The use of gonadotropin-releasing hormone antagonist in a flexible protocol: a pilot study

OBJECTIVE: The purpose of this study was to investigate the efficacy of a flexible protocol of starting gonadotropin-releasing hormone antagonist according to the size of the leading follicle. STUDY DESIGN: This was a pilot study that included 123 couples who were undergoing in vitro fertilization/intracytoplasmic sperm injection cycles at the Egyptian IVF-ET Center. Couples were recruited into two groups: group I (n=64), gonadotropin-releasing hormone antagonist was administered when the diameter of the leading follicle reached 16 mm; group II (n=59), gonadotropin-releasing hormone antagonist was administered on day 6 of stimulation. RESULTS: The mean number of antagonist injections was significantly lower in the flexible protocol compared to the fixed protocol (3.4+/-1.1 vs 5.3+/-1.8, P<.05). There was no significant difference between the two protocols regarding the number of embryos, implantation rate, clinical pregnancy rate (odds ratio, 0.85; 95% CI, 0.45-1.59) or multiple pregnancy rate (odds ratio, 1.26; 95% CI, 0.45-3.51). CONCLUSION: Starting the gonadotropin-releasing hormone antagonist according to the size of the leading follicle is as effective as starting on a fixed day and reduces the antagonist administration.     

Mild stimulation with clomiphene citrate in combination with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonist and its influence on serum estradiol level and pregnancy rate

Aim:  The mild ovarian stimulation protocol for in vitro fertilization (IVF) is carried out to minimize adverse side-effects as well as cost. While performing mild ovarian stimulation with a gonadotropin-releasing hormone (GnRH) antagonist, the pregnancy rate was examined in cases that exhibited a serum estradiol (E2) drop down.
Methods:  In this study, 174 patients who requested mild ovarian stimulation for IVF began clomiphene citrate on day 3 and recombinant follicle-stimulating hormone (FSH) on day 5 of their menstrual cycles. A GnRH antagonist was administered when the dominant follicle reached a diameter of 14 mm. Serum luteinizing hormone and estradiol were measured at the time of GnRH antagonist administration and at the time of human chorionic gonadotropin (hCG) injection. Pregnancy rates and implantation rates were compared between 24 cycles in which the E2 level fell at the time of hCG injection and 150 cycles in which it did not fall.
Results:  The pregnancy rate in the cases in which the E2 level fell (25% decrease) at the time of hCG injection was significantly lower than it was in the cases in which it did not fall (16.7 vs 41.0%). The implantation rate for the cases in which the E2 level fell was also lower than that of the control group (7.0 vs 31.0%). There was no significant difference in the number of good-quality embryos between the two groups.
Conclusion:  When performing the mild ovarian stimulation protocol, serum E2 should be followed. It is prudent to avoid embryo transfer in the same cycle in cases that exhibit E2 drop down. (Reprod Med Biol 2008; 7 : 85–89)     

Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome

OBJECTIVE: To determine the prevalence and the effect of premature luteinization in GnRH antagonist IVF-ET cycles. DESIGN: Prospective observational study. SETTING: In vitro fertilization-embryo transfer (IVF-ET) program at the Instituto Valenciano de Infertilidad. PATIENT(S): Eighty-one infertile patients undergoing controlled ovarian hyperstimulation with gonadotropins and GnRH antagonist for IVF-ET. INTERVENTION(S): Gonadotropin-releasing hormone (GnRH) antagonist was administered from stimulation day 6. Serum P, E(2), and LH were determined on the day of hCG administration. MAIN OUTCOME MEASURE(S): Cycles were grouped according to serum P level on the day of hCG administration (<1.2 ng/mL or > or =1.2 ng/mL). Clinical pregnancy and implantation rates were determined. RESULT(S): The incidence of premature luteinization was 38.3%. Total recombinant FSH dose and stimulation days differed significantly between the groups. Pregnancy rate (25.8% vs. 54.0%) and implantation rate (13.8% vs. 32.0%) were significantly lower in the premature luteinization group. CONCLUSION(S): Premature luteinization during GnRH antagonist IVF-ET cycles is a frequent event that is associated with lower pregnancy and implantation rates. Progesterone elevations are not related to serum LH levels and may reflect the mature granulosa cell response to high FSH exposure.     

The impact of luteinizing hormone supplementation in gonadotropin-releasing hormone antagonist cycles: a retrospective cohort study

The impact of exogenous luteinizing hormone (LH) supplementation to patients undergoing controlled ovarian stimulation with gonadotropin-releasing hormone (GnRH) antagonists on cycle outcomes is controversial. Here, we present a retrospective cohort study including cycles from December 2015 to December 2016. Totally 320 cycles were divided into two groups according to with or without exogenous LH supplementation. No significant differences regarding the number of retrieved oocytes, the number of good-quality embryos, and clinical pregnancy rate between the two groups were found. The logistic regression analysis revealed that LH supplementation was not independently associated with clinical pregnancy rate (OR?=?0.577, 95% CI: 0.272–1.222, p?=?.58) or a biochemical pregnancy rate (OR?=?0.922, 95% CI: 0.444–1.916, p?=?.83). When patients were divided into subgroups based on age, more retrieved oocytes (5.60 vs. 3.97, p?=?.04) and good-quality embryos (3.07 vs. 1.93, p?=?.01) were achieved in cycles with exogenous LH supplementation for 40 years and over group. We conclude that for aged women (40 years old and over), LH supplementation has a positive impact on the number of retrieved oocytes and good-quality embryos in GnRH antagonist cycles.     

血清性激素含量与体外受精-胚胎移植结局的关系分析

目的 探讨在控制性超排卵中血清性激素变化与妊娠结局的关系。方法 随机选择兰州大学第一医院辅助生殖医学中心2003—2004已接受试管婴儿技术治疗，采用黄体期长方案进行控制性超排卵临床妊娠病例147例，未妊娠140例，分析比较组间各项观察指标。结果 两组间患者降调节时间、促性腺激素（Gn）总量、募集卵泡数、获卵数、MII卵数差异均有显著性（P〈0．05），HCG注射日血清孕酮（P）值、血清雌二醇／孕酮（E2／P）比值差异有显著性（P〈0．05）；促性腺激素释放激素激动剂（GnRH—a，达菲林）用量、Gn天数差异无显著性（P〉0．05），降调节后血清黄体生成素（LH）、HCG注射日血清E2、取卵日血清E2、胚胎移植日血清催乳激素（PRL）水平差异无显著性（P〉0、05）。结论 在控制性超排卵治疗中，观察调控血清性激素含量至关重要。HCG注射日血清P值、E2／P比值是预测助孕结局的重要指标，血清E2／P值在1．32—6．11，血清P值在0．637—1.645μg/L时，临床妊娠率增加。     

Improved pregnancy rates with luteinizing hormone supplementation in patients undergoing ovarian stimulation for IVF

Introduction

Luteinizing hormone (LH) is believed to play a role in follicle maturation during the natural cycle. However, the need for co-treatment with recombinant LH (rLH) for controlled ovarian stimulation is controversial.

Purpose

The primary objective of our study was to determine if pregnancy rates are improved when rLH is used in addition to rFSH for ovarian stimulation. Secondary outcomes were fertilization rate, implantation rate and live birth rate.

Methods

A retrospective cohort study was performed of 1565 IVF or ICSI cycles. Outcomes were compared between ovarian stimulation cycles from 2007 when rLH and rFSH was used (n = 765) to 2006 when rFSH only was used (n-800).

Results

Improved outcomes were found for rLH + rFSH versus rFSH alone for; pregnancy rate (61% and 54% respectively, p = 0.006), live birth rate (49% and 42% respectively, P = 0.01), fertilization rate (74% versus 72% respectively, p = 0.04 and implantation rate (41% versus 37% respectively, p = 0.03).

Conclusions

Our large retrospective cohort study showed an improved pregnancy rate and live birth rate with rLH supplementation. This was associated with an improved fertilization and implantation rate and therefore may reflect an improvement in oocyte quality and/or uterine receptivity.     

The choice of a gonadotropin-releasing hormone analog influences outcome of in vitro fertilization treatment

OBJECTIVE: Our purpose was to determine if there is a difference in outcome associated with choice of gonadotropin-releasing hormone analog in in vitro fertilization treatment cycles. STUDY DESIGN: A retrospective analysis of 510 consecutive in vitro fertilization cycles with patient-selected use of either nafarelin (Synarel) or leuprolide (Lupron) was performed. RESULTS: Of 510 consecutive patient cycles, 284 patients (56%) chose nafarelin and 226 (44%) chose leuprolide. In the nafarelin group 64 cycles (34% of retrievals) resulted in deliveries. In the leuprolide group 37 (24%) resulted in delivery (p < 0.05). There were 260 patients in their first cycle of treatment, with 157 (60%) choosing nafarelin, resulting in 33 deliveries (34% per retrieval). Leuprolide, used in 103 (40%) of first cycles, resulted in 12 deliveries (20% per retrieval), (p = 0.052). CONCLUSIONS: In a large population of unselected patients undergoing in vitro fertilization the choice of nafarelin was associated with a significantly better outcome in terms of successful pregnancies achieved. (AM J Obstet Gynecol 1994;170:1629-34.)     

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.     

Fine tuning cycle day 3 hormonal assessment of ovarian reserve improves in vitro fertilization outcome in gonadotropin-releasing hormone antagonist cycles

OBJECTIVE: To identify the cut-off values of the baseline (cycle day 3) levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E(2)) for improving the outcome prediction of GnRH antagonist in vitro fertilization (IVF) cycles and to determine whether the predictive accuracy of these values is affected by the patient's clinical prognosis. DESIGN: Retrospective analysis. SETTING: An IVF clinic in a tertiary medical center.Women undergoing 230 consecutive IVF cycles using a GnRH antagonist protocol. INTERVENTION: None. MAIN OUTCOME MEASURE(S): Outcome of IVF, measured by ovarian response and pregnancy rates. RESULT(S): Lower baseline levels of FSH and E(2), but not LH, correlated with improved ovarian response and pregnancy rates in IVF cycles using a GnRH antagonist. Compared with our currently used criteria, the cut-off values of FSH <10 IU/L and E(2) <56 pg/mL would have significantly improved the IVF outcome in a population of patients with normal prognosis. However, a stricter baseline FSH cut-off value of 8 IU/L would have been required to improve the IVF outcome in a population of patients with a poor prognosis. CONCLUSION(S): The outcome of IVF may be improved by modifying the hormonal starting criteria to take into account individual patient characteristics such as clinical prognosis.     

Infertile polycystic ovary syndrome patients undergoing in vitro fertilization with the gonadotropin-releasing hormone-antagonist protocol: role of hyperandrogenism

This retrospective cohort study is to assess the effects of hyperandrogenism (HA) in polycystic ovary syndrome (PCOS) patients with gonadotropin-releasing hormone (GnRH)-antagonist protocol during in vitro fertilization (IVF). Total 892 infertile Patients between 20 and 35 years of age with normal body mass index (BMI, 18.50 ?24.99 kg/m²), including those with tubal factor infertility (control, n?=?318), PCOS infertility with HA (HA PCOS, n?=?244), and PCOS infertility without HA (non-HA PCOS, n?=?330), were included. Number of retrieved oocytes was significantly higher and total Gonadotropin consumption was significant lower in the HA PCOS group, whereas abortion rate was significantly higher and live birth rate was significantly lower in the HA PCOS group, compared with the control and non-HA PCOS groups. In the HA PCOS group, the number of available embryos tended to be higher with no significance. The GnRH-antagonist protocol is more suitable for HA PCOS patients, with lower cost and more number of embryos available for transfer. Due to the high abortion rate and low live birth rate, a freeze-all approach might be a preferable option for HA PCOS patients so as to create a buffer for reducing androgen levels before transferring freeze-thawed embryos.     

In vitro fertilization outcomes in patients experiencing a premature rise in luteinizing hormone during a gonadotropin-releasing hormone antagonist cycle

Patients undergoing controlled ovarian hyperstimulation and pituitary suppression with a GnRH antagonist who experienced a transient premature rise in LH were compared with those who did not have an early surge. Those experiencing a premature LH surge had equivalent clinical and ongoing pregnancy rates per ET.     

The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation

Objective: To discuss the clinical therapeutic window for LH during the follicular phase.

Design: Review of selected papers that were retrieved through a Medline search and a review of clinical trials, the results of which are in the process of publication.

Patient(s): Women undergoing infertility treatment.

Intervention(s): Recombinant human LH (r-hLH) was administered SC as a supplement to FSH during controlled ovarian hyperstimulation.

Main Outcome Measure(s): Follicular development, E₂ production, and endometrial thickness.

Result(s): Optimal follicular maturation is the result of both FSH and LH stimulation. In patients with hypogonadotropic hypogonadism, 75 IU of r-hLH and 150 IU of FSH per day resulted in more follicles and provided sufficient E₂ for optimal endometrial proliferation. Additional r-hLH (>250 IU/day), in patients with either hypogonadotropic hypogonadism or polycystic ovary disease, may precipitate a series of deleterious physiological actions leading to atresia of developing follicles. Adding r-hLH to FSH in women treated with GnRH agonist showed no benefits in terms of number of mature oocytes, fertilization, and cleavage. However, those who experience profound pituitary desensitization may benefit from adding LH to the stimulation protocol. No obvious clinical criteria have been established to define this group of patients.

Conclusion(s): A “threshold” and “ceiling” level for LH (therapeutic window) is proposed, below which E₂ production is not adequate and above which LH may be detrimental to follicular development.     

Minimal stimulation using recombinant follicle-stimulating hormone and a gonadotropin-releasing hormone antagonist in women of advanced age

OBJECTIVE: To determine whether minimal stimulation with short-term application of low-dose recombinant follicle-stimulating hormone (FSH) together with a gonadotropin-releasing hormone (GnRH) antagonist represents a cost-effective treatment regimen for patients with elevated FSH levels, aged 40 and above. DESIGN: Retrospective cohort study. SETTING: Academically affiliated private in vitro fertilization (IVF) program. PATIENT(S): Eighty-five IVF cycles using minimal ovarian stimulation and 85 cycles with a standard long-stimulation protocol, conducted between January 2000 and January 2002, in women aged 40 and above who had slightly increased FSH levels. INTERVENTION(S): Patients on the long protocol underwent standard cycle monitoring and stimulation. In contrast, women with minimal stimulation had transvaginal sonography initiated on day 8 of the menstrual cycle and at a follicle size of 13 mm. We administered 0.25 mg of GnRH antagonist and 75 IU recombinant FSH daily until ovulation induction. MAIN OUTCOME MEASURE(S): Numbers of oocytes, and rates of cancellation and pregnancy. RESULT(S): Minimal stimulation cycles resulted in a clinical pregnancy rate of 8.2% per started cycle and 10% per embryo transfer (ET), whereas the control group yielded a clinical pregnancy rate of 10.6% per started cycle and of 10.7% per ET (not statistically significant). CONCLUSION(S): In women aged 40 and above with abnormal FSH levels, minimal stimulation protocol achieves similar pregnancy rates to a standard protocol, and thus represents a cost-effective alternative.     

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.     

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.     

Supplementation with human menopausal gonadotropin in the gonadotropin-releasing hormone antagonist cycles of women with high AMH: Pregnancy outcomes and serial hormone levels

ObjectiveTo evaluate the value of using both HMG and recombinant FSH (r-FSH) in the GnRH antagonist protocol for women with high AMH.Materials and methodsThis retrospective, single-center cohort study was conducted from January 2013 to December 2018. Of 277 GnRH antagonist IVF/ICSI cycles in women with anti-Mullerian hormone (AMH) ≥5 μg/L, 170 cycles receiving the combination of r-FSH and HMG (77 with HMG added at the beginning of the GnRH antagonist cycle and 93 with HMG added after GnRH antagonist administration) and 107 cycles receiving r-FSH alone were analyzed. The dynamic hormone profiles and embryonic and clinical outcomes of the patients were evaluated.ResultsWe observed significantly lower serum LH levels in the r-FSH + HMG groups during ovarian stimulation. The serum estradiol and progesterone levels were lower in the r-FSH + HMG groups on the trigger day. Nevertheless, there were no significant differences with respect to the number of oocytes retrieved, maturation, fertilization, blastocyst formation rate or ovarian hyperstimulation syndrome (OHSS). The implantation and live birth rates were increased in the r-FSH + HMG groups compared with the r-FSH alone group, with no statistical significance.ConclusionsHMG for LH supplementation in the GnRH antagonist protocol for patients with high AMH is not significantly superior to r-FSH alone in terms of ovarian response and pregnancy outcome. Nevertheless, HMG supplementation might be appropriate for women with an initially inadequate response to r-FSH or intracycle LH deficiency.