GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of endometrial receptivity

To examine whether the choice of the GnRH analogues used during controlled ovarian hyperstimulation (COH), may influence endometrial receptivity, we studied 712 IVF cycles, in patients undergoing COH with GnRH agonist or antagonist and with the transfer of at least one top-quality embryo. The GnRH agonist group showed significantly higher endometrial thickness and higher pregnancy rate, suggestive of a higher endometrial receptivity, compared with the GnRH antagonist group.     

High ovarian response to ovarian stimulation: effect on morphokinetic milestones and cycle outcomes

Journal of Assisted Reproduction and Genetics - To assess the effect of high ovarian response on oocyte quality and ovarian stimulation cycle outcomes. A retrospective cohort study conducted at...     

AMH type II receptor and AMH gene polymorphisms are not associated with ovarian reserve,response, or outcomes in ovarian stimulation

Purpose

Genetic variation may influence women’s response to ovarian stimulation therapy. The purpose of this study was to investigate any effects of genetic variants in the anti-Müllerian hormone (AMH) and AMH type II receptor genes on ovarian response/treatment outcomes and on current markers of ovarian reserve in individuals undergoing in vitro fertilisation (IVF) treatment.

Methods

In this prospective observational study, we genotyped the AMH c.146G>T, p.(Ile49Ser) and AMHR2 -482A>G variants in 603 unrelated women undergoing their first cycle of controlled ovarian stimulation for IVF and ICSI (intracytoplasmic sperm injection) using gonadotrophins at a tertiary referral centre for reproductive medicine. Pelvic ultrasound and blood hormone levels were taken on days 2–3 of the cycle. Genotypes were determined using TaqMan allelic discrimination assay. Regression analysis was performed to assess the relationship between the genotypes and the ovarian reserve markers (FSH, AMH, antral follicle count) and the early outcomes of response (number of oocytes retrieved and gonadotropin dose) as well as the treatment outcome (live birth).

Results

There were no significant associations between the variants AMH c.146G>T and AMHR2 -482A>G with ovarian response in terms of number of oocytes retrieved (p?=?0.08 and p?=?0.64, respectively), live births (p?=?0.28 and p?=?0.52) and/or markers of ovarian reserve.

Conclusions

Genotyping of the AMH c.146G>T and AMHR2 -482A>G polymorphisms does not provide additional useful information as a predictor of ovarian reserve or ovarian response and treatment outcomes.

     

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.     

GnRH agonist versus GnRH antagonist in ovarian stimulation: the influence of body mass index on in vitro fertilization outcome

In an attempt to examine whether body mass index (BMI) may influence IVF outcome in patients undergoing COH with either GnRH-agonist (agonist group) or GnRH-antagonist (antagonist group), we studied 799 IVF cycles: 481 in the agonist group and 318 in the antagonist group. In patients with BMI >25 kg/m(2), COH with either GnRH-agonist or GnRH-antagonist achieved a comparable outcome; whereas in patients with BMI <25 kg/m(2), the use of GnRH-agonist suppressive protocol revealed significantly higher pregnancy rates.     

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.     

Antitumor effect of GnRH agonist in epithelial ovarian cancer.

OBJECTIVE: The effects of the gonadotropin releasing hormone (GnRH) agonist (D-Trp(6)) were examined in two human ovarian cancer cell lines and in severe combined immune deficiency (SCID) mice to evaluate its potential as a cytocidal, cytostatic, or differentiating antitumor agent. METHODS: We treated the human ovarian cancer cell lines OVCAR-3 and SKOV-3 for 5 or 7 days and sex-matched SCID mice with GnRH agonist for 29 days. The antitumor effect of GnRH agonist were studied in various aspects. To confirm the antiproliferative effect, we used 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide colorimetric assay, in vitro, and a serial measurement of tumor growth in vivo. The disturbances of progression in the cell cycle and the changes of cyclin-dependent kinase 1 following treatment with GnRH agonist were evaluated with flow cytometric analysis in vitro. The induction of apoptosis following treatment with GnRH agonist was studied using in situ terminal deoxyribonucleotidyl transferase (Tdt) and further quantitated with ELISA in vitro. The presence of telomerase activity following treatment with GnRH agonist was measured by PCR-based telomeric repeat amplification protocol and ELISA detection in cell lines and xenografts in vitro and in vivo. RESULTS: Continuous exposure of cell lines and xenografts to GnRH agonist resulted in growth inhibition of cancer cells in a dose- and time-dependent manner. In cultured cells, the GnRH agonist blocked cell cycle progression in G0/G1 phase and thus reduced the number of cells in S and G2/M phases. The phenomenon of apoptosis was documented in cultured cells treated with GnRH agonist by in situ Tdt assay. The frequency of apoptotic cells in the in situ Tdt assay was 5-6% compared with control, 4-5%. Apoptosis quantified by ELISA revealed a high incidence in cultured cells treated with GnRH agonist. The activities of telomerase in cell lines and xenografts were not decreased by GnRH agonist. There were not any significant changes of expression of CA-125 by flow cytometry and of the cellular morphology observed with light microscopy. CONCLUSIONS: Our results indicate that the antiproliferative effect of GnRH agonist in epithelial ovarian cancer cells may be mainly attributed to cytostatic activities resulting in blocking of cell cycle progression in the G0/G1 phase and minimally related to the induction of apoptosis.     

GnRH agonist and GnRH antagonist protocols: comparison of outcomes among good-prognosis patients using national surveillance data

Implantation and live birth rates resulting from IVF cycles using gonadotropin-releasing hormone (GnRH) agonist and (GnRH) antagonist IVF protocols were compared among good-prognosis patients using the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System 2009–2010 data (n = 203,302 fresh, autologous cycles). Bivariable and multivariable analyses were conducted between cycles to compare outcomes. Cycles were restricted as follows: age younger than 35 years, maximum FSH less than 10 mIU/mL, first assisted reproduction technology cycle and FSH dose less than 3601 IU. A subgroup analysis including only elective single embryo transfer was also carried out. Among good-prognosis patients, the GnRH-agonist protocol was associated with a lower risk of cancellation before retrieval (4.3 versus 5.2%; P < 0.05) or transfer (5.5 versus 6.8%; P < 0.05), and a higher live birth rate per transfer (adjusted odds ratio [OR] 1.13, confidence interval [CI] 1.03 to 1.25) than the GnRH-antagonist group. Among the elective single embryo transfer group, the GnRH-agonist protocol was associated with a higher implantation rate (adjusted odds ratio [OR] 1.36, CI 1.08 to 1.73) and a higher live birth rate (adjusted OR 1.33, CI 1.07 to 1.66) compared with the GnRH-antagonist protocol. The GnRH-antagonist group had lower rates of ovarian hyperstimulation syndrome. Among good-prognosis patients, agonist protocols decreased cancellation risk and increased odds of implantation and live birth. Antagonist protocols may confer decreased risk of hyperstimulation.     

Luteal phase oestradiol administration in ovarian stimulation cycles with GnRH antagonist is comparable to the GnRH agonist (long) protocol

Purpose: The purpose of the study was to compare the effectiveness of GnRH antagonist with luteal phase estradiol administration to GnRH agonist cycles, long protocol. Methods: 55 IVF-ICSI patients received oestradiol in the luteal phase of the cycle, before a cycle with GnRH antagonist. Fifty-five patients submitted to IVF-ICSI with the use of agonist were allocated, age matched, as a control group (historical control). The primary outcome was the number of retrieved oocytes. Results: Patients were similar in terms of clinical characteristics. No differences were found in the number of oocytes retrieved (study group, 8.1 ± 4.7; control group, 7.4 ± 4.5) or in oocyte quality. Conclusions: We clearly demonstrated that the effectiveness of GnRH antagonist when combined with luteal phase estradiol is comparable to GnRH agonist cycles. Capsule Oestradiol associated to GnRH antagonist may increase the rates of oocytes causing reproductive results to be comparable to the results with the use of agonists.     

GnRH agonist and GnRH antagonist protocols in ovarian stimulation: differential regulation pathway of aromatase expression in human granulosa cells

Gonadotrophin-releasing hormone (GnRH) agonists and antagonists have been widely used to prevent premature LH surge during ovarian stimulation. However, studies have shown a significantly lower serum oestradiol concentration on the day of human chorionic gonadotrophin administration for cycles using GnRH antagonist. This study compared aromatase gene expression in granulosa lutein cells from 50 women randomly assigned to receive either GnRH agonist (group 1, n = 28) or GnRH antagonist (group 2, n = 22). The cellular mechanism involved in the observed effects was also investigated. GnRH antagonist treatment significantly affected serum oestradiol concentration (1894 ± 138 versus 1074 ± 63 pg/ml; P ? 0.001), follicular-fluid oestradiol concentration in large follicles (18,565 ± 2467 versus 10,184 ± 1993 pg/ml; P ? 0.05), aromatase activity (9600 ± 1179 versus 5376 ± 997 fmol/10⁶ cells/h; P ? 0.05) and mRNA aromatase/mRNA glyceraldehyde 3-phosphate dehydrogenase (15 ± 3 versus 6 ± 1; P < 0.05). Protein kinase C (PKC) activity in granulosa lutein cells from the GnRH antagonist group was 2.5-fold higher than in the GnRH agonist group. In-vitro experiments showed that selective down-regulation of PKC was only observed in GnRH-desensitized granulosa lutein cells. This report suggests that, in granulosa lutein cells, the modulation of the FSH-induced protein kinase A pathway by PKC was different in agonist versus antagonist cycles.     

GnRH agonist versus GnRH antagonist in poor ovarian responders: a meta-analysis

The aim of this meta-analysis was to compare the efficacy of gonadotrophin antagonist (GnRH-ant) versus GnRH agonist (GnRHa) as coadjuvant therapy for ovarian stimulation in poor ovarian responders in IVF/intracytoplasmic sperm injection cycles. Search strategies included on-line surveys of databases such as MEDLINE , EMBASE and others. A fixed effects model was used for odds ratio (OR) and effect size (weighted mean difference, WMD). Six trials fulfilled the inclusion criteria (randomized controlled trials). There was no difference between GnRH-ant and GnRHa (long and flare-up protocols) with respect to cycle cancellation rate, number of mature oocytes and clinical pregnancy rate per cycle initiated, per oocyte retrieval and per embryo transfer. When the meta-analysis was applied to the two trials that had used GnRH-ant versus long protocols of GnRHa, a significantly higher number of retrieved oocytes was observed in the GnRH-ant protocols [P=0.018; WMD: 1.12 (0.18, 2.05)]. However, when the meta-analysis was applied to the four trials that had used GnRH-ant versus flare-up protocols, a significantly higher number of retrieved oocytes (P=0.032; WMD: -0.51, 95% CI -0.99, -0.04) was observed in the GnRHa protocols. Nevertheless, additional randomized controlled trials with better planning are needed to confirm these results.     

Comparison of clinical outcomes among dual ovarian stimulation,mild stimulation and luteal phase stimulation protocols in women with poor ovarian response

This study aimed to determine whether consecutive ovarian stimulation in follicular and luteal phases within a single menstrual cycle (dual stimulation) is achievable and superior to conventional stimulation for poor ovarian responders (PORs). Data of 260 PORs were retrospectively collected and divided into three groups. Group A comprised of cycles with dual ovarian stimulation (n?=?76), which were divided into two subgroups (follicular [group A-F] and luteal phase stimulation [group A-L]); group B comprised of cycles with ovarian stimulation that was performed only in the luteal phase (n?=?52). Group C comprised of mild ovarian stimulation cycles (n?=?132). Baseline parameters were not different among the three groups. The numbers of oocytes and embryo obtained were less in group A-F than group B and C, while group A overall had significantly more oocytes and viable embryo retrieved than did group B and C. Group A-L consumed significantly less gonadotropin than group B, without compromising the number of retrieved oocytes and embryo. The pregnancy outcomes of transfer of embryo from different stimulation phases were similar. We conclude that dual ovarian stimulation protocol is effective and potentially optimal for PORs.     

Triggering with GnRH agonist in oocyte-donation cycles: oestradiol monitoring is not necessary during ovarian stimulation

This prospective observational study evaluated the efficacy and safety of oocyte-donation cycles triggered with a gonadotrophin-releasing hormone (GnRH) agonist without monitoring oestradiol concentrations during ovarian stimulation. A total of 97 oocyte donors received recombinant FSH (150-225/day) and GnRH antagonists (0.25mg/day). Oocyte maturation was triggered with 0.2mg triptorelin s.c. Donors aged 25.4 ± 4.1 years were stimulated for 8.8 ± 0.9 days and underwent 2.9 ± 0.5 (2-4) ultrasound assessments. Total FSH dose was 1703.4 ± 304.7IU, antagonists were administered for 4.3 ± 1.0 days, 14.7 ± 8.8 oocytes were retrieved and there were no cases of ovarian hyperstimulation syndrome. Recipients (n=123) aged 40.3 ± 3.4 years received 10.9 ± 4.3 oocytes, 88.7% of which were metaphase II. Intracytoplasmic sperm injection fertilization rate was 79% and 2.18 ± 0.6 (1-3) embryos were transferred. The pregnancy, clinical pregnancy and twin pregnancy rates were 64.2%, 57.7% and 19.7%, respectively. In conclusion, given the high efficacy and safety of the GnRH-antagonist protocol triggered with a GnRH agonist, the monitoring of oestradiol concentrations is not necessary. Ultrasound monitoring is enough for an adequate follow up of the stimulation cycle in oocyte donors.     

Beneficial effects of GnRH agonist administration prior to ovarian stimulation for patients with a short follicular phase

A short follicular phase is an early clinical feature of declining reproductive competence. The shortening of the follicular phase length is related to both advanced recruitment and selection of the dominant follicle secondary to an earlier and higher FSH rise during the luteal-follicular transition, while the late follicular growth is normal. As a short follicular phase may be detrimental for reproduction, it was postulated that increasing the duration of follicular phase could improve conception rate. For that purpose, gonadotrophin-releasing hormone agonist minidoses were administered in the mid-luteal phase to prevent the intercycle FSH rise before tailoring follicular growth by controlled exogenous FSH administration. This regimen, applied to 69 infertile ovulatory women with a short follicular phase (9.6 +/- 1.2 days) actually lengthened the follicular phase by about 3 days. It proved to be effective in 179 cycles to induce paucifollicular development (1.8 +/- 0.9 follicles) with a low cancellation rate (4%) and a moderate requirement for gonadotrophins [13.3 +/- 6.3 ampoules (75 IU)]. In those women with a high frequency (80%) of elevated basal FSH or oestradiol concentrations, the pregnancy rate reached 15.1%/cycle but the miscarriage rate remained high (44%). Thus, increasing the follicular phase length in patients with a short follicular phase may partially restore fecundity.     

Effects of gonadotropin-releasing hormone (GnRH) agonist on pituitary and ovarian responses to pulsatile GnRH therapy in polycystic ovarian disease

Nine clomiphene citrate-resistant polycystic ovarian disease (PCOD) patients received intravenous gonadotropin-releasing hormone (GnRH) pulses before and immediately after 1 month of GnRH agonist (GnRH-a) therapy. Circulating gonadotropin and ovarian steroid levels, as well as follicular development, were measured throughout therapy. Results were compared with those obtained from five hypogonadotropic patients treated with GnRH pulses only who ovulated during six of seven treatment cycles. Only two PCOD patients ovulated normally with GnRH pulses before GnRH-a therapy. Aberrant gonadotropin and ovarian steroid secretory patterns were noted in the others. After GnRH-a, gonadotropin and ovarian steroid hormone levels were similar to those of the hypogonadotropic patients. Subsequent secretory responses to GnRH pulses were partially normalized. However, only two additional PCOD patients ovulated.     

Substituting HCG with GnRH agonist to trigger final follicular maturation--a retrospective comparison of three different ovarian stimulation protocols

The study retrospectively evaluated the influence of triggering final oocyte maturation with gonadotrophin-releasing hormone (GnRH) agonist on the outcome of IVF cycles. Four hundred and sixty consecutive women admitted to the IVF unit during a 4-year period were enrolled in the study. Ovarian stimulation characteristics and clinical pregnancy rate were compared between three groups: patients at risk of developing ovarian hyperstimulation syndrome (OHSS), undergoing either the long GnRH-agonist protocol (agonist group) or the flexible multidose GnRH-antagonist protocol who received GnRH-agonist for final oocyte maturation (antagonist-agonist group); and patients not at risk of developing severe OHSS undergoing the flexible multidose GnRH-antagonist protocol who received human chorionic gonadotrophin (HCG) for final oocyte maturation (antagonist-HCG group). Implantation and clinical pregnancy rates were lowest in the antagonist-agonist group despite the fact that no difference were was observed in fertilization rates between the groups. Moreover, the high-responder antagonist-agonist group required shorter stimulation and had higher numbers of oocytes retrieved as compared with the high-responder agonist-group. No case of severe OHSS was observed in the antagonist-agonist group. The use of flexible multidose GnRH-antagonist protocol with GnRH-agonist for final oocyte maturation, in high-responder patients, eliminates the risk of OHSS but results in decreased implantation and pregnancy rates.     

A randomised study of GnRH antagonist (cetrorelix) versus agonist (busereline) for controlled ovarian stimulation: effect on safety and efficacy

OBJECTIVE: To assess safety and efficacy of cetrorelix utilisation in controlled ovarian stimulation (COS). STUDY DESIGN: Phase III, randomized, single center study of 131 patients undergoing COS and IVF with or without ICSI, in a University affiliated Hospital. Sixty-six patients were allocated to the protocol with antagonist and 65 to the agonist protocol arm. The Student's t-test, the Mann-Whitney test and the chi-square test were applied as required, using SPSS for Windows with a two-sided 5% significance level. RESULTS: The mean (+/-S.D.) duration of stimulation was 9.5+/-1.7 days in the antagonist group and 10.6+/-2.1 days in the agonist group (P=0.02). The mean (+/-S.D.) duration of suppression was 4.6+/-1.3 days in the antagonist group and 27.3+/-5.2 days in the agonist group (P<0.0001). No significant differences were noted in other outcome measures: amount of rFSH required, estradiol level on hCG day, number of follicles>or=15 mm and endometrial thickness on oocyte retrieval day, number of oocytes retrieved, fertilization rate and number of OHS cases. Clinical pregnancy rates per-attempt and per-transfer were 15.1% and 17.0% in the antagonist group and 16.9% and 20.0% in the agonist group (P=0.79 and 0.71, respectively). CONCLUSIONS: GnRH antagonists are an effective, safe and well tolerated alternative to agonists for COS.     

Effectiveness of mild ovarian stimulation versus GnRH agonist protocol in women undergoing assisted reproductive technology: a meta-analysis

Objective: our meta-analysis was conducted to evaluate the effectiveness of the mild ovulation induction protocol using CC/gonadotropin/GnRH antagonist compared to the conventional GnRH agonist protocol in women undergoing ART. Method: Six electronic databases were searched from their date of establishment until August 2016. Outcomes in our analysis were calculated in terms of relative risk (RR) and weighted mean differences (WMD) and standard mean differences (SMD) with 95% confidence intervals (CI) using random effect models or fixed effect models.

Results: Six prospective controlled clinical trials with 1543 women comparing the clinical impacts of the two protocols were included. The synthesized results suggested a significant reduction in the quantity of gonadotropins (SMD: ?1.96, 95% CI: ?2.28 to 1.64, I²?=?78.5%), the incidence of OHSS (RR: 0.16, 95% CI 0.03–0.86, I²?=?0%) and an increase in the cycle cancelation rate (RR: 1.46, 95% CI 1.05–2.03, I²?=?89.4%). While no evidence of statistically signi?cant differences between the groups existed in the other clinical outcomes.

Conclusion: This study suggested that the probable benefits of the mild protocol, including its less costs and safer process without reducing the overall IVF treatment success rates, seemed to make it a better treatment option. Larger sample prospective trials evaluating live birth, clinical pregnancy, OHSS, multiple pregnancy incidence and so on were desired to establish.     

Efficacy of low-dose hCG in late follicular phase in controlled ovarian stimulation using GnRH agonist protocol

Objective

Safe, simple and cost-effective protocol is an important goal in ART cycles. The aim of this prospective study was whether administration of low-dose hCG in late follicular phase can be used clinically to replace gonadotropin administration in GnRH long protocol.

Materials and methods

122 patients who were candidates for ART enrolled the study and randomly divided into two groups. The control group (n?=?62) received standard long protocol and gonadotropin administration continued until the day of hCG injection (10,000?IU) for final follicular maturation. The study group (n?=?60) received GnRH long protocol and when at least ??6 follicles with mean diameter ??12?mm were observed in both ovaries, hMG was displaced by 200?IU per day of hCG until final follicular maturation.

Results

There were no significant differences in age, basal FSH, infertility duration and infertility etiology between two groups. There were no statistically significant differences between two groups regarding chemical pregnancy, clinical pregnancy, ongoing pregnancy, and abortion per cycle (50, 40, 40, and 20?% in study group vs. 45.2, 35.5, 35.5, and 21.4?% in control group, respectively). Mean dose of used gonadotropins was significantly higher in control group than that in the study group (2,524?±?893?IU in control group and 1,439?±?433?IU in study group) (p?=?0.000).

Conclusion

According to our data, we recommend the use of low-dose hCG in GnRH long protocol because of lower doses of used gonadotropins.