GnRH Agonist Suppression Research Articles

P-620 First step for personalized luteal support in frozen-thaw embryo transfer: Understanding the factors associated with serum progesterone concentrations on embryo transfer day

Abstract Study question What factors determine serum progesterone (P) concentration on embryo transfer (ET) day after artificially prepared (AP) cycles receiving intramuscular progesterone (IM-P)? Summary answer Lower serum P concentrations on ET day in AP frozen-thaw cycles are associated with high body mass index(BMI) and low estradiol(E2) levels on ET day. What is known already Large sample sized studies reported low serum P levels on ET day in AP cycles related to low success rates. There are limited studies evaluating the pregnancy rates in patients with low serum P on ET day after the rescue doses. These studies included the patients who received vaginal P. There is no study evaluating rescue doses with low serum P concentration after IM-P. Common sense is that personalization of luteal phase support may increase the success rates. To adjust the P dosages, patient and cycle characteristics need to be analyzed for prediction of low serum P concentration. Study design, size, duration This retrospective cohort study conducted at Bahçeci Ankara IVF Center between November 2019 and February 2022. The study included 637 single or double frozen-thawed blastocyst transfers undergoing AP endometrium receiving 100 mg IM-P after incremental oestrogen treatment. Serum P concentrations were evaluated from the blood samples which were obtained between 117-119 hours after the first IM-P administration and 21±2 hours after last IM-P administration. Participants/materials, setting, methods A total of 637 patients, first frozen-thawed blastocyst ET cycles were analyzed. The mean age, BMI, duration of oestrogen treatment, ET day E2 and ET day P concentration of the study population were 31.9±5.1 years, 26.7 ±4.7 kg/m2, 13.9±1.3 days, 266.1±90.9 pg/ml and 30.2±9.3 ng/ml respectively. Correlation analysis for patient and cycle characteristics and serum P concentrations were evaluated. Multivariate linear regression analysis was performed to determine the independent factors. Main results and the role of chance The overall live birth rate in total study group was 50.7% (323/637). Female age, serum P concentrations on ET day, and number of embryos transferred were significantly associated with live birth. Bivariate correlation analysis revealed that ET day P concentrations were negatively correlated to BMI (r:-0.12, p: 0.002) and positively correlated to ET day E2 concentrations (r:0.14, p:0.001). However, no correlation to female age, causes of infertility, E2, P and LH concentrations on P administration day, duration of oestrogen treatment and presence or absence of GnRH agonist suppression. When a multivariate linear regression was performed to correct potential confounders, increasing BMI presented a negative correlation to ET day serum P concentrations (p = 0.003; 95% CI -0.384 to -0.079 ). On the contrary, significant positive correlations to ET day serum P concentrations were shown with ET day E2 levels (p = 0.01; 95% CI 0.003 to 0.018). Other patient and cycle characteristics were not found to be an independent factor for ET day P concentration. Limitations, reasons for caution The retrospective nature of the study is the main limitation. Only patients with IM-P were included therefore the results cannot be extrapolated to other P administration forms and needs to be validated. After determining the low serum P threshold in large sample size, the parameters should be re-evaluated. Wider implications of the findings Monitoring P levels and adjusting the doses of P administration (via personalization) may have a positive impact on outcome. Not only patient and cycle characteristics, also pharmacokinetic and pharmacogenetic studies are warranted to optimize luteal phase support. Personalization of the luteal phase can be achieved by this way. Trial registration number NA

P-679 Comparison of hormone replacement treatment (HRT) and true-natural cycle (t-NC) protocols for endometrial priming: An analysis of 1,815 warmed blastocyst transfer cycles

Abstract Study question Does the ongoing pregnancy rate (OPR) of HRT with or without GnRH-agonist suppression and t-NC protocols differ in patients undergoing warmed blastocyst transfer? Summary answer HRT, with or without GnRH-agonist suppression, and t-NC protocols are associated with comparable OPRs in patients undergoing warmed blastocyst transfer. What is known already Despite the worldwide increase in frozen embryo transfer cycles, the most optimal protocol for priming of the endometrium is debated. Although HRT offers flexibility, recent evidence points tot-NC being superior to HRT regarding safety, i.e., maternal, obstetric, and neonatal outcomes.However, there are still conflicting data regarding pre-clinical losses and reproductive outcomes when comparing the two protocols. Study design, size, duration In this longitudinal prospective study, 1,815 consecutive patients undergoing 1,815 warmed blastocyst transfer cycles at the Anatolia IVF Centre, Ankara, between 2015-2021, were included. HRT with pituitary suppression was the protocol of choice during 2015- 2017, whereas HRT without suppression and t-NC were more commonly employed during the latter part of the period. Participants/materials, setting, methods All patients with an available day-5/6 vitrified blastocyst(s) were included. Each patient was included only once. The three protocols were t-NC and HRT - with or without suppression. The prerequisites for t-NC was being a local patient with regular menstrual cycles. For t-NC, neither human chorionic gonadotropin (hCG) nor luteal phase support was administered. The primary outcome measure was OPR, defined as pregnancy >12 weeks of gestation. Main results and the role of chance Of the 1,815 cycles,124 were t-NC, 477 were HRT with suppression, and 1,214 were HRT without suppression. For the stimulated cycles leading to FET, no difference was seen among the three groups regarding female age, body mass index, duration of infertility, number of previous embryo transfer attempts, ovarian stimulation protocol, estradiol levels on the day of hCG trigger, number of oocytes retrieved, number of preimplantation genetic testing-aneuploidy, freeze-all cycles and number of embryos transferred. The positive pregnancy test rates of the HRT protocol with or without suppression were higher when compared with that of t-NC (63.7%, 66.6%, and 58.1%,respectively; p = 0.05). The respective figure for clinical pregnancy rates were 56.6%, 60.8% and 55.6% (p = 0.07). However, the pre-clinical (biochemical) loss rates (11.9%, 10.9%, and 4.9%, respectively; p = 0.05), as well as the miscarriage rates (11.9%, 10.9%, and 4.9%, respectively; p = 0.04), were higher in the HRT groups with or without suppression compared to those of t-NC. The OPRs of t-NC, HRT with or without suppression were comparable (53.2%, 45.1%, and 49.0%, respectively; p = 0.73). The protocol for endometrial priming was not an independent predictor of ongoing pregnancy at logistic regression analysis when potential confounders were used as covariates (OR = 0.998; 95%CI 0.669-1.490, p = 0.99). Limitations, reasons for caution The longitudinal study design and the lack of obstetric and perinatal outcome data are limitations. Wider implications of the findings Compared with t-NC, the HRT protocol with/without suppression is associated with higher positive pregnancy test rates albeit increased pre-clinical and clinical loss rates, resulting incomparable OPRs. When compared with t-NC, the HRT protocol could be associated with enhanced endometrial receptivity at the expense of decreased selectivity. Trial registration number not applicable

P–301 Intrauterine instillation of autologous platelet rich plasma for thin endometrium improves the outcome of frozen embryo transfer cycles

Abstract Study question How does the intrauterine instillation of autologous platelet rich plasma (PRP) affect the endometrial thickness and live birth rate in frozen embryo transfer cycles? Summary answer Intrauterine instillation of autologous PRP resulted in significant improvement in endometrial thickness. The live birth rates were satisfactory post-PRP instillation. What is known already Autologous Platelet rich plasma (PRP) had resulted in significant improvement in endometrial thickness, when instilled intrauterine in women with thin endometrium in FET cycles. Study design, size, duration A retrospective observational study was performed at a tertiary care university teaching hospital in South India. 35 women who received intrauterine autologous PRP during endometrial preparation for frozen embryo transfer from June 2017 to December 2020, were included. Patients who underwent donor oocyte recipent cycles, those with a history of tubercular endometritis, Asherman syndrome, previous intrauterine manipulations such as manual removal of placenta, and uterine anomalies were excluded. Participants/materials, setting, methods All the women underwent endometrial preparation in artificial cycles by depot GnRH agonist suppression and HRT (Hormone replacement therapy) was initiated by 4–6 mg of estradiol valerate and stepped up as required. Autologous PRP was offered to all women who had endometrial thickness < 7 mm on day 16 of HRT. PRP was prepared by the two-step centrifugation method and administered intrauterine by IUI catheter. The patients underwent repeat evaluation after 5 days post-PRP instillation. Main results and the role of chance Optimal response to PRP was considered as the attainment of an endometrial thickness (ET) ≥ 7mm after 5 days of post-PRP. 25 (71.4%) had an optimal response to PRP. There was a significant improvement in the endometrial thickness(mm) in the study participants following PRP instillation: 6.3 ± 0.6 vs. 7.1 ± 1.2; P = 0.0001.The study participants were divided into two groups based on their response to intrauterine PRP instillation. Those who optimally responded to PRP were categorized as Group A and those who didn’t were categorized as Group B. The study participants of both the groups were comparable by their demographic characteristics such as age, cause of infertility, indications for ART, and the dose of estradiol valerate before PRP. The dose of estradiol valerate (mg) after PRP was significantly higher in Group B compared to Group A: 19.9 ± 4.9 vs. 15.6 ± 3.9; P = 0.014. A total of 26 women underwent embryo transfer and 9 (25.7%) women had cycle cancellation. Of these 22 were from Group A and 4 from Group B. The pregnancy, clinical pregnancy, miscarriage and live birth rates were 36.3%(8/22) and 25% (1/4); 31.8% (7/22) and 25% (1/4); and 31.8% (7/22) and 25% (1/4), respectively. Limitations, reasons for caution As the study was retrospective in nature and the PRP was offered only in patients who had consented, there was a significant bias. Hence the results of the study should be interpreted with caution. Further large prospective RCTs (Randomised controlled trials) are required to confirm our findings. Wider implications of the findings: Autologous PRP may enhance the response to the estrogen preparations. It may produce satisfactory live birth rates and reduce cycle cancellations in a reasonable proportion of patients with thin endometrium in FET cycles. However, these findings should be confirmed by dose finding clinical trials, and studies involving a comparison group. Trial registration number Not applicable

IGF-1 and IGFBP-3 serum concentrations in patients undergoing programmed frozen-thawed embryo transfer of euploid PGT-A embryos

IGF-1 has been shown to induce embryonic development in vitro, but at high concentrations exhibits toxic effects by decreasing embryonic glucose uptake. IGFBP-3 binds IGF-1, modulating its bioavailability and is essential to its function. Prior reports have associated elevated follicular phase IGF-1 with pregnancy loss in frozen-thawed embryo transfer in natural cycles (n-FET), but an association in programmed (p-FET) cycles or in the luteal phase has not been analyzed. We sought to determine whether serum levels of IGF-1 and IGFBP-3 correlate with the outcome of p-FET cycles. Retrospective cohort study. Patients who underwent p-FET of single, good quality (Grade ≥2BB), PGT-normal embryos were included in the study. GnRH-agonist suppression was started in the preceding luteal phase, overlapped with estradiol patches, and stopped with the start of progesterone. Serum samples were collected on cycle day 2 (CD2), the day of progesterone start (CDP4), and cycle days 28 (CD28) and 30 (CD30). Embryo transfer occurred on the 7th day of P4 administration. Serum levels of IGF-1 and IGFBP-3 were compared between those who did not achieve pregnancy, those who had a live birth, and those who had a pregnancy loss. Serum IGF-1 and IGFBP-3 levels were measured by chemiluminescent immunoassays using the Immulite 2000 XPi. Statistical analysis was performed using Chi-square and Fisher’s exact test. P<0.05 was deemed statistically significant. A total of 102 patients who underwent p-FET of single euploid embryos over 2 years were analyzed. The mean age at retrieval was 35.7 ± 4.1 years, BMI 24.2 ± 4.8 kg/m2, gravity 1.8 ± 1.6, parity 0.4 ± 0.6 and peak endometrial thickness 9.7 ± 2.0 mm. 76.5% of patients were pregnant and 78.2% of those had a live birth. Among women who conceived, those who had a subsequent pregnancy loss had significantly higher serum IGF-1 levels on CDP4 and CD28 compared to those who achieved live birth when analyzing patients whose serum IGF-1 levels were above the mean value of IGF-1 level on CDP4 (136 ng/ml, p= 0.044) and CD28 (138 ng/ml, p=0.007), and between patients with CD28 IGF-1 levels one standard deviation above the mean (≥160 ng/ml, p=0.007). There was no significant difference in the serum levels of IGFBP-3 in any of the treatment cycle days.Tabled 1p-FET, Deliveredp-FET, Pregnancy losspIGF-1 CDP4 (≥ mean value)63.6%33%0.044IGF-1 CD 28(≥ mean value)58%14%0.044IGF-1 CD28 (≥ 160 ng/ml)70.8%14%0.007 Open table in a new tab In p-FET cycles with transfer of a single, euploid, high quality embryo, IGF-1 serum levels on day of progesterone start and CD28 are significantly higher in patients who subsequently had a pregnancy loss compared to those who had a live birth. This is in contrast to the findings of prior studies in n-FET.

Transdermal versus oral estrogen: clinical outcomes in patients undergoing frozen-thawed single blastocyst transfer cycles without GnRHa suppression, a prospective randomized clinical trial

PurposeTo conduct a non-inferiority study to compare the clinical outcomes of transdermal estrogen patch and oral estrogen in patients undergoing frozen-thawed single blastocyst transfer non-donor cycles without GnRHagonist (GnRHa) suppression.MethodsA total of 317 women with irregular menses or anovulatory cycle undergoing frozen-thawed embryo transfer (FET) non-donor cycles without GnRHa suppression were involved in a prospective randomized clinical trial between May 2017 and October 2017. The trial was conducted in an ART and Reproductive Genetics Centre within a private hospital. The unit is designated as a teaching center by the Turkish Ministry of Health. Oral or transdermal estrogen was administered in patients undergoing frozen-thawed single blastocyst transfer. The outcomes of the study were the following: endometrial thickness on the day of progesterone administration, implantation rate, and clinical and viable ongoing pregnancy rates.ResultsEndometrial thickness and clinical outcomes of oral and transdermal estrogen administration were equally successful (p > 0.05).ConclusionNo significant difference was found in endometrial thickness on the day of progesterone administration nor in clinical outcomes between transdermal estrogen and oral estrogen in patients undergoing frozen-thawed single blastocyst stage transfer cycles without GnRHa suppression.

Impact of method of endometrial preparation for frozen blastocyst transfer on pregnancy outcome: a retrospective cohort study

To determine whether live birth rates differ by type of endometrial preparation in frozen embryo transfer (FET) cycles. Retrospective cohort study. Academic fertility center. Reproductive-aged women undergoing autologous vitrified-warmed blastocyst FETs. Comparison of two methods of endometrial preparation: programmed FET (known as group A: luteal phase GnRH agonist suppression, oral E2, and IM P starting 5days before ET) versus unstimulated FET (known as group B: hormone and ultrasound monitoring for follicle collapse to time transfer). Live birth rates in group A and group B. Group A consisted of 923 cycles, and group B consisted of 105. When stratified by age at transfer, there was no difference in any of the measured outcomes, including live birth rates in adjusted models (adjusted odds ratio 1.0, 95% confidence interval 0.6-1.5), except in patients older than 40years. These patients in group B had a 100% failure rate (n = 6). In most women, unstimulated endometrial preparation with luteal support before FET has similar success compared with exogenous hormone preparation. Women older than 40years may benefit from programmed FETs owing to the challenges of increased cycle variability expected in that age group.

Determinants of monozygotic twinning in ART: a systematic review and a meta-analysis.

The incidence of monozygotic twins (MZT) after ART appears to be higher than the incidence after spontaneous conceptions contradicting the aim of ART to avoid multiple pregnancies because of the associated risks. The aim was to study the frequency of MZT after IVF and ICSI and how it is influenced by the day of embryo transfer, maternal age, zona pellucida manipulation, controlled ovarian stimulation, stimulation protocol, culture media and embryo quality. Original studies and reviews were identified by searching the PubMed, Embase and Cochrane databases up to March 2017. The inclusion criterion was publications focusing on the five study questions related to MZT in our study. The exclusion criteria were articles that did not include blastocyst transfer, were on non-humans, were not published in peer-reviewed journals, and were based only on case studies. All of the articles were categorized according to the Oxford Centre for Evidence-based Medicine's 'Levels of Evidence', and quality and risk of bias assessment was performed with 'The Cochrane Collaboration's Risk of Bias Tools'. A meta-analysis was performed to study the impact of the day of embryo transfer on the MZT rate. The literature search resulted in a total of 42 articles, including 38 original studies, for analysis. The included original studies reported a MZT rate with blastocyst transfer from zero to 13.2%. Our meta-analysis found a higher frequency of MZT after blastocyst transfer compared with cleavage-stage embryos transfer: odds ratio = 2.18, 95% CI: 1.93-2.48 (fixed effect meta-analysis). A younger maternal age may increase the MZT rate, and recent studies regarding the use of zona pellucida manipulating techniques have disagreed with the previous suspicion of a higher MZT rate after the use of these methods. The extended culture to-blastocyst stage is a potential risk factor for MZT, but it is uncertain whether this phenomenon is due to the extended time, culture media or greater likelihood of younger oocytes to reach the blastocyst stage. An increased frequency of MZT following the GnRH-agonist suppression protocol has been suggested, as well as a decreased frequency of MZT with high gonadotrophin doses, which could reflect an age-related effect. Only limited literature has focused on the role of embryo morphology in the MZT rate, therefore, this issue remains unresolved. We found blastocyst transfer to be a risk factor for MZT. Hence, the results of this meta-analysis may weaken the previously proposed view that greater experience with blastocyst transfer and improved culture media could decrease the high rate of MZT after blastocyst transfer. To minimize the rate of MZT and the associated complications, the mechanisms underlying blastocyst transfer and MZT pregnancy must be elucidated.

Fertility preservation for medical reasons in girls and women: British fertility society policy and practice guideline

Fertility preservation in the female poses several challenges due to the invasive nature of the techniques available to achieve it. The guideline aims to bring together the evidence available for the measures for fertility preservation and their outcome. The guideline addresses fertility preservation for medical reasons and includes both oncological and non-oncological causes. The techniques that the guideline considers are: (i) embryo and oocyte cryopreservation; (ii) ovarian tissue cryopreservation; (iii) GnRH agonist suppression and (iv) ovarian transposition. Although ovarian tissue cryopreservation is still considered experimental, the availability of this technique is gaining momentum as more live births from auto-transplanted tissue are reported. The guideline also highlights use of current treatment modalities for benign and malignant conditions that have a better fertility sparing profile. The guideline recommends a multidisciplinary approach in counselling women and girls about the risk to their fertility and available techniques. The role of psychological support in assisting women and girls with decision-making is highlighted. The guideline also highlights the risks associated with these techniques. Women need to be medically fit to undergo invasive procedures. Fertility preservation techniques are appropriate when treatment has curative intent. Fertility preservation is a subject of on-going research on outcomes of different techniques and at the time of publication, studies are still likely to emerge adding to the available literature.

The future of IVF: vitrified-warmed blastocyst transfer

Introduction: The development of blastocyst vitrification has significantly changed the approach to embryo transfer. In cases where there is a high risk for developing ovarian hyperstimulation syndrome, all embryos can be vitrified and transferred in subsequent menstrual cycles. On the other hand, vitrification of surplus embryos at the time of transfer allows for higher cumulative pregnancy rates. The optimal method of endometrium preparation for frozen-thawed embryo transfer (FET) still remains uncertain. The aim of this study was to compare the outcomes of vitrified-warmed blastocyst transfers in natural and artificially prepared cycles. Methods: All vitrified-warmed blastocyst transfers performed in the last two years (2013 and 2014) at our IVF centre were included in this retrospective study. In women with predictable and regular ovulatory cycles, FETs were performed in natural cycles without hCG triggering. In patients with irregular and anovulatory cycles, FETs were performed in artificially prepared cycle using the combination of oestradiol and micronized progesterone without GnRH agonist suppression. Patients’ characteristics, treatment parameters and pregnancy outcomes were compared using Pearson's Chi-squared test and Student's t-test. Results: In the study period, 835 vitrified-warmed blastocyst transfers were performed in natural and 278 in artificially prepared cycles. There were no statistically significant differences in patients’ characteristics and treatment parameters between both groups, with the exception of the average number of transferred embryos (1.30 in natural cycles vs. 1.41 in artificial cycles, p < 0.05). The biochemical pregnancy rate observed was higher in artificial cycles (8.90% vs. 17.64%), but there were no statistically significant differences in clinical pregnancy rate (36.03% vs. 34.89%), implantation rate (31.26% vs. 28.94%), abortion rate (14.54% vs. 21.00%) and live birth/ongoing pregnancy rate (30.53% vs. 25.18%) in natural compared to artificial cycles. Conclusion: Vitrified-warmed blastocyst transfers in natural and artificially prepared cycles are equally successful in terms of implantation, ongoing pregnancy and live birth rate. The outcome of vitrified-warmed blastocyst transfer in natural as well as artificial cycles appears to be comparable to blastocyst transfer in fresh IVF cycles.

Effectiveness of HP-hMG vs r-FSH in Patients undergoing IVF/ICSI Cycles with Moderate Male Factor Infertility

ABSTRACTAimThe aim of this case-control study was to compare the efficacy of highly purified human menopausal gonadotropin (HPhMG) vs recombinant follicle stimulating hormone (r-FSH) treatments following GnRH agonist suppression in patients undergoing intracytoplasmic sperm injection (ICSI) with moderate male factor infertility in terms of oocyte and embryo quality and clinical pregnancy outcomes.Materials and methodsA total of 240 infertile women were treated with HP-hMG group (n: 120 patients) or (r-FSH group, n: 120 patients) following GnRH agonist suppression (long regimen). Inclusion criteria for the study groups were infertility due to moderate oligoastheno-teratospermia with no associated female infertility factor, previous ART cycles &lt;2, female patients aged 19 to 35 years with normal basal FSH, regular ovulatory cycles and BMI &lt;30 kg/m2.ResultsTreatment durations and gonadotropin doses were similar in both groups. Cycle cancellation rates, clinical pregnancy and miscarriage rates, total and metaphase II oocytes retrieved, fertilization rate, number of embryos transferred were all similar in both groups. The clinical pregnancy rates were 45.9% (n: 50/109) in the r-FSH group and 40.4% (n: 44/109) in the HP-hMG group.ConclusionHP-hMG is effective as r-FSH in terms of oocyte and embryo quality and clinical pregnancy outcomes in patients undergoing ICSI with moderate male factor infertility.How to cite this articleDalal RJ, Pai H, Palshetkar N. Effectiveness of HP-hMG vs r-FSH in Patients undergoing IVF/ICSI Cycles with Moderate Male Factor Infertility. Int J Infertility Fetal Med 2012;3(2):51-56.

Asian ethnicity is associated with reduced pregnancy outcomes after IVF using a downregulated GnRH agonist suppression protocol

OBJECTIVE: We have previously shown Asian women have significantly fewer pregnancies than Caucasian women when undergoing IVF (OR 0.69, CI 0.49,0.99). Similarly, SART data have corroborated these findings at a national level. However, these data included patients with varying prognoses utilizing multiple different simulation protocols. By restricting this analysis to those undergoing downregulated GnRH protocol, we aimed to determine if these differences existed in patients with presumed good prognosis. DESIGN: Cross-sectional analysis and multivariate modeling. MATERIALS AND METHODS: Self-identified Caucasian and Asian women undergoing a long agonist stimulation protocol between 2002 and 2006 were included in the analyses. The main outcome was clinical pregnancy defined as fetal heart motion by ultrasound. Univariate analyses were performed to determine baseline characteristic differences between the Asian population and the Caucasian population. To estimate the independent contribution of Asian ethnicity, multivariable logistic regression analyses were performed. A backward conditional elimination was used to generate the most parsimonious model, using p=0.20. The final model included ethnicity, age, diagnosis of endometriosis, AFC, and day 3 FSH (Table 1). RESULTS: Five hundred thirty-one Caucasian women and 294 Asian women underwent long agonist stimulation as their first IVF cycle at UCSF from 2002-06. There were no significant differences in baseline characteristics. Peak estradiol levels were significantly higher in Asian women (p<0.001). Regression analyses yielded an unadjusted OR of achieving clinical pregnancy for Asian women of 0.62 (95% CI 0.46,0.83) when compared to Caucasian women, and an adjusted OR of 0.56 (95% CI 0.40,0.78). CONCLUSIONS: Asian ethnicity is an independent predictor of poor IVF outcome in patients undergoing downregulated agonist suppression protocol for their first cycle of IVF. The persistent difference in pregnancy outcomes despite a presumed good prognosis suggests that the effect may be mediated by factors not currently defined in clinical practice.Table 1Asian (n=294)Caucasian (n=531)p valueAge36.4 +/- 4.036.7 +/- 4.0NSNulligravid53.9%55.1%NSMale Factor Diagnosis43.2%41.8%NSDay 3 FSH7.2 +/- 3.27.2 +/- 3.2NSAFC9.9 +/-6.89.7 +/-6.8NSPeak Estradiol2591.9 +/- 14472302.4 +/- 1371p=0.0002Embryo Transfer Number2.9 +/- 1.33.0 +/- 1.4NSClinical Pregnancy Rate35.5%45.6%p=0.0003Delivery Rate28.1%38.7%p=0.0001 Open table in a new tab

Leuprolide acetate: a drug of diverse clinical applications

Leuprolide acetate is a synthetic nonapeptide that is a potent gonadotropin-releasing hormone receptor (GnRHR) agonist used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. As its basic mechanism of action, leuprolide acetate suppresses gonadotrope secretion of luteinizing hormone and follicle-stimulating hormone that subsequently suppresses gonadal sex steroid production. In addition, leuprolide acetate is presently being tested for the treatment of Alzheimer's disease, polycystic ovary syndrome, functional bowel disease, short stature, premenstrual syndrome and even as an alternative for contraception. Mounting evidence suggests that GnRH agonist suppression of serum gonadotropins may also be important in many of the clinical applications described above. Moreover, the presence of GnRHR in a multitude of non-reproductive tissues including the recent discovery of GnRHR expression in the hippocampi and cortex of the human brain indicates that GnRH analogs such as leuprolide acetate may also act directly via tissue GnRHRs to modulate (brain) function. Thus, the molecular mechanisms underlying the therapeutic effect of GnRH analogs in the treatment of these diseases may be more complex than originally thought. These observations also suggest that the potential uses of GnRH analogs in the modulation of GnRH signaling and treatment of disease has yet to be fully realized.

Prospective randomized study to compare frozen-thawed embryo transfer cycles outcome in women with functioning ovaries and hrt for endometrium preparation with or without prior GnRHa suppression

Our study has been focused to determinate if it is necessary to use GnRH agonist suppression in women with functioning ovaries, undergoing frozen-thawed embryo transfer, in artificially prepared cycles.

IVF treatment cancellation following prolonged GnRH agonist for endometriosis

Prolonged GnRH agonist suppression prior to IVF treatment for endometriosis has been suggested to improve pregnancy success. However, in clinical practice, prolonged GnRHa suppression can also lead to IVF treatment cancellation from suboptimal ovarian response to FSH stimulation. The current study was undertaken to determine the prevalence of treatment cancellation and any predictors for such occurrences.

The outcome of different dose GnRH agonist suppression on in vitro fertilization-embryo transfer (IVF-ET) cycle outcome in patients with stage III/IV endometriosis

To evaluate the efficacy of different dose of GnRH agonist hormonal suppression on IVF-ET outcome in the patients with moderate or severe endometrosis. Retrospective study in tertiary university hospital encompassing the time period January 1, 2003∼December 30, 2006. Chinese women for IVF-ET with a primary diagnosis of stages III to IV endometriosis surgically confirmed and their first cycles in our center were included. Group I (61 patients) received standard COH employing mid-luteal phase GnRHa down regulation. Group II (35 patients) received monthly GnRHa 3.75 mg IM ×2 followed by ovarian hyperstimulation. Group III (44 patients) received monthly GnRH agonist 3.75 mg IM ×3 followed by ovarian hyperstimulation. All patients received ovarian stimulation with Gonadotrophin and hCG for triggering. Oocytes retrieval were scheduled 36 hours after hCG. Embryos were transferred at 4∼8 cell stage. Pregnancy rate (PR) were defined as sonographically visualized pregnancy sac. One-way analysis of variance (ANOVA) and Chi square analysis where appropriate. There were no significant differences among the groups with regards to age, duration of infertility, fertilization rate, embryos transferred. Women pretreatment with two or three months of GnRHa required significantly higher gonadotropin doses (ampoules:75IU) (group I: 42.76 ± 16.30, group II: 55.94 ± 23.38, group III: 63.88 ± 26.72, P<0.0001) and longer duration of Gn stimulation than women with standard long protocol (group I: 10.69 ± 1.68, group II: 12.59 ± 2.19, group III: 12.33 ± 2.26, P<0.0001). The number of oocytes was lower in group III than group I and II (group I: 10.22 ± 7.18, group II: 10.24 ± 6.89, group III: 7.07 ± 4.96, P=0.034). Pregnancy rate in group II was higher than group I and III, but that was not significant (group I: 28.6%, group II: 45.2%, group III: 35.1%, P>0.05). Implantation rate was also higher in group II than group I and III, but not significantly (group I: 14.9%, group II: 29.3%, group III: 17.57%, P>0.05). The administration of GnRH agonists to COH in women with moderate or severe endometriosis for a period of two to three months tend to increase the pregnancy rate. Two months of GnRHa (3.75 mg IM) prior to IVF appears to be a better option in Chinese women.

Effectiveness of highly purified human menopausal gonadotropin vs. recombinant follicle-stimulating hormone in first-cycle in vitro fertilization–intracytoplasmic sperm injection patients

To compare the effectiveness of highly purified hMG with recombinant FSH (rFSH) in IVF-intracytoplasmic sperm injection patients who were treated with a GnRH agonist. An open-label, prospective, randomized comparison of fixed gonadotropin regimens. Eighteen Dutch IVF centers. Six hundred twenty-nine patients who were selected for IVF-intracytoplasmic sperm injection. Patients were randomized to receive either highly purified hMG or rFSH in a fixed dosage of 150 IU/d after GnRH-agonist suppression (long protocol). Ongoing pregnancy rate per started cycle. Difference between the two treatment groups was tested by using odds ratios, including the 95% confidence limits (intention-to-treat sample), and by using the Fisher's exact test (per-protocol sample). The ongoing pregnancy rates per started cycle were 26.3% and 25.2% for highly purified hMG and rFSH, respectively (no statistically significant difference). Treatment with highly purified hMG resulted in statistically significantly fewer oocytes (n = 7.8) than did treatment with rFSH (n = 10.6). There were no differences with respect to fertilization rates and implantation rates. Cycles with highly purified hMG were statistically significantly less often canceled as a result of ovarian hyperresponse (2.0% vs. 6.0% for highly purified hMG and rFSH, respectively). Compared with rFSH, highly purified hMG did not result in superiority in ongoing pregnancy rates in first-cycle IVF-intracytoplasmic sperm injection patients who were treated with a fixed dosage of 150 IU of gonadotropin per day. Compared with rFSH, treatment with highly purified hMG resulted in retrieval of fewer oocytes, a lower incidence of hyperresponse, and comparable pregnancy rates.

The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study

To determine whether the use of luteal phase vaginal E(2) supplementation improves clinical pregnancy rates in patients undergoing IVF treatment. Prospective randomized controlled trial. University-based tertiary fertility center. One hundred sixty-six patients undergoing their first cycle of IVF treatment. Patients underwent three different protocols for controlled ovarian hyperstimulation for IVF treatment with long GnRH agonist suppression, use of GnRH antagonist, or a microdose GnRH agonist protocol. Luteal phase support was in the form of IM P. Patients randomized into the study group (n = 84) received E(2) supplementation in the form of vaginal estrace 2 mg twice a day starting on the day of ET. Patients randomized to the control group (n = 82) received no E(2) supplementation. Clinical pregnancy rates. There were no significant differences in the implantation (56/210 [26.7%] vs. 64/203 [31.5%]), clinical pregnancy (42/84 [50%] vs. 52/82 [63.4%]), and ongoing pregnancy rates (40/84 [47.6%] vs. 46/82 [56.1%]) between the study and control groups, respectively. In the subgroup of patients who used the long GnRH agonist suppression protocol, there was a lower clinical pregnancy rate in the study group compared with the control group (27/55 [49.1%] vs. 42/59 [71.2%]). There were, however, no differences in clinical pregnancy rates between the two groups in patients who used either the GnRH antagonist or microdose GnRH agonist protocols. The addition of vaginal E(2) supplementation to routine P supplementation for luteal support does not improve the probability of conception after IVF treatment.

Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome

To evaluate serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) levels during stimulation in polycystic ovary syndrome (PCOS) and control populations as factors predictive of IVF outcome. Observational study. Academic medical center-based IVF practice. Forty-three PCOS and 33 male-factor control patients undergoing IVF from 2002 to 2004. Treatment with a dual suppression protocol incorporating oral contraceptive pills (OCPs) and GnRH agonist suppression followed by low-dose gonadotropin therapy. The PCOS and control patients' serum IGF-I and IGFBP-3 levels were compared and correlated with IVF outcome. PCOS and control patients were comparable in terms of demographics and IVF outcome. In both, mean serum IGF-I levels increased during stimulation. PCOS patients whose IGF-I levels decreased from day 3 to day of hCG had a significantly higher mean number of immature oocytes retrieved (4.8 +/- 1.1 vs. 2.4 +/- 0.4; P=.02). IGFBP-3 levels increased during stimulation in PCOS patients but tended to decrease in control patients. In PCOS patients, an increase in IGFBP-3 levels during stimulation was associated with a greater likelihood of becoming pregnant (P=.03) and of ongoing pregnancy (P=.02). The bioavailability of IGF-I appears to play a key role in oocyte maturation in PCOS patients. Alterations in IGFBP-3 concentration during stimulation may be a critical mechanism in modulating IGF-I activity.

Cumulative exposure to high estradiol levels during the follicular phase of IVF cycles negatively affects implantation

To investigate the effect of the cumulative exposure to estradiol (E(2)) during the follicular phase on IVF outcome. Patients were stimulated with recombinant FSH after GnRH agonist suppression and had a day 3-embryo transfer. Estrogen exposure was determined as the area under the curve (AUC) for serum E(2) levels measured from the first day of stimulation through the day after hCG administration. E(2) AUC thresholds for 10th and 90th percentiles were 4704 pg/ml and 16338 pg/ml, respectively. The pregnancy and implantation rates were highest in the 10th-90th percentile group, and were statistically higher in this group than in the >90th percentile group (54.6% vs. 33.3% and 24.8% and 12.9%, respectively, for pregnancy and implantation rates, P < 0.05). Recovered mature oocytes, fertilization, and number and mean score of transferred embryos were similar. High cumulative E(2) exposure during the follicular phase of IVF cycles has detrimental effects on implantation.

P-865: In vitro fertilization outcomes in women with polycystic ovarian syndrome using recombinant follicle-stimulating hormone with or without the addition of human menopausal gonadotropin

While women with PCOS often have high sensitivity to stimulation with gonadotropins, their IVF cycles may be complicated by overstimulation, poor oocyte quality, decreased pregnancy rates and increased miscarriages. Increased LH levels may be responsible for these difficulties posing an interesting possibility that COH with FSH alone rather than with LH-containing products may offer better cycle outcomes for these women. We sought to compare IVF outcomes in PCOS patients when stimulated with FSH alone versus a combination of FSH+hMG after midluteal GnRH agonist suppression.