Initiation Of Ovarian Stimulation Research Articles

P-419 Oocytes quality in random start protocols for fertility preservation: insights from follicular steroidogenesis.

Abstract Study question Is follicular steroidogenesis impaired in women undergoing random start protocols for fertility preservation? Summary answer The phase of menstrual cycle at initiation of ovarian stimulation does not influence the endocrine microenvironment surrounding oocytes. What is known already Cryopreservation of oocytes is the gold standard for fertility preservation in women with cancer. Random start protocols have been introduced for oocytes cryopreservation in these patients to shorten the duration of ovarian stimulation. However, albeit generally reassuring, available evidence is still insufficient to rule out a sub-optimal cycle outcome of random start protocols. Study design, size, duration The present study was conducted to provide evidence on the validity of random start protocols by exploring the quality of ovarian steroidogenesis. The primary outcome was comparing levels of steroids in the follicular fluid between women initiating the random start protocol in the luteal phase and those initiating in the follicular phase (considered as controls since equivalent to the conventional protocols). We excluded those requiring concomitant letrozole assumption. Participants/materials, setting, methods Seventy-one women with cancer were prospectively recruited during a 24-month period. Thirty-three initiated in luteal phase while 38 in follicular phase. All women were stimulated with recombinant FSH and GnRH antagonists. At the time of oocytes retrieval, follicular fluids were pooled, and a sample was frozen at -80 °C. All samples were assayed concomitantly after thawing, by liquid chromatography tandem mass spectrometry. The concentration of 15 different steroid hormones was determined. Main results and the role of chance Baseline characteristics of the two groups were similar. No differences emerged in anamnestic data and ovarian reserve variables. Cycle outcome did not also differ, the two study groups being similar in terms of total dose of gonadotropins, duration of stimulation, number of developed follicles and number of oocytes retrieved. The median [interquartile range] number of frozen mature oocytes was 9 [5-14] and 10 [5-21] in women who initiated in the luteal and the follicular phase, respectively (p = 0.42). None of the 15 tested steroid hormones differed. Two subgroup secondary analyses were performed to rule out confounders. First, we excluded women who were on estroprogestins at the time of recruitment (leaving 31 women initiating in the follicular phase and 32 in the luteal phase). Levels of steroids in the follicular fluids were still mainly similar. We observed a significant difference only for androstenedione, levels being higher for women initiating stimulation in the follicular phase. Second, we compared women in the early (up to day 5) and late follicular phase (26 and 12 cases, respectively). Levels of steroids in the follicular fluids did not differ except for cortisone, the concentration being higher in the early follicular phase. Limitations, reasons for caution Our study is not randomized, inevitably exposing our results to confounders. Assessment of intraovarian steroidogenesis is an indirect evidence of oocyte quality. Multiple comparisons were done, exposing our findings to type I errors (such as, in our opinion, the differences that emerged in the secondary analyses). Wider implications of the findings Random start protocols have become the standard of care for fertility preservation in women with cancer in the absence of robust evidence. Our data supports the validity of random start protocols in terms of quality of ovarian response since none of the tested hormones differed. Trial registration number Not applicable

Comparison of blastocyst euploidy rates following luteal versus follicular phase stimulation in a GnRH antagonist protocol: a prospective study with repeated ovarian stimulation cycles.

Is there any difference in the mean number of euploid embryos following luteal phase start (LS) and follicular phase start (FS) of ovarian stimulation? The mean number of euploid blastocysts is equivalent independent of whether the inseminated oocytes are derived from FS or LS. Starting ovarian stimulation at any time of the cycle ('random-start') is commonly used for emergency fertility preservation in cancer patients. A few retrospective studies have been published evaluating LS in women undergoing ovarian stimulation in the context of IVF, but there is a lack of robust data on the comparative efficacy of LS versus FS.Although 'random start' is commonly used in cancer survivors, few retrospective and uncontrolled studies have been published evaluating luteal phase stimulation in women undergoing ovarian stimulation in the context of IVF. Owing to this evident lack of robust data on the efficacy of LS, guidelines typically recommend the LS approach only for medical reasons and not in the context of IVF. This is a prospective, equivalence study, with repeated stimulation cycles, conducted between May 2018 and December 2021. Overall, 44 oocyte donors underwent two identical consecutive ovarian stimulation cycles, one initiated in the FS and the other in the LS. The primary outcome of the study was to evaluate whether FS and LS in the same patient would result in equivalent numbers of euploid embryos following fertilization of oocytes with the same sperm sample. Overall, 44 oocyte donors underwent two consecutive ovarian stimulation protocols with 150 μg corifollitropin alpha followed by 200 IU recombinant FSH (rFSH) in a fixed GnRH antagonist protocol. The only difference between the two cycles was the day of initiation of ovarian stimulation, which was in the early follicular phase (FS) in one cycle, and in the luteal phase (LS) in the other. Forty-four oocyte recipients participated in the study receiving a mean of six metaphase II (MII) oocytes from each stimulation cycle (FS and LS). All MIIs were inseminated with the corresponding recipient's partner sperm (which had been previously frozen) or donor sperm, in order to safeguard the use of the same sample for either the FS or LS. Following fertilization and blastocyst culture, all generated embryos underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuploidy). FS resulted in a significantly shorter duration of ovarian stimulation (difference between means (DBM) -1.05 (95% CI -1.89; -0.20)) and a lower total additional dose of daily rFSH was needed (DBM -196.02 (95% CI -319.92; -72.12)) compared with LS. The donors' hormonal profile on the day of trigger was comparable between the two stimulation cycles, as well as the mean number of oocytes (23.70 ± 10.79 versus 23.70 ± 8.81) (DBM 0.00 (95% CI -3.03; 3.03)) and MII oocytes (20.27 ± 9.60 versus 20.73 ± 8.65) (DBM -0.45 (95% CI -2.82; 1.91)) between FS and LS cycles, respectively. Following fertilization, the overall blastocyst formation rate was 60.70% with a euploid rate of 57.1%. Comparisons between the two stimulation cycles did not reveal any significance differences in terms of fertilization rates (71.9% versus 71.4%), blastocyst formation rates (59.4% versus 62%) and embryo euploidy rates (56.9 versus 57.3%) for the comparison of FS versus LS, respectively. The mean number of euploid blastocysts was equivalent between the FS (1.59 ± 1.30) and the LS (1.61 ± 1.17), (DBM -0.02 (90%CI -0.48; 0.44)). The study was performed in young, potentially fertile oocyte donors who are patients with high blastocyst euploidy rates. Although results may be extrapolated to young infertile women with good ovarian reserve, caution is needed prior to generalizing the results to infertile women of older age. The current study provides evidence that initiation of ovarian stimulation in the luteal phase in young potentially fertile women may result in a comparable number of oocytes and comparable blastocyst euploidy rates compared with follicular phase stimulation. This may imply that in case of a freeze-all protocol in young patients with good ovarian reserve, clinicians may safely consider initiation of ovarian stimulation during the luteal phase. This research was supported by an unrestricted grant from MSD/Organon. N.P.P. has received Research grants and honoraria for lectures from: Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins Intenational, Roche Diagnostics, IBSA, Theramex, Gedeon Richter. F.M., E.C., M.R. and S.G. declared no conflict of interests. The study was registered at Clinical Trials Gov (NCT03555942).

P-613 Association between basal androgen concentrations and number of follicles on the day of triggering final oocyte maturation in poor responders undergoing IVF; A prospective study

Abstract Study question Are basal androgen concentrations associated with the number of follicles on the day of triggering final oocyte maturation in poor responders undergoing in vitro fertilization (IVF)? Summary answer A significant negative association is present between (dehydroepiandrosterone sulfate) DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation. What is known already Studies in animals have shown that androgens promote early follicular development and granulosa cell proliferation, by augmenting follicle-stimulating hormone (FSH) receptor expression in granulosa cells. Several retrospective studies have evaluated the association between basal androgen concentrations and follicular development in normal and poor responders undergoing ovarian stimulation for IVF with conflicting results. Study design, size, duration This prospective study was performed between 02/2020 and 01/2022 in 103 poor responders according to the Bologna criteria. Androgens, including total testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), Δ4-androstenedione and 17-OH progesterone (17-OHP), were measured at the initiation of ovarian stimulation, using the automated Elecsys immunoanalyser (Roche Diagnostics, Mannheim, Germany). Ovarian stimulation was performed using a fixed dose of 300 IU of recombinant gonadotrophins and gonadotrophin-releasing hormone (GnRH) analogues. Participants/materials, setting, methods Triggering of final oocyte maturation was performed in the presence of three follicles of ≥ 17mm. The primary outcome measure was the number of follicles ≥11mm on the day of triggering final oocyte maturation. The association between androgen concentrations and the number of follicles ≥11mm on the day of triggering was evaluated using generalized estimating equations, accounting for female age and body mass index (BMI). Values were expressed as coefficient (coef) or mean (95% confidence interval). Main results and the role of chance Female age was 41.9 (41.2-42.6) years, while BMI was 26.1 (24.9-27.3) kg/m2. The duration of ovarian stimulation was 10.3 (9.7-10.8) days and the total dose of gonadotrophins required was 3058 (2903-3213) IU. The number of follicles ≥11 mm on the day of triggering final oocyte maturation was 6.1 (5.3-7.0). The number of COCs retrieved was 3.9 (3.2-4.6), the number of MII oocytes was 3.4 (2.8-3.9) and the number of 2pn oocytes was 2.5 (2.1-2.8). No significant association was found between basal testosterone (coef: -0.008, -0.019 to + 0.003, p = 0.17), 17-OHP (coef: -0.044, -0.391 to + 0.303, p = 0.80), SHBG (coef: -0.002, -0.007 to + 0.002, p = 0.25) Δ4-androstenedione (coef: -0.101, -0.306 to + 0.104, p = 0.33) concentrations and the number of follicles ≥11mm on the day of triggering final oocyte maturation. In contrast, a significant negative association was found between basal DHEAS (coef: -0.011, -0.019 to -0.003, p = 0.007) concentrations and the number of follicles ≥11 mm on the day of triggering final oocyte maturation. Higher DHEAS concentrations were associated with the development of fewer follicles ≥11 mm. Limitations, reasons for caution This prospective study evaluated the association between basal androgen concentrations and the number of follicles on the day of triggering final oocyte maturation in poor responders stimulated with a fixed dose of recombinant FSH. However, the precision of the estimates could be increased by analyzing a larger study population. Wider implications of the findings DHEA supplementation in poor responders undergoing IVF has not been shown to improve ovarian response. Given the significant negative association between DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation, future studies on DHEA supplementation should consider basal DHEAS concentrations. Trial registration number N/A

P–678 Increased luteinizing hormone in ovarian dysfunction attenuates follicle development and oocyte quality in human

Abstract Study question Can increased luteinizing hormone impair follicular development and oocyte quality in patients with ovarian dysfunction? Summary answer Increased luteinizing hormone attenuates follicular development and oocyte quality, resulting in arrest of follicle growth and empty follicles and low-quality embryos. What is known already Patients with ovarian dysfunction exhibit elevated gonadotropins and low estrogen levels reflecting their low ovarian reserve. For ovarian stimulation in these patients, natural or mild stimulation protocols are likely used, but we often experienced the arrest of follicle growth and empty follicles at oocyte retrieval. Animal studies demonstrated that chronic high LH exposure impaired the growth of antral follicles by suppressing the expression of FSHR in granulosa cells via a modulation of intraovarian regulators, including the LH-induced thecal factors. Study design, size, duration: Retrospective analysis was conducted in 72 patients with ovarian dysfunction who received ovarian stimulations followed by IVF-ET from April 2018 to March 2020 after obtaining written informed consents under an approval from the ethical committee of our hospital. Participants/materials, setting, methods The data of hormonal levels, transvaginal ultrasound during ovarian stimulation and clinical outcome of IVF were extracted from electric chart. For evaluation of embryo, high quality embryos referred to embryos having Veeck classification >grade 3 and >4 blastomeres. Statistical significance was determined using Dunnett or chi-square tests, with P < 0.05 being statistically significant. Main results and the role of chance The median age of participants was 42 years of age (range 26–49) with low serum AMH levels (median 0.9 ng/ml, range 0–1.83). We analyzed 361 cycles of ovarian stimulation in total (median 4 cycles/patient, range 1–21). These stimulation cycles were classified into 3 groups; group A (n = 230): normal LH level, group B (n = 93): elevated LH level (> 10 mIU/ml) after ovarian stimulation and group C (n = 33): elevated LH level from the initiation of ovarian stimulation. Among 361 cycles, the arrest of follicle growth was detected in 5 cycles (group A: 0%, group B: 60%, group C: 40%). The proportions of empty follicle in group A, B and C were 17.3±2.0%, 20.9±3.3%and 38.6±7.2%, respectively. The rate of empty follicle was significantly high in group C. Although there was no significant difference in the rates of oocyte degeneration and fertilization, the rate of high-quality embryos in group C was 0.8-fold lower than that of group A. Limitations, reasons for caution Due to limitation of participants, we could not determine the appropriate LH level for ovarian stimulation in patients with ovarian dysfunction based on receiver operatorating characteristic curve. Wider implications of the findings: Normalization of LH levels for ovarian simulation in patients with ovarian dysfunction could improve follicle development and oocyte quality. Trial registration number Not applicable

Anti-Müllerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta.

The stability of anti-Müllerian hormone (AMH) across and between menstrual cycles has been the subject of debate. The objective of this analysis was to study the inter- and intracycle variability in repeated measurements and assess the impact on an individualized gonadotropin dosing algorithm and predicted oocyte yield. Retrospective analysis of repeat AMH measures from a randomized controlled trial. A total of 1326 women aged 18-40years. Serum AMH levels at screening and at cycle day 2-3 in up to three ovarian stimulation cycles. AMH variability and its impact on gonadotropin dose and the predicted number of oocytes. Repeat serum AMH measurements were strongly correlated within individual women (correlation coefficient 0.92). AMH exhibited limited within-subject variation (coefficient of variation 23%), a small time-related decline (mean 6% decrease/y), but no systematic variation across the menstrual cycle. Irrespective of whether the AMH screening value or the AMH at the initiation of ovarian stimulation was used, for women with an AMH level <15pmol/L, 93% would receive the same gonadotropin dose and attain an identical number of oocytes in 97% of cases. For women with an AMH level ≥15pmol/L, 80% would receive an individualized dose within ±1.5μg and 90% would attain ±1 oocyte. AMH variability had limited impact on individualized gonadotropin dosing, with 95% of women predicted to obtain an oocyte yield that does not vary beyond 1 oocyte count, irrespective of whether a random or early follicular AMH measurement was used to determine the individualized gonadotropin dose.

Initiation of Ovarian Stimulation with Recombinant FSH in a GnRH An-tagonist Cycle: Day 2 versus Day 5?

Recent approaches in IVF are trending towards more physiological and patient friendly stimulation cycles, with reduction in cost and stress associated with ovarian stimulation. Delaying onset of stimulation from day 2 to day 5 in a GnRH antagonist protocol is a novel approach which helps maintain a more physiological hormonal milieu. The present review compares the follicular growth patterns and endocrine profiles in women undergoing delayed onset versus the conventional day 2 start of ovarian stimulation.

Microdose flare protocol with interrupted follicle stimulating hormone and added androgen for poor responders—an observational pilot study

To investigate whether temporarily withholding FSH and adding androgen could improve follicular response during a microdose flare protocol in women with slow follicular growth or asynchronous follicular development. Observational pilot study. University-affiliated private fertility center. Twenty-six women aged 34-47 years with poor response to stimulation or a previous cancelled IVF cycle and with slow or asynchronous follicular growth during a microdose flare cycle. For 13 women, after initiation of ovarian stimulation using the microdose flare protocol, gonadotropin administration was interrupted and transdermal testosterone gel was added for several days (4.4 ± 1.2 d) starting after cycle day 7 (mean cycle day 10 ± 2.6). FSH, E2, follicular growth, and total number of mature oocytes retrieved were determined for all of the patients. Cycle cancellation rate as well as pregnancy rate following embryo transfer were also documented when applicable. FSH levels declined (25.2 ± 6.5 to 6.8 ± 3.2 IU/L), E2 levels increased (896 ± 687 to 2,163 ± 1,667 pmol/L), and follicular growth improved significantly during gonadotropin interruption and were tracked for 2 days during this time frame. The average number of oocytes retrieved was 5.3 ± 2.6, and the ratio of mature to total oocytes was 4:5. Four of the 13 women in the interruption group conceived following frozen embryo transfer, whereas none in the control group did. The androgen-interrupted FSH protocol may improve follicular response to gonadotropins in cycles that might otherwise be cancelled.

To pill or not to pill in GnRH-antagonist cycles: the answer is in the data already!

The planning of IVF treatment by scheduling menstruation and hence initiation of ovarian stimulation using sex-steroid pre-treatment is commonly used. Pooling data from six randomized-controlled trials encompassing 1343 patients, with and without combined oral contraceptive pill pre-treatment, suggests that the ongoing pregnancy rate per randomized woman is significantly lower in patients with oral contraceptive pill pre-treatment (relative risk [RR]: 0.80, 95% confidence interval [CI]: 0.66–0.97; rate difference [RD]: −5%, 95% CI: −10% to −1%; fixed effects model). This finding remains remarkably robust in multiple sensitivity analyses: exclusion of a study on poor responders, exclusion of the three smallest studies or exclusion of studies with a pill-free interval of less than 5 days, results in RR of 0.78 (95% CI: 0.64–0.94), 0.80 (95% CI: 0.65–0.98) and 0.79, (95% CI: 0.64–0.99), respectively. Furthermore, the finding of a significant reduction in ongoing pregnancy rate is not inconsistent with other evidence from the literature. The potential benefit of using oral contraceptive pill pre-treatment for cycle planning should therefore be balanced against its detrimental effect. Further randomized studies should test whether an effect similar to the one observed after combined oral contraceptive pill usage exists after other sex steroid pre-treatment regimens.

Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial

BackgroundWe sought to determine the impact of treatment flexibility on clinical outcomes in either a corifollitropin alfa or recombinant follicle-stimulating hormone (rFSH) protocol.MethodsPost hoc analysis of a prospective, multicenter, randomized, double-blind, double-dummy non-inferiority clinical trial (Engage). Efficacy outcomes were assessed on patients from the Engage trial who started treatment on menstrual cycle day 2 versus menstrual cycle day 3, patients who received rFSH step-down or fixed-dose rFSH, patients who received rFSH on the day of human chorionic gonadotropin (hCG) compared with those who did not, and patients who received hCG when the criterion was reached versus those with a 1-day delay.ResultsThe effect of each of the treatment flexibility options on ongoing pregnancy rate was not significant. The estimated difference (95% confidence interval) in ongoing pregnancy rate was -4.3% (-9.4%, 0.8%) for patients who started ovarian stimulation on cycle day 2 versus day 3, 1.8% (-4.1%, 7.6%) for patients who received hCG on the day the hCG criterion was met versus 1 day after, 3.2% (-2.1%, 8.6%) for patients who received rFSH on the day of hCG administration versus those who did not, and -5.8% (-13.0%, 1.4%) for patients who received a reduced versus fixed-dose of rFSH from day 8.ConclusionsTreatment flexibility of ovarian stimulation does not substantially affect the clinical outcome in patients’ treatment following initiation of ovarian stimulation with either corifollitropin alfa or with daily rFSH in a gonadotropin-releasing hormone antagonist protocol.Trial registrationTrial was registered under ClinicalTrials.gov identifier NCT00696800.

Hepatic Dysfunction in a Case of Severe Ovarian Hyperstimulation Syndrome

Purpose: Clinical manifestations of ovarian hyperstimulation syndrome (OHSS) have been described as abdominal discomfort, ascites, nausea and vomiting. Hepatic dysfunction as a result of OHSS has occasionally been reported. We observed a rare case of acute reversible hepatic dysfunction associated with ascites in a patient undergoing in vitro fertilization (IVF) with ovarian stimulation. A 41-year-old African American female presented with abdominal pain, distension, and edema one month after initiation of her second IVF attempt. Her initial attempt was one year prior, had involved minimal ascites and edema, but the pregnancy was ectopic and unsuccessful. During this second course of IVF, she received a combination of Follistim and Menopur (follicle stimulating hormones), and Ganirelix (gonadotropin releasing hormone antagonist) for two weeks, followed by egg retrieval five days later and subsequent implantation two weeks later. At the time of implantation, she was hospitalized with moderate ascites, abdominal pain, pleural effusion and weight gain of 20 pounds since initiation of ovarian stimulation. She underwent a five liter paracentesis with improvement in abdominal pain symptoms. Liver enzymes were normal upon admission, but increased throughout her hospital course. AST and ALT peaked at 405 and 496, respectively. Alkaline phosphatase remained normal at 95, total bilirubin was 0.5, platelets were 348 and INR was 0.9. Her serum albumin declined by more than 50 percent initially, but normalized to 4.0 with a normal globulin. She had no risk factors or underlying liver disease prior to this episode. She was treated supportively and subsequently, liver enzymes returned to normal one month later. This pregnancy resulted in a miscarriage, but a third IVF attempt led to a successful pregnancy. The literature has documented few cases of hepatic dysfunction as a consequence of OHSS. This case demonstrates a severe form of OHSS given the severity of liver dysfunction as well as edema, pleural effusions, ascites and weight gain. Currently, OHSS is classified as mild, moderate or severe. The severe form is defined as significant fluid shifts, ascites, pleural effusions and large ovarian cysts. Although not part of this classification, acute hepatic dysfunction, while uncommon, can be characteristic of severe OHSS given the associated increase in fluid shifts and decrease in albumin. This condition appears to be reversible and transient, dissipating as hormone therapy is weaned. As more cases of hepatic dysfunction are discovered with severe OHSS, liver abnormalities should be included in the recognized criteria for the classifications.

The relationship between the change in serum high sensitivity C-reactive protein levels and IVF success

The aim of this study was to assess whether the extent of the change in high sensitivity C-reactive protein (hs-CRP) levels is related with in vitro fertilization (IVF) success. A total of 69 IVF cycles using long luteal GnRH agonist protocol at the IVF unit, were prospectively studied. The serum levels of hs-CRP were measured on the day of initiation of gonadotrophin stimulation and 7 days after embryo transfer. CRP ratio was defined as the levels of CRP on day 7 of transfer/day of initiation of ovarian stimulation. Clinical pregnancy rates were examined. The mean concentrations of hs-CRP were not significantly different on the first day of ovarian stimulation and on day 7 after embryo transfer among pregnant and non-pregnant women. There was a significant rise in hs-CRP levels at 7th day after embryo transfer as compared with the first day of gonadotrophin treatment in both groups (10.58 ± 11.35 versus 3.61 ± 2.86 mg/L for pregnant women and 9.14 ± 11.36 versus 3.24 ± 2.68 mg/L for non-pregnant women, p = 0.001). In addition, the mean CRP ratio was not different between the pregnant and non-pregnant groups. Our data show that serum hs-CRP levels increase during IVF treatment, but the extent of the rise in CRP levels is not a predictive marker of IVF success.

Letrozole does not aid in the prevention of ovarian hyperstimulation syndrome inspite of lower peak estradiol levels

OBJECTIVE: To determine if the addition of Letrozole to the ovarian stimulation protocol for Assisted Reproductive Technology reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in a group of high risk patients.DESIGN: Prospective controlled Pilot study.MATERIALS AND METHODS: Ten high risk patients for OHSS were selected based on prior history of hyperstimulation or the presence of polycystic ovaries. The control group n=5 used a stimulation protocol consisting of the use leuprolide acetate at 0.1 mg subcutaneously (SC) 8 days prior the cessation of oral contraceptives, the dose of leuprolide acetate was then decreased to 0.05 mg SC upon initiation of ovarian stimulation with purified urinary FSH. In the Letrozole group (n=5), on the day of gonadotropin start, Letrozole was added to the protocol at a dose of 2.5 mg orally daily until human chorionic gonadotropin administration (hCG).RESULTS: The SAS software was used to calculate p-values from five Student's two-sample t tests. There was no statistical significance in the number of oocytes retrieved or the number of embryos cryopreserved due to hyperstimulation. The degree of hyperstimulation was Moderate in both groups. All the patients in the Letrozole group underwent a “freeze all” cycle due to clinical findings of hyperstimulation. There were only two statistical significant differences. The estradiol levels were much higher in the control group mean=3144pg/ml compared to the Letrozole group 640pg/ml p<0.0001 as expected. The fertilization rate was lower in the Letrozole group 21% vs. 57% p<0.0005. The lower fertilization rates seen in the Letrozole group did not impact statistically the number of embryos cryopreserved in each group.Table 1ControlLetrozoleP valueAge (mean)(32.8)(36)0.20Oocytes retrieved(25)(29)0.46Fertilization rate (%)5721<0.0005Embryos Transferred20NSCryopreserved embryos(8.2)(5.8)0.14Peak Estradiol (pg/ml)(3144)(640)<0.0001Degree of OHSSmoderatemoderateNSFSH (amps) total used(31.8)(40)NS Open table in a new tab OBJECTIVE: To determine if the addition of Letrozole to the ovarian stimulation protocol for Assisted Reproductive Technology reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in a group of high risk patients. DESIGN: Prospective controlled Pilot study. MATERIALS AND METHODS: Ten high risk patients for OHSS were selected based on prior history of hyperstimulation or the presence of polycystic ovaries. The control group n=5 used a stimulation protocol consisting of the use leuprolide acetate at 0.1 mg subcutaneously (SC) 8 days prior the cessation of oral contraceptives, the dose of leuprolide acetate was then decreased to 0.05 mg SC upon initiation of ovarian stimulation with purified urinary FSH. In the Letrozole group (n=5), on the day of gonadotropin start, Letrozole was added to the protocol at a dose of 2.5 mg orally daily until human chorionic gonadotropin administration (hCG). RESULTS: The SAS software was used to calculate p-values from five Student's two-sample t tests. There was no statistical significance in the number of oocytes retrieved or the number of embryos cryopreserved due to hyperstimulation. The degree of hyperstimulation was Moderate in both groups. All the patients in the Letrozole group underwent a “freeze all” cycle due to clinical findings of hyperstimulation. There were only two statistical significant differences. The estradiol levels were much higher in the control group mean=3144pg/ml compared to the Letrozole group 640pg/ml p<0.0001 as expected. The fertilization rate was lower in the Letrozole group 21% vs. 57% p<0.0005. The lower fertilization rates seen in the Letrozole group did not impact statistically the number of embryos cryopreserved in each group.

GnRH antagonists in ovarian stimulation for IVF

The present review describes, on the basis of the currently available evidence, the consensus reached by a group of experts on the use of gonadotropin-releasing hormone (GnRH) antagonists in ovarian stimulation for IVF. The single or multiple low-dose administration of GnRH antagonist during the late-follicular phase effectively prevents a premature rise in serum luteinizing hormone (LH) levels in most women. Although controversy remains, most comparative studies suggest a slight, not significant reduction in the probability of pregnancy after IVF using GnRH antagonist versus GnRH agonist co-treatment. Published meta-analyses suggest that this slight difference in pregnancy rates is not attributed to chance. Further studies applying varying treatment regimens and outcome measures are required. Data are not in favour of a need to modify the starting dose of gonadotropins. Data are not in favour of increasing gonadotropin dose at GnRH antagonist initiation. The addition of LH from the initiation of ovarian stimulation or from GnRH antagonist administration does not appear to be necessary. Replacement of human chorionic gonadotropin (HCG) by GnRH agonist for triggering final oocyte maturation is associated with a lower probability of pregnancy. The optimal timing for HCG administration needs to be explored further. GnRH antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14-16 mm, although earlier GnRH antagonist administration is worth further evaluation. Luteal phase supplementation in GnRH antagonist protocols remains mandatory in IVF. Effects of GnRH antagonist co-treatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present in favour of the GnRH antagonists. The role of GnRH antagonists in ovarian stimulation for IVF appears to be promising, although many questions regarding preferred dose regimens and effects on clinical outcomes remain.

Dose of GnRH agonist (nafarelin acetate) affects intrafollicular PAPP-A expression in controlled ovarian hyperstimulation cycle

Objective: To determine the effect of dose of GnRH agonist on the follicular environment in controlled ovarian hyperstimulation (COH) cycles. Study design: Twenty-eight IVF patients with normal ovarian function were divided into three groups: group I received GnRHa (nafarelin acetate/Synarel) intranasally at 200 μg daily, group II received 400 μg daily until hCG injection, and group III was given 400 μg daily before the initiation of ovarian stimulation, then 200 μg daily before the day of hCG injection. Serum estradiol, progesterone, and leptin levels were measured on the day of hCG injection. After aspiration, expression of pregnancy-associated α-plasma protein (PAPP)-A in the follicular fluid of dominant follicles (>20 mm) was determined by Western blot analysis. Results: No significant difference was noted in serum estradiol, progesterone, and leptin levels. But intrafollicular PAPP-A expression was significantly higher in group II compared to other groups ( P<0.05). Conclusion: The dose of GnRHa may have an impact on the intrafollicular environment of dominant follicles in COH cycles.

The role of ovarian volume in an in vitro fertilization programme as assessed by 3D ultrasound.

The study was designed to investigate the role of ovarian volume, as assessed by three-dimensional (3D) sonography, in predicting conception in an in-vitro fertilization-embryo transfer (IVF-ET) programme. Transvaginal 3D sonography was performed in 152 cycles before initiation of ovarian stimulation (day 1) and on the day of oocyte retrieval. Ovarian volume showed no significant correlation with IVF outcome. On the contrary, all ovarian measurements were lower, albeit nonsignificantly, in the conception group. Fifteen patients (15/152, 9.9%) had a minimum unilateral ovarian volume of < or =3 mL (1 SD below the mean) on day 1 of the stimulation cycle. In this subgroup, the likelihood of conception was 6.7% (1/15) versus 21.9% (30/137) in patients with an initial minimum ovarian volume of >3 mL. This difference did not reach statistical significance. In both groups, cancellation rates due to poor ovarian response or lack of fertilization were similar. In conclusion, ovarian volumetry as assessed by three-dimensional ultrasound failed to predict conception in women undergoing IVF treatment.