Mini-dose long gonadotropin-releasing hormone (GnRH) agonist versus agonist flare stimulation protocol for in vitro fertilization poor responders

ObjectivesTo compare 2 stimulation protocols, mini-dose long gonadotropin releasing hormone (GnRH) agonist versus agonist flare for in vitro fertilization poor responders.DesignProspective comparative nonrandomized clinical trial.SettingDr. Samir Abasss IVF center, Jeddah, Kingdom of Saudi Arabia from april 2012 to December 2012 on 50 women undergoing IVF/ICSI fulfilling the criteria of poor responders.Material and methodsPatients were allocated into 2 groups, group 1 (n = 25) received mini-dose long agonist and group 2 (n = 25) received agonist flare protocol.Main outcomeNumber of oocytes retrieved (primary outcome), duration of stimulation (days), peak E2 level on the day of hCG injection, number of fertilized oocytes, number of transferred embryos and pregnancy rate/cycle.ResultsBoth groups were comparable regarding age, body mass index and duration of infertility (years). The difference in basal FSH and duration of stimulation (days) does not reach statistical significance (p value 0.833 and 0.373 respectively). There was a high statistical difference between both groups regarding peak E2 on day of hCG injection, number of oocytes retrieved, number of fertilized oocytes, number of transferred embryos; which is higher in the mini-dose agonist group (p value 0.00).Pregnancy rate/cycle was higher in the mini-dose agonist group (9/25 vs. 6/25) however this difference does not reach statistical significance (p value 0.355) which may be attributed to small sample size or advanced maternal age.ConclusionMini-dose long GnRHa stimulation protocol appears to be more beneficial for poor responders than GnRHa agonist flare.     

Ovarian stimulation protocol for in vitro fertilization with gonadotropin-releasing hormone agonist widens the implantation window

Pregnancy rates vary considerably with the type of ovarian stimulation used for in vitro fertilization and embryo transfer (IVF-ET). The window of implantation may represent one of the rate-limiting steps in IVF success. We therefore investigated estimated implantation times of 10 consecutive IVF singleton pregnancies, achieved using pituitary suppression with gonadotropin-releasing hormone agonist (GnRH-a) before and during ovarian stimulation with human menopausal gonadotropins (hMG), and compared those with 9 consecutive IVF pregnancies achieved by hMG stimulation only. Estimated implantation times were calculated by regression analysis of serial human chorionic gonadotropin (hCG) measurements between days 7 and 16 after ET. The GnRH-a/hMG pregnancies implanted between days 7 and 11, whereas hMG pregnancies implanted between days 7 and 9 after ET. The hCG regression curve for the GnRH-a/hMG pregnancies revealed a delay of 1.5 days in estimated implantation time compared with the hMG only group. There were no significant differences in pretransfer in vitro embryos development between the two groups. Thus, the delay in hCG rise probably reflects a delay in embryo implantation. We therefore conclude that a GnRH-a/hMG stimulation protocol appears to widen the implantation window in comparison with a hMG only protocol. This observation may at least in part explain the improved IVF pregnancy success with GnRH-a/hMG stimulation protocols.     

Prospective study of short and long regimens of gonadotropin-releasing hormone agonist in in vitro fertilization program.

OBJECTIVE: To assess the usefulness of a short regimen in ovulation induction in an in vitro fertilization (IVF) program. DESIGN: A prospective randomized trial was set up to compare long and short regimens of gonadotropin-releasing hormone agonist administration for ovulation induction in IVF. SETTING: Aberdeen Assisted Reproduction Unit. PATIENTS: Eighty-seven patients undergoing IVF were randomized between the two protocols. Stimulation regimen was the only variable being tested. MAIN OUTCOME MEASURES: Stimulation response and occurrence of luteinizing hormone (LH) surges. RESULTS: There was no difference in the stimulation requirements, response to stimulation, number of follicles aspirated, or the number of oocytes obtained. The fertilization rates, number of embryos transferred, and pregnancy rates were also similar in both groups. Like the long regimen, it prevents the occurrence of a premature LH surge. CONCLUSION: The short regimen is a useful and cheaper alternative in ovarian stimulation of patients undergoing IVF.     

控制性超排卵长、短方案在IVF-ET中的疗效比较

目的:比较促性腺激素释放激素激动剂(GnRHa)长、短方案控制性超排卵在体外受精-胚胎移植(IVF-ET)中的疗效。方法:将2001年7月-2002年4月因双侧输卵管梗阻IVF-ET的患者100人随机分为长方案组(50人)和短方案组(50人)进行超排卵。长方案组从使用促性腺激素(Gn)治疗前1月经周期黄体期(月经21天)使用GnRHa 0.3mg/d,至垂体完全降调节后加用Gn;短方案组从月经周期第2天开始用GnRHa0.1mg/d,同时加用Gn。当患者有3个以上卵泡直径>18mm时肌肉注射人绒毛膜促性腺激素(HCG),36小时后取卵行IVF,取卵48小时后行ET。结果:两组患者平均获卵数、受精率、卵裂率、优质胚胎率、移植胚胎数、临床妊娠率、胚胎种植率及流产率差异无显著性。而两者的Gn使用量有差别,短方案组少于长方案组,两组差异有显著性。两组用Gn第7天雌激素水平不同,短方案组明显高于长方案组,两者差异有显著性。结论:GnRHa长、短方案在IVF-ET中控制性超排卵效果相同,但所需Gn数量不同。     

Value of suppression with a gonadotropin-releasing hormone agonist prior to gonadotropin stimulation for in vitro fertilization

This study examined the use of gonadotropin-releasing hormone agonist (GnRHa) suppression before gonadotropin stimulation in 26 patients with failed prior in vitro fertilization (IVF) attempts and variable basal serum gonadotropin levels. Leuprolide, 1 mg subcutaneously per day, was administered from the midluteal phase of the cycle before IVF treatment. Concomitantly, stimulation was initiated on cycle day 3 with human menopausal gonadotropin (hMG) and follicle stimulating hormone (FSH). Based on their prior IVF attempts and serum gonadotropin levels on cycle day 3, 9 patients were high responders with elevated mean basal luteinizing hormone (LH)/FSH, 8 were low responders with elevated mean basal FSH/LH, 7 were intermediate responders with normal mean basal FSH/LH and a history of premature LH surge, and 2 had elevated (perimenopausal) mean FSH and LH. Leuprolide was discontinued on the day of human chorionic gonadotropin (hCG) administration. Prior IVF attempts in the same patients with the same protocol, but without GnRHa suppression, were used as controls. The mean number of ampules of hMG and FSH was significantly higher in leuprolide cycles than in controls. The mean day of hCG administration was also higher for leuprolide cycles than for controls. The mean LH and progesterone levels on the day of hCG were significantly lower in leuprolide cycles. The mean number of preovulatory oocytes aspirated and transferred was higher in leuprolide cycles. Cancellation and pregnancy rates were improved in leuprolide cycles. It is concluded that prior GnRHa suppression is beneficial for follicular recruitment for IVF. More patients with variable basal serum gonadotropin levels need to be studied before definite recommendations are made.     

Ovarian stimulation in in vitro fertilization with or without the "long" gonadotropin-releasing hormone agonist protocol: effect on cycle duration and outcome

OBJECTIVE: To study the correlation between stimulation duration of IVF cycles, with and without GnRH agonist (GnRH-a), and cycle outcome. DESIGN: Retrospective analysis of data. SETTING: University-affiliated IVF clinic. PATIENT(S): 998 IVF cycles in which long GnRH-a protocol was used, and 155 cycles with hMG only. INTERVENTION(S): IVF cycles. MAIN OUTCOME MEASURE(S): Cycle outcome in number of oocytes and embryos, and pregnancy rate. RESULT(S): The mean stimulation duration (+/-SD) was 9.6+/-1.7 and 6.7+/-1.0 for the GnRH-a and the hMG-only cycles, respectively (P<0.01). In the GnRH-a group, no statistically significant correlation between cycle duration and pregnancy rate was found. Interestingly, the patients treated for 9 days had the highest number of oocytes retrieved and the highest pregnancy rate. Stimulation duration was not affected by age in either protocol. GnRH-a cycles yielded a significantly higher number of oocytes and embryos compared to cycles without GnRH-a. The pregnancy rate was similar in both groups. CONCLUSION(S): Stimulation duration in the long GnRH-a protocol group was significantly longer than in the hMG-only group. Stimulation duration was not affected by age. No statistically significant correlation was found between stimulation duration and cycle outcome in the long protocol group.     

Novel follicular-phase gonadotropin-releasing hormone antagonist stimulation protocol for in vitro fertilization in the poor responder

Poor responders continue to be vexing in infertility therapy. By using GnRH antagonists before ovarian stimulation, we demonstrate an improvement in oocyte, embryo, and zygote yield in patients with a prior poor response.     

促性腺激素释放激素激动剂长、短方案在体外受精-胚胎移植中的比较性研究

目的　探讨促性腺激素释放激素激动剂（GnRH-a）长、短方案控制性超排卵在体外受精-胚胎移植（IVF-ET）中的疗效。方法　将2000年1～5月进行IVF和单精子卵胞浆注射（ICSI）助孕的不孕患者,按病历奇、偶数编号分为GnRH-a长方案组（55例）和短方案组（54例）。长方案组从使用促性腺激素（Gn）治疗周期前的黄体中期开始使用GnRH-a0.9mg/d,至垂体完全降调节后,加用Gn;短方案组从月经第2天开始使用GnRH-a0.45mg/d,同时加用Gn。两组均在优势卵泡达18mm时,肌内注射人绒毛膜促性腺激素（hCG）,36h后取卵行IVF及ICSI。结果　长方案组较短方案组,使用Gn前血清促卵泡激素（FSH）和黄体生成素（LH）水平降低［（4.4±1.2）IU/L比（6.3±1.7）IU/L,（2.7±1.5）IU/L比（4.4±2.8）IU/L,P<0.01］;注射hCG前血清雌二醇（E2）和LH水平降低［（7119±3584）pmol/L比（9523±3587）pmol/L,（1.0±1.0）IU/L比（4.0±3.4）IU/L,P<0.01］;每个卵子E2水平降低［（610±315）pmol/L比（935±450）pmol/L,P<0.01］;Gn用量增多［（28.0±8.6）支比（23.4±8.7）支,P<0.01］,用药时间增长［（11.1±1.2）d比（10.1±1.5）d,P<0.01］;两组平均获卵数、第2次成熟分裂中期卵子数、受精卵数、卵裂数、优质胚胎数及妊娠率无显著差异。结论　在IVF-ET,GnRH-a长、短方案能获得相同的控制性超排卵效果,且GnRH-a短方案能减少Gn用量和缩短治疗时间。     

Ovarian hyperstimulation for in vitro fertilization preceded by prolonged administration of a gonadotropin-releasing hormone agonist

In 51 patients, controlled ovarian hyperstimulation with clomiphene citrate (CC)/human menopausal gonadotropin (hMG), or hMG only, in 102 IVF cycles had previously resulted in a cancellation rate of 52% and no pregnancies. In 54 subsequent cycles the women were treated with prolonged administration of a gonadotropin-releasing hormone agonist (GnRHa) followed by hMG stimulation, the GnRHa group. The results were compared with the outcome of 47 cycles in patients who came for their first IVF attempt. In this group a CC/hMG regimen was used, the CC/hMG group. In the GnRHa group, 17 pregnancies were achieved, compared with 10 in the CC/hMG group. Only four cycles were cancelled in the GnRHa group, vis-à-vis 13 in the CC/hMG group, a significant difference. The study showed that prolonged use of GnRHa as a preparatory treatment is effective following previous failures of IVF.     

The gonadotropin-releasing hormone agonist stimulation test--a sensitive predictor of performance in the flare-up in vitro fertilization cycle

OBJECTIVE: To evaluate the initial versus early pattern of estradiol (E2) change after administration of a gonadotropin-releasing hormone agonist (GnRH-a), i.e., the GnRH-a stimulation test versus E2 pattern, respectively, as predictors of ovarian response and pregnancy in in vitro fertilization (IVF) patients stimulated with a flare-up protocol. DESIGN: Prospective study in a consecutive group of patients. SETTING: Tertiary care, institutional setting. PATIENTS: Two hundred twenty-eight patients entered and completed the study. The only patients excluded from study were those anticipated to have polycystic ovarian disease, those with a single ovary, or those with an ovarian cyst(s). INTERVENTIONS: Patients were stimulated with a GnRH-a flare-up protocol beginning on menstrual day 2. MAIN OUTCOME: Evaluation of the GnRH-a stimulation test and the E2 pattern as predictors of the number of mature oocytes retrieved and pregnancy. RESULTS: The GnRH-a stimulation test but not the E2 pattern was predictive of the number of mature oocytes retrieved (r = 0.53, P less than 1 X 10(-5) and pregnancy (chi 2 = 8.5, P = 0.04). The E2 pattern was predictive of the duration and number of ampules of gonadotropin required for stimulation. CONCLUSION: The GnRH-a stimulation test is a sensitive predictor of performance in the flare-up IVF cycle.     

Ovarian stimulation by a combination of a gonadotropin-releasing hormone agonist and gonadotropins for in vitro fertilization

In the first of two studies, 20 patients were selected on the basis of tubal infertility and were randomly assigned to two groups receiving different ovarian stimulation protocols. In group A, 10 patients were given follicle-stimulating hormone (FSH), FSH was continued until the criteria for human chorionic gonadotropin (hCG) administration were satisfied. In group B, 10 patients received Buserelin (0.3 ml twice a day subcutaneously) for 14 days to induce pituitary desensitization. Stimulation with FSH was then started, and Buserelin treatment was continued until hCG administration. In the second study, patients were included if they had had at least two previous attempts at ovarian stimulation that failed to reach the stage of follicular aspiration. Ovarian stimulation was conducted with a combination of Buserelin and human menopausal gonadotropin. Use of the gonadotropin-releasing hormone (GnRH) agonist in in vitro fertilization increased the number of oocytes collected, the fertilization rate, the length of the luteal phase and the pregnancy rate. The GnRH agonist also contributed to a generally better ovarian response in patients whose estradiol production had previously responded poorly to conventional ovarian stimulation protocols.     

Prospective study of short and ultrashort regimens of gonadotropin-releasing hormone agonist in an in vitro fertilization program.

OBJECTIVE: To assess the usefulness of the ultrashort regimen of gonadotropin-releasing hormone agonist (GnRH-a) in ovulation induction in an in vitro fertilization (IVF) program. DESIGN: A prospective randomized trial comparing short and ultrashort regimens of GnRH-a. SETTING: Aberdeen Assisted Reproduction Unit. PATIENTS: Forty-eight patients having IVF for the first time were randomized between the two protocols. MAIN OUTCOME MEASURES: Response to ovarian stimulation and occurrence of spontaneous luteinizing hormone (LH) surges. RESULTS: In ovulation induction, fertilization, and pregnancy rates the ultrashort regimen produces results that were no different to the short regimen but it did not always prevent an LH surge. CONCLUSION: The ultrashort regimen can be a useful alternative for ovarian stimulation of patients undergoing IVF.     

A prospective randomized comparison between long and discontinuous-long protocols of gonadotropin-releasing hormone agonist for in vitro fertilization

Objective: To investigate the efficacy of a discontinuous-long protocol in an IVF program.

Design: Prospective randomized study.

Setting: University hospital.

Patient(s): One hundred thirty-seven IVF cycles of 92 patients in an outpatient IVF program from April 1995 to December 1995.

Intervention(s): In the discontinuous-long protocol group (n = 68), GnRH agonist (GnRH-a) was administered from the luteal phase until cycle day 7, when pure FSH administration was begun. In the long protocol group (n = 69), GnRH-a was administered until the day before hCG administration.

Main Outcome Measure(s): Serum LH and ovarian steroid hormone levels, and IVF outcome.

Result(s): The period and the total dosage of hMG were increased in the discontinuous-long protocol group. Although the fertilization rate was similar under both protocols, the number of embryos transferred was smaller and the cancellation rate was higher in the discontinuouslong protocol group because of the greater failure of oocyte retrieval and fertilization. Serum E₂ levels in the late follicular phase were lower in the discontinuous-long protocol group.

Conclusion(s): Early discontinuation of GnRH-a is not beneficial because of its adverse effects on follicular development.     

Stimulation of endogenous surge of luteinizing hormone with gonadotropin-releasing hormone analog after ovarian stimulation for in vitro fertilization

The effect of induction of preovulatory endogenous surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) with intranasal administration of GnRH-analog (GnRH-a) in an in vitro fertilization (IVF) program is reported. The use of GnRH-a resulted in a significantly better percentage of replaceable embryos (91% versus 85%). The pregnancy rate was 51% in comparison with 32% in control cycles in which follicular maturation was achieved by human chorionic gonadotropin administration. There was no significant difference in the postoocyte recovery serum progesterone patterns between the two groups. Our results indicate that the induction of endogenous LH and FSH surge with GnRH-a may be successfully employed for final follicular maturation after ovarian suprastimulation without affecting the outcome of IVF adversely. Apart from being a more physiological approach to oocyte maturation, it also has potential economic and clinical advantages.     

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.     

Comparison of different regimens of a gonadotropin-releasing hormone analog during ovarian stimulation for in vitro fertilization

Three treatment protocols were used in 156 in vitro fertilization cycles. Leuprolide acetate was begun on day 1 of the cycle in one group (n = 20), on day 3 in another (n = 48), and the third control group (n = 88) did not receive the gonadotropin-releasing hormone analog. Human menopausal gonadotropin was initiated on day 3 in all groups. Peak estradiol (E2) levels and the mean numbers of mature oocytes and embryos transferred per cycle were significantly greater in the day 3 group than in either the day 1 or control groups. Patients who received the day 3 protocol had significantly fewer cancelled cycles. A decline in E2 was observed on the third day of analog administration in certain patients, particularly those on the day 1 protocol. Follicle-stimulating hormone and luteinizing hormone (LH) levels increased two- to fivefold 24 hours after initiation of the analog. Thereafter the gonadotropin levels fell, but nevertheless remained above those of controls for most of the cycle. Hence, it appears that enhanced follicular growth attributed to the early transient rises in gonadotropins can be coupled to a suppression of endogenous LH surges in leuprolide-treated women. These beneficial effects seem to be more likely to occur if leuprolide is initiated on cycle day 3 rather than day 1.     

黄体期长方案控制性卵巢刺激周期体外受精-胚胎移植临床分析

目的探讨黄体期GnRH-a 1.25 mg长方案控制性卵巢刺激周期体外受精-胚胎移植的临床效果。方法回顾性分析在广西妇幼保健院生殖中心实施的137个黄体期GnRH-a 1.25 mg长方案控制性卵巢刺激周期体外受精-胚胎移植（IVF-ET）资料,对比妊娠组与未妊娠组的体外受精情况,并将获卵数≤8设为1组,获卵数9～17个为2组,获卵数≥18个为3组,比较分析三组的卵巢刺激过程的内分泌变化及临床结局。结果妊娠组与未妊娠组对比获卵数差异无统计学意义（P〉0.05）,正常受精率差异有统计学意义（P〈0.05）;按三组不同获卵数分析的结果,三组年龄最小,卵巢反应性高,胚胎冷冻率较1组、2组显著升高（P〈0.05）,但三组单次移植周期妊娠率差异无统计学意义（P〉0.05）,随着获卵数增多,发生卵巢过度刺激综合征的风险明显增高（P〈0.05）。结论黄体期长方案控制性卵巢刺激周期在维持一定的正常受精率的基础上可以获得满意的临床效果。     

Hormonal changes induced by short-term administration of gonadotropin-releasing hormone agonist during ovarian hyperstimulation for in vitro fertilization and their consequences for embryo development

Several regimens have been developed to administer gonadotropin-releasing hormone agonists in association with human menopausal gonadotropins (hMG) during follicular growth stimulation for in vitro fertilization. The aim of this study was to characterize hormonal changes induced by short-term administration of agonist, and to evaluate a putative impact of the flare-up effect on follicular recruitment and subsequent IVF. Eighteen highly selected patients were randomely divided in two groups. Nine patients received a short-term administration of Buserelin (Hoechst, AG, Franfurt/Main, FRG) (day 1). They were compared with 9 patients who were exposed to a long-term protocol (day 21), and 13 control patients. Agonist-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increase, in early follicular phase, stimulated follicular growth, shortened follicular phase, and induced a transient rise in progesterone. This was followed by a phase of reduced LH secretion associated with a significant modification of LH immunoreactivity. The short-term regimen did not improve the follicular recruitment, and appeared to reduce the oocytes fertilization rate and embryo quality when compared with prolonged administration of peptide.     

Effectiveness of short pituitary suppression with gonadotropin-releasing hormone agonist leuprolide during induction of ovulation for in vitro fertilization

A short suppression regimen with daily 0.5 mg leuprolide commencing the first day of in vitro fertilization (IVF) cycles was evaluated in 10 women who previously underwent similar IVF cycle without suppression. Induction of ovulation, oocyte retrieval, incubation, and embryo transfer were similar in all the cycles. Assessment included the amount of human menopausal gonadotrpin (hMG) used, length of stimulation, serum estradiol and luteinizing hormone (LH) levels, number of oocytes retrieved and their quality, cleavage rate, and number of embryos. The results showed that when leuprolide was used, no endogenous LH surge was detected, and there was a significant increase in hMG injected, from 19.0±5.8 to 34.4±17 ampoules, and in estradiol, levels, from 1276±470 to 2618±1084 pg/ml (mean ± SD). In addition, there was an increase in the total oocytes retrieved from 54 to 94, their cleavage rate from 59 to 86%, and the number of embryos from 24 to 70 in the suppressed cycle. No deleterious effects were observed and there were two pregnancies in this group.