GnRH antagonist versus follicular-phase single-dose GnRH agonist protocol in patients of normal ovarian responses during controlled ovarian stimulation

Objective: This study aims to explore the differences of the ovarian stimulation (OS) characteristics, laboratory, and clinical outcomes between follicular-phase single-dose gonadotropin-releasing hormone (GnRH) agonist protocol and GnRH antagonist protocol during controlled ovarian hyperstimulation (COH).

Methods: About 1883 consecutive IVF/ICSI fresh cycles of normal ovarian responders were retrospectively analyzed, with 1229 in the single-dose GnRH agonist protocol group and 654 in the GnRH antagonist protocol group at Reproductive Medical Center of Tongji Hospital from 1 January 2014 to 31 December 2017.

Results: The follicular-phase single-dose GnRH agonist group showed significantly more oocytes obtained, higher implantation rate and pregnancy rate, as well as lower luteinizing hormone (LH) level and estradiol (E2)/oocyte ratio on the day of human chorionic gonadotropin (hCG) administration. However, differences were not significant in meiosis II (MII) oocyte rate, two pronuclear zygote (2PN) embryo rate, viable embryo rate or high-quality embryo rate, compared with the GnRH antagonist group. Further comparison of clinical outcomes in the first frozen-thawed cycles did not show significant difference in either implantation or clinical pregnancy rate between the two protocol groups.

Conclusions: Follicular-phase single-dose GnRH agonist protocol may achieve better clinical outcomes in normal ovarian responders, which could be explained more by positive effect on endometrial receptivity rather than embryo quality.     

Cyst aspiration or GnRH antagonist administration for ovarian cysts detected at the start of fresh in vitro fertilization cycles*

The primary objective of this study is to investigate the effect of transvaginal ultrasonogram (TVUS)-guided cyst aspiration or gonadotropin releasing hormone antagonist (GnRH-ant) administration for the management of solitary ovarian cysts detected at the start of in vitro fertilization (IVF) cycles on the outcomes of the same cycles. This is a single-center, retrospective, cohort study of patients who had TVUS-guided cyst aspiration or GnRH-ant treatment for ovarian cysts detected at the start of IVF during a 5-year period. Four hundred and three patients met inclusion criteria: 41 (10.2%) underwent cyst aspiration and 362 (89.2%) were treated with GnRH-ant. There was no difference in the demographics or baseline IVF cycle characteristics of the two groups. Patients treated with GnRH-ant had a longer duration of ovarian stimulation (10.8?±?3.45 days versus 9.05?±?4.06 days, p?=?0.003) and required higher gonadotropin doses (3887.7?±?1097.8?IU versus 3293.7?±?990.5?IU; p?=?0.01) compared with the cyst aspiration group. There was no difference in the clinical pregnancy (43.9% versus 41.4%), spontaneous miscarriage (9.76% versus 8.01%) and live birth (34.1% versus 33.4%) rates between the groups. Our findings suggest that cyst aspiration is comparable to GnRH-ant administration for the management of solitary ovarian cysts detected at the start of IVF cycles.     

Hormone profiles under ovarian stimulation with human menopausal gonadotropin (hMG) and concomitant administration of the gonadotropin releasing hormone (GnRH)-antagonist Cetrorelix at different dosages

Purpose: The premature LH surge in ART programs seems to be avoided by daily administration of the GnRH-antagonist Cetrorelix during the midcycle phase in controlled ovarian hyperstimulation with hMG. The dosage necessary for sufficient suppression of the pituitary gland is not yet defined. Methods: To elucidate this question three daily dosages (3, 1, 0.5 mg) were administered and the hormone profiles obtained as well as the number of oocytes retrieved, the fertilization rate, and the consumption of HMG were compared. Results: No premature LH surge could be observed at any of the three dosages administered. Both gonadotropins were deeply suppressed. The fertilization rates of the oocytes obtained were 45.3% in the 3-mg group, 53.1% in the 1-mg group, and 67.7% in the 0.5-mg group. The average uses of hMG ampoules were 30 in the 3-mg group, 27 in the 1-mg group, and 26 in the 0.5-mg group. Conclusions: Cetrolix, 0.5 mg/day, administered during the midcycle phase of controlled ovarian hyperstimulation with hMG is enough to prevent completely the premature LH surge. Perhaps even lower dosages would be sufficient. Regarding fertilization rates and use of hMG, the lower dosage seems to be the most favorable.Presented in part at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Gonadotropin-releasing hormone antagonists increase follicular fluid insulin-like growth factor-I and vascular endothelial growth factor during ovarian stimulation cycles

The aim of the present study was to investigate the effect of gonadotropin-releasing hormone (GnRH) antagonists (GnRH-ant) on follicular fluid (FF) insulin-like growth factor-I (IGF-I) and FF vascular endothelial growth factor (VEGF) levels. Sixty women undergoing assisted reproduction were randomized and assigned to two different GnRH analog regimens: GnRH agonist (GnRH-a) and GnRH-ant. FF VEGF and FF IGF-I concentrations were significantly increased in the patients treated with GnRH-ant (p < 0.001). In the same patients we observed a statistically significant reduction in serum luteinizing hormone (LH) and estradiol (E₂) levels (p < 0.001 and p < 0.05, respectively), FF E₂ and FF androstenedione levels (p < 0.05 and p < 0.001, respectively), as well as a reduction in the number of pregnancies although this was not statistically significant. In the GnRH-ant group, FF VEGF levels were positively correlated with FF IGF-I levels, and both were negatively correlated with serum LH levels. The increase in FF IGF-I and FF VEGF levels in women treated with GnRH-ant could be explained by a deleterious follicular environment in response to profound suppression of LH and E₂ levels.     

The influence of estradiol/follicle and estradiol/oocyte ratios on the outcome of controlled ovarian stimulation for in vitro fertilization

Objective. The aim of the study was to evaluate the influence of the ratios of estradiol (E₂) to either the number of follicles >14 mm on the day of human chorionic gonadotropin administration (E₂/follicle) or the number of oocytes retrieved (E₂/oocytes) during controlled ovarian hyperstimulation (COH) with gonadotropin-releasing hormone (GnRH)-agonist (agonist group) and GnRH-antagonist (antagonist group), on the outcome of in vitro fertilization (IVF) cycles.

Patients and methods. All consecutive women aged <35 years admitted to our IVF unit during a 6-year period with normal to high response to COH were retrospectively studied. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryos transferred and pregnancy rate were assessed.

Results. Six hundred and ninety consecutive IVF cycles were evaluated, 301 in the agonist group and 389 in the antagonist group. The ratios of E₂/follicle and E₂/oocyte were significantly higher in the agonist group (p < 0.001 for both). Moreover, while pregnancy rates within E₂/oocyte ratio of 100–200 pg/ml were comparable between the agonist and antagonist groups, when E₂/oocyte ratios were <100 pg/ml or >200 pg/ml, pregnancy rates were significantly higher in the agonist group. Furthermore, no difference in pregnancy rates was observed within the agonist group between different E₂/oocytes ratios, while within the antagonist group, higher pregnancy rates were observed when comparing those with E₂/oocyte ratio of 100–200 pg/ml with those with E₂/oocyte ratio <100 pg/ml or >200 pg/ml.

Conclusion. While E₂/oocyte ratio cannot predict the success of GnRH-agonist protocol, patients undergoing GnRH-antagonist protocol should reach E₂/oocyte ratio within the 100–200 pg/ml range in order to achieve the best IVF outcome.     

Ovarian hyperstimulation syndrome following GnRH agonist trigger for final follicular maturation in a patient undergoing random start ovarian stimulation for egg-donation cycle with an inadvertent concomitant early pregnancy

Abstract

We report the first case of OHSS following GnRH agonist trigger for final follicular maturation in random start ovarian stimulation for egg-donation cycles during inadvertent concomitant early pregnancy. As an additional note, the sustained activity exerted by the increasing endogenous hCG production seemed to be responsible for the suboptimal performance in terms of oocyte yield in the current case. OHSS can occur in random-start stimulations protocols even after the use of a GnRH agonist for triggering in case of concomitant unnoticed early pregnancy especially if stimulation is commenced in the periovulatory/luteal phase. The present case report introduces a note of extreme caution when proceeding with this protocol in an otherwise fertile population (egg-donors, elective or oncologic oocyte cryopreservation).     

Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a gonadotropin-releasing hormone (GnRH) agonist: Results of a randomized study

In order to diminish the cancellation rate due to a premature endogeneous LH surge and/or to a poor ovarian response and thus increasing the pregnancy rate, a GnRH agonist (Buserelin) was applied in patients starting their first ovarian stimulation with gonadotropins for IVF. All patients suffered from tubal infertility and were not older than 40 years. Each woman was allocated randomly to one of three groups: the conventional treatment with hMG alone (group I), patients from group II started the hMG treatment shortly after the LH rise caused by the GnRH agonist and patients in group III commenced the hMG treatment when an hypogonadotropic state was achieved after a long treatment of Buserelin. All male partners had a normal spermiogram. A reduction of poor responders to the superovulation is seen in the short-term group (6%), compared with the other two groups (14%). In some cases from group III ovarian cyst formation led to the cancellation of the treatment. The long-term group differs significantly from the other two in the duration of the gonadotropin stimulation and the number of ampoules hMG used. A severe ovarian overstimulation syndrome was not observed. There is no difference in the number of retrieved oocytes and the fertilization rate among the three groups. The pregnancy rate per cycle or per patients in the group with a short-term GnRH-agonist regimen is significantly higher compared to that of the group using the conventional hMG treatment.     

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.     

The use of long-acting gonadotropin-releasing hormone agonist (GnRH-a; decapeptyl) and gonadotropins versus short-acting GnRH-a (Buserelin) and gonadotropins before and during ovarian stimulation for in vitro fertilization (IVF)

The efficiency of two ovarian stimulation protocols using different gonadotropin-releasing hormone agonists (GnRH-a) for in vitro fertilization (IVF) was examined and compared with human menopausal gonadotropin (hMG)-only stimulation. Fifty-four patients who had 57 aspiration cycles were treated with protocol 1, which consisted of long-acting GnRH-a D-Trp⁶ (Decapeptyl Depot) and hMG. Protocol 2 entailed intranasal administration of short-acting GnRH-a (Buserelin) and human menopausal gonadotropin (hMG) in 66 women, who underwent 70 aspiration cycles. Fifty-five patients who had 59 ovum pickups (OPU) treated with hMG only served as a control. No differences were observed in cycle parameters and hormonal concentrations among the three groups. The total clinical pregnancy rates per OPU for patients receiving protocols 1 and 2 were 12.3 and 27.1%, respectively (P<0.05). The pregnancy loss was significantly lower in protocol 2 than in protocol 1 (26.3 versus 71.4%;P<0.05). Our data show superiority of short-acting GnRH-a over the long-acting agents in achievement of pregnancy and its outcome, though neither was significantly different from the hMG-only protocol.     

GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of elevated peak serum progesterone levels

Abstract

Aim: We sought to evaluate the influence of subtle serum progesterone elevation on in vitro fertilization (IVF) cycle outcome and to assess the impact of the type of gonadotropin-releasing hormone (GnRH)-analogue used during controlled ovarian hyperstimulation (COH) on the probability of clinical pregnancy.

Patients and methods: We reviewed the files of all consecutive patients undergoing COH with either GnRH-agonist or antagonist in our IVF unit during a 10-year period and who had their peak serum progesterone levels determined on the day of human chorionic gonadotropin (hCG) administration.

Results: Of the 2244 IVF cycles evaluated, 2103 had peak progesterone level of <1.5?ng/mL (normal-P group) and 141 of >1.5?ng/mL (high-P group) (6.28% of all the study population). Clinical pregnancy rate was significantly higher in the normal-P group (25.4% versus 16.6%; p?<?0.006). Moreover, among the high-P group patients, the use of the long GnRH-agonist suppressive protocol (GnRH-ag) was more prevalent in patients who conceived as compared to those who did not (60.9% versus 39%, respectively; p?<?0.05), with a tendency toward an increase pregnancy rate in those using GnRH-ag compared with GnRH-antagonist protocol (GnRH-antag; p?<?0.059) COH protocols.

Conclusion: While subtle progesterone elevation in patients undergoing COH using GnRH-antag COH protocols, should dictate embryo cryopreservation and cancelation of the fresh transfer, in those undergoing the GnRH-ag COH protocol, a fresh embryo transfer should be recommended.     

Controlled ovarian hyperstimulation using multi-dose gonadotropin-releasing hormone (GnRH) antagonist results in less systemic inflammation than the GnRH-agonist long protocol

Objective. The aim of the study was to investigate whether controlled ovarian hyperstimulation (COH) using multi-dose gonadotropin-releasing hormone (GnRH) antagonist results in a lesser degree of systemic inflammation than the GnRH-agonist long protocol.

Design. Prospective, observational study.

Patients and methods. Blood was drawn three times during the COH cycle from patients undergoing the long GnRH-agonist protocol (agonist group) (n = 12) or the multi-dose GnRH-antagonist protocol (antagonist group) (n = 15): the day on which adequate suppression was obtained (agonist group), or day 2 or 3 of the menstrual cycle and before gonadotropin treatment (antagonist group) (Day-0); the day of or prior to administration of human chorionic gonadotropin (Day-hCG); and the day of ovum pick-up (Day-OPU). Levels of sex steroids and serum C-reactive protein (CRP) were compared between the two study groups among the three time points.

Results. While no between-group differences were observed in patient age or ovarian stimulation characteristics, a significantly higher number of oocytes were retrieved in the antagonist compared with the agonist group. In both groups, serum CRP levels were significantly higher on Day-OPU than on Day-hCG and Day-0. While serum CRP levels were higher on Day-hCG than Day-0, the difference was statistically significant only for the agonist group (p < 0.05). Moreover, Day-OPU serum CRP levels were significantly higher in the agonist than in the antagonist subgroup.

Conclusion. COH using the multi-dose GnRH-antagonist protocol yields a lesser degree of systemic inflammation, as reflected by CRP levels, than the GnRH-agonist long protocol.     

Serum luteinizing hormone level on the third day after ovarian stimulation in GnRH agonist short protocol is predictive of outcome in poor responders but not in normal responders

Objectives: To identify whether prognostic value of LH measurement in normal responders (NR) is different from poor responders (POR).

Methods: A retrospective, single-center study was conducted among patients who underwent ovarian stimulation with short protocol, with 300 NR and 101 POR, according to Bologna Consensus criteria. LH was measured on 3rd and 5th day after stimulation and HCG administration day.

Results: There was significant difference in the clinical pregnancy rate per cycle initiated among those with LH level on the third day after stimulation (a) below the 25 centile (b) between the 25 and 75 centile and (c) above the 75 centile in women with POR (7.7%, 15.1% vs. 36.4%, p?=?0.02) but not in NR. There was significant correlation between LH ranks and clinical pregnancy rate in POR (p?=?0.02) but not in NR. Factors associated with clinical pregnancy rate in POR were age and LH on the third of stimulation, while factors in NR were age, AFC and FSH.

Conclusion: LH level on the 3rd day of stimulation was predictive of clinical pregnancy in POR but not in NR.     

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。