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The objective of the present study was to evaluate the effect of estradiol valerate administered at the beginning of the ovulation synchronization protocol on the pregnancy rate of Bos indicus cows. In the experiments, the following products from MSD, Sao Paulo, Brazil were used: estradiol valerate (EV), estradiol benzoate (EB), intravaginal progesterone device (P4), estradiol cypionate (EC), equine chorionic gonadotropin (eCG) and cloprostenol (PGF). In Experiment 1, Bos indicus cows (n=899) with a body condition score (BCS) of 2.76 ± 0.01 were included in a 3 (device) × 2 (protocol: 5 mg of EV or 2 mg of EB) factorial design. There were three types of P4 devices: a new device (New), a device previously used for 9 days (1×), and a device previously used for 18 days (2×). Nine days later (D9), the P4 device was removed, and cows received 300 IU of eCG. In addition, cows in the EB group received 1 mg of EC and 265 µg of PGF. Timed artificial insemination (TAI) was performed 48 h after P4 device removal in the EB group (TAI48) and 54 h after P4 device removal in the EV group (TAI54). In Experiment 2, Bos indicus cows (n=434) with a BCS of 2.62 ± 0.01 received a new P4 device or one previously used for 9 days and 5 mg of EV. On D9, all cows received 300 IU of eCG, and the P4 devices were removed and distributed in TAI48 and TAI54 cows. In Experiment 3, Bos indicus cows (n=429) with a BCS of 2.80 ± 0.01 were divided into the control and EV/EC groups. All cows received a P4 device. In addition, cows in the control group received 2 mg of EB, and cows in the EV/EC group received 5 mg of EV on D0. On D9, all cows received 1 mg of EC and 300 IU of eCG, and the P4 devices were removed. Cows in the control group also received 265 µg of PGF. All cows were inseminated 48 h after the removal of the P4 device. In Experiment 1, there was no effect of the interaction between protocol and P4 device on the occurrence of estrus (P=0.45) or on the pregnancy per artificial insemination ratio (P/AI; P=0.30). In addition, the occurrence of estrus and P/AI were not different between in the two estradiol groups (P=0.12 and P=0.82) and across the types of intravaginal P4 device (P=0.91 and P=0.47). In Experiment 2, the pregnancy rate was lower (tendency) in TAI48 cows (P=0.07). In Experiment 3, the estrus rate (P=0.12) and P/AI (P=0.56) were similar between the experimental groups. In summary, protocols using estradiol valerate without exogenous ovulation induction require adjustments in the timing of AI from 48 to 54 h after P4 device removal. However, a combination of estradiol valerate at the beginning of the protocol and estradiol cypionate nine days later successfully induced ovulation in Bos indicus cows inseminated 48 h after P4 device removal.

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BACKGROUND: The maximum daily dose of follitropin delta for ovarian stimulation in the first in vitro fertilization cycle is 12 µg (180 IU), according to the algorithm developed by the manufacturer, and based on patient's ovarian reserve and weight. This study aimed to assess whether 150 IU of menotropin combined with follitropin delta improves the response to stimulation in women with serum antimullerian hormone levels less than 2.1 ng/mL. METHODS: This study involved a prospective intervention group of 44 women who received 12 µg of follitropin delta combined with 150 IU of menotropin from the beginning of stimulation and a retrospective control group of 297 women who received 12 µg of follitropin delta alone during the phase 3 study of this drug. The inclusion and exclusion criteria and other treatment and follow-up protocols in the two groups were similar. The pituitary suppression was achieved by administering a gonadotropin-releasing hormone (GnRH) antagonist. Ovulation triggering with human chorionic gonadotropin or GnRH agonist and the option of transferring fresh embryos or using freeze-all strategy were made according to the risk of developing ovarian hyperstimulation syndrome. RESULTS: Women who received follitropin delta combined with menotropin had higher estradiol levels on trigger day (2150 pg/mL vs. 1373 pg/mL, p < 0.001), more blastocysts (3.1 vs. 2.4, p = 0.003) and more top-quality blastocysts (1.8 vs. 1.3, p = 0.017). No difference was observed in pregnancy, implantation, miscarriage, and live birth rates after the first embryo transfer. The incidence of ovarian hyperstimulation syndrome did not differ between the groups. However, preventive measures for the syndrome were more frequent in the group using both drugs than in the control group (13.6% vs. 0.6%, p < 0.001). CONCLUSIONS: In women with serum antimullerian hormone levels less than 2.1 ng/mL, the administration of 150 IU of menotropin combined with 12 µg of follitropin delta improved the ovarian response, making it a valid therapeutic option in situations where ovulation triggering with a GnRH agonist and freeze-all embryos strategy can be used routinely. TRIAL REGISTRATION: U1111-1247-3260 (Brazilian Register of Clinical Trials, available at https://ensaiosclinicos.gov.br/rg/RBR-2kmyfm ).

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Background and Aim: Despite the wide spectrum of uses, one of the chief drawbacks to expanding microalgae as a food supplement in livestock is the lack of a regimen protocol with established dosage and time length of supplementation. Therefore, this study aimed to investigate the effect of short-term supplementation with increasing doses of microalgae on ovarian response in goats reared in northeast Brazil. Materials and Methods: Twenty-eight goats had their follicular waves synchronized using three injections of a prostaglandin analog at 7-day intervals. Goats were allocated to groups that received daily oral Chlorella supplementation for 7 days, respectively: 5 g, GMA5 group (n = 7), 10 g (GMA10; n = 7), and 20 g (GMA20; n = 7). The control group (GMA 0; n = 7) received a drench of water. Results: The groups showed a quadratic increase (p = 0.0156) in kidney fat thickness but there was a significant reduction in dry matter intake in the GMA20 group. The GMA20 group showed higher glucose levels and glutathione peroxidase (p < 0.05). There was a decrease in plasma cholesterol (p < 0.05) in the 10 and 20 g treatments. The number of total follicles increased quadratically. Follicles <3 mm increased linearly (p = 0.0113) for microalgal supply. The GMA10 and GMA20 groups had the highest values (p < 0.05) among the treatments. After inducing ovulation, there was a significant increase in follicles >3 mm in the GMA10 group, which also showed a greater (p < 0.05) area of intraovarian blood perfusion and pulsatility index of the ovarian artery. Conclusion: We conclude that for 7 days of supplementation, the administration of 10 g of microalgae appears to be the most efficient dosage for stimulating the ovarian response in tropical goats.

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OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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Corifollitropin alpha has been demonstrated to be non-inferior to other gonadotropins in reproductive outcomes. However, its impact on follicular ovarian responsiveness has never been evaluated. Follicular Output Rate (FORT) is an option for objective assessment of the follicular responsiveness. A prospective study was conducted with 306 infertile patients undergoing in vitro fertilisation. Ovarian stimulation protocol was performed with a single dose of 100 µg (<60kg) or 150 µg (≥60kg) corifollitropin alpha in group 1 (n = 147), and 150-300 IU/day human menopausal gonadotropin in group 2 (n = 150). Comparing ovarian stimulation between corifollitropin alpha and human menopausal gonadotropin, no differences regarding FORT were found (40.0% for group 1 versus 40.83% for group 2; p = 0.930). Patients treated with corifollitropin alpha had a higher number of embryos when compared with human menopausal gonadotropin group (3.0 for group 1 versus 2.0 for group 2; p = 0.04). Other secondary outcomes preset were similar between groups. Therefore, corifollitropin alpha can be an excellent option to simplify in vitro fertilisation treatment due to the "patient-friendly" protocol.

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OBJECTIVE: Information on the pregnancy rate after successive in-vitro fertilization (IVF) cycles and their associated costs is relevant for couples undergoing assisted reproduction treatments (ARTs). This study, therefore, sought to investigate the effectiveness and the cost-effectiveness of two ARTs, the minimal ovarian stimulation IVF (MS-IVF) compared to the conventional ovarian stimulation IVF (C-IVF) from the payer's perspective. METHODS: A 10-months follow-up prospective observational study was conducted in a sample of couples who sought ARTs in a private clinic in Southern Brazil. Women had to satisfy the Bologna Criteria and be older than 35 years. The effect outcome was pregnancy rate per initiated cycle. Medication costs were based on medical records. Costs and effect differences were estimated using seemingly unrelated regressions adjusted for the propensity score estimated based on women's characteristics. RESULTS: All 84 eligible women who agreed to participate received a total of 92 IVF cycles (MS-IVF, n=27[35 cycles]; C-IVF n=57[57 cycles]. The effect difference between MS-IVF and C-IVF was -5.1% (95%CI, -13.2 to 5.2). Medication costs of MS-IVF were significantly lower than C-IVF by €-1260 (95%CI, -1401 to -1118). The probabilities of MS-IVF being cost-effective compared to C-IVF ranged from 1 to 0.76 for willingness-to-pay of €0 to €15,000 per established pregnancy, respectively. CONCLUSIONS: Even though there were no positive effect differences between groups, MS-IVF might be cost-effective compared to C-IVF from the payer's perspective due to its relatively large cost savings compared to C-IVF. However, further investigation is needed to confirm these findings in a larger sample.

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OBJECTIVE: To investigate the effect of endometriosis and its different stages over Intracytoplasmic Sperm Injection (ICSI) outcomes among infertile women without previous history of ovarian surgery. METHODS: A total of 440 women enrolled in ICSI cycles were recruited and divided into two groups: endometriosis (n=220) and control group (n=220). Endometriosis patients without previous surgical treatment and with diagnostic laparoscopy were further stratified based on disease stage. Clinical and laboratory parameters, ovarian reserve markers, the number and quality of oocytes and embryos and fertilization rate were analyzed and compared among the various severity grades of endometriosis and the control group. RESULTS: Patients with advanced endometriosis had significantly fewer retrieved oocytes with small effect size (p<0.001, η2=0.04), lower metaphase II oocytes (p<0.001, η2=0.09) and fewer total numbers of embryos (p<0.001, η2=0.11) compared with less severe disease or women with tubal factor infertility. The fertilization rate in women with severe endometriosis was similar to that of the control group and in those with minimal/mild endometriosis (p=0.187). CONCLUSIONS: Severe endometriosis negatively affects ovarian response, oocyte quality and embryos. However, fertilization rate is not different among the various stages of endometriosis.

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OBJECTIVE: This paper aimed to assess the correlation between LH, LHR, GDF9, FSHR, AMH, AMHR2, and BMP15 polymorphisms, which are related to follicular development, and decreased ovarian response in women undergoing controlled ovarian hyperstimulation (COH) for IVF. METHODS: This age-matched case-control study included three or four controls per woman undergoing COH. Controls were women with normal ovarian response (NOR) and cases were women with poor ovarian response (POR) in oocyte retrieval (three or fewer oocytes). DNA was extracted from peripheral blood and potential associations with gene polymorphisms related to follicular development (LH, LHR, GDF9, FSHR, AMH, AMHR2, and BMP15) were analyzed. RESULTS: Sixty-six patients were included, 52 in the NOR and 14 in the POR group. Two GDF9 polymorphisms were associated with follicular response after COH, one associated with POR - the presence of a mutant polymorphism in heterozygosis and homozygosis of the GDF9 398-39 (C to G) [23% NOR versus 68% POR (OR 4.01, CI 1.52-10.6, p=0.005)] - and another associated with protective response - the presence of normal homozygosis of GDF9 (C447T) [19.2% NOR versus 50% POR (OR 0.34, IC 0.14-0.84, p=0.019)]. No additional associations were found between the other analyzed polymorphisms and POR. CONCLUSIONS: This study found that GDF9 appears to play an important role in follicular development, whereas polymorphisms in its DNA chain may negatively affect ovarian reserve, such as 398-39 (C to G), or positively, as seen in C447T.

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OBJECTIVE: To identify low prognosis in-vitro fertilization (IVF) patients treated at Centro de Fertilidad y Ginecología del Sur (CFGS) based on the POSEIDON criteria. METHODS: This retrospective study included 412 IVF patients and assessed them based on the POSEIDON criteria to describe the cumulative live birth rates seen in each group. RESULTS: 13.1% of patients met the POSEIDON criteria, and the proportion of cases in POSEIDON groups 1, 2, 3 and 4 were 20.4%, 31.5%, 14.8%, and 33.3%, respectively. The cumulative live birth rate for the individuals meeting the POSEIDON criteria was 25.9%, while for patients in POSEIDON groups 1, 2, 3, and 4 the rates were 45.5%, 29.4%, 25.0%, and 11%, respectively. The differences were not statistically significant due to the small number of cases. CONCLUSIONS: Patients belonging to the four POSEIDON groups were described at CFGS. Age and number of retrieved mature oocytes were determining parameters in the prognosis of pregnancy in IVF/ICSI patients.

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PURPOSE: To study the use of in silica model to better understand and propose new markers of ovarian response to controlled ovarian stimulation before IVF. METHODS: A systematic review and in silica model using bioinformatics. After the selection of 103 papers from a systematic review process, we performed a GRADE qualification of all included papers for evidence-based quality evaluation. We included 57 genes in the silica model using a functional protein network interaction. Moreover, the construction of protein-protein interaction network was done importing these results to Cytoscape. Therefore, a cluster analysis using MCODE was done, which was exported to a plugin BINGO to determine Gene Ontology. A p value of < 0.05 was considered significant, using a Bonferroni correction test. RESULTS: In silica model was robust, presenting an ovulation-related gene network with 87 nodes (genes) and 348 edges (interactions between the genes). Related to the network centralities, the network has a betweenness mean value = 102.54; closeness mean = 0.007; and degree mean = 8.0. Moreover, the gene with a higher betweenness was PTPN1. Genes with the higher closeness were SRD5A1 and HSD17B3, and the gene with the lowest closeness was GDF9. Finally, the gene with a higher degree value was UBB; this gene participates in the regulation of TP53 activity pathway. CONCLUSIONS: This systematic review demonstrated that we cannot use any genetic marker before controlled ovarian stimulation for IVF. Moreover, in silica model is a useful tool for understanding and finding new markers for an IVF individualization. PROSPERO: CRD42020197185.

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Poor ovarian response remains one of the most challenging tasks for an IVF clinician. In this review, we aim to highlight the ongoing research for optimizing the prognosis in poor ovarian response patients. The newly introduced POSEIDON criteria argue that the first step is to move from a poor response to a poor prognosis concept, while improving identification and stratification of the different sub-types of poor prognosis patients prior to ovarian stimulation. The immediate marker of success is the ability of the ovarian stimulation to retrieve the number of oocytes needed to obtain at least one euploid blastocyst for transfer in each patient. This surrogate marker of success should not replace live birth as the most important outcome, but it should be approached as a useful tool for clinicians to evaluate their strategy for achieving live birth in the shortest timespan possible in the individual patient/ couple.

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STUDY QUESTION: Are cumulative and live birth rates (LBRs) comparable in poor ovarian response women treated with different protocols of mild stimulation IVF (i.e. oral compounds, lower doses or shorter treatments) versus conventional IVF? SUMMARY ANSWER: Mild ovarian stimulation (MOS) results in comparable outcomes to those of conventional stimulation in poor ovarian response patients with low ovarian reserve. WHAT IS KNOWN ALREADY: Several randomized trials and meta-analyses have been published evaluating the role of mild (MOS) versus conventional ovarian stimulation in poor ovarian response patients. Most report a potentially higher safety profile, patient satisfaction and lower costs, suggesting that the higher cycle cancellation rate and fewer oocytes retrieved following MOS does not affect the final reproductive outcome. Additionally, over the last few years, new publications have added data regarding MOS, and shown the possible benefit of a higher oocyte yield which may also improve prognosis in patients with poor ovarian response. STUDY DESIGN SIZE DURATION: We conducted a systematic search of relevant randomized controlled trials (RCTs). We searched electronic databases, including MEDLINE, EMBASE, LILACS-BIREME, CINAHL, The Cochrane Library, CENTRAL (Cochrane Register), Web of Science, Scopus, Trip Database and Open Grey, to identify all relevant studies published up to March 2020. We examined trial registries for ongoing trials. No publication-year or language restrictions were adopted. We explored the reference list of all included studies, reviews and abstracts of major scientific meetings. The primary outcomes were cumulative and fresh LBR (CLBR and FLBR) per woman randomized. PARTICIPANTS/MATERIALS SETTING METHODS: We included subfertile women undergoing IVF/ICSI characterized as poor responders and compared primary and secondary outcomes between the different protocols of mild stimulation IVF (i.e. oral compounds, lower doses or shorter treatments) and conventional IVF. We used the PICO (Patients, Intervention, Comparison and Outcomes) model to select our study population. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 15 RCTs were included in the meta-analysis. CLBR and FLBR were comparable between mild versus conventional stimulation (RR 1.15; 95% CI: 0.73 - 1.81; I2 = 0%, n = 424, moderate certainty and RR 1.01; 95% CI: 0.97 - 1.04; I 2 = 0%, n = 1001, low certainty, respectively). No difference was observed either when utilizing oral compounds (i.e. letrozole and clomiphene) or lower doses. Similarly, ongoing pregnancy rate (OPR) and clinical pregnancy rate (CPR) were equivalent when comparing the two groups (RR 1.01; 95% CI: 0.98 - 1.05; I 2 = 0%, n = 1480, low certainty, and RR 1.00; 95% CI: 0.97 - 1.03; I2 = 0%, n = 2355, low certainty, respectively). A significantly lower oocyte yield (mean differences (MD) -0.80; 95% CI: -1.28, -0.32; I2 = 83%, n = 2516, very low certainty) and higher rate of cycle cancellation (RR 1.48; 95% CI: 1.08 - 2.02; I2 = 62%, n = 2588, low certainty) was observed in the MOS group. LIMITATIONS REASONS FOR CAUTION: The overall quality of the included studies was low to moderate. Even though strict inclusion criteria were used, the selected studies were heterogeneous in population characteristics and treatment protocols. We found no differences in CLBR between MOS and COS (95% CI: 0.73 - 1.81.). WIDER IMPLICATIONS OF THE FINDINGS: MOS could be considered as a treatment option in low prognosis poor responder patients, given that it results in similar fresh and CLBRs compared with COS. A milder approach is associated with a lower number of oocytes retrieved and a higher cancellation rate, although treatment cost is significantly reduced. Future research should focus on which type of ovarian stimulation may be of benefit in better prognosis women. STUDY FUNDING/COMPETING INTERESTS: There were no sources of financial support. N.P.P. received research grants, honoraria for lectures from: Merck Serono, MSD, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex and Gedeon Richter. P.D. received unrestricted grants and honoraria from Merck Serono, MSD and Ferring Pharmaceuticals. I.G.F. received unrestricted grants and honoraria from Merck Serono, MSD, Ferring Pharmaceuticals, Gedeon-Richter and IBSA. P.M.B. reported no conflict of interest. TRIAL REGISTRATION NUMBER: CRD42020167260.

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OBJETIVE: Several biomarkers of ovarian reserve have been proposed as possible predictors of the response to controlled ovarian stimulation (COS). We aimed to evaluate age, FSH, AMH, antral follicle count (AFC), and ovarian response prediction index (ORPI), as potential predictors of response to COS. METHODS: Cross-sectional study enrolling of 188 infertile women who underwent the first cycle of IVF/ICSI. AFC was evaluated; serum FSH and AMH levels were measured by ELISA. ORPI was calculated as AMH x AFC/patient´s age. RESULTS: As expected, hypo-responder group had less retrieved oocytes, MII, and embryos compared to the good responders. The hyper-response patients were younger, with lower FSH, increased AMH, AFC, and ORPI values. Regarding the assessment of the predictive capacity of ovarian reserve tests, none of them individually or combined showed a good predictive capacity for hypo-response. With respect to the hyper-responder group, individually AMH was the best predictor, while in the multivariable model, ORPI demonstrated the best predictive capacity. Furthermore, patients with serum AMH < 2.09 ng/mL (p25) had fewer AFC than patients with higher AMH values. CONCLUSIONS: Our findings suggest that none of the ovarian reserve tests showed a good predictive capacity for hypo-response, while the ORPI was the strongest predictor of hyper-response in normovulatory infertile women.

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BACKGROUND: To determine if a modified ovarian sensitivity index (MOSI), based on initial follicular measurements and the initial follicle-stimulating hormone (FSH) dose, can predict the production of high-quality embryos for successful implantation during in vitro fertilization (IVF). METHODS: This study consisted of two phases: 1) a retrospective study and 2) a prospective observational study. For the first phase, 363 patients charts were reviewed, of which 283 had embryos transferred. All women underwent a standardized antagonist-based IVF protocol. At the first follow-up (Day 3/4), the number and size of the follicles were determined. MOSI was calculated as ln (number follicles (≥6 mm) × 1000 / FSH initial dose). Afterward, the number and quality of the ova, embryo development, and the number and quality of the blastocysts were determined. Embryo implantation was confirmed by ß-hCG. For the second phase, 337 IVF cycles were followed to determine MOSI's accuracy. RESULTS: MOSI could predict the production of ≥4 high-quality embryos by Day 2 (AUC = 0.69, 95%CI:0.63-0.75), ≥2 blastocysts (AUC = 0.74, 95%CI:0.68-0.79), and ≥ 35% rate of blastocyst formation (AUC = 0.65, 95%CI:0.58-0.72). Using linear regression, MOSI was highly associated with the number of ova captured (ß = 5.15), MII oocytes (ß = 4.31), embryos produced (ß = 2.90), high-quality embryos (ß = 0.98), and the blastocyst formation rate (ß = 0.06, p < 0.01). Using logistic regression, MOSI was highly associated with achieving ≥4 high-quality embryos (odds ratio = 2.80, 95%CI:1.90-4.13), ≥2 blastocysts (odds ratio = 3.40, 95%CI:2.33-4.95), and ≥ 35% blastocysts formation rate (odds ratio = 1.96, 95%CI:1.31-2.92). This effect was independent of age, BMI, and antral follicle count. For implantation, MOSI was significantly associated with successful implantation (odds ratio = 1.79, 95%CI:1.25-2.57). For the prospective study, MOSI was highly accurate at predicting ≥6 high-quality embryos on Day 2 (accuracy = 68.5%), ≥6 blastocysts (accuracy = 68.0%), and a blastocyst formation rate of ≥35% (accuracy = 61.4%). CONCLUSION: MOSI was highly correlated with key IVF parameters that are associated with achieved pregnancy. Using this index with antagonist cycles, clinicians may opt to stop an IVF cycle, under the assumption that the cycle will fail to produce good blastocysts, preventing wasting the patient's resources and time.

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This article represents a viewpoint on the POSEIDON criteria by a group of clinicians and embryologists. Its primary objective is to contextualize the Poseidon criteria and their metric of success for the relevant Frontiers Research Topic "POSEIDON's Stratification of Low Prognosis Patients in ART: The WHY, the WHAT, and the HOW". "Low prognosis" relates with reduced oocyte number, which can be associated with low or sometimes a normal ovarian reserve and is aggravated by advanced female age. These aspects will ultimately affect the number of embryos generated and consequently, the cumulative live birth rate. The novel system relies on female age, ovarian reserve markers, ovarian sensitivity to exogenous gonadotropin, and the number of oocytes retrieved, which will both identify the patients with low prognosis and stratify such patients into one of four groups of women with "expected" or "unexpected" impaired ovarian response to exogenous gonadotropin stimulation. Furthermore, the POSEIDON group introduced a new measure of clinical success in ART, namely, the ability to retrieve the number of oocytes needed to obtain at least one euploid blastocyst for transfer in each patient. Using the POSEIDON criteria, the clinician can firstly identify and classify patients who have low prognosis in ART, and secondly, aim at designing an individualized treatment plan to maximize the chances of achieving the POSEIDON measure of success in each of the four low prognosis groups. The novel POSEIDON classification system is anticipated to improve counseling and management of low prognosis patients undergoing ART, with an expected positive effect on reproductive success and a reduction in the time to live birth.

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This study aimed to minimize the number of times cattle need to be confined during protocols for TAI in beef cows treated for induction of ovulation with EB at the time of P4 device removal (P4r). In Experiment 1, cows were treated with P4 plus EB (Day 0; AM) and were allocated to one of three groups at P4r: EB8.5, EB at P4r on Day 8.5 (PM; three confinements); EB9, EB 24 h after P4r on Day 8 (AM; four confinements) and EC8, EC at P4r on Day 8 (AM; positive control; three confinements). At P4r, cows were treated with PGF2a plus eCG. Ultrasonography was performed from D8 to D12. The interval from P4r to ovulation was less in the EB8.5 compared to EB9 and EC8 group. There was no difference in the ovulation rate between groups. The variability of ovulation was greater in the EB8.5 and EC8 compared to EB9 group. In Experiment 2, cows of EC8 and EB9 groups were submitted to TAI 48 to 52 h (AM) or 54 to 58 h (PM) after P4r (D10). Cows of the EB8.5 group were submitted to TAI 38 to 42 h (AM) or 44 to 48 h (PM) after P4r (D10). There was no interaction between treatments and timing of AI and no treatment effect and timing of AI on P/AI. In conclusion, the delay compared to what typically occurs by 10 h of P4r concomitant with EB administration (Day 8.5) reduced the frequency of animal confinement for the TAI protocol without affecting the reproductive efficiency and the flexibility to perform the TAI in suckled beef cows.

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Patients with poor ovarian response (POR) to exogenous gonadotropins stimulation for assisted reproductive technology (ART) have decreased circulating androgens during spontaneous cycles. The Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) is a 4-tier stratification of women with POR to controlled ovarian stimulation (COH) based on age and biomarkers of ovarian reserve has been proposed to maximize the clinical management of this group for ART. The aim of the present study was to characterize the levels of androgens during COH in follicular fluid (FF) and serum in POSEIDON subgroups and compared them with women of normal ovarian response. Sixty nine consecutive patients undergoing ART were included and testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), estradiol, sex hormone-binding globulin (SHBG), and insulin-like growth factor 1 (IGF-1) were measured in serum and FF collected at the time of oocyte pick-up. The number of retrieved oocytes was registered for each patient for their allocation to the respective POSEIDON subgroup. The control group comprised 19 women and the POSEIDON group 1 (age < 35, normal ovarian reserve biomarkers) n = 14, group 2 (age ≥ 35, normal ovarian reserve biomarkers) n = 8, group 3 (age < 35, poor ovarian reserve biomarkers) n = 6 and group 4 (age ≥ 35, poor ovarian reserve biomarkers) n = 22. Serum levels of total testosterone, androstenedione and DHEA-S were not different in group 1 vs. control but significantly decreased in group 3 vs. control. DHEA-S in FF was also significantly decreased in group 3 vs. control. In addition, serum testosterone was decreased in groups 2 and 4 vs. control; and serum androstenedione and estradiol were reduced in group 4 vs. control. No differences were observed for estradiol, SHBG and IGF-1 in FF. Finally, a high correlation between serum and FF DHEA-S was observed when data from samples of all groups were pooled. Group 1 did not show hypoandrogenemia however group 3 had low levels of all measured androgens in serum and DHEA-S in FF. Such differences might help to better characterize and/or improve the clinical management of women with POR according to their respective POSEIDON stratification.

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Women with impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation present a challenge for reproductive specialists. The primary reasons relate to the still limited knowledge about the POR pathophysiology and the lack of practical solutions for the management of these conditions. Indeed, clinical trials using the current standards to define POR failed to show evidence in favor of a particular treatment modality. Furthermore, critical factors for reproductive success, such as the age-dependent embryo aneuploidy rates and the intrinsic ovarian resistance to gonadotropin stimulation, are not taken into consideration by the current POR criteria. As a result, the accepted definitions for POR have been criticized for their inadequacy concerning the proper patient characterization and for not providing clinicians a guide for therapeutic management. A novel system to classify infertility patients with "expected" or "unexpected" inappropriate ovarian response to exogenous gonadotropins-the POSEIDON criteria-was developed to provide a more nuanced picture of POR and to guide physicians in the management of such patients. The new standards are provoking as they challenge the current terminology of POR in favor of the newly defined concept of "low prognosis." This article provides readers a critical appraisal of the existing criteria that standardize the definition of POR and explains the primary reasons for the development of the POSEIDON criteria.

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The aim of this review is to determine if the use of DHEA increases the likelihood of success in patients with POR. We searched MEDLINE and EMBASE using the terms "DHEA and diminished ovarian reserve", "DHEA and poor response", "DHEA and premature ovarian aging". A fixed effects model was used and Peto's method to get the odds ratio (OR) with 95% confidence intervals (CI 95%). For quantitative variables, Cohen's method was used to present the standardized mean differences (SMD) with their corresponding confidence intervals. Only five studied fulfilled the selection criteria. DHEA was administered in 25 mg doses, three times a day. In all studies, the authors corrected for the presence of confounding variables such as partner's age, infertility diagnosis and number of transferred embryos. The meta-analysis of the five selected studies assessed a total of 910 patients, who underwent IVF/ICSI, of which 413 had received DHEA. DHEA use was associated with a significant increase in pregnancy likelihood (OR 1.8, CI 95% 1.29 to 2.51, p=0.001). When analyzing the association between DHEA use and the likelihood of abortion, we found low heterogeneity between studies (I2=0.0%) and the use of DHEA to be associated to a significant reduction in the likelihood of abortion (OR 0.25, CI 0.07 to 0.95; p=0.045). Analysis of the association of DHEA with average oocyte retrieval showed high variability between studies (I2=98.6%), as well as no association between DHEA use and the number of oocytes retrieved (SMD -0.01, CI 95% -0.16 to 0.13; p<0.05).

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