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1.  Rescue in vitro fertilization using a GnRH antagonist in hyper-responders from gonadotropin intrauterine insemination (IUI) cycles 
To evaluate the outcomes in the conversion of high-response gonadotropin intrauterine insemination (IUI) cycles to “rescue” in vitro fertilization (IVF) using a Gonadotropin-Releasing Hormone (GnRH) antagonist, with regards to implantation rates, pregnancy rates, cost, and ovarian hyperstimulation syndrome (OHSS) as compared to matched, hyper-responder, IVF controls.
This prospective cohort study was conducted between January 2007 and December 2009 at our institution. In order to decrease high-order multiple pregnancy, minimize the incidence of OHSS, and avoid cycle cancellation, high-response stimulated-IUI patients opted to convert to “rescue” IVF using the GnRH antagonist cetrorelix acetate. We then compared their clinical outcomes with matched patients from high-response IVF cycles of the standard long mid-luteal GnRH agonist protocol (14 or more collected oocytes). Only cases of conventional IVF without intra-cytoplasmic sperm injection (ICSI) were included in the control group.
Out of 184 patients undergoing stimulated-IUI cycles with gonadotropins, 87 patients developed a hyper-response, and 20 opted to convert to “rescue” IVF. These patients were compared with 157 matched, hyper responder IVF controls from our registry. The implantation rate was 25.6 % in the “rescue” IVF group and 20.7 % in the control IVF group (p < 0.0047). The ongoing clinical pregnancy rate per embryo transfer was 45.0 % and 33.6 % in the “rescue” IVF and the control IVF groups, respectively (p < 0.0001). The mean duration of stimulation was comparable between cohorts (10.0 vs.10.4 days, p = 0.6324). The mean dose of gonadotropin used per cycle was higher in the control group, 2664 international units (IU) of follicle stimulation hormone (FSH) compared to 1450 IU of FSH in the “rescue” IVF group (p < 0.0001). The incidence of severe OHSS is also higher in the control group, 5.1 % versus no cases in the “rescue” IVF group (p < 0.0001).
Our study demonstrates that conversion of high-response gonadotropin-IUI cycles to “rescue” IVF using a GnRH antagonist is a cost-effective strategy that produces better results than regular IVF with relatively minimal morbidity, and shorter duration to achieve pregnancy. Implantation and ongoing clinical pregnancy rates tend to be higher than those from hyper-responder regular IVF patients.
PMCID: PMC3696442  PMID: 23715874
Stimulated IUI; Hyper-responders; Rescue IVF; GnRH antagonist
2.  Impact of GnRH analogues on oocyte/embryo quality and embryo development in in vitro fertilization/intracytoplasmic sperm injection cycles: a case control study 
Despite the clinical outcomes of ovarian stimulation with either GnRH-agonist or GnRH-antagonist analogues for in vitro fertilization (IVF) being well analysed, the effect of analogues on oocyte/embryo quality and embryo development is still not known in detail. The aim of this case-control study was to compare the efficacy of a multiple-dose GnRH antagonist protocol with that of the GnRH agonist long protocol with a view to oocyte and embryo quality, embryo development and IVF treatment outcome.
Between October 2001 and December 2008, 100 patients were stimulated with human menopausal gonadotrophin (HMG) and GnRH antagonist in their first treatment cycle for IVF or intracytoplasmic sperm injection (ICSI). One hundred combined GnRH agonist + HMG (long protocol) cycles were matched to the GnRH antagonist + HMG cycles by age, BMI, baseline FSH levels and by cause of infertility. We determined the number and quality of retrieved oocytes, the rate of early-cleavage embryos, the morphology and development of embryos, as well as clinical pregnancy rates. Statistical analysis was performed using Wilcoxon's matched pairs rank sum test and McNemar's chi-square test. P < 0.05 was considered statistically significant.
The rate of cytoplasmic abnormalities in retrieved oocytes was significantly higher with the use of GnRH antagonist than in GnRH agonist cycles (62.1% vs. 49.9%; P < 0.01). We observed lower rate of zygotes showing normal pronuclear morphology (49.3% vs. 58.0%; P < 0.01), and higher cell-number of preembryos on day 2 after fertilization (4.28 vs. 4.03; P < 0.01) with the use of GnRH antagonist analogues. The rate of mature oocytes, rate of presence of multinucleated blastomers, amount of fragmentation in embryos and rate of early-cleaved embryos was similar in the two groups. Clinical pregnancy rate per embryo transfer was lower in the antagonist group than in the agonist group (30.8% vs. 40.4%) although this difference did not reach statistical significance (P = 0.17).
Antagonist seemed to influence favourably some parameters of early embryo development dynamics, while other morphological parameters seemed not to be altered according to GnRH analogue used for ovarian stimulation in IVF cycles.
PMCID: PMC2762973  PMID: 19781070
3.  In Vitro Fertilization and Multiple Pregnancies 
Executive Summary
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.
Clinical Need: Target Population and Condition
Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.
The Technology Being Reviewed
IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman’s egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility.
An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%.
An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost.
Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.
Ontario Health Insurance Plan Coverage
Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS.
Diffusion of Technology
According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually.
Literature Review
Royal Commission Report on Reproductive Technologies
The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not.
Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990’s as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF.
Studies After the Royal Commission Report: Review Strategy
Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.
Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.
Cost effectiveness of IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewed
Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.
OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies.
Summary of Findings
Comparative Clinical Effectiveness of IVF
Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...).
Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings:
A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.
A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.
In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility.
Cost-Effectiveness of IVF
Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option.
Clinical Outcomes After Single Versus Double Embryo Transfer Strategies of IVF
Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs.
All of these studies reached similar conclusions:
Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).
SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT).
Most trials on SET included women younger than 36 years old with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to older women.
Estimate of the Target Population
Based on results of the literature review and consultations with experts, four categories of infertile patients who may benefit from increased access to IVF/ICSI were identified:
Patients with severe male factor infertility, where IVF should be offered in conjunction with ICSI;
Infertile women with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET;
Infertile patients who want to avoid the risk of multiple pregnancy and thus opt for IVF-SET; and
Patients who failed treatment with IUI and wish to try IVF.
Since, however, the latter indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered in this analysis.
Economic Analysis
Economic Review: Cost–Effectiveness of SET Versus DET
Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent. While some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies, other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.
Ontario-Based Economic Analysis
An Ontario-based economic analysis compared cost per birth using three treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed three cycles for each treatment option. Two separate models were considered; the first included only fresh cycles of IVF, while the second had a combination of fresh and frozen cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancies (only short-term complications), IVF-SET was still associated with a highest cost per birth. The approximate budget impact to cover the first three indications for IVF listed above (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of only first two indications, namely, ICSI in patients with severe male factor infertility and infertile women with serious medical contraindications to multiple pregnancy, is estimated at $3.8 to $5.5 million Cdn.
Other Considerations
International data shows that both IVF utilization and the average number of embryos transferred in IVF cycles are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by governments.
Surveys of patients with infertility demonstrated that a significant proportion (~40%) of patients not only do not mind having multiple babies, but consider twins being an ideal outcome of infertility treatment.
A women’s age may impose some restrictions on the implementation of a SET strategy.
Conclusions and Recommendations
A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancies after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.
Thus, 2 indications where additional IVF access should be considered include:
IVF/ICSI for patients with severe male factor infertility
IVF-SET in infertile women with serious medical contraindications to multiple pregnancy
PMCID: PMC3379537  PMID: 23074488
4.  Is a GnRH Antagonist Protocol Better in PCOS Patients? A Meta-Analysis of RCTs 
PLoS ONE  2014;9(3):e91796.
To review published randomized controlled trials (RCTs) evaluating the outcomes of in vitro fertilization/intra-cytoplasmic sperm injection (IVF/ICSI) utilization of gonadotropin-releasing hormone (GnRH) antagonists for ovarian stimulation in polycystic ovarian syndrome (PCOS) patients compared with classic luteal long agonist protocols.
A meta-analysis of prospective randomized trials published in English between 2002 and 2013.
Patient(s) and Interventions
Nine RCTs examining PCOS patients undergoing IVF/ICSI including 588 women who underwent long agonist protocols and 554 women who underwent GnRH antagonist protocols.
Main Outcome Measure(s)
Clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR) and ovarian hyperstimulation syndrome (OHSS) rate.
Nine RCTs were included in this analysis. The CPR-per-embryo transferred was similar in the two groups (relative risk (RR): 0.97, 95% confidence interval (CI): 0.85–1.10). Non-significant estimates comparing the two protocols were found for age, BMI, total dose of gonadotropin administered, number of days of stimulation and number of oocytes retrieved. After meta-analysis of 4 of the RCTs, it was concluded that a GnRH antagonist protocol is better than an agonist long protocol to reduce the rate of severe OHSS (odds ratio (OR): 1.56, 95% CI: 0.29–8.51).
With respect to CPR, a GnRH antagonist protocol is similar to a GnRH agonist long protocol. However, for severe OHSS, a GnRH antagonist protocol is significantly better in PCOS patients.
PMCID: PMC3958392  PMID: 24642641
5.  IVF/ICSI outcomes between cycles with luteal estradiol (E2) pre-treatment before GnRH antagonist protocol and standard long GnRH agonist protocol: a prospective and randomized study 
To study if luteal E2 pre-treatment before GnRH antagonist protocol improves IVF/ICSI outcomes compared with standard long GnRH agonist protocol.
A prospective, randomized and controlled study.
ART center of a state public hospital
Two hundred twenty infertile women underwent IVF/ICSI treatments.
Participants received oral Estradiol Valerate 4 mg/day preceding the IVF cycle from day 21 until day 2 of next cycle before GnRH antagonist protocol (E2 pre-treatment group n = 109) or received standard long GnRH agonist protocol as control group (n = 111).
Main outcome measure(s)
Number of oocytes collected, MII oocytes, fertilization, implantation, live birth and early pregnancy rate, and hormone profiles.
E2 pre-treatment exerted a significant suppressive effect on FSH but not LH secretion compared with basal FSH and LH levels. In E2 pre-treatment group serum LH level was significantly higher during COH and serum P was also significantly higher on the day of HCG injection compared with control group. Five patients from E2 pre-treatment group had elevated LH at all time (≥10 IU/L) and also a concomitantly high P (>1 ng/mL). Two of the five women achieved pregnancy but had early pregnancy loss. Overall, IVF/ICSI outcomes such as implantation, clinical pregnancy and live birth rates were similar between E2 pre-treatment and control groups.
Luteal E2 pre-treatment before GnRH antagonist protocol significantly increases serum LH level and incidence rate of premature LH but no significant effect is observed on implantation, clinical pregnancy, live birth and early pregnancy loss rates compared with long GnRH agonist protocol. However, more studies in large numbers of cycles are needed to confirm that increased serum LH level by E2 pre-treatment during COH has no negative effect on the IVF/ICSI outcomes.
PMCID: PMC2654939  PMID: 19225876
FSH; Estradiol pre-treatment; Controlled ovarian hyperstimulation; IVF
6.  Early-cleavage is a reliable predictor for embryo implantation in the GnRH agonist protocols but not in the GnRH antagonist protocols 
To test if early-cleavage was a strong predictor of pregnancy in patients receiving either a GnRH agonist long protocol or a GnRH antagonist protocol for in-vitro fertilization treatment (IVF) and intracytoplasmic sperm injection (ICSI).
This retrospective study included 534 patients undergoing a fresh cycle of oocyte retrieval and the day-3 embryo transfer (from 22 to 46 years old). Of the 534 patients treated, 331 received a GnRH agonist long stimulation protocol (GnRH agonist group) for ovarian stimulation and 203 patients received a GnRH antagonist protocol (GnRH antagonist group). In each group, patients who had at least one early-cleavage embryo transferred were designated as the 'early-cleavage' subgroup. Patients who had no early-cleavage embryos transferred were designated as the 'late-cleavage' subgroup.
The early cleavage rate was significantly lower in the GnRH antagonist group compared with that in the GnRH agonist group (IVF cycles: 34% versus 20%; ICSI cycles: 50% versus 37.8%, respectively, P < 0.0001). In the GnRH agonist group, the pregnancy rates were significantly higher in the early-cleavage subgroup than those in the late-cleavage subgroup (53.7% vs 33.9%, P < 0.0001). In the GnRH antagonist group, the pregnancy rates were not significantly different between the early-cleavage and late-cleavage subgroups (45.9% vs 43.8%, P > 0.05).
Early cleavage of zygote is not a reliable predictor for embryo implantation potential in using the GnRH antagonist protocol. Furthermore, the implantation rates between the GnRH agonist and GnRH antagonist groups were comparable.
PMCID: PMC2654454  PMID: 19254386
7.  Effect of estrogen priming through luteal phase and stimulation phase in poor responders in in-vitro fertilization 
To verify whether a novel protocol administering E2 during the luteal phase of the preceding cycle and during ovarian stimulation in GnRH antagonist cycle could enhance follicular response and hence improve outcomes in poor responders.
In this retrospective analysis, a total of 155 poor responder patients subjected to IVF/ICSI were analyzed. All the patients had history of more than one prior IVF cycle failure with poor response (less than 5 oocytes retrieved and/or maximal E2 level less than 500 pg/mL) by using conventional long agonist or antagonist protocol. In luteal E2 treatment protocol (n = 86), oral estradiol valerate 4 mg/day was initiated on luteal day 21 and either stopped at menstrual cycle day 3 (Protocol A, n = 28) or continued during the period of ovarian stimulation until the day of hCG injection (Protocol B, n = 58). IVF parameters and pregnancy outcome of luteal E2 treatments group were compared with a standard GnRH antagonist protocol (n = 69) which the patients received no hormonal pretreatment.
Compared to standard GnRH antagonist protocol, cancellation rate was lower with luteal E2 group (15.1% vs 37.7%, p < 0.01). Moreover, patients treated with luteal estrogen resulted in an increased number of oocytes retrieved (4.5 ± 2.9 vs 3.2 ± 1.9; p < 0.01). A trend toward increase in number of normally fertilized embryos (2.9 ± 2.1vs 2.3 ± 1.9; p = 0.043), and increased prevalence of good quality embryos (51.2% vs 25%; p = 0.047) were noted. Comparing protocol A and B, there were no significant difference between embryologic data, however there were slight increase in ongoing pregnancy rate in protocol B compared to A (27.1% vs 20%, p = 0.357), although statistical significance was not achieved.
Estrogen priming through luteal phase and stimulation phase improved ovarian responsiveness and this may lead to an increase in pregnancy rate in poor responders with failed cycle.
PMCID: PMC3288134  PMID: 22160464
Luteal estradiol supplementation; Poor responder; In vitro fertilization; Embryo morphology
8.  GnRH antagonist multiple dose protocol with oral contraceptive pill pretreatment in poor responders undergoing IVF/ICSI 
To investigate the effectiveness of GnRH antagonist multiple-dose protocol (MDP) with oral contraceptive pill (OCP) pretreatment in poor responders undergoing IVF/ICSI, compared with GnRH antagonist MDP without OCP pretreatment and GnRH agonist low-dose long protocol (LP).
A total of 120 poor responders were randomized into three groups according to controlled ovarian stimulation (COS) options; GnRH antagonist MDP after OCP pretreatment (group 1), GnRH antagonist MDP without OCP pretreatment (group 2) or GnRH agonist luteal low-dose LP without OCP pretreatment (group 3). Patients allocated in group 1 were pretreated with OCP for 21days in the cycle preceding COS, and ovarian stimulation using recombinant human FSH (rhFSH) was started 5 days after discontinuation of OCP.
There were no differences in patients' characteristics among three groups. Total dose and days of rhFSH used for COS were significantly higher in group 3 than in group 1 or 2. The numbers of mature oocytes, fertilized oocytes and grade I, II embryos were significantly lower in group 2 than in group 1 or 3. There were no significant differences in the clinical pregnancy rate and implantation rate among three groups.
GnRH antagonist MDP with OCP pretreatment is at least as effective as GnRH agonist low-dose LP in poor responders and can benefit the poor responders by reducing the amount and duration of FSH required for follicular maturation.
PMCID: PMC3283075  PMID: 22384447
Gonadotropin-releasing hormone; Antagonist; Agonist; Oral Contraceptives; Poor Responders; In vitro fertilization; Intracytoplasmic sperm injection; Human
9.  Gonadotropin-Releasing Hormone (GnRH)-Antagonist Versus GnRH-Agonist in Ovarian Stimulation of Poor Responders Undergoing IVF 
Purpose: The objective of this study was to compare the efficacy of GnRH-antagonists to GnRH-agonists in ovarian stimulation of poor responders undergoing IVF.
Methods: Retrospective analysis of our data revealed that 56 patients underwent treatment with a GnRH-agonist according to the flare-up protocol. Patients failing to achieve an ongoing pregnancy (n=53) were subsequently treated in the next cycle with a GnRH-antagonist according to the multiple-dose protocol. Main outcome measures included the clinical pregnancy and implantation rates.
Results: While ovulation induction characteristics and results did not differ between the two protocols, the number of embryos transferred was significantly higher (P=0.046) in the GnRH-antagonist than in the GnRH-agonist stimulation protocol (2.5 ± 1.6 vs. 2.0 ± 1.4, respectively). The clinical pregnancy and implantation rates per transfer in the GnRH-antagonist group appeared higher than in the GnRH-agonist, but did not differ statistically (26.1 and 10.7 compared with 12.2 and 5.9%, respectively). However, the ongoing pregnancy rate per transfer was statistically significantly higher (P=0.03) in the GnRH-antagonist than in the GnRH-agonist group (23.9 vs. 7.3%, respectively).
Conclusion: Applying GnRH-antagonists to ovarian stimulation protocols may offer new hope for IVF poor responder patients. However, further controlled randomized prospective studies with larger sample sizes are required to establish these results.
PMCID: PMC3455641  PMID: 14714824
Cetrorelix; GnRH-agonist; GnRH-antagonist; IVF; Poor responders
10.  GnRH Antagonist IVF Protocol in PCOS 
The aim of the present study was to compare the GnRH agonist long protocol with the flexible GnRH antagonist protocol in infertile PCOS women undergoing COS in terms of clinical pregnancy rate (CPR), with special reference to the incidence of OHSS. Materials and Methods. The study was conducted at the Hospital Obstetrics and Gynecology Cuza Vodă Iaşi and Fertility Reproductive Medical Center Omini Clinic Iaşi from June 1, 2010, to September 31, 2012. PCOS as defined by the Rotterdam 2003 consensus, i.e. presence of two of the following three features: presence of oligo- and/ or anovulation, clinical and/or biochemical signs of hyperandrogenism, polycystic ovaries and exclusion of other endocrinopathies. Results. No differences were observed in clinical pregnancy rate (CPR) in the agonist and antagonist protocols, respectively. Incidence of OHSS was lower in the antagonist compared with agonist group (4% versus 28%). Duration of stimulation (13,80 + 1,4 vs 11,85 + 2,4 p < 0,001) and total gonadotrophin required (2435,5 + 884,5 versus 2005, 5 + 545,5 IU p < 0.003) were also lower in the antagonist compared with agonist protocol. Conclusions. The current study suggests that the flexible GnRH antagonist protocol is associated with a similar ongoing pregnancy rate, lower incidence of OHSS grade II, lower gonadotrophin requirement and shorter duration of stimulation, compared with GnRH agonist. The GnRH antagonist might be the treatment choice for patients with PCOS undergoing IVF
PMCID: PMC3945257  PMID: 24778852
polycystic ovary syndrome; GnRH antagonist; infertility
11.  GnRH Antagonist Improved Blastocyst Quality and Pregnancy Outcome After Multiple Failures of IVF/ICSI–ET with a GnRH Agonist Protocol 
Background: To determine the efficacy of a gonadotrophin-releasing hormone (GnRH) antagonist, cetrorelix, in improving the quality of embryos and pregnancy outcome, we performed a study in patients with a history of multiple failures of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles with a GnRH agonist (GnRHa) long protocol.
Methods: Forty women with no live births after conventional IVF or ICSI embryo transfer (ET) and subsequent blastocyst transfer (BT) with a GnRHa long protocol entered this study. The treatment protocol consisted of a daily dose of clomiphene citrate 100 mg for 5 days and gonadotrophin injections daily from cycle day 4 onward. Cetrorelix, 0.25 mg/day, was started when the leading follicle reached 14 mm. Induction of ovulation was triggered with human chorionic gonadotrophin (HCG) (N=36) or GnRHa (N=4). It was possible to perform BT in 38 patients.
Results: Comparison of the results with the results for BT with the previous GnRHa protocol showed no significant differences in number of oocytes retrieved or the zygote- and blastocyst-development rate. With the cetrorelix protocol, however, number of patients whose embryos had developed to at least one expanded blastocyst on day 5 was significantly higher than with the GnRHa protocol (25 vs. 9) (p<0.001), and 16 of the women became pregnant (42.1%), with 7 delivering 9 infants, 4 ending in abortion (25%), and 5 in progressing.
Conclusions: The use of a GnRH antagonist in controlled ovarian hyperstimulation improves the outcome of pregnancy of patients with a history of multiple failure of IVF/ICSI–ET in a GnRHa protocol, most likely due to improvement of the quality of the blastocysts generated.
PMCID: PMC3468267  PMID: 15587144
Blastocyst; GnRH agonist; GnRH antagonist; multiple ET failures
12.  Gonadotrophin releasing hormone antagonist in IVF/ICSI 
To study the efficacy of gonadotrophin releasing hormone (GnRH) antagonist in In-vitro-fertilization/Intracytoplasmic sperm injection (IVF/ICSI) cycles.
Observational study.
Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, Tamil Nadu.
GnRH antagonists were introduced into our practice in November 2005. Fifty-two women undergoing the antagonist protocol were studied and information gathered regarding patient profile, treatment parameters (total gonadotrophin dosage, duration of treatment, and oocyte yield), and outcomes in terms of embryological parameters (cleavage rates, implantation rates) and clinical pregnancy. These parameters were compared with 121 women undergoing the standard long protocol. The costs between the two groups were also compared.
Clinical pregnancy rate.
The clinical pregnancy rate per embryo transfer in the antagonist group was 31.7% which was comparable to the clinical pregnancy rate in women undergoing the standard long protocol (30.63%). The costs between the two groups were comparable.
GnRH antagonist protocol was found to be effective and comparable to the standard long protocol regimen. In addition it was simple, convenient, and patient friendly.
PMCID: PMC2700675  PMID: 19562061
Assisted reproduction; Gonadotrophin releasing hormone antagonists; ICSI; IVF
13.  Comparison of the GnRH agonist and antagonist protocol on the same patients in assisted reproduction during controlled ovarian stimulation cycles 
Despite the fact that both gonadotropin-releasing hormone (GnRH) agonist and antagonist protocol are effective in suppressing the incidence of premature luteinizing hormone (LH) surges through reversibly blocking the secretion of pituitary gonadotropins, the exact impact of these two distinctive protocols on the clinical setting of patients for in vitro fertilization and embryo transfer (IVF-ET) treatment, however, remained controversial. We thus in the present report conducted a retrospective study to compare the impact of GnRH agonist and antagonist protocol on the same patients during controlled ovarian stimulation cycles. A total of 81 patients undergoing 105 agonist and 88 antagonist protocol were analyzed. We failed to detect a significant difference between two protocols for the difference in duration of ovarian stimulation, number of recombinant FSH (Gonal-F) ampoules used, number of oocytes retrieved, serum levels for estradiol (E2) and progestone (P), thickness of endometrium, and the zygote- and blastocyst-development rate. It is seemly that high quality embryo rate was higher in the antagonist protocol, but the data did not reach a statistical significance. Nevertheless, Implantation rate and clinical pregnancy rate were significantly higher in the antagonist protocol (10.64% and 30.26%, respectively) than that of the agonist protocol (5.26% and 15.82%, respectively). Our data also suggest that the GnRH antagonist protocol is likely to have the advantage for improving the outcome of pregnancy in those patients with a history of multiple failures for the IVF-ET treatment.
PMCID: PMC3759499  PMID: 24040457
Gonadotropin-releasing hormone (GnRH); agonist; antagonist; in vitro fertilization; embryo transfer; assisted reproduction; controlled ovarian stimulation cycles
14.  Effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase compared with GnRH agonist long protocol in non-obese and obese patients with polycystic ovary syndrome undergoing IVF/ICSI 
To evaluate the effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase (MDP-EL) in comparison with standard GnRH agonist luteal long protocol (LP) in each non-obese and obese polycystic ovary syndrome (PCOS) women undergoing IVF.
Two hundred eleven infertile women with PCOS were recruited and randomized to undergo either GnRH antagonist MDP-EL (antagonist group) or standard GnRH agonist luteal LP (agonist group). IVF cycle outcomes were compared between the two groups.
Total dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the antagonist group than in the agonist group. Incidence of severe ovarian hyperstimulation syndrome was significantly lower in the antagonist group. However, IVF and pregnancy outcomes were similar in the two groups. When all subjects were divided into non-obese and obese subgroups, in non-obese PCOS subgroup, IVF and pregnancy outcomes were comparable in the antagonist and agonist groups but total dose and days of rhFSH were also significantly fewer in the antagonist group. Similar findings were also observed in obese PCOS subgroup.
GnRH antagonist MDP-EL is at least as effective as GnRH agonist LP and may be a more patient-friendly alternative in controlled ovarian stimulation for PCOS patients undergoing IVF, independent of body mass index.
PMCID: PMC3341448  PMID: 22563547
Polycystic ovary syndrome; GnRH antagonist; GnRH agonist; Body mass index; Controlled ovarian stimulation; In vitro fertilization
15.  GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology 
The selection of developmentally competent human gametes may increase the efficiency of assisted reproduction. Spermatozoa and oocytes are usually assessed according to morphological criteria. Oocyte morphology can be affected by the age, genetic characteristics, and factors related to controlled ovarian stimulation. However, there is a lack of evidence in the literature concerning the effect of gonadotropin-releasing hormone (GnRH) analogues, either agonists or antagonists, on oocyte morphology. The aim of this randomized study was to investigate whether the prevalence of oocyte dysmorphism is influenced by the type of pituitary suppression used in ovarian stimulation.
A total of 64 patients in the first intracytoplasmic sperm injection (ICSI) cycle were prospectively randomized to receive treatment with either a GnRH agonist with a long-term protocol (n: 32) or a GnRH antagonist with a multi-dose protocol (n: 32). Before being subjected to ICSI, the oocytes at metaphase II from both groups were morphologically analyzed under an inverted light microscope at 400x magnification. The oocytes were classified as follows: normal or with cytoplasmic dysmorphism, extracytoplasmic dysmorphism, or both. The number of dysmorphic oocytes per total number of oocytes was analyzed.
Out of a total of 681 oocytes, 189 (27.8 %) were morphologically normal, 220 (32.3 %) showed cytoplasmic dysmorphism, 124 (18.2%) showed extracytoplasmic alterations, and 148 (21.7%) exhibited both types of dysmorphism. No significant difference in oocyte dysmorphism was observed between the agonist- and antagonist-treated groups (P ≫ 0.05). Analysis for each dysmorphism revealed that the most common conditions were alterations in polar body shape (31.3%) and the presence of diffuse cytoplasmic granulations (22.8%), refractile bodies (18.5%) and central cytoplasmic granulations (13.6%). There was no significant difference among individual oocyte dysmorphisms in the agonist- and antagonist-treated groups (P ≫ 0.05).
Our randomized data indicate that in terms of the quality of oocyte morphology, there is no difference between the antagonist multi-dose protocol and the long-term agonist protocol. If a GnRH analogue used for pituitary suppression in IVF cycles influences the prevalence of oocyte dysmorphisms, there does not appear to be a difference between the use of an agonist as opposed to an antagonist.
PMCID: PMC3464873  PMID: 22540993
Oocyte morphology; in vitro fertilization; Gonadotropin-releasing hormone analogues; Assisted reproduction technique
16.  Comparison of assisted reproductive technology outcomes in infertile women with polycystic ovary syndrome: In vitro maturation, GnRH agonist, and GnRH antagonist cycles 
We compared the assisted reproductive technology (ART) outcomes among infertile women with polycystic ovary syndrome (PCOS) treated with IVM, conventional IVF, GnRH agonist, and GnRH antagonist cycles.
The prospective study included a total of 67 cycles in 61 infertile women with PCOS. The women with PCOS were randomized into three IVF protocols: IVM/IVF with FSH and hCG priming with immature oocyte retrieval 38 hours later (group A, 14 cycles), GnRH agonist long protocol (group B, 14 cycles), and GnRH antagonist multi-dose flexible protocol (group C, 39 cycles). IVF outcomes, such as clinical pregnancy rate (CPR), implantation rate (IR), miscarriage rate (MR), and live birth rate (LBR), were compared among the three groups.
Age, BMI, and basal FSH and LH levels did not differ among the three groups. The number of retrieved oocytes and 2 pronucleus embryos was significantly lower in group A compared with groups B and C. The CPR, IR, MR, and LBR per embryo transfer showed no differences among the three groups. There was no incidence of ovarian hyperstimulation syndrome in group A.
The IR, MR, and LBR in the IVM cycles were comparable to those of the GnRH agonist and GnRH antagonist cycles. The IVM protocol, FSH and hCG priming with oocyte retrieval 38 hours later, is an effective ART option that is comparable with conventional IVF for infertile women with PCOS.
PMCID: PMC3548075  PMID: 23346527
Polycystic ovary syndrome; In vitro maturation; GnRH antagonist; GnRH agonist; Assisted reproductive technology outcome
17.  Comparative multiplex analysis of cytokines, chemokines and growth factors in follicular fluid of normoresponder women undergoing ovum donation with gonadotropin-releasing hormone agonist versus gonadotropin-releasing hormone antagonist protocols 
Conflicting results were yielded about the superiority of gonadotropin-releasing hormone agonist (GnRH-a) versus gonadotropin-releasing hormone antagonist (GnRH-ant) protocols used in ovarian stimulation in in vitro fertilization (IVF) set-up. Reports also indicate that any single specific individual marker in follicular fluid collected at the time of oocyte retrieval bears inconclusive value as a predictor of oocyte quality.
Simultaneous analyses of large numbers of cytokines, chemokines and growth factors in ovarian follicular fluid and perifollicular vascularity in both protocols for ovarian stimulation in IVF program to address the above mentioned lacunae.
Normoresponder women (n = 45) were subjected to either GnRH-a (Group 1; n = 23) or GnRH-ant (Group 2; n = 22) for ovarian stimulation in IVF clinics.
The fluid samples of dominant follicles collected at oocyte retrieval from women in Group 1 (GnRH-a; n = 20) and Group 2 (GnRH-ant; n = 16) were used for simultaneous quantitative assays of 48 cytokines. Perifollicular vascularity was assessed by Doppler hemodynamics to assess the ovarian vascular response in all participants in Groups 1 and 2.
Despite demographic and reproductive parameters studied remained comparable, higher follicular fluid concentration of interleukins, IL-3 (P < 0.01), IL12p70 (P < 0.05) and vascular endothelial growth factor (P < 0.01), P4 (P < 0.05) and pulsatility index (P < 0.04) along with a lower number of oocytes in metaphase II stage (P < 0.03) was observed in Group 2 compared with Group 1. GnRH-a protocol appeared to be superior to GnRH-ant protocol for ovarian stimulation in normoresponder women.
PMCID: PMC3853878  PMID: 24347936
Cytokines; follicular fluid; multiplex analysis; ovarian stimulation; perifollicular hemodynamics
18.  The effect of aromatase inhibitor letrozole incorporated in gonadotrophin-releasing hormone antagonist multiple dose protocol in poor responders undergoing in vitro fertilization 
Obstetrics & Gynecology Science  2014;57(3):216-222.
To evaluate whether letrozole incorporated in a gonadotrophin-releasing hormone (GnRH) antagonist multiple dose protocol (MDP) improved controlled ovarian stimulation (COS) and in vitro fertilization (IVF) results in poor responders who underwent IVF treatment.
In this retrospective cohort study, a total of 103 consecutive IVF cycles that were performed during either the letrozole/GnRH antagonist MDP cycles (letrozole group, n=46) or the standard GnRH antagonist MDP cycles (control group, n=57) were included in 103 poor responders. COS results and IVF outcomes were compared between the two groups.
Total dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the letrozole group than in the control group. Duration of GnRH antagonist administered was also shorter in the letrozole group. The number of oocytes retrieved was significantly higher in the letrozole group. However, clinical pregnancy rate per cycle initiated, clinical pregnancy rate per embryo transfer, embryo implantation rate and miscarriage rate were similar in the two groups.
The letrozole incorporated in GnRH antagonist MDP may be more effective because it results comparable pregnancy outcomes with shorter duration and smaller dose of rhFSH, when compared with the standard GnRH antagonist MDP.
PMCID: PMC4038688  PMID: 24883293
Gonadotrophin-releasing hormone antagonist; In vitro fertilization; Letrozole; Poor responder
19.  A prospective, randomised, controlled clinical study on the assessment of tolerability and of clinical efficacy of Merional (hMG-IBSA) administered subcutaneously versus Merional administered intramuscularly in women undergoing multifollicular ovarian stimulation in an ART programme (IVF) 
Multifollicular ovarian stimulation (MOS) is widely used in IVF and the compliance to treatment is deeply influenced by the tolerability of the medication(s) used and by the ease of self-administration. This prospective, controlled, randomised, parallel group open label, multicenter, phase III, equivalence study has been aimed to compare the clinical effectiveness (in terms of oocytes obtained) and tolerability of subcutaneous (s.c.) self-administered versus classical intramuscular (i.m.) injections of Merional, a new highly-purified hMG preparation.
A total of 168 normogonadotropic women undergoing IVF were enrolled. Among them, 160 achieved pituitary suppression with a GnRH-agonist long protocol and were randomised to MOS treatment with Merional s.c. or i.m. They started MOS with a standard hMG dose between 150–300 IU, depending upon patient's age, and underwent a standard IVF procedure.
No statistically significant difference in the mean number of collected oocytes (primary endpoint) was observed between the two study subgroups (7.46, SD 4.24 vs. 7.86, SD 4.28 in the s.c. and i.m. subgroups, respectively). As concerns the secondary outcomes, both the pregnancy and the clinical pregnancy rates were comparable between subgroups. The incidence of adverse events was similar in the two groups (2.4% vs. 3.7%, respectively). Pain at injection site was reported only the i.m. group (13.9% of patients).
Merional may be used by s.c. injections in IVF with an effectiveness in terms of retrieved oocytes that is equivalent to the one obtained with i.m administration and with a better local tolerability. With the limitations due to the sample size af this study, s.c. and i.m. administration routes seem to have the same overall safety.
PMCID: PMC2216030  PMID: 18053198
20.  Comparison of the ultrashort gonadotropin-releasing hormone agonist-antagonist protocol with microdose flare -up protocol in poor responders: a preliminary study 
To determine the potential effect of the ultrashort gonadotropin-releasing hormone (GnRH) agonist/GnRH antagonist protocol versus the microdose GnRH agonist protocol in poor responders undergoing intracytoplasmic sperm injection (ICSI).
Material and Methods
The patients in the Agonist-Antagonist Group (n=41) were administered the ultrashort GnRH-agonist/ antagonist protocol, while the patients in the Microdose Group (n=41) were stimulated according to the microdose flare-up protocol. The mean number of mature oocytes retrieved was the primary outcome measure. Fertilization rate, implantation rate per embryo and clinical pregnancy rates were secondary outcome measures.
There was no differenc between the mean number of mature oocytes retrieved in the two groups. There were also no statistical differences between the two groups in terms of peak serum E2 level, canceled cycles, endometrial thickness on hCG day, number of 2 pronucleus and number of embryos transferred. However, the total gonadotropin consumption and duration of stimulation were significantly higher with the Agonist-Antagonist Group compared with the Microdose Group. The implantation and clinical pregnancy rates were similar between the two groups.
Despite the high dose of gonadotropin consumption and longer duration of stimulation with the ultrashort GnRH agonist/ antagonist protocol, it seems that the Agonist-Antagonist Protocol is not inferior to the microdose protocol in poor responders undergoing ICSI.
PMCID: PMC3939149  PMID: 24591934
Poor responder; mature oocytes; Agonist-Antagonist protocol; microdose flare-up protocol
21.  Letrozole in a low-cost in vitro fertilization protocol in intracytoplasmic sperm injection cycles for male factor infertility: A randomized controlled trial 
Letrozole, a selective aromatase inhibitor, reduces the total dose of gonadotrophin required for inducing follicular maturation. We evaluated if incorporation of letrozole could be an effective alternative for low-cost in vitro fertilization (IVF) protocol particularly in intracytoplasmic sperm injection (ICSI) cycles where male factor infertility is the sole indication for IVF.
It is a randomized controlled single-blind trial. 94 women with history of severe male factor infertility were selected. 42 women (study group) received letrozole, 5 mg daily from day 3-7 and recombinant FSH (rFSH) 75IU/day from day 5 continuously till hCG injection. 52 women (control group) underwent continuous stimulation by rFSH (150-225IU/day) from day 2. GnRH-antagonist (Inj. Orgalutran 0.25 ml sub-cutaneous) was started at maximum follicle size of 14 in both groups. Ovulation was triggered by 10,000IU of hCG followed by IVF-ET. Main outcome measures were total dose of rFSH (IU/cycle), terminal E2 (pg/ml), number of mature follicles, number of oocyte retrieved, transferable embryo, endometrial thickness, pregnancy rate and mean expenditure. Statistical analysis is done by using SPSS11.
As compared to control group (1756 ± 75IU), the study group i.e., Let-rFSH received (625 ± 98IU) significantly lower (P = 0.0001) total dose of rFSH. Terminal E2 was significantly lower (P = 0.0001) in study group than control (830 ± 36 vs. 1076 ± 41 pg/ml) with significant increment in endometrial thickness (P = 0.0008) in study group, (9.1 ± 0.32 vs. 8.7 ± 0.69) which maintained an improved pregnancy rate though nonsignificant. The risk of hyperstimulation had significantly (P = 0.01) reduced in study group than control (0 vs. 7).Treatment outcome in all other aspects including pregnancy rate were statistically comparable. Per cycle mean expenditure was reduced by 34% in study group than control.
Adjunctive use of letrozole may be an effective mean of low-cost IVF therapy.
PMCID: PMC3493831  PMID: 23162355
Antagonist; ICSI; letrozole; low-cost IVF; male factor infertility
22.  Is there a Need for Luteinizing Hormone (LH) Estimation in Patients Undergoing Ovarian Stimulation with Gonadotropin-Releasing Hormone (GnRH) Antagonists and Recombinant Follicle-Stimulating Hormone (rFSH)? 
Aim: To find out effect of serum luteinizing hormone (LH) levels on Day 1 (Day 2 of cycle) and Day 5 of stimulation and Day of trigger hCG in controlled ovulation stimulation with antagonist protocol of IVF-ICSI cycle on cycle outcome.
Materials and Methods: This retrospective study was conducted in a University Hospital setting. One hundred and 62 patients underwent 165 cycles of controlled ovarian stimulation (COS) with recombinant Follicle stimulating hormone (rFSH) and Gonadotropin releasing hormone (GnRH) antagonist protocol in one year were included. Serum LH levels estimated on Day 1, Day 5 and the day of trigger hCG injections were divided into three groups based on the percentile and outcome measured.
Results: The average number of follicles >18 mm in size were significant in the patients with LH levels between 25th to 75th percentile group on Day 1, Day 5 and Day of trigger hCG. The fertilization rate was significant (p= 0.04) in the patients with LH levels < 25thpercentile on the day of trigger hCG. Oocyte recovery rate, oocyte maturation rate and average number of best quality embryos (Grade 1) were not affected significantly in all three groups.
Conclusion: In GnRH antagonist and rFSH protocols, low serum LH concentrations on the day of trigger hCG has better fertilization rate. LH levels between 25th and 75th percentile have an influence on the average number of > 18 mm size follicles. However, the LH level on Day 1, Day 5 and Day of hCG does not affect the cycle outcome in COS with antagonist protocol of IVF cycle. Hence, LH estimation is not mandatory in ART cycles with GnRH antagonist protocol.
PMCID: PMC3939598  PMID: 24596733
Luteinizing hormone; recombinant Follicle stimulating hormone (rFSH); Gonadotropin releasing hormone (GnRH) antagonist ligament
23.  Effect of GnRH down-regulation on cumulus cell viability and apoptosis as measured by fluorescence-activated cell sorting 
To determine whether gonadotropin releasing hormone (GnRH)-agonist or -antagonist induces higher percentages of cumulus cell apoptosis and if the use of either is detrimental to ART outcomes.
Women in a private facility under treatment for IVF had their cumulus cells isolated and analyzed by flow cytometry. Viable, apoptotic, and dead cumulus cell rates related to ovarian stimulation by GnRH-agonist or -antagonist were measured and compared with fertilization and implantation rates.
Treatment with GnRH-agonist produced a greater number of follicles than treatment with GnRH-antagonist. No differences in implantation and pregnancy rates were found. While cumulus cell (CC) apoptosis was positively correlated with estradiol on the day of hCG administration, no significant difference in the percentage of apoptotic cells between treatments was detectable. Additionally, implantation rate and the average follicular estradiol production on the day of hCG administration were no different between treatments.
GnRH-agonist or -antagonist treatment protocols induce similar levels of apoptosis in CCs and are not detrimental to ART outcomes.
PMCID: PMC2582090  PMID: 18937065
ART; Cumulus cells; Apoptosis; GnRH; Ovarian stimulation; Flow cytometry
24.  Cessation of Gonadotropin-Releasing Hormone Antagonist on Triggering Day: An Alternative Method for Flexible Multiple-Dose Protocol 
Journal of Korean Medical Science  2009;24(2):262-268.
This study was performed to analyze retrospectively outcomes of stimulated in vitro fertilization (IVF) cycles where the gonadotropin-releasing hormone (GnRH) antagonist was omitted on ovulation triggering day. A total of 92 consecutive IVF cycles were included in 65 women who are undergoing ovarian stimulation with recombinant FSH. A GnRH antagonist, cetrorelix 0.25 mg/day, was started when leading follicle reached 14 mm in diameter until the day of hCG administration (Group A, 66 cycles) or until the day before hCG administration (Group B, 26 cycles). The duration of ovarian stimulation, total dose of gonadotropins, serum estradiol levels on hCG administration day, and the number of oocytes retrieved were not significantly different between the two groups. The total dose of GnRH antagonist was significantly lower in Group B compared to Group A (2.7±0.8 vs. 3.2±0.9 ampoules). There was no premature luteinization in the subjects. The proportion of mature oocytes (71.4% vs. 61.7%) and fertilization rate of mature (86.3±19.7% vs. 71.8±31.7%) was significantly higher in Group B. There were no significant differences in embryo quality and clinical pregnancy rates. Our results suggest that cessation of the GnRH antagonist on the day of hCG administration during a flexible multiple-dose protocol could reduce the total dose of GnRH antagonist without compromising IVF results.
PMCID: PMC2672126  PMID: 19399268
GnRH Antagonist; hCG Administration; Oocyte Maturation; Fertilization; Ovulation Induction; Cetrorelix
25.  Outcome of in vitro fertilization in patients with proven poor ovarian responsiveness after early vs. mid-follicular LH exposure: a prospective, randomized, controlled study 
To compare early vs. mid-follicular exposure to LH in patients with poor ovarian responsiveness undergoing in vitro fertilization (IVF).
Prospective, randomized, controlled trial.
University Hospital, University-affiliated private Clinic.
Five hundred-thirty women with poor ovarian responsiveness during the first IVF cycle, undergoing their second IVF attempt.
In a GnRH-analogue long protocol, ovarian stimulation with recombinant FSH (300 IU/day) plus randomly assigned addition of recombinant LH (150 IU/day) from day 1 (early LH exposure; n = 264) or from day 7 (late LH exposure; n = 266).
Main outcome measure(s)
Primary outcome was the number of oocytes retrieved. Secondary outcomes were: cancellation rate, total gonadotropin dose, duration of ovarian stimulation, number of embryos available for transfer, pregnancy rate per started cycle, per OPU and per embryo transfer, implantation rate, delivered/ongoing pregnancy rate.
Apart from the totally administered LH dose, that was significantly higher in the group receiving it from day 1, all parameters related to IVF outcome were non significantly different in the two groups.
Adding LH to FSH from day 1 or from day 7 of ovarian stimulation in a GnRH-agonist long protocol exerts comparable effects on IVF outcome in poor responders.
PMCID: PMC3463670  PMID: 22644636
Follicle-stimulation hormone; In vitro fertilization; Luteinizing hormone; Ovarian sensitivity index; Ovarian stimulation; Poor ovarian responsiveness

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