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.
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.
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.
FSH; Estradiol pre-treatment; Controlled ovarian hyperstimulation; IVF
To study the efficacy of gonadotrophin releasing hormone (GnRH) antagonist in In-vitro-fertilization/Intracytoplasmic sperm injection (IVF/ICSI) cycles.
TYPE OF STUDY:
Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, Tamil Nadu.
MATERIALS AND METHODS:
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.
Assisted reproduction; Gonadotrophin releasing hormone antagonists; ICSI; IVF
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.
Gonadotropin-releasing hormone (GnRH); agonist; antagonist; in vitro fertilization; embryo transfer; assisted reproduction; controlled ovarian stimulation cycles
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.
Cetrorelix; GnRH-agonist; GnRH-antagonist; IVF; Poor responders
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.
Gonadotropin-releasing hormone; Antagonist; Agonist; Oral Contraceptives; Poor Responders; In vitro fertilization; Intracytoplasmic sperm injection; Human
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.
Blastocyst; GnRH agonist; GnRH antagonist; multiple ET failures
The purpose of the study was to compare the effectiveness of GnRH antagonist with luteal phase estradiol administration to GnRH agonist cycles, long protocol.
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.
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.
We clearly demonstrated that the effectiveness of GnRH antagonist when combined with luteal phase estradiol is comparable to GnRH agonist cycles.
GnRH antagonists; GnRH agonist; Follicular cohort; Homogenization; Luteal phase oestradiol
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.
SETTINGS AND DESIGNS:
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.
MATERIALS AND METHODS:
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.
Cytokines; follicular fluid; multiplex analysis; ovarian stimulation; perifollicular hemodynamics
Purpose: To investigate the efficacy of gonadotrophin-releasing hormone (GnRH) antagonist supplementation during natural cycles in poor responders undergoing IVF-ET treatment.
Methods: We retrospectively evaluated 540 cycles of 433 suitable patients who were divided by treatment protocol into modified natural, antagonist, and long agonist groups. There were 52 modified natural cycles with GnRH antagonist supplementation, 200 stimulated cycles with GnRH antagonist, and 288 long GnRH agonist cycles. Cycle characteristics and treatment outcomes were compared between the groups.
Results: The mean number of oocytes retrieved in the modified natural group was significantly lower than in the stimulated antagonist and long agonist groups (1.4± 0.5 vs. 2.3± 1.1 and 2.5± 1.1, respectively, p < 0.05). The respective implantation and pregnancy rates were 10% and 14.3%, 6.75% and 10.2%, and 7.4% and 10.6%. Cycle outcome and cycle properties were similar.
Conclusions: Modified natural IVF cycle with GnRH antagonist supplementation is a feasible alternative to ovarian stimulation protocols in poor responders.
GnRH antagonists; IVF; natural cycle; ovulation induction; poor ovarian response
Ovarian hyperstimulation syndrome (OHSS) still remains a life-threatening complication of in vitro fertilization treatment (IVF), keeping patients and especially those, who previously experienced OHSS, from attempting infertility treatment and childbearing. The recent implementation of four new modalities: the GnRH antagonist protocol, GnRH agonist (GnRHa) triggering of ovulation, blastocyst transfer and embryo/oocyte vitrification, renders feasible the elimination of OHSS in connection with ovarian hyperstimulation for IVF treatment. The proposed current algorithm is based on the number of follicles developed after ovarian stimulation, setting a cut-off level at the development of 18 or more follicles. Further, fulfilling this criterion, the algorithm is based on four decision-making points: the final day of patient work-up, the day of triggering final oocyte maturation, day-1 post oocyte pick-up (OPU) and day-5 post OPU.
If the physician decides to administer hCG for final oocyte maturation regardless the type of analogue used, he has the option on day-1 to either freeze all embryos or to proceed to day-5. On this day, based on the clinical condition of the patient, a decision should be made to either transfer a single blastocyst or to vitrify all blastocysts available. However, this strategy will not guarantee an OHSS free luteal phase especially if a pregnancy occurs. If the physician decides to trigger ovulation with GnRHa, feasible only with the antagonist protocol, embryos can be cultured until day-5. On this day a transfer can be performed with no risk of OHSS and spare blastocysts may be vitrified. Alternatively, on day-1 or day-2 post OPU, all embryos could be frozen.
Hopefully, in a near future, GnRHa triggering and vitrification of oocytes will become everyday practice. Only the combined use of a GnRH antagonist protocol with GnRHa triggering and subsequent single blastocyst transfer or embryo/oocyte freezing will completely abolish the risk of OHSS after ovarian hyperstimulation.
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.
ART; Cumulus cells; Apoptosis; GnRH; Ovarian stimulation; Flow cytometry
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.
Polycystic ovary syndrome; In vitro maturation; GnRH antagonist; GnRH agonist; Assisted reproductive technology outcome
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.
Polycystic ovary syndrome; GnRH antagonist; GnRH agonist; Body mass index; Controlled ovarian stimulation; In vitro fertilization
Both oral contraceptive pills (OCPs) and estradiol (E2) valerate have been used to schedule gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles and, consequently, laboratory activities. However, there are no studies comparing treatment outcomes directly between these two pretreatment methods. This randomized controlled trial was aimed at finding differences in ongoing pregnancy rates between GnRH antagonist IVF cycles scheduled with OCPs or E2 valerate.
Between January and May 2012, one hundred consecutive patients (nonobese, regularly cycling women 18–38 years with normal day 3 hormone levels and <3 previous IVF/ICSI attempts) undergoing IVF with the GnRH antagonist protocol were randomized to either the OCP or E2 pretreatment arms, with no restrictions such as blocking or stratification. Authors involved in data collection and analysis were blinded to group assignment. Fifty patients received OCP (30 μg ethinyl E2/150 μg levonorgestrel) for 12–16 days from day 1 or 2, and stimulation was started 5 days after stopping OCP. Similarly, 50 patients received 4 mg/day oral E2 valerate from day 20 for 5–12 days, until the day before starting stimulation.
Pretreatment with OCP (mean±SD, 14.5±1.7 days) was significantly longer than with E2 (7.8±1.9 days). Stimulation and embryological characteristics were similar. Ongoing pregnancy rates (46.0% vs. 44.0%; risk difference, –2.0% [95% CI –21.2% to 17.3%]), as well as implantation (43.5% vs. 47.4%), clinical pregnancy (50.0% vs. 48.0%), clinical miscarriage (7.1% vs. 7.7%), and live birth (42.0% vs. 40.0%) rates were comparable between groups.
This is the first study to directly compare these two methods of cycle scheduling in GnRH antagonist cycles. Our results fail to show statistically significant differences in ongoing pregnancy rates between pretreatment with OCP and E2 for IVF with the GnRH antagonist protocol. Although the study is limited by its sample size, our results may contribute to a future meta-analysis. An interesting future direction would be to extend our study to women with decreased ovarian reserve, as these are the patients in whom an increase in oocyte yield—due to the hypothetical beneficial effect of steroid pretreatment on follicular synchronization—could more easily be demonstrated.
IVF; GnRH antagonist; Cycle scheduling; Oral contraceptives; Estrogen pretreatment
Several protocols are actually available for in Vitro Fertilization and Embryo Transfer. The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol. The majority of randomized clinical trials clearly shows that in “in Vitro” Fertilization and Embryo Transfer, the combination of exogenous Gonadotropin plus a Gonadotropin Releasing Hormone (GnRH) agonist, which is able to suppress pituitary FSH and LH secretion, is associated with increased pregnancy rate as compared with the use of gonadotropins without a GnRH agonist. Protocols with GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol. However, a different synchronization of follicular recruitment and growth occurs with GnRH agonists than with GnRH antagonists. Future developments have to be focused on timing of the administration of GnRH antagonists, by giving a great attention to new strategies of stimulation in patients in which radio-chemotherapy cycles are needed.
ivf; GnRH; Oocytes; GnRH protocols
Serum anti-Mullerian hormone (AMH) is currently considered the best marker of ovarian reserve and of ovarian responsiveness to gonadotropins in in-vitro fertilization (IVF). AMH assay, however, is not available in all IVF Units and is quite expensive, a reason that limits its use in developing countries. The aim of this study is to assess whether the "ovarian sensitivity index" precisely reflects AMH so that this index may be used as a surrogate for AMH in prediction of ovarian response during an IVF cycle.
AMH serum levels were measured in 61 patients undergoing IVF with a "long" stimulation protocol including the GnRH agonist buserelin and recombinant follicle-stimulating hormone (rFSH). Patients were divided into four subgroups according to the percentile of serum AMH and their ovarian stimulation was prospectively followed. Ovarian sensitivity index (OSI) was calculated dividing the total administered FSH dose by the number of retrieved oocytes.
AMH and OSI show a highly significant negative correlation (r = -0.67; p = 0.0001) that is stronger than the one between AMH and the total number of retrieved oocytes and than the one between AMH and the total FSH dose.
OSI reflects quite satisfactory the AMH level and may be proposed as a surrogate of AMH assay in predicting ovarian responsiveness to FSH in IVF. Being very easy to calculate and costless, its use could be proposed where AMH measurement is not available or in developing countries where limiting costs is of primary importance.
In in vitro fertilization (IVF) cycles controlled ovarian hyperstimulation (COH) is established by gonadotropins in combination with gonadotropin-releasing hormone (GnRH) agonists or antagonists, to prevent premature luteinizing hormone (LH) surge. The aim of our study was to improve the understanding of gene expression profile of cumulus cells (CC) in terms of ovarian stimulation protocol and oocyte maturity. We applied Affymetrix gene expression profiling in CC of oocytes at different maturation stages using either GnRH agonists or GnRH antagonists. Two analyses were performed: the first involved CC of immature metaphase I (MI) and mature metaphase II (MII) oocytes where 359 genes were differentially expressed, and the second involved the two GnRH analogues where no differentially expressed genes were observed at the entire transcriptome level. A further analysis of 359 differentially genes was performed, focusing on anti-Müllerian hormone receptor 2 (AMHR2), follicle stimulating hormone receptor (FSHR), vascular endothelial growth factor C (VEGFC) and serine protease inhibitor E2 (SERPINE2). Among other differentially expressed genes we observed a marked number of new genes connected to cell adhesion and neurotransmitters such as dopamine, glycine and γ-Aminobutyric acid (GABA). No differential expression in CC between the two GnRH analogues supports the findings of clinical studies where no significant difference in live birth rates between both GnRH analogues has been proven.
To investigate the effects of pioglitazone on controlled ovarian stimulation (COS), IVF outcomes, and follicular fluid (FF) cytokine concentrations in patients with polycystic ovary syndrome (PCOS).
Eighty-six infertile patients with PCOS resistant to clomiphene citrate were randomized to receive pioglitazone (30 mg/day) or placebo on the starting day of oral contraceptive (OC) pretreatment, followed by an IVF protocol using a GnRH antagonist. Pioglitazone or placebo was administered once daily from the starting day of OC to the day of hCG injection.
Total dose and days of recombinant follicle-stimulating hormone administered, and the numbers of retrieved and mature oocytes, were significantly lower in the pioglitazone group than in the control group. FF tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations at oocyte retrieval were also significantly lower in the pioglitazone group. The clinical pregnancy rate was higher and the incidence of severe ovarian hyperstimulation syndrome was lower in the pioglitazone group, but the differences were not statistically significant.
Pioglitazone reduces FF TNF-α and IL-6 levels, and may improve ovarian response to COS in patients with PCOS.
Pioglitazone; Follicular Fluid; Tumor Necrosis Factor-alpha; Interleukin-6; In Vitro Fertilization; Polycystic Ovary Syndrome; Human
To determine why a subgroup of coasted patients developed moderate/severe ovarian hyperstimulation syndrome (OHSS) in an assisted reproduction setting.
MATERIALS AND METHODS:
Retrospective study of 2948 in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycles with 327 patients requiring coasting. Long protocol gonadotrophin releasing hormone analogue (GnRH-a) regimen was used and serum estradiol (E2) checked when ≥20 follicles were noted on follicular tracking. Coasting was initiated when leading three follicles were ≥15mm with E2 ≥1635pg/ml.
The incidence of moderate/severe OHSS was 10.4% in coasted patients (equivalent 1.15% of the total IVF/ICSI cycles in the Center). Coasted patients who subsequently developed OHSS showed a significantly higher number of retrieved oocytes, higher serum E2 level on the day of human chorionic gonadotrophin (hCG) administration, and multiple pregnancies. No significant differences were noted with female age, BMI, cause of infertility, gonadotrophin dosage, coasting duration, and % of E2 drop.
Moderate/severe OHSS might be predicted in coasted patients by a combination of total oocyte numbers and E2 level on the day of hCG. Multiple pregnancies also significantly increased the risk.
Coasted patients; IVF treatment cycle; ovarian hyperstimulation syndrome
To compare the effectiveness of two stimulation protocols in non-polycystic ovary (PCO) high responders undergoing in vitro fertilization (IVF).
Prospective randomized trial.
A Reproductive Medicine and IVF Unit of a University Hospital and a private IVF Clinic.
Four hundred-and-twelve normoovulatory women with good ovarian responsiveness were randomized to receive either the “mild” (FSH 150 IU/day from day 4 of a spontaneous cycle followed by GnRH-antagonist from day 8; n = 205) or the “long” (FSH 150 IU/day; n = 207) stimulation protocol. The outcome of these two regimens was compared including “fresh” and thawing cycles.
The total FSH dose and the peak estradiol level were significantly lower in the “mild” protocol, whereas the retrieved oocytes, fertilization rate, number and quality of embryos, pregnancy and implantation rates, cumulative “fresh plus thaw” success rate, and incidence of severe ovarian hyperstimulation syndrome were comparable with the two regimens.
In young, normoovulatory patients with good ovarian responsiveness undergoing IVF the “mild” stimulation protocol has effectiveness and risks comparable to the “long” protocol with low FSH starting dose, even when thawing cycles are included in the comparison.
Mild ovarian stimulation; IVF; GnRH antagonist; FSH
While performing the mild ovarian stimulation protocol with a GnRH antagonist, the pregnancy rate was compared between the groups, which were divided by the degree that the luteinizing hormone (LH) level decreased.
Materials and methods
Patients aged 27 to 42years (36.1 ± 3.79) underwent 308 IVF cycles who opted for IVF via the mild ovarian stimulation protocol began clomiphene citrate on day 3 and recombinant FSH on day 5. A GnRH antagonist was administered when the dominant follicle reached 14mm. Serum LH was measured at the time of GnRH antagonist administration and at the time of hCG injection. The pregnancy rate and implantation rate were compared between 50 cycles in which the LH level dropped less than one-third and the control (LH level within 1/3).
The pregnancy rate for the group in which the LH level fell less than one third was 18%. Conversely, the pregnancy rate for the control group was 39%. The implantation rate was 18% for the less than one-third group and 26% for the control group. Both the pregnancy rate and the implantation rate for the group in which the LH level fell less than one-third were significantly lower than that of control (p < 0.02).
When performing the mild ovarian stimulation protocol, serum LH should be followed. If the serum LH level is less than one-third at the time of hCG injection, both the pregnancy rate and implantation rate are significantly lower.
Clomiphene citarate; Recombinant follicle-stimulation hormone; Gonadotropin-releasing hormone antagonist; In vitro fertilization
To evaluate whether oocyte quality, implantation and pregnancy outcomes in in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) are related to the duration of gonadotropin-releasing hormone (GnRH)-antagonist use or the timing of its initiation.
Retrospective cohort study of 178 conventional IVF/ICSI cycles. All patients underwent ovarian stimulation with gonadotropins and GnRH-antagonist for pituitary down-regulation. Spearman correlations and logistic regression were used for statistical analysis.
There was no correlation between the duration of use or the timing of initiation of GnRH-antagonist with oocyte quality or implantation and pregnancy outcomes. Oocyte quality was influenced by the peak estradiol. Implantation was influenced by the patient’s age. Early pregnancy loss, by the endometrial thickness on human chorionic gonadotropin-day. Ongoing pregnancy was independent from the variables evaluated.
GnRH-antagonist duration of use or starting day did not influence oocyte quality, implantation rates, and pregnancy rates. We hypothesize that a follicle stimulating hormone/luteinizing hormone dose increase when antagonist was started, may have had an impact on our findings.
GnRH antagonist; Implantation; IVF/ICSI; Oocyte; Pregnancy
Purpose:Our purpose was to assess the effect of pretreatment with oral contraceptives (OCs) on the formation of functional ovarian cysts during pituitary supression with gonadotropin-releasing hormone (GnRH) agonists, subsequent follicular development, and pregnancy rates.
Methods:A retrospective case-controlled study of 31 in vitro fertilization (IVF) patients, all of whom in a previous cycle had commenced the long protocol of GnRH-agonist (Buserelin) in the early follicular phase and were pretreated in a subsequent cycle with 2 weeks of an OC containing 30 μg of ethinyl estradiol and 150 μg of desogestrel prior to GnRH-agonist administration, was undertaken. Follow-up visits were arranged after a minimum of 11 days of GnRH-agonist administration and weekly thereafter until pituitary suppresion was achieved.
Results:Cysts were detected in 16 (51.6%) of the 31 patients not pretreated with OCs, and in 0 (0%) of the 31 patients pretreated with OCs (odds ratio = 67.1; 95% confidence interval = 5.6–350.7). Patients pretreated with OCs achieved pituitary suppression more rapidly (median difference = 4 days; 95% confidence interval = 2–7) and had comparable gonadotropin requirements and pregnancy rates.
Conclusions:Pretreatment with OCs prior to pituitary suppression in the early follicular phase decreases ovarian cyst formation, without an apparent effect on subsequent follicular recruitment or pregnancy rates.
oral contraceptive; long protocol; pituitary suppression; gonadotropin releasing-hormone agonist