Dose Of Recombinant Follicle Stimulating Hormone Research Articles

Exploring Independent Effects of Follicle-Stimulating Hormone In Vivo in a Mouse Model.

During the transition from a reproductive to a nonreproductive phase (menopause), many women experience significant physiological and pathological changes, including decreased bone mass, increased blood lipids, and increased visceral adiposity. Levels of follicle-stimulating hormone (FSH) rise during the menopausal transition. Many studies have shown that FSH in various extragonadal tissues and organs is associated with the pathogenesis of multiple diseases. Thus, building an animal model that can help study the independent effects of FSH in vivo is particularly important. In this study, C57BL/6 female mice were ovariectomized and supplemented with estradiol valerate (OVX + E2) to eliminate the effect of the hypothalamic-pituitary-gonadal axis. The OVX + E2 mice received solvent (N.S.) or different doses of recombinant FSH via intraperitoneal injection to create a mouse model (OVF) characterized by relatively stable estrogen and rising FSH levels. Thus, we successfully generated an experimental mouse model to mimic the early stage of menopause transition, characterized by elevated serum FSH levels. The OVF model has the advantages of being stable, low cost, and easy to operate, which is suitable for studies to explore the extragonadal actions of FSH. Here, we describe detailed protocols for the mouse OVF model.

Conventional follicular-phase ovarian stimulation vs. luteal-phase stimulation in suboptimal responders: a randomized controlled trial

To compare the oocyte yield between follicular-phase stimulation (FPS) and luteal-phase stimulation (LPS) in suboptimal responders. Prospective, randomized, crossover clinical trial. Forty-one patients with infertility according to the POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria (1b/2b). Crossover study on 2 assigned ovarian stimulations that started randomly in the follicular or luteal phase. The invitro fertilization cycles were not consecutive but separated in time (45 days to 6 months). The random crossover design ensured that all subjects received the first treatment by chance. The primary objective was the number of cumulus-oocyte complexes retrieved in each cycle. Secondary objectives were number of metaphase II and fertilized oocytes, additional doses of recombinant follicle-stimulating hormone, and the duration of ovarian stimulation (days). The mean number of cumulus-oocyte complexes retrieved was similar between the FPS and LPS groups (7.5 ± 4.6 vs. 7.0 ± 4.1; 95% confidence interval [CI] for the mean, 5.8-8.7 vs. 5.6-8.3, respectively; the difference between means, -0.5; 95% CI, -1.8 to +1.5). Similarly, the mean number of metaphase II oocytes retrieved was not different between the FPS and LPS groups (5.4 ± 3.6 vs. 5.2 ± 2.8; 95% CI for the mean, 4.2-6.5 vs. 4.3-6.1, respectively; the difference between means, -0.2; 95% CI, -1.2 to +1.1). Moreover, the secondary objectives were similar between FPS and LPS groups. In this study, the oocyte yield in LPS did not increase in suboptimal responders compared with that in FPS when the onset of LPS was separated in time from FPS. NCT039393990 https://beta.clinicaltrials.gov/study/NCT03939390.

The Ala307Thr polymorphism of the follicle-stimulating hormone receptor (FSHR) gene is associated with the dose of recombinant FSH received during IVF/ICSI treatment.

Follicle-stimulating hormone (FSH) is essential for folliculogenesis, acting through the follicle-stimulating hormone receptor (FSHR) that is present on the membrane of granulosa cells. Polymorphisms in the FSHR gene may lead to an altered pattern of receptor expression on the cell surface or to changes in affinity for FSH. The aim of this prospective study was to detect any association between the follicle-stimulating hormone receptor (FSHR) gene Ala307Thr polymorphism (rs6165) and ovarian reserve, ovarian response or clinical results in IVF/ICSI treatment. This prospective cohort study included 450 women who underwent IVF/ICSI cycles. DNA was extracted from peripheral blood, and the Ala307Thr FSHR polymorphism (rs6165) was genotyped using the TaqMan SNP genotyping assay. Participants were divided into three groups according to their Ala307Thr FSHR genotype: Thr/Thr (n:141), Thr/Ala (n=213) and Ala/Ala (n=96). The results were tested for associations with age, anti-Mullerian hormone (AMH) levels, antral follicle count (AFC), total dose of r-FSH, follicle size, number of retrieved oocytes, and clinical outcome of IVF/ICSI cycles. The statistical analyses were performed using Fisher's exact test and the Kruskal‒Wallis test. An association between the genotype of the FSHR (Ala307Thr) polymorphism and the dose of r-FSH was observed. Patients with the Ala/Ala genotype received a higher r-FSH dose than patients with the Ala/Thr (p=0.0002) and Thr/Thr (p=0.02) genotypes. No other correlation was observed. The Ala/Ala genotype was associated with the use of higher doses of recombinant FSH (r-FSH), suggesting that homozygosis of this allelic variant (Ala) provides lower sensitivity to r-FSH.

High expression of CFTR in cumulus cells from mature oocytes is associated with high-quality of oocyte and subsequent embryonic development.

The purpose of this study was to explore the association of expression of cystic fibrosis transmembrane conductance regulator (CFTR) in cumulus cells (CCs) from mature oocytes with oocyte quality and embryonic development. A total of 338 infertile women who underwent ovarian stimulation cycle of oocyte retrieval in Zhejiang University School of Medicine were retrospectively enrolled in this study. The relative mRNA expression levels of CFTR, bone morphogenetic protein 15 (BMP15), and growth differentiation factor 9 (GDF9) in CCs were detected by qPCR technology. ROC curve was applied for the diagnosis of oocyte maturation. The serum levels of anti-Müllerian hormone (AMH), E2, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and androstenedione were measured. Oocyte maturation rate, fertilization rate, cleavage rate, high-quality embryo formation rate, and implantation rate after embryo transfer were also determined. The mRNA expression levels of CFTR in CCs were significantly increased in metaphase II (MII) oocytes compared to that in metaphase I (MI) or germinal vesicle (GV) oocytes. The ROC curve analysis illustrated that CFTR mRNA expression could efficiently discriminate MII oocytes from MI or GV oocytes (AUC = 0.954), and revealed that 0.695 RQU is the optimal cut-off value for diagnosis. So the cut-off value of 2-ΔΔCT = 0.70 was used to divide the patients into two groups: low- (n = 114) and high-CFTR group (n = 224). The mRNA expression of CFTR in CCs was positively correlated with the antral follicular count (AFC), number of oocytes retrieved, number of MII oocytes, serum E2 level on hCG day, and BMP15 and GDF9 expression in CCs. Under continuous stimulation with the same dose of recombinant follicle-stimulating hormone (rFSH), the number of follicles, average recovered oocytes, recovered oocytes, MII oocytes, as well as the oocyte recovery rate, fertilization rate, oocyte cleavage rate, high-quality embryo formation rate, and implantation rate were decreased in patients with lower CFTR. This study suggests that CFTR expression in CCs is associated with the developmental potential of human oocytes.

P-644 The Δ4-Androstenedione baseline serum level reflects the ovarian response to stimulation: set-up of a novel index to predict the outcomes of IVF cycles

Abstract Study question Aim of this study was to investigate whether baseline androgen levels had a predictive value on stimulation outcomes in IVF cycles. Summary answer Baseline Δ4-Androstenedione (Δ4-A) and particularly the derived G-index, which also reflects the ovarian reserve capability, may serve as additional predictors of ovarian response to stimulation. What is known already Despite the several clinical, serological and ultrasound markers proposed so far, none have proved exempt from a high rate of false positives and negatives. The identification of reliable predictors of ovarian response continues to pose a challenge for reproductive physicians. Study design, size, duration Prospective study. Multiple linear regression and multivariate logistic regression were used to evaluate the predictive value of markers of response to controlled ovarian stimulation (COS). To compare the specificity of different biomarkers, receiver operating characteristic (ROC) curves were constructed to identify the global accuracy of our parameters of interest. Participants/materials, setting, methods The study included 91 infertile patients aged 30-45 years,awaiting the first IVF cycle at the Reproductive Medicine Unit of the San Paolo University Hospital in Milano.All women underwent the same long-protocol stimulation and the same starting dose of recombinant follicle-stimulating hormone (rFSH) was administered. As stimulation outcomes, the number of follicles recruited, Estradiol and Progesterone levels on the day of trigger, the total dose of gonadotropins administered and the number of oocytes collected were recorded. Main results and the role of chance Pearson’s correlation revealed a statistically significant inverse correlation between oocytes collected and age (r= -0.333,p<0.001) and a positive correlation with AMH (r = 0.360,p<0.001), antral follicle count (AFC) (r = 0.639, p < 0.001) and Androstenedione (Δ4-A) (r = 0.359,p<0.001). No significant correlation was reported with FSH (r=-0.133,p=0.207) and total Testosterone (r = 0.180,p=0.088). The G-Index (=AMH ng/ml*AFC/Δ4-A ng/dl) revealed a significant higher level in COS good responders (p < 0.001) compared to AMH, AFC and Δ4-A alone. Limitations, reasons for caution Although the same stimulation regimen and starting dose of gonadotropin were used, subsequent individualization of treatment certainly influenced the results. This was considered as an insurmountable bias. Furthermore, the conclusions of this study, due to the population size, need to be validated in studies with larger populations. Wider implications of the findings Baseline serum Δ4-A, presumably crucial for ensuring a regular early follicular growth, is a reliable marker of ovarian response to stimulation.Since the ovarian capacity to respond to gonadotropins does not depend exclusively on the presence of follicles,we suggest a new index able to contemplate both ovarian reserve and Δ4-A level. Trial registration number N/A

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

The relationship between serum FSH level and ovarian response during controlled ovarian stimulation.

To evaluate whether serum follicle stimulating hormone (FSH) level during the early controlled ovarian stimulation can be used as a predictor of the ovarian response in the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. The participants of this retrospective study were chosen from Reproductive Medicine Center, Weifang People's Hospital between January 2015 and December 2020.The participants of this study met the age of 20~43 years old, anti-Müllerian hormone (AMH) ≥ 1.2 ng/mL, antral follicle count (AFC) ≥ 5, and the data was complete and no cancellation cycle. Each participant was given GnRH agonist protocol and given a fixed dose of recombinant FSH in the first four days during the controlled ovarian stimulation (COS). According to the number of oocytes retrieved, the participants were divided into two different ovarian response groups. Serum FSH level after the fourth recombinant follicle stimulating hormone (rFSH) injection were compared during the different ovarian responders. The number of participants who met both the inclusion criteria and exclusion criteria was 235. Serum sFSH levels (mean: 11.76 ± 3.10 IU/L) in the inappropriate responders was significantly higher than serum sFSH levels (mean: 10.79 ± 2.52 IU/L) in the superior responders(p = 0.029). There was a weak correlation between serum sFSH levels and the number of oocytes retrieved (r = -0.134, p = 0.041). Serum sFSH levels had significant clinical valuable (p = 0.0346) in predicting the number of oocytes retrieved. Serum sFSH levels may be a potential marker to predict the ovarian response during the early COS in the IVF/ICSI cycles, which can guide the adjustment of the exogenous rFSH dose.

Early Follicular Phase Human Chorionic Gonadotropin Addition May Improve the Outcomes of In Vitro Fertilization/Intracytoplasmic Sperm Injection in Patients With "Unpredictable" Poor Response to Gonadotropin-Releasing Hormone Antagonist Protocol.

PurposeTo compare the effects of early and mid-late follicular phase administration of 150 IU of human chorionic gonadotropin (hCG) on gonadotropin-releasing hormone (GnRH) antagonist protocol in “unpredictable” poor ovarian response (POR) women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment.MethodsA retrospective single-center cohort study was conducted on 67 patients with “unpredictable” POR in their first IVF/ICSI cycle receiving GnRH antagonist protocol. Patients were treated with a second IVF/ICSI cycle using the same GnRH antagonist protocol with the same starting dose of recombinant follicle-stimulating hormone (rFSH) as the first cycle; a daily dose of 150 IU of hCG was administrated on either stimulation day 1 (Group A, n = 35) or day 6 (Group B, n = 32). The number of oocytes retrieved, number of usable embryos, serum level of estradiol (E2) on day of hCG trigger, and clinical pregnant outcomes were studied.ResultsThe addition of 150 IU of hCG on either the first day or sixth day of stimulation increases the serum level of E2, luteinizing hormone (LH), and hCG on the day of hCG trigger. Only the use of 150 IU of hCG on the first stimulation day improved the number of oocytes retrieved, mature of oocytes, and usable embryos, but not the addition of hCG on stimulation day 6. Implantation rate, clinical pregnancy rate, and ongoing pregnancy rate showed an increasing trend in patients receiving 150 IU of hCG in the early phase compared with mid-late phase, even thought there was no statistically significant difference.ConclusionsOur study demonstrated that adding 150 IU of hCG in subsequent GnRH antagonist cycle in “unpredictable” poor responders is associated with the improvement of response to stimulation. Furthermore, early follicular phase addition of 150 IU of hCG significantly increased the number of oocytes retrieved and usable embryos than did the mid-late addition of the same dose.

P–659 Artificial intelligence (AI) as an assisting tool in generating patient-friendly corifollitropin alfa ovarian stimulation protocol during in vitro fertilization

Abstract Study question How machine learning assisted in generating patient-friendly corifollitropin alfa protocol in normal responders? Summary answer In retrospective experiments, our machine learning model integrated physiological measurements of patients and clinical experience to generate a patient-friendly corifollitropin alfa protocol. What is known already Long-acting corifollitropin alfa can simplify the regimen, minimizing injections during the whole cycle. The previous study has described the patient-friendly protocol using corifollitropin alfa without routine pituitary suppression in normal responder can result in non-compromised clinical outcomes. Some studies showed machine learning can help with making clinical decisions and have the ability to learn from physiological measurements. Those methods effectuate certain points throughout short-acting menotropin protocols, however, there are still no robust AI tools for long-acting corifollitropin alfa protocols. Study design, size, duration 1,309 cycles were collected at Stork Fertility Center from November 2016 to October 2019, and 1,221 cycles were available after data cleaning and applying exclusion criteria, which Anti-Mullerian Hormone (AMH) is lower than 2. The data from electronic medical records (EMRs) consisted of age, AMH, body weight, luteinizing hormone (LH), and estradiol (E2) concentrations measured on revisit. Evaluation is performed by one physician who has more than 20 years of experience in IVF. Participants/materials, setting, methods: The protocol generator consisted of 5 parts: doses of Elonva, trigger type, doses of recombinant follicle-stimulating hormone (rFSH), doses of recombinant luteinizing hormone (rLH), and day of oocyte retrieval. The protocol was predicted by age, AMH, and weight firstly, then fine-tuned by LH and E2 after the first revisit. We used the gradient boosting decision tree algorithm to learn the protocol. The dataset was randomly split into 80% for training and 20% for testing. Main results and the role of chance In classification, the model predicted the dose of Elonva achieved an accuracy of 0.913 and an AUC of 0.946, and trigger type got an accuracy of 0.901 and AUC of 0.852 only using features on stimulation day (SD) 1 and gained 0.012 and 0.056 in accuracy and AUC correspondingly after adding features on the first revisit day. In regression, the mean absolute error (MAE) of rFSH dose, rLH dose, and oocytes retrieved day was 156.30 IU, 232.75 IU, and 0.80 days respectively, and after refining, the MAE dropped to 92.37 IU, 100.07 IU, and 0.46 days. The error of predictions in rFSH and rLH was almost equal to half increments of rFSH (150 IU) and one increment rLH (75 IU). This indicated that our model could provide a better prediction of these clinical decisions with one revisit only. Limitations, reasons for caution The present study was a single-center retrospective, and only analyzed the data from normal responders, whose AMH was equal or greater than 2. Though, the recommendations of our system act as references, the physician will make the final decision. Wider implications of the findings: Our result showed the potential of machine learning in generating protocols is promising. Recommendations generated by our model can provide the junior clinical teams to optimize the clinical plans and learn from the experience of experts. We look forward to applying our machine learning model to different protocols. Trial registration number Not applicable

Predictive factors of ovarian response to GnRH antagonist stimulation protocol: AMH and age are potential candidates

BackgroundPrediction of ovarian response prior to the ovarian stimulation cycle is useful in determining the optimal starting dose of recombinant follicle-stimulating hormone (r-FSH). This study was designed to (I) evaluate which of the following parameters (age, AMH, and FSH) can be used as a predictor of ovarian response to GnRH antagonist stimulation protocol, (II) determine the cutoff value of AMH and age for predicting poor and high ovarian response, and (III) investigate the relationship between age, AMH level, and other clinical parameters. It is a retrospective study. A total of 318 women with a mean age of 28.2 ± 5.9 years old were included in this study. Hormone levels (FSH, LH, PRL, E2, and AMH) and the number of collected oocytes were determined. Based on the number of retrieved oocytes, the participants were divided into three groups: poor response (oocytes < 4, n= 51), normal response (oocytes 4–14, n= 192), and high response (oocytes > 14, n= 75).ResultsA significant increase has been found in AMH level and number of retrieved oocytes and mature oocytes from low to normal and high ovarian response group (P < 0.001). Also, the age in the poor ovarian response group was significantly greater than normal and high ovarian response groups (P < 0.001). A significant positive correlation has been found between the number of retrieved oocytes and mature oocytes and level of AMH (P < 0.001). The receiver operating characteristic (ROC) curves showed that both AMH and age had the highest accuracy in the prediction of poor ovarian response with a cutoff value < 1.45 and > 31.5 years, respectively. Additionally, the ROC analysis has shown that the AMH had the highest accuracy, followed by age in the prediction of high ovarian response with a cutoff value > 3.55 and < 27.5 years, respectively.ConclusionsThis study demonstrates that AMH level and women’s age may be used as potential predictors of ovarian response to GnRH antagonist stimulation protocol.

Medroxyprogesterone acetate is a useful alternative to a gonadotropin-releasing hormone antagonist in oocyte donation: a randomized, controlled trial

To compare ovarian response and reproductive outcomes in oocyte donors undergoing pituitary suppression with medroxyprogesterone acetate (MPA) versus those undergoing conventional treatment with a gonadotropin-releasing hormone (GnRH) antagonist. A prospective, randomized, controlled trial of cycles was conducted from October 2017 to June 2019 to evaluate ovarian response in terms of the number of oocytes. The reproductive outcomes of the recipients were retrospectively analyzed later. A university-affiliated private invitro fertilization center. We randomly divided 318 donors into 2 groups in a 1:1 ratio. The oocytes obtained were assigned to 364 recipients. One hundred sixty-one donors were treated with a daily dose of 10 mg of MPA administered orally from the beginning of ovarian stimulation (OS), and 156 were treated with a GnRH antagonist (initiated once the leading follicle reached a diameter of 13 mm). Transvaginal ultrasound was performed, and serum estradiol, luteinizing hormone, and progesterone levels were recorded during monitoring. The following additional parameters were analyzed: endocrine profile (in follicular fluid), number of metaphase II oocytes, and pregnancy outcome. The donors included in the study group were stimulated using recombinant follicle-stimulating hormone and MPA at 10 mg/day, simultaneously begun on cycle day 2 or 3. Ovulation was induced using a GnRH agonist when dominant follicles matured. A short protocol with ganirelix at 0.25 mg/day was used for the control group. Oocytes were assigned to the recipients, followed by routine invitro fertilization procedures in which 1 embryo was usually transferred. The primary outcome measure was the numbers of oocytes and metaphase II oocytes retrieved. The secondary outcomes were the incidence of premature luteinizing hormone surge, serum and follicular fluid hormone profiles, and clinical pregnancy outcomes in the recipient group. The number of oocytes retrieved was 21.4 ± 11.7 in the MPA group and 21.2 ± 9.2 in the antagonist group (mean difference 0.14; 95% confidence interval -2.233, 2.517). The total dose of recombinant follicle-stimulating hormone, duration of OS, and endocrine profiles of the serum and follicular fluids were comparable in the 2 groups. No early ovulation was observed in either group. No statistically significant differences with respect to implantation rate (68.1% in the MPA group vs. 62% in the antagonist group), clinical pregnancy rate (64.5% in the MPA group vs. 57.8 in the antagonist group), ongoing pregnancy rate (55.4% in the MPA group vs. 48.5% in the antagonist group), live birth rate (55.1% in the MPA group vs. 48.5% in the antagonist group), or cumulative live birth rate (73.8% in the MPA group vs. 70.7% in the antagonist group) were observed between the groups. The administration of MPA resulted in oocyte retrieval rates, endocrine profiles, viable embryo numbers, and pregnancy outcomes similar to those achieved with the GnRH antagonist. Therefore, MPA can be recommended for OS in oocyte donation because it permits a more patient-friendly approach. NCT03300960.

Artificial intelligence in in vitro fertilization: a computer decision support system for day-to-day management of ovarian stimulation during in vitro fertilization

To describe a computer algorithm designed for invitro fertilization (IVF) management and to assess the algorithm's accuracy in the day-to-day decision making during ovarian stimulation for IVF when compared to evidence-based decisions by the clinical team. Descriptive and comparative study of new technology. Private fertility practice. None. Data were derived from monitoring during ovarian stimulation from IVF cycles. The database consisted of 2,603 cycles (1,853 autologous and 750 donor cycles) incorporating 7,376 visits for training. An additional 556 unique cycles were used for challenge and to calculate accuracy. There were 59,706 data points. Input variables included estradiol concentrations in picograms per milliliter; ultrasound measurements of follicle diameters in two dimensions in millimeters; cycle day during stimulation and dose of recombinant follicle-stimulating hormone during ovarian stimulation for IVF. Accuracy of the algorithm to predict four critical clinical decisions during ovarian stimulation for IVF: [1] stop stimulation or continue stimulation. If the decision was to stop, then the next automated decision was to [2] trigger or cancel. If the decision was to return, then the next key decisions were [3] number of days to follow-up and [4] whether any dosage adjustment was needed. Algorithm accuracies for these four decisions are as follows: continue or stop treatment: 0.92; trigger and schedule oocyte retrieval or cancel cycle: 0.96; dose of medication adjustment: 0.82; and number of days to follow-up: 0.87. These accuracies are for first iteration of the algorithm. We describe a first iteration of a predictive analytic algorithm that is highly accurate and in agreement with evidence-based decisions by expert teams during ovarian stimulation during IVF. These tools offer a potential platform to optimize clinical decision making during IVF.

Clinically significant intra-day variability of serum progesterone levels during the final day of oocyte maturation: a prospective study with repeated measurements

Is there significant variability in progesterone levels during the final day of oocyte maturation in women undergoing ovarian stimulation? Progesterone levels drop from the basal level up to 44% during the final day of oocyte maturation in women undergoing ovarian stimulation. It has been suggested that elevated progesterone levels on the final day of ovarian stimulation may be related to poorer outcomes in in vitro fertilization fresh cycles due to a negative impact on the endometrium. However, despite conflicting results regarding the actual effect of progesterone on pregnancy rates and the lack of a well-established cut off, currently many IVF patients have their embryo transfer deferred when progesterone values surpass a threshold of 1.5ng/ml on the day of ovulation triggering. This was a prospective cohort study conducted in 22 oocyte donors of a university-affiliated fertility centre between November 2017 and January 2018. We calculated the sample size to detect a difference of 15% between the first and last progesterone measurements with a 5% false-positive rate in a two-sided test with 80% statistical power and a 95% confidence interval (CI). Progesterone circulating levels were evaluated at four different times during the final day of oocyte maturation (08:00, 12:00, 16:00 and 20:00) before ovulation triggering in healthy oocyte donors. A flexible antagonist protocol was used, and ovarian stimulation was achieved with recombinant follicle-stimulating hormone (FSH) in all cases. The pairwise percentage differences in progesterone levels for each patient were calculated. Univariate linear regression analysis was adopted in order to evaluate variables associated with progesterone levels on the first measurement. The intra-day variability of progesterone was analysed using mixed models. Mean serum progesterone values at 08:00, 12:00, 16:00 and 20:00 were 1.75ng/ml, 1.40ng/ml, 1.06ng/ml and 0.97ng/ml. The progesterone difference between 08:00 and 20:00 was 0.77 (95% CI, 0.56-0.99), which is equivalent to a 44% decline in the mean progesterone values between the first (08:00) and the last determination (20:00; P< 0.001). Among those patients with basal (08:00) progesterone levels >1.5ng/ml (n= 10), 70% (n= 7) showed levels reduced to <1.5ng/ml on the last determination of the day (20:00). A mixed model analysis revealed that the progesterone reduction during the day was significantly associated with time and total recombinant FSH dose administered. Only young healthy oocyte donors stimulated with an antagonist protocol using recombinant FSH were included. Extrapolation to the general IVF population, with different stimulation protocols and gonadotropins, needs to be confirmed. This study suggests that a single progesterone determination on the final day of oocyte maturation is not reliable enough to make clinical decisions due to the enormous variation in progesterone during the day. Further studies are needed to better define the impact of the follicular progesterone rise on the endometrium of IVF cycles. Funding was granted from Fundació Santiago Dexeus Font. N.P.P. received unrestricted grants and/or lectures fees from Roche Diagnostics, MSD, Merck, Ferring Pharmaceuticals, IBSA, Theramex and BESINS International, not associated with the current study. The remaining authors have no competing interests. Clinicaltrials.gov NCT03366025.

A high dose of total recombinant FSH suppresses granulosa cell apoptosis and maintains oocyte quality in endometriosis: A cross-sectional study

Background: Endometriosis is one of the most common conditions causing infertility and an indication to undergo in vitro fertilization (IVF). High apoptosis rate and oxidative stress in patients with endometriosis are believed to negatively affect the IVF success rate. However, there have been conflicting results on the effect of endometriosis on IVF success, and there have been limited studies that directly assess endometriosis and its effect on oocyte quality. This study was performed to explore the correlation between mRNA BAX/BCL-2 expression and oocyte quality in endometriosis compared to non-endometriosis subjects. Methods: This was a cross-sectional study. 15 endometriosis and 15 non-endometriosis subjects were recruited through convenience sampling at Cipto Mangunkusumo Hospital, Jakarta. All subjects underwent follicle stimulation with recombinant follicle-stimulating hormone (FSH). Granulosa cells were collected and tested for BAX and BCL-2 expression and the results were compared to the oocyte quality and fertilization rate of the patients. Results: The total dose of recombinant FSH received by the endometriosis group was significantly higher compared with that of the non-endometriosis group (p = 0.005). There was a difference in BAX level (p = 0.029) and BCL-2 level (p&lt;0.001) between groups. However, the BAX/BCL-2 ratio did not differ significantly (p = 0.787) between groups. No significant correlation was found between the BAX/BCL-2 ratio and any of the oocyte quality parameters measured. Conclusion: We found that there is a significantly higher dose in total dose recombinant FSH received by the endometriosis group compared with the non-endometriosis group. We also found that there was no significant difference in BAX/BCL-2 ratio between the endometriosis and non-endometriosis groups.

The cutoff values of serum AMH levels and starting recFSH doses for the individualization of IVF treatment strategies

Objective: The main purpose of our study is to categorize starting doses of recombinant follicle-stimulating hormone (recFSH) based on various cutoff values of anti-Mullerian hormone (AMH) and to determine the effectiveness of serum AMH levels in the prediction of poor ovarian response. Material and methods: Prospective data analysis was conducted at IVF center. A total of 323 patients were included. All patients were divided into four groups according to the patients’ serum AMH concentrations: Group 1 (AMH < 1 ng/ml; 450 IU/day n = 157); Group 2 (AMH 1–2 ng/ml; 375 IU/day, n = 55); Group 3 (AMH 2–3 ng/ml; 225 IU/day, n = 48); and Group 4 (AMH > 3 ng/ml; 150 IU/day, n = 63). Collected data included age, total gonadotropin dosage, duration of stimulations, the total number of oocytes retrieved, ovarian response, cancelation rate, and cPRs. Results: As serum AMH levels increased, there were significant decreases in the starting recFSH dose and total gonadotropin dosage, and a significant increase in the total number of oocytes retrieved. There was a significant trend toward increasing cycle cancelation rates and decreasing cPRs with decreasing serum AMH levels. Although there were no significant differences with regard to the proportion of cycles with hypo-response between all groups. A result of ≤0.83 was considered the cutoff value of AMH to predict a hypo-response to ovarian stimulation. Conclusions: AMH is a useful marker in selecting the starting dose of recFSH and prediction of poor ovarian response. Our protocol may allow clinicians to modulate the starting dose of recFSH according to these cutoff values for serum AMH levels.

In Estimated Good Prognosis Patients Could Unexpected "Hyporesponse" to Controlled Ovarian Stimulation be Related to Genetic Polymorphisms of FSH Receptor?

It has been reported that 10% to 15% of young normogonadotrophic women show suboptimal response to standard gonadotropin-releasing hormone-a long protocol. These patients require higher doses of exogenous follicle-stimulating hormone (FSH). This phenomenon could be associated with genetic characteristics. In this study, FSH receptor polymorphism was retrospectively evaluated in 42 normoresponder young women undergoing an in vitro fertilization/intracytoplasmic sperm injection cycle; patients were stratified according to recombinant human FSH (r-hFSH) consumption. We selected 17 normoresponder young patients who required a cumulative dose of recombinant FSH (rFSH) >2500 UI (group A). A control group was randomly selected among patients who required a cumulative dose of rFSH <2500 UI (group B). Follicle-stimulating hormone receptor (FSH-R) 307Ala and 680Ser variants were analyzed in all our patients. Our results show that the mean number of rFSH vials (36.3 ± 7.5 vs 28.6 ± 4.5, P = .0001) and days of stimulation (12.7 ± 2.4 vs 10.8 ± 2.8, P = .03) were significantly lower in group B, whereas the number of oocytes retrieved (7.1 ± 1.5 vs 9.6 ± 2.4; P = .0005) and the average number of embryos transferred (2.1 ± 0.7 vs 2.7 ± 0.4; P = .001) were significantly lower in group A. Estradiol serum levels on the human chorionic gonadotrophin day were significantly lower in group A (997.8 ± 384.9 pg/mL vs 1749.1 ± 644.4; P = .0001). The incidence of the Ser/Ser genotype was higher in patients with higher r-hFSH consumption (group A; P = .02). Based on our results, we hypothesize an association between the FSH-R polymorphisms and a "hyporesponse" to exogenous FSH.

Does thalassemia influence ovarian response? An analysis of 127 cycles involving pre-implantation genetic diagnosis of thalassemia in southern China

To evaluate the impact of thalassemia carrier status on the response to controlled ovarian stimulation (COS) and outcome of intracytoplasmic sperm injection (ICSI). Seventy couples that both carried a mutation attributed to thalassemia (PGD group) and 57 couples in which only the father was a thalassemia carrier (CON group) were enrolled. All female subjects received long protocol GnRH agonist stimulation and received equivalent doses of recombinant follicle-stimulating hormone and the number of retrieved oocytes and utilisable embryos did not differ significantly. The endometrial thickness at human chorionic gonadotropin (hCG) administration day and the number of transferable embryos was lower in the PGD groups. However, pregnancy outcomes, including the clinical pregnancy rate and ongoing pregnancy rate, did not differ significantly between the two groups per cycle. Ovarian response to COS is not impaired by maternal thalassemia carrier status and embryo biopsy did not impair preimplantation embryo development or pregnancy outcomes.

The fshr gene polymorphism (rs 6165 - ala/ala genotype) is associated with the use of higher doses of recombinant FSH during IVF/ICSI treatment

Follicle-stimulating hormone (FSH) is essential to folliculogenesis and acts through the FSH receptor (FSHR) present on the membrane of granulosa cells. Polymorphisms in the FSHR gene may lead to altered pattern of receptor expression on the cell surface or differential affinity toward FSH. The Ala307Thr polymorphism is located in the extracellular domain within the hormone binding region, which can influence the response to endogenous and exogenous FSH stimulation. Herein we investigated the association of this FSHR polymorphism with the ovarian response to exogenous recombinant FSH (r-FSH).

Low-dose GnRH antagonist protocol is as effective as the long GnRH agonist protocol in unselected patients undergoing in vitro fertilization and embryo transfer

Objective The present retrospective and controlled comparative study was designed to evaluate the pregnancy rate achieved using a modified, fixed, multiple-dose 0.125 mg gonadotropin-releasing hormone (GnRH) antagonist protocol with the long GnRH agonist protocol as the control group. Materials and methods One hundred and twenty unselected women between 30 and 40 years of age, in their first cycle of IVF/ICSI, with a baseline follicle-stimulating hormone (FSH) <10 IU and an antral follicle count >3 were assigned into two groups: (1) the study group received 0.125 mg of cetrorelix daily starting on Day 6 of stimulation; and (2) the control group received leuprolide daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a flexible dose of recombinant FSH for stimulation. An ongoing pregnancy rate of more than 12 weeks was the primary outcome measure of the study. Results Primary and secondary outcomes were comparable in both groups. A shorter duration of stimulation, a lower dosage of recombinant FSH consumption and a thinner endometrium on the day of human chorionic gonadotropin administration were all observed in the GnRH antagonist group. Conclusion A dosage of 0.125 mg GnRH antagonist protocol was effective for these unselected patients during IVF/ET.

Does metformin affect the ovarian response to gonadotropins for in vitro fertilization treatment in patients with polycystic ovary syndrome and reduced ovarian reserve? A randomized controlled trial

To evaluate the effects of metformin on the ovarian response to gonadotropins given for invitro fertilization (IVF) programs in patients with polycystic ovary syndrome (PCOS) and reduced ovarian reserve. Prospective, parallel, randomized, double-blind, placebo-controlled clinical trial. Academic departments of obstetrics and gynecology, and a private IVF center. Primary infertile patients with PCOS older than 35 years and/or with a basal follicle-stimulating hormone (FSH) level higher than 10 IU/L who were scheduled for IVF cycles. Gonadotropin-releasing hormone agonist flare-up protocol and high starting doses of recombinant FSH plus metformin or placebo tablets. Primary end point: cancellation rate for low ovarian response. Secondary end-points: other clinical, biochemical, and reproductive data. Enrollment was stopped after 88 participants had been randomized and analyzed due to an unacceptable increased risk of poor ovarian response in the metformin arm. Statistically significant differences between the metformin and placebo groups were observed in the dose of gonadotropins used, peak estradiol levels, and the number of dominant follicles, retrieved oocytes, and metaphase II oocytes. In patients with PCOS and reduced ovarian reserve, metformin worsened the response to gonadotropins, and its administration should be stopped before the start of controlled ovarian hyperstimulation for IVF programs. CLINICAL TRIALS IDENTIFICATION NUMBER: NCT01208740.