the menstrual cycle, before the first s.c. administration of buserelin acetate 0.5 mg and on day 3, 24 h later. Inhibin B and oestradiol concentrations were compared with the ovarian response to stimulation. The ovarian response was defined in two ways: 'number of oocytes/total recombinant (r) follicle stimulating hormone (FSH) dose'; and 'square-root (number of follicles/total rFSH dose)'. The following measurements were highly correlated with the ovarian response to stimulation: increase in oestradiol (day 3-day 2 oestradiol concentration) [correlation coefficient (r) = 0.68, P: < 0.0001] and sum of inhibin B (day 2 + day 3 inhibin B concentrations) (r = 0.6, P: < 0.0001). Age and basal concentrations of FSH and inhibin B were inferior to the above measurements in terms of correlation with the ovarian response. In conclusion, dynamic measurements of inhibin B and oestradiol following single administration of buserelin acetate were highly correlated with the ovarian response to stimulation for IVF treatment.     

Predictors of low response to mild ovarian stimulation initiated on cycle day 5 for IVF

BACKGROUND: Milder stimulation protocols are being developed to minimize adverse effects of ovarian stimulation in in vitro fertilization (IVF) programs. A drawback is the possibility of an increased rate of insufficient ovarian response. This study aimed to develop a prognostic model for the prediction of cycle cancellation due to insufficient response to mild stimulation. METHODS: A total of 174 IVF patients aged<38 years and with a body mass index (BMI)<28 Kg/m2 were treated with mild ovarian stimulation using a fixed daily dose (150 IU) of recombinant follicle-stimulating hormone (rFSH) from cycle day 5 and GnRH antagonist from the late follicular phase. In women with mono- or bifollicular growth (17%), the cycle was cancelled and the treatment was adjusted in a second treatment cycle by starting rFSH on cycle day 2. RESULTS: In a multivariable logistic regression analysis, duration of infertility, menstrual cycle length, secondary infertility and BMI were included in the prediction model. The area under the receiver-operating characteristics curve of the model was 0.69. A probability cut-off for cancellation of 0.3 yielded an expected sensitivity of 33% and specificity of 92%. Analysis of ovarian response in the subsequent treatment cycle showed an improved ovarian response and a significant reduction in the cancellation rate. CONCLUSIONS: With the presented model, it is possible to identify patients at risk for cycle cancellation, during mild ovarian stimulation, due to insufficient response. The contributing factors of the model suggest that ovarian aging and BMI are related to insufficient response to mild stimulation.