卵巢反应不良患者第二周期促排卵个体化治疗结局

目的探讨第1周期促排卵卵巢反应不良患者第2周期采用个体化方案治疗的结局。方法 2008年1月至2010年12月在山东大学附属省立医院生殖医学中心行体外受精-胚胎移植或卵母细胞浆内单精子注射（IVF/ICSI-ET）第1周期常规方案促排卵发生卵巢反应不良患者239例,第2周期采用个体化促排卵方案,将其分为两组：第1周期、第2周期获卵数均〈5个者104例为A组;第1周期获卵数〈5个,但第2周期获卵数≥5个者135例为B组;比较两组的治疗情况和临床结局。结果①A组和B组第2周期长方案的应用较第1周期减少,而短方案、微刺激方案、其他方案应用比例增加（P〈0.05）;②A组第2周期生长激素应用率（56.7%）高于第1周期（26.0%;P〈0.05）;B组第2周期生长激素应用率（45.9%）均高于第1周期（17.0%;P〈0.01）;③A组第2周期Gn启动量[（244±101）U]高于第1周期[（218±56）U;P〈0.05];B组第2周期Gn启动量[（229±68）U]高于第1周期[（204±61）U;P〈0.01],但两组Gn总量及Gn刺激时间比较,差异均无统计学意义（P〉0.05）。④A组两个周期hCG日血E2峰值、〉14mm卵泡数、获卵数、优质胚胎数及胚胎移植取消率比较,差异均无统计学意义（P〉0.05）,但第2周期移植胚胎数目[（2.0±0.8）个]及临床妊娠率（30.9%）均较第1周期[（1.6±0.7）个;4.7%]显著增加（P〈0.01）。B组第2周期的hCG日血E2峰值、〉14mm卵泡数、获卵数、优质胚胎数、移植胚胎数及临床妊娠率分别为（10789.8±6246.3）pmol/L、（7.1±3.9）个、（8.1±3.5）个、（3.3±2.1）个、（2.6±0.6）个和40.3%,第1周期分别为（6595.0±4470.1）pmol/L、（4.3±2.5）个、（3.0±1.1）个、（1.5±1.1）个、（2.0±0.7）个和11.6%,两周期各指标比较,差异均有统计学意义（P〈0.01）。B组第2周期无胚胎移植取消周期率（8.1%）低于第1周期（25.9%;P〈0.01）。结论第1周期常规方案促排卵卵巢反应不良患者,在第2周期加大Gn启动量、增加短方案或微刺激方案、加用生长激素等个体化治疗,43.5%的患者仍发生卵巢反应不良,但所有患者的治疗结局均显著改善。     

Updated meta-analysis of recombinant follicle-stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction

OBJECTIVE: To determine the relative efficacy of recombinant FSH (rFSH) and urinary FSH (uFSH) for ovarian stimulation in assisted reproductive techniques (ART). DESIGN: Systematic review and meta-analysis of randomized, controlled trials comparing rFSH and uFSH. SETTING: Infertility centers providing treatment with ART. PATIENT(S): Patients undergoing IVF with or without ICSI. INTERVENTION(S): Controlled ovarian stimulation using uFSH or rFSH (follitropin alpha or follitropin beta). MAIN OUTCOME MEASURE(S): Primary: rate of clinical pregnancy per cycle. Secondary: rates of spontaneous abortion, multiple pregnancy, and severe ovarian hyperstimulation syndrome (OHSS); total gonadotropin dose; serum E(2) level and number of follicles at hCG administration; number of oocytes retrieved. RESULT(S): Eighteen trials were included in the meta-analysis. Subgroup analyses demonstrated higher pregnancy rates with both follitropins compared with uFSH. However, statistical significance was reached only in the follitropin alpha versus uFSH comparison in IVF cycles, with an additional pregnancy for every 19 patients treated. Fewer units of rFSH than uFSH achieved the same E(2) level and oocyte yield. No differences were found between treatments in rates of spontaneous abortion, OHSS, and multiple gestation. CONCLUSION(S): rFSH produced higher pregnancy rates per cycle than uFSH when follitropin alpha was used in IVF, and the total gonadotropin dose required was lower.     

Reduced In Vitro Fertilization of Human Oocytes Correlates with Raised Circulating FSH Levels During Ovarian Stimulation in Normogonadotropic Women Downregulated with GnRH-Analogues

Purpose: The possible effects of circulating FSH levels as used during IVF treatment on oocyte maturation and subsequent preembryo development were evaluated. Methods: Serum levels of FSH and LH on days 1 and 8 of ovarian stimulation and on the day of oocyte retrieval (OR) were correlated with subsequent preembryo development in vitro. After pituitary downregulation, 244 normogonadotropic women followed a fixed protocol for the first 7 days of stimulation. Results: The average FSH concentration on day 8 of stimulation was 11.5 IU/L and exceeded the expected midcycle surge of FSH by more than 25%. In contrast, levels of LH were below an average of 2 IU/L throughout the stimulation period. The concentration of FSH on day 8 and on the day of OR showed a significant inverse correlation with cleavage rate, whereas levels of LH, age, and body mass index showed no such correlation. Conclusions: Supraphysiologic levels of FSH seems to affect oocyte maturation negatively. Premature resumption of meiosis, leading to retrieval of postmature oocytes with a reduced developmental potential, is suggested as the underlying mechanism.     

Day 4 Estradiol Levels Predict Pregnancy Success in Women Undergoing Controlled Ovarian Hyperstimulation for IVF

Objective: To evaluate the usefulness of serum estradiol levels obtained on the fourth day of gonadotropin stimulation in predicting the likelihood of pregnancy during controlled ovarian hyperstimulation (COH) using luteal phase leuprolide acetate (LA).

Design: A 4-year retrospective analysis of day 4 estradiol levels and subsequent clinical pregnancy and delivery rates.

Setting: A university hospital tertiary referral center.

Patient(s): Couples undergoing IVF treatment.

Main Outcome Measure(s): Primary outcome measures included clinical pregnancy and delivery rates. Secondary outcome measures included the number of oocytes retrieved and the number of embryos available for transfer per COH cycle.

Result(s): The clinical pregnancy and delivery rates for cycles with day 4 estradiol levels of >75 pg/mL were 42.3% (30/71) and 32.4% (23/71), respectively. These rates differed significantly from those for cycles with day 4 estradiol levels of ≤75 pg/mL, which were only 9.1% (4/44) and 6.8% (3/44), respectively. The number of oocytes retrieved and the number of embryos available for transfer for cycles with day 4 estradiol levels of >75 pg/mL also differed significantly from those for cycles with day 4 estradiol levels of ≤75 pg/mL (11.4 and 7.8 versus 6.8 and 4.3, respectively).

Conclusion(s): Estradiol levels obtained on the fourth day of gonadotropin therapy are highly predictive of successful ovulation induction and pregnancy outcome in cycles using luteal phase LA.     

A randomized prospective study on the effect of short and long Buserelin treatment in women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response

Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I—long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II—short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group II (P<0.01). Cancellation rate was significantly lower in Group I than in Group II (P<0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos trans-ferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response.     

Follicular Development and Hormonal Levels Following Highly Purified or Recombinant Follicle-Stimulating Hormone Administration in Ovulatory Women and WHO Group II Anovulatory Infertile Patients

Purpose: Our purpose was to compare ovarian performance and hormonal levels, after ovulation induction, in both normal ovulatory women undergoing intrauterine insemination (group 1) and World Health Organization (WHO) group II anovulatory infertile patients (group 2), using two different gonadotropin drugs. Methods: Patients (n = 20 per group) were treated during consecutive cycles, using the same stimulation protocol, with highly purified urinary FSH (HP-FSH) in the first treatment study cycle and recombinant FSH (rFSH) in the second one. Patients in group 1 were treated according to a late low-dose technique, and WHO group II anovulatory patients (group 2) received chronic low-dose FSH therapy. Results: Compared with HP-FSH, treatment with rFSH in group 2 required significantly less ampules of drug to induce follicular development but resulted in significantly higher plasma levels of estradiol and inhibin A on the day of human chorionic gonadotropin injection. No differences were found when both treatment modalities were compared in group 1. Conclusions: rFSH is more efficacious than urinary HP-FSH for ovulation induction in WHO group II anovulatory infertile patients as assessed by follicular development, hormonal levels, and the amount of FSH required.     

Short Communication: In Vitro Fertilization in Patients with Ovarian Endometrioma

PURPOSE: To assess the influence of ovarian endometrioma during IVF. METHODS: Patients were submitted to cystectomy by the laparoscopic route for exeresis of ovarian endometrioma. Group I (n = 28) consisted of patients without ovarian endometrioma and group II (n = 14) consisted of patients with recurrence of ovarian endometrioma during IVF. RESULTS: Fertilization and cleavage rates were higher in group I and the pregnancy rate per transfer was similar in the two groups. CONCLUSIONS: The presence of endometrioma during IVF causes a worsening of oocyte fertilization and embryo cleavage but does not affect the pregnancy rate per transfer.     

Clinical Assisted Reproduction: The Number of Embryos Available for Transfer Predicts Successful Pregnancy Outcome in Women over 39 Years with Normal Ovarian Hormonal Reserve Testing

Purpose: The purpose was to determine whether the number of embryos available for transfer following IVF in women over age 39 predicted a successful pregnancy outcome. Methods: Retrospective analysis of 455 consecutive IVF cycles in women years of age. Results: Few cycles were canceled (29/455, 6.4%) or produced no embryos (5/455, 1.1%). Women 40–43 years of age with normal ovarian reserve had a significantly greater delivery rate when 4 embryos were available for transfer than when <4 embryos were available (17.8% versus 2.4%, P = 0.002). Subsequent IVF cycles, from women with normal FSH whose first cycle produced <4 embryos, produced delivery rates of 13.0% when 4 embryos were available. Women with abnormal ovarian reserve or age 44 years had very low delivery rates (1.2% and 1.4% respectively). Conclusions: The number of embryos available for transfer significantly predicts delivery from IVF–ET among reproductively older women. Many women age 40–43 with normal ovarian reserve can achieve pregnancy through IVF.     

Ovarian stimulation for in vitro fertilization using pure follicle-stimulating hormone with and without gonadotropin-releasing hormone agonist in high-responder patients

There is a distinct pattern of response to gonadotropin stimulation in some patients marked by high peak estradiol (E₂) levels, multifollicular ovarians response, and elevated basal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratios. We reviewed the stimulation profiles of five such high-responder patients who failed to conceive during in vitro fertilization with ovarian stimulation using pure FSH. All patients had baseline LH/FSH >1.5 and peak E₂>800 pg/ml. One cycle was canceled prior to hCG administration because of marked ovarian response (E₂>2500 pg/ml, multiple small follicles). In a subsequent cycle, all patients were pretreated with the gonadotropin releasing-hormone agonist (GnRHa) leuprolide acetete for 10–14 days prior to initiation of FSH for ovarian stimulation. Leuprolide was continued until the day of hCG administration. During cycles using GnRHa, there was a statistically significant decrease (P <0.05) in serum FSH on day 3 (<5 vs 8.3 mIU/ml), serum E₂ on day 3 (14.6 vs 34.6 pg/ml), and peak serum E₂ (1197.6 vs 1923.0 pg/ml). Patients during cycles with GnRHa had a greater number of preovulatory (8.6 vs 3.0) and total (12.4 vs 6.0) oocytes retrieved (P<0.05). The fertilization rate of preovulatory oocytes was also higher during cycles using GnRHa (83 vs 64%). Two pregnancies occurred in the cycles pretreated with GnRHa. These preliminary data indicate that in high-responder patients, a combination of GnRHa and pure FSH results in lower E₂ levels during the stimulation cycle and a greater number of total and mature oocytes retrieved and fertilized.     

Atypical response to luteinizing hormone-releasing hormone (LH-RH) agonist (Suprefact nasal) in induction of ovulation in in vitro fertilization (IVF)

Animal and human research has indicated the presence of receptors to luteinizing hormone-releasing hormone (LH-RH) in the ovaries. However, the role of these receptors is not yet clear. Forty-five patients were treated with Suprefact (d-Serg-Des-Gly10-GnRGH), starting in the midluteal phase of a nonstimulatory menstrual cycle. The Suprefact (300 g t.i.d.) was administered as a nasal spray until the administration of human chorionic gonadotropin (hCG). On the third to fifth day of the following menstrual cycle, the patients were treated with a high dose of human menopausal gonadotropin (hMG). hCG was administered when at least two follicles reached a mean diameter of 18 mm. Five of these patients who ovulated spontaneously and had normal menstrual cycles did not respond to the stimulation with hMG. Treatment was stopped after 12 days of hMG administration. During the following cycle of the five patients, levels of gonadotropins were found to be in the normal range, and all of them responded as expected to hMG administered for 3 days only (hMG test). These findings suggest that LH-RH agonist may interfere with ovarian steroidogenesis.     

Intracytoplasmic sperm injection pregnancy after low-dose human chorionic gonadotropin alone to support ovarian folliculogenesis

OBJECTIVE: To prove that several days of low-dose hCG alone can be used to stimulate folliculogenesis, complete FSH-initiated follicle/oocyte maturation, and achieve pregnancy in assisted reproduction technology. DESIGN: Case report. SETTING: Reproductive endocrinology center at an academic institution. PATIENT(S): A 35-year-old female patient and her partner with male-related infertility. INTERVENTION(S): After an 8-day priming with hMG (225 IU/d), we administered low-dose hCG (200 IU/d) alone for 5 days in one GnRH-agonist suppressed patient until proper follicle development was obtained and intracytoplasmic sperm injection was performed. MAIN OUTCOME MEASURE(S): Daily serum levels of LH, FSH, hCG, E(2), P, and T; measurements of follicle number and size; oocytes retrieved and fertilized; pregnancy. RESULT(S): Although FSH levels rapidly declined after hMG discontinuation, E(2) and large follicles increased during hCG-only administration. Several good quality oocytes were retrieved and fertilized by intracytoplasmic sperm injection; three embryos were transferred and a twin pregnancy ensued. CONCLUSION(S): Replacement of FSH with low-dose hCG for several days in the late ovulation induction stages of assisted reproduction technology resulted in: [1] continued growth of large ovarian follicles and E(2); [2] an optimal preovulatory follicle pattern consisting of many large and few medium and small follicles; and [3] reproductively competent oocytes and pregnancy.     

Pituitary down-regulation using leuprolide for the intensive ovulation management of poor prognosis patients having in vitro fertilization (IVF)-related treatments

A review of 118 treatment cycles in 115 women under prolonged GnRH analogue (GnRHa; leuprolide) treatment is presented. Patients were selected for treatment primarily on the grounds of poor previous response to stimulation (n=40). advanced age (>35 years; n=29), previous premature luteinizing hormone (LH) surge (n=30), polycystic ovarian disease (PCO; n=12), and elevaved androgens without evidence of PCO (n=5). An overall pregnancy rate of 28.8% per treatment cycle was attained, compared with a pregnancy rate of 6.2% (6/97, of which none went to term) in the previous completed treatment cycle for the same patients. Ovarian response, as measured by oocytes recovered and maximum estradiol levels observed, was significantly improved in all groups and this was associated with a prolonged follicular phase, significantly more human menopausal gonadotropin (hMG) stimulation and a relatively high incidence of ovarian hyperstimulation, particularly in pregnant patients Of specific techniques in the GnRHa cycle, GIFT produced a pregnancy rate per treatment of 50% (10/20); IVF-ET, 22% (8/36); PROST, 28% (13/46); and TEST 19% (3/16). No cyles were abandoned, compared with a cancellation rate of 24% in previous cycles without GnRHa. Patients with PCO performed paricularly well on GnRHa management, with a pregnancy rate per treatment of 58% (7/12). Pregnancy rates per treatment for the other groups were as follows: elevated age, 27% (9/33), high androgen, 40% (2/5); premature LH surges, 32% (9/28); and poor responders, 17.5% (7/40). A comparison using patients undertaking IVF-ET cycles in 1987 and 1988 shows that the use of GnRHa treatment in the poorprognosis groups lifts their performance into line with that seen in the good-prognosis groups. We conclude that pituitary down-regulation with GnRHa (long regimen) offers significant advantages for ovarian management in most groups of infertility patients and it is now being evaluated for routine use in the majority of cases in our practice.     

High-dose follicle-stimulating hormone (FSH) ovarian stimulation in low-responder patients for in vitro fertilization

Follicle-stimulating hormone (FSH) was used in high doses (6 ampoules/day:6FSH) for ovarian hyperstimulation for in vitro fertilization in women with a previous voor response to stimulation with the equivalent of 4FSH. Luteinizing hormone levels did not differ between stimulations, but both FSH and estradiol levels were higher in the 6FSH compared to the 4FSH cycle. There were fewer cancellations in the 6FSH cycle, but similar numbers of preovulatory oocytes were retrieved, fertilized, and transferred. The pregnancy rates per attempt and retrieval were higher in the 6FSH cycle. We conclude that raising and maintaining FSH levels during stimulation in low responders reduced cancellations and may improve in vitro fertilization outcome.Presented in part at the 44th Annual Meeting of the American Fertility Society, Atlanta, Georgia, 1989, Abstract No. 52.     

输卵管切除术对超排卵的影响

目的:探讨单侧输卵管切除,切除侧卵巢对超排卵的反应性。方法:以因输卵管妊娠行单侧输卵管切除后不孕接受IVF-ET治疗的患者45例共52个周期为研究组,并以同期因输卵管阻塞(无输卵管积水)不孕行IVF-ET治疗的患者875例共913个周期为对照,分析输卵管切除侧卵巢与对侧卵巢对超排卵的反应性。结果:①两组的促性腺激素(Gn)用量、用药天数、hCG日E_2水平、卵裂率、平均移植胚胎数、种植率、临床妊娠率、流产率、异位妊娠率差异无统计学意义(P>0.05)。但单侧输卵管切除组的获卵数减少,差异有统计学意义(P<0.05)。②研究组卵泡晚期(注射hCG日)两侧卵巢大小(分别为35.1±6.5mm、38.2±5.9 mm)有差异,P<0.05。取卵日两组卵泡数(个)分别为6.7±4.5、8.6±3.3(P<0.05),回收卵子数(个)分别为4.9±3.7、6.4±3.6,P<0.05。结论:单侧输卵管切除者切除侧卵巢在行超排卵时,其卵泡晚期(注射hCG日)卵巢较小,取卵日的卵泡数和回收卵子数明显减少,手术可能影响卵巢的血液供应和超排卵效果。     

生长激素对不同年龄卵巢储备功能趋于低下患者IVF-ET治疗结局的影响

目的:探讨生长激素(GH)对不同年龄卵巢储备功能趋于低下患者在IVF-ET中是否有影响。方法:行IVF-ET的卵巢储备功能趋于低下的不孕患者240例,均采用普通长方案降调节。观察不同年龄患者加用GH后的卵巢反应,并以不加用GH者为对照组。结果:年龄<35岁GH组81例,对照组90例;年龄≥35岁GH组39例,对照组30例。年龄<35岁的不孕症患者Gn使用天数、Gn使用支数、hCG注射日E2水平、获卵数、2PN受精率、优质胚胎率、种植率、妊娠率等观察指标,对照组和GH组间均无统计学差异(P>0.05)。年龄≥35岁的不孕症患者Gn用量(Gn支数)实验组显著低于对照组,有统计学差异(P<0.05);hCG注射日E2水平、获卵数实验组显著高于对照组,差异有统计学意义(P<0.05)。结论:GH对年龄<35岁卵巢储备功能低下患者的卵巢反应及IVF-ET治疗结局无影响;而对年龄≥35岁则有一定影响,可减少Gn使用量,提高hCG注射日的E2水平,增加获卵数。     

Comparison of the morphokinetic parameters of embryos according to ovarian reserve in IVF cycles

The aim of this study is to evaluate the impact of ovarian reserve and age of women on early morphokinetic parameters of embryos with a time-lapse monitoring system. In total, 197 infertile couples with poor ovarian reserve (Group 1, n?=?41), normal ovarian reserve (Group 2, n?=?59), or polycystic ovaries (Group 3, n?=?97) were included. The time from insemination to the following events were analyzed: pronuclear fading (Pnf) and cleavage to 2, 3, 4 and 5 cells. The optimal ranges for morphokinetic parameters of t5, s2 and cc2 in each group were also evaluated. In total, 1144 embryos were evaluated. Morphokinetic parameters did not differ statistically between the groups. Data were analyzed according to different age groups (20–30, 30–40,?>40). The morphokinetic parameters did not differ statistically in Group 1 and 3. In Group 2, the times from insemination to tPnf, t2, t3, t4 were significantly shorter in the younger age group than the older age group (p?相似文献   

基础FSH/LH比值及晚卵泡期LH水平对体外受精-胚胎移植结局的影响

目的:探讨患者基础FSH/LH比值及控制性超促排卵(COH)时降调后hCG注射日血清LH水平对IVF-ET结局的影响及与COH各参数的关系。方法:回顾性分析首次进行IVF/ICSI-ET助孕、应用GnRH-a长方案降调节的不孕妇女,共427个周期。结果:ROC曲线显示FSH/LH比值与IVF-ET临床妊娠率无明显相关性;FSH/LH≥2与FSH/LH<2组间虽然临床妊娠率无差异,但FSH/LH≥2组Gn用量增加,获卵数少,优质胚胎数少,存在统计学差异(P<0.05)。hCG注射日血清LH≥0.65IU/L者妊娠率(55.8%)明显高于LH<0.65IU/L者(24.6%)。结论:基础FSH/LH比值增高能较早反映卵巢储备功能并指导超排方案及Gn用量;降调节后卵泡晚期(hCG注射日)的LH水平过低(<0.65IU/L),将会导致临床妊娠率下降。     

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.