Effects of total gonadotropin dose on embryo quality and clinical outcomes with AMH stratification in IVF cycles: a retrospective analysis of 12,588 patients.

BACKGROUND: Recent studies about the effect of gonadotropin (Gn) dose on the clinical outcomes of IVF are still controversial, and no studies have analyzed the relationship between Gn dose and embryo quality. Since AMH is a strong predictor of oocyte quality, we aim to evaluate the relationship between total Gn dose and embryo quality and clinical outcomes at different AMH levels in IVF cycles. METHODS: A total of 12,588 patients were enrolled in the retrospective study. The included cycles were categorized by serum AMH levels (AMH ≤ 1 ng/ml, 1 ng/ml < AMH ≤ 3 ng/ml, 3 ng/ml < AMH ≤ 5 ng/ml, AMH > 5 ng/ml), total Gn dosage (< 1875 IU, 1875-3750 IU and ≥ 3750 IU) and female age (< 35 years and 35-42 years). The embryo quality and clinical outcomes were the measure outcomes. RESULTS: The top-day3 embryos rate decreased with the increase of total Gn dose in nearly all age and AMH subgroups, but this trend was not obvious in the AMH > 5 ng/ml group and AMH ≤ 1 ng/ml group. The blastocyst formation rate and high-quality blastulation rate had a negative relationship with Gn does for women aged < 35 years in the AMH ≤ 5 ng/ml groups, except for the AMH > 5 ng/ml group (P < 0.001). However, when women were 35-42 years old, regardless of AMH levels, the blastocyst formation rate and high-quality blastulation rate decreased as Gn dose increased. Clinical outcomes (implantation rate, clinical pregnancy rate and live birth rate) decreased with the increase of Gn dose in all ages and AMH stratifications. CONCLUSIONS: The total dose of Gn may have different effects on embryo quality at different serum AMH levels, and the negative effects of total dose of Gn on clinical outcomes may be realized by impairing both embryo quality and endometrium.

Pregnancy outcomes after oral and injectable ovulation induction in women with infertility with a low antimüllerian hormone level compared with those with a normal antimüllerian hormone level.

OBJECTIVE: To determine the ongoing pregnancy rate among patients with infertility with a low antimüllerian (AMH) level compared with those with a normal AMH level after oral and injectable ovulation induction (OI)/intrauterine insemination (IUI). DESIGN: Retrospective cohort. SETTING: Academic center. PATIENT(S): Patients completing ≥1 medicated OI/IUI cycle at our center between 2015 and 2019 were included. The AMH levels were measured within 12 months of treatment initiation. The cohort was stratified into low AMH (AMH level, <1.0 ng/mL) and normal AMH (AMH level, ≥1.0 ng/mL) groups. All subsequent medicated OI/IUI cycles occurring within 1 year of initial cycle start date were included up to the third completed cycle or until an ongoing pregnancy was recorded. Patients were stratified by age (<35, 35-40, and >40 years), and the relationship between the low and normal AMH groups and each binary endpoint were quantified as risk ratios using the age-adjusted Poisson models. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ongoing pregnancy. RESULT(S): A total of 3,122 patients completed 5,539 oral antiestrogen cycles, and 1,060 completed 1,630 injectable gonadotropin cycles. For oral antiestrogen treatment, pregnancy outcomes, including ongoing pregnancy rate per cycle, for patients with a low AMH level were comparable with those for patients with a normal AMH level (<35 years, 15.4% vs. 14.9%; 35-40 years, 10.0% vs. 11.0%; and >40 years, 2.8% vs. 3.3%). For injectable gonadotropin treatment, the ongoing pregnancy rate was lower in the low AMH group than in the normal AMH group for the ages of <35 (12.1% vs. 23.5%; relative risk [RR], 0.52 [95% confidence interval {CI}, 0.28-0.97]) and 35-40 (12.5% vs. 18.5%; RR, 0.70 [95% CI, 0.49-0.99]) years but comparable with that for patients aged >40 years (3.0% vs. 4.0%; RR, 0.86 [95% CI, 0.31-2.35]). The proportion of multifetal gestations was similar between the low and normal AMH groups treated with oral antiestrogens (13.1% vs. 10.8%); however, for injectable gonadotropin treatment, patients with a normal AMH level had a higher proportion of multifetal gestations (18.6% vs. 31.1%). CONCLUSION(S): Compared with normal ovarian reserve, treatment with oral antiestrogens for OI/IUI for patients with low ovarian reserve results in comparable follicular development and ongoing pregnancy rates for all age groups. When patients with low ovarian reserve are treated with gonadotropins for OI/IUI, multifollicular recruitment is less likely resulting in a significantly decreased ongoing pregnancy rate for patients aged <35 and 35-40 years but also a decrease in multifetal gestations. Overall, the ongoing pregnancy rates of 8.7% per oral antiestrogen cycle and 8.1% per injectable gonadotropin cycle in patients with low ovarian reserve are comparable with the expected rates in the general infertility population.

Increased versus standard gonadotrophin dosing in predicted poor responders of IVF: an open-label randomized controlled trial.

STUDY QUESTION: Does an increased dosing of FSH improve the live birth rate as compared to standard FSH dosing in expected poor responders who undergo IVF? SUMMARY ANSWER: In this trial, women with an expected poor response allocated to increased FSH dosing did not have a statistically significant increase in cumulative live births as compared to a standard FSH dose. WHAT IS KNOWN ALREADY: Poor ovarian reserve leads to worse IVF outcomes owing to the low number and quality of oocytes. Clinicians often individualize the FSH dose using ovarian reserve tests, including antral follicle count (AFC), and basal plasma FSH or anti-Müllerian hormone level. However, the evidence that increased FSH dosing improves fertility outcomes in women with an expected poor response is lacking. STUDY DESIGN, SIZE, DURATION: We performed a parallel, open-label randomized controlled trial between March 2019 and October 2021 in an assisted reproduction centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women <43 years of age with AFC <10 referred for their first IVF cycle were randomized for increased or standard FSH dosing. In participants allocated to increased FSH dosing, women with AFC 1-6 started with 300 IU/day, while women with AFC 7-9 started with 225 IU/day. In participants allocated to the standard care, women started with 150 IU/day. The primary outcome was cumulative live birth attributable to the first IVF cycle including fresh and subsequent frozen-thawed cycles within 18 months of randomization. Live birth was defined as the delivery of one or more living infants ≥24 weeks' gestation. This trial was powered to detect an 11% difference in live birth attributable to the first IVF cycle. Outcomes were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We randomized 661 women to start FSH at increased dosing (n = 328) or standard dosing (n = 333). The primary outcome cumulative live birth occurred in 162/328 (49.4%) women in the increased group versus 141/333 (42.3%) women in the standard group [risk ratio (RR) 1.17 (95% CI, 0.99-1.38), risk difference 0.07 (95% CI, -0.005, 0.15), P = 0.070]. The live birth rate after the first embryo transfer in the increased versus standard group was 125/328 (38.1%) versus 117/333 (35.1%), respectively [RR 1.08 (95% CI, 0.83-1.33), P = 0.428]. Cumulative clinical pregnancy rates were 59.1% versus 57.1% [RR 1.04 (95% CI, 0.91-1.18), P = 0.586] with miscarriage rates of 9.8% versus 14.4% [RR 0.68 (95% CI, 0.44-1.03), P = 0.069] in the increased versus standard group, respectively. Other secondary outcomes, including biochemical pregnancy, ongoing pregnancy, multiple pregnancy and ectopic pregnancy, were not significantly different between the two groups both from the first and cumulative embryo transfer. LIMITATIONS, REASONS FOR CAUTION: As this study is open-label, potential selective cancelling and small dose adjustments could have influenced the results. WIDER IMPLICATIONS OF THE FINDINGS: In women with predicted poor response, we did not find evidence that increased FSH dosing improves live birth rates. A standard dose of 150 IU/day is recommended at the start of IVF in these women to reduce potential adverse effects and costs. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the General Projects of Social Development in Shaanxi Province (No. 2022SF-565). B.W.M. is supported by NHMRC (GNT1176437). B.W.M. reports personal fees from ObsEva, and funding from Merck and Ferring outside the submitted work. TRIAL REGISTRATION NUMBER: Registered at Chinese clinical trial registry (www.chictr.org.cn). Registration number ChiCTR1900021944. TRIAL REGISTRATION DATE: 17 March 2019. DATE OF FIRST PATIENT'S ENROLMENT: 20 March 2019.

Added value of anti-Müllerian hormone serum concentration in assisted reproduction clinical practice using highly purified human menopausal gonadotropin (HP-hMG).

INTRODUCTION: The individual response to controlled ovarian stimulation (COS) depends on several factors, including the initial dose of gonadotropin. In repeated in vitro fertilization (IVF) cycles, the initial dose of gonadotropin is mainly established on the basis of the previous attempts' outcomes. Conversely, in naive patients, the ovarian response should be estimated using other criteria, such as the serum concentration of anti-Müllerian hormone (AMH). However, in clinical practice, the initial gonadotropin dose is not systematically adapted to the AMH level, despite the known relationship between AMH and ovarian reserve. MATERIAL AND METHODS: French non-interventional, longitudinal, prospective, multicentre, cohort study that included infertile women who underwent COS with highly purified human menopausal gonadotropin (HP-hMG 600 IU/mL) during their first IVF/intracytoplasmic sperm injection (ICSI) cycle. Data were collected prospectively during routine follow-up visits from COS initiation to 10-11 weeks after embryo transfer. RESULTS: Data from 235 of the 297 enrolled women were used for the study. Serum AMH level was negatively correlated with the initial and total HP-hMG doses (p<0.001), and positively correlated with the number of retrieved oocytes (p<0.007). Embryos were obtained for 94.0% of women, and fresh embryo transfer was performed in 72.8% of them. The clinical pregnancy rate was 28.5% after the first embryo transfer. CONCLUSION: Selecting the appropriate starting dose of gonadotropin is crucial to optimize the IVF/ICSI procedure. For the first attempt, the serum AMH level is a good biomarker to individualize treatment.

Evaluation of Ovarian Reserve Tests and Age in the Prediction of Poor Ovarian Response to Controlled Ovarian Stimulation-A Real-World Data Analysis of 89,002 Patients.

Aims: This study aimed to explore the value of ovarian reserve tests (ORTs) for predicting poor ovary response (POR) and whether an age cutoff could improve this forecasting, so as to facilitate clinical decision-making for women undergoing in vitro fertilization (IVF). Methods: A retrospective cohort study was conducted on poor ovary response (POR) patients using real-world data from five reproductive centers of university-affiliated hospitals or large academic hospitals in China. A total of 89,002 women with infertility undergoing their first traditional ovarian stimulation cycle for in vitro fertilization from January 2013 to December 2019 were included. The receiver operating characteristic (ROC) curve was performed to estimate the prediction value of POR by the following ORTs: anti-Mullerian hormone (AMH), antral follicle count (AFC), basal FSH (bFSH), as well as patient age. Results: In this retrospective cohort, the frequency of POR in the first IVF cycle was 14.8%. Age, AFC, AMH, and bFSH were used as predicting factors for POR, of which AMH and AFC were the best indicators when using a single factor for prediction (AUC 0.862 and 0.842, respectively). The predictive values of the multivariate model included age and AMH (AUC 0.865), age and AFC (AUC 0.850), age and all three ORTs (AUC 0.873). Compared with using a single factor alone, the combinations of ORTs and female age can increase the predictive value of POR. Adding age to single AMH model improved the prediction accuracy compared with AMH alone (AUC 0.865 vs. 0.862), but the improvement was not significant. The AFC with age model significantly improved the prediction accuracy of the single AFC model (AUC 0.846 vs. 0.837). To reach 90% specificity for POR prediction, the cutoff point for age was 38 years old with a sensitivity of 40.7%, 5 for AFC with a sensitivity of 55.9%, and 1.18 ng/ml for AMH with a sensitivity of 63.3%. Conclusion: AFC and AMH demonstrated a high accuracy when using ROC regression to predict POR. When testing is reliable, AMH can be used alone to forecast POR. When AFC is used as a prediction parameter, age is suggested to be considered as well. Based on the results of the cutoff threshold analysis, AFC ≤ 5 and AMH ≤ 1.18 ng/ml should be recommended to predict POR more accurately in IVF/ICSI patients.

Does the additional use of clomiphene citrate or letrozole for in vitro fertilization deserve more attention?

BACKGROUND: Adding clomiphene citrate (CC) and/or letrozole (LE) to in vitro fertilization (IVF) cycles for mild ovarian stimulation is a general approach. Although lots of researches have demonstrated partial benefits of the strategy, all-around effects of oral medications remained deficient. This paper aims to assess whether an addition of oral medication will result in considerable outcomes on T-Gn (total dose of gonadotropin), Gn days, total retrieved ova, high quality embryos, blastocyst number, ovarian hyperstimulation syndrome (OHSS) rate, clinical pregnancy rate and cumulative pregnancy rate, even if it was not conventional mild/minimal stimulations. RESULTS: Participants were categorized to three diverse populations as high responders, normal responders and poor responders according to basal antral follicle count. T-Gn in patients treated with CC/LE distinctly decreased from 2496.96 IU/d to 1827.68 IU/d, from 2860.28 IU/d to 2119.99 IU/d, and from 3182.15 IU/d to 1802.84 IU/d, respectively. For high ovary responders and normal responders, the OHSS incidence rate also declined from 29.2 to 4.3% (P < 0.001) and from 1.1 to 0.0% (P = 0.090). Other, there was no statistical difference with respect to the T-retrieved ova (total retrieved ova), high quality embryos, cultured blastocyst and blastocyst number in high responders. For normal responders and poor ovary responders, T-Gn, Gn days, T-retrieved ova, high quality embryos, cultured blastocyst and blastocysts number in oral medications group all apparently decreased. Clinical pregnancy rate per fresh cycle of poor responders with prior oral medications was significantly decreased (25.7% vs. 50.8%, P = 0.005), and no significant differences in high responders and normal responders were expressed (52.5% vs. 44.2%, P = 0.310; 51.9% vs. 42.4%, P = 0.163) between two groups of participants. The numbers of cumulative pregnancy rates were lower in the conventional group compared to the add group for high (75.90% versus 81.03%, P = 0.279), normal (62.69% versus 71.36%, P = 0.016) and poor (39.74% versus 68.21%, P < 0.001) responders. CONCLUSIONS: The addition of CC/LE to the ovulation induction during IVF has certain efficacy in terms of low cost, low OHSS incidence. CC/LE deserves more recommendations as a responsible strategy in high responders due to advantageous pregnancy outcomes. For normal responders, the strategy needs to be considered with more comprehensive factors.

Minimal ovarian stimulation is an alternative to conventional protocols for older women according to Poseidon's stratification: a retrospective multicenter cohort study.

OBJECTIVE: To investigate whether minimal ovarian stimulation (mOS) is as effective as conventional ovarian stimulation (cOS) for older women belonging to different groups according to the Poseidon criteria. MATERIAL AND METHODS: Observational retrospective multicentre cohort including women from Poseidon's groups 2 and 4 that underwent in vitro fertilization (IVF). We performed a mixed-effects logistic regression model, adding as a random effect the patients and the stimulation cycle considering the dependence of data. Survival curves were employed as a measure of the cumulative live birth rate (CLBR). The primary outcomes were live birth rate per embryo transfer and CLBR per consecutive embryo transfer and oocyte consumed until a live birth was achieved. RESULTS: A total of 2002 patients underwent 3056 embryo transfers (mOS = 497 and cOS = 2559). The live birth rates per embryo transfer in mOS and cOS showed no significant difference in both Poseidon's groups. Likewise, the logistic regression showed similar live birth rates between the two protocols in Poseidon's groups 2 (OR 1.165, 95% CI 0.77-1.77; p = 0.710) and 4 (OR 1.264 95% CI 0.59-2.70; p = 0.387). However, the survival curves showed higher CLBR per oocyte in women that received mOS (Poseidon group 2: p < 0.001 and Poseidon group 4: p = 0.039). CONCLUSIONS: Minimal ovarian stimulation is a good alternative to COS as a first-line treatment for patients belonging to Poseidon's groups 2 and 4. The number of oocytes needed to achieve a live birth seems inferior in mOS strategy than cOS.

Obtaining Xenopus laevis Eggs.

Nearly a century ago, studies by Lancelot Hogben and others demonstrated that ovulation in female Xenopus laevis can be induced via injection of mammalian gonadotropins into the dorsal lymph sac, allowing for egg production throughout the year independent of the normal reproductive cycles. Hormonally induced females are capable of producing thousands of eggs in a single spawning, which can then be fertilized to generate embryos or used as a substrate for generation of egg extracts. The protocol for induction of ovulation and subsequent egg collection is straightforward and robust, yet some of its details may vary among laboratories based on prior training, availability of necessary reagents, or the experimental objectives. As the goal of this protocol is not to describe every single variation possible for acquiring eggs but to provide a simple and clear description that can be easily applied by researchers with no prior working experience with X. laevis, we focus on describing the method we use at the National Xenopus Resource-that is, inducing ovulation in X. laevis via dorsal lymph sac injection of gonadotropic hormones and the stimulation of egg laying through application of gentle pressure to the females.

Effect of ejaculatory abstinence period on sperm DNA fragmentation and pregnancy outcome of intrauterine insemination cycles: A prospective randomized study.

PURPOSE: To evaluate the effect of the ejaculatory abstinence period on sperm DNA fragmentation and pregnancy rates in IUI cycles. METHODS: One hundred and twenty couples with unexplained infertility were prospectively randomized into two groups on the second day of their cycle. In group A, patients had 1-day ejaculatory abstinence period; in group B patients had 3-day ejaculatory abstinence period. Each patient was stimulated with gonadotropins, and IUI was performed. The primary outcome measure was clinical pregnancy and sperm DNA fragmentation rate. RESULTS: The pregnancy rate was 17.3% and 18.5% in group A and group B, respectively. No significant difference was found among the groups (p = 0.803). The sperm DNA fragmentation rate for group A (20.71 ± 11.01) and group B (23.78 ± 12.64) were almost similar (p = 0.187). The sperm DNA fragmentation rate was 24.89 ± 12.89 in pregnant couples and 21.71 ± 11.69 in non-pregnant couples (p = 0.288). CONCLUSION: Even after a short abstinence period of 1 day, compared to the standard abstinence period of 3 days, pregnancy rates are similar among unexplained infertility couples undergoing ovarian stimulation and IUI. CLINICALTRIALS: The study was registered at ClinicalTrials.gov with ID NCT04361292. Date of registration: 27 April 2020. The study was registered retrospectively.

Endometrial thickness after ovarian stimulation with gonadotropin, clomiphene, or letrozole for unexplained infertility, and association with treatment outcomes.

OBJECTIVE: To study the association of endometrial thickness (EMT) with live birth rates (LBR) in ovarian stimulation with intrauterine insemination (OS-IUI) treatments for unexplained infertility. DESIGN: Prospective cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial. SETTING: Multicenter randomized controlled trial. PATIENTS: A total of 868 couples with unexplained infertility (n=2,459 cycles). INTERVENTIONS: OS-IUI treatment cycles (n = 2,459) as part of the AMIGOS clinical trial. MAIN OUTCOME MEASURES: Live birth rates; unadjusted and adjusted risk ratios (RR) for live birth by EMT category, calculated using generalized estimating equations. RESULTS: The overall mean EMT on day of human chorionic gonadotropin administration in cycles with a live birth was significantly greater than in those without. Compared to the referent EMT group of 9 to 12 mm, the unadjusted RR for live birth for the EMT groups of ≤5 and 6-8 were 0.48 and 0.92, respectively. The test for trend indicated evidence of decreasing LBR with decreasing EMT. After adjustment for ovarian stimulation medication, a linear trend was no longer supported. Stratified analyses revealed no differences in associations by treatment group. CONCLUSIONS: In OS-IUI for unexplained infertility, higher LBR are observed with increasing EMT; however, EMT is not significantly associated with LBR when adjusted for OS treatment type. Appreciable LBR are seen at all EMT, even those of ≤5 mm, suggesting that OS-IUI cycles should not be canceled for thin endometrium. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862.

The impact of endometrioma on in vitro fertilisation/intra-cytoplasmic injection IVF/ICSI reproductive outcomes: a systematic review and meta-analysis.

BACKGROUND: Assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) are often used to aid fertility in women with endometrioma; however, the implications of endometrioma on ART are unresolved. OBJECTIVE: To determine the effect of endometrioma on reproductive outcomes in women undergoing IVF or ICSI. METHODS: A systematic review and meta-analysis was conducted to identify articles examining women who had endometrioma and had undergone IVF or ICSI. Electronic searches were performed in PubMed, BIOSIS and MEDLINE up to September 2019. The primary outcome was live birth rate (LBR). Secondary outcomes included clinical pregnancy rate (CPR), implantation rate (IR), number of oocytes retrieved, number of metaphase II (MII) oocytes retrieved, number of embryos and top-quality embryos and the duration of gonadotrophin stimulation and dose. RESULTS: Eight studies were included. Where significant heterogeneity between studies was identified, a random-effects model was used. The number of oocytes (weighted means difference; WMD-2.25; 95% CI 3.43 to - 1.06, p = 0.0002) and the number of MII oocytes retrieved (WMD-4.64; 95% CI 5.65 to - 3.63, p < 0.00001) were significantly lower in women with endometrioma versus controls. All other outcomes, including gonadotrophin dose and duration, the total number of embryos, high-quality embryos, CPR, IR and LBR were similar in women with and without endometrioma. CONCLUSION: Even though women with endometriomas had a reduced number of oocytes and MII oocytes retrieved when compared to women without, no other differences in reproductive outcomes were identified. This implies that IVF/ICSI is a beneficial ART approach for women with endometrioma.

How fixed versus variable gonadotropin dose during controlled ovarian stimulation could influence the management of infertility patients undergoing IVF treatment: a national Delphi consensus.

AIM: Define how and when fixed starting gonadotropin doses can be used in current clinical ART practices in Italy. METHODS: A Delphi conference consisting of three rounds was performed in order to define the ideal clinical conditions in which fixed-gonadotropin-dose during COS should be applied. During the conference, 19 statements about the current ART practice were provided to a panel of twenty-nine national experts. Median score was 5 (IQ:4-6) in all Delphi rounds. RESULTS: Eleven statements (57.9%) were classified as shareable with high-degree of convergence, 2 (10.5%) as shareable with low convergence and 6 (31.6%) as un-shareable with high convergence. The panel reached high consensus regarding some statements: (i) fixed FSH-dose in normoresponders and poor-responder, (ii) importance of predicting ovarian response before COS, considering multiple markers to select the right stimulation protocol for each patient, (iii) importance of therapy simplification and standardization to improve efficiency during COS. Moreover, a low-convergence was reached about use of GnRH antagonist as first treatment line and drug storage at room temperature. However from these findings, the debate remains open regarding some other statements: (a) usefulness of Bologna-criteria to define poor-responders; (b) efficacy to change always stimulation protocol after a failure IVF; (c) utility of AMH-dosed with standardized automatic mode to define normo-responder patients; (d) usefulness to modify the dosage of 12.5 IU/die during COS to improve stimulation effectiveness. CONCLUSION: Controlled ovarian stimulation remains a challenging clinical step in Assisted Reproductive Technique, especially in some specific patient groups for which no clinical consensus is available. This study is the first attempt to describe the shared clinical opinion regarding the fixed versus variable gonadotropin dose in the real IVF practice.

The effect of Gonadotropin releasing hormone administration on fertility and embryonic loss in goats during the anoestrus period

Following the induction of oestrus out of season in small ruminants, low fertility and variations in fertility rates are associated with embryonic losses. One of the main causes of embryonic loss is luteal dysfunction. Gonadotropin Releasing Hormone (GnRH) supports the luteal structure, and increasing progesterone levels may be beneficial in terms of promoting embryonic life. The main objective of the present study was to evaluate the efficacy of GnRH administration following an oestrus induction protocol in the anoestrus season for preventing embryonic loss in goats having failure to conceive during the season. In the study, 106 Damascus goats aged 3-5 years and weighing 45-60 kg were used. The oestrus of 106 goats in the anoestrous group was stimulated with progesterone and pregnant mare serum gonadotropin (PMSG) treatment. Out of breeding season, goats were divided into the 4 following groups: GnRH0 (n = 27), GnRH7 (n = 26), GnRH0+7 (n = 27) and control (n = 26). In each goat, an intravaginal sponge (IS) containing 20 mg of fluorogestone acetate (FGA) was placed into the vagina and left for 9 days. With the withdrawal of the sponge, 550IU PMSG and 125 µg of d-cloprostenol were injected intramuscularly. Oestrus detection was made via teaser bucks for 3 days starting 24 h after withdrawal of the IS. Eighteen bucks known to be fertile were used for breeding. Goats in the oestrus period were mated via natural breeding. The GnRH analogue lecirelin was injected intramuscularly at breeding in the GnRH0 group, on day 7 post-breeding in the GnRH7 group, and both at breeding and on day 7 post-breeding in the GnRH0+7 group. No injections were given to the control group. Blood samples for progesterone measurement were taken by jugular vena puncturing on days 3, 6, 7, 10, 13, 16, and 19 after breeding from 10 randomly chosen goats in all groups. The goats with a level of > 3.5 ng/mL of progesterone on day 21 post-breeding were evaluated as pregnant. Pregnancy was also viewed on day 50 after breeding by real-time ultrasonography (USG) with a 5-7.5 MHz convex probe. The oestrus rate was 96.23% (102/106) in the goats. The rates of onset of oestrus between 36-48 h, 48-60 h and 60 h and beyond were 38.7% (41/106), 21.7% (23/106) and 35.8% (38/106), respectively. The total pregnancy rate was 35.8% (38/106). There were no statistically significant differences (P > 0.05) found for the pregnancy rate, embryonic death rate or progesterone concentration of the groups. However, serum progesterone levels were statistically different in the GnRH7 group compared with the control group (P < 0.05). After synchronisation, various anti-luteolytic strategies can be used to support corpus luteum development and elevate progesterone concentration in the luteal phase to decrease embryonic loss and increase reproductive performance. Therefore, application of GnRH to support the luteal structure and to increase progesterone levels may be beneficial in terms of supporting embryonic life. The results showed that GnRH treatment on the day 7 post-breeding following oestrus induction, including FGA and PMSG, can increase serum progesterone levels in Damascus goats in the anoestrus period. However, following oestrus induction in the anoestrus period, it was seen that GnRH treatment at breeding or on day 7 after breeding did not have any positive effect on embryonic loss or reproductive performance. In conclusion, it was considered that this protocol could be implemented successfully, yielding a 35% pregnancy rate in Damascus goats in the anoestrus period, but embryonic loss must be deeply studied in detail.(AU)

Predictor for supraphysiologic serum estradiol elevation on hCG triggering day of controlled ovarian stimulation using letrozole and gonadotropins in women with estrogen-dependent cancers.

The objective of this study was to evaluate predicting factors for supraphysiologic serum estradiol elevation during controlled ovarian stimulation (COS) with administration of letrozole and gonadotropins in patients with estrogen-dependent cancer. Use of aromatase inhibitors is recommended to prevent the potential effects of elevated serum estradiol levels and recurrence of tumor in patients with estrogen-dependent cancers during COS. Although previous studies reported that letrozole have shown an effective lowering of peak estrogen levels, a part of patients shows supraphysiologic levels of estrogen associated with ovarian stimulation despite the administration of letrozole. From January 2009 to December 2019, patients with estrogen-dependent cancer who underwent COS with antagonist protocol using a letrozole (5 mg/ day) to keep estrogen levels low were included in this study. Early monitoring serum estradiol was measured in all patients on the 4-6th day of stimulation. Subjects were classified into two groups according to the serum estradiol level on hCG triggering day, physiologic estradiol group (≤400 pg/mL) and supraphysiologic estradiol group (>400 pg/mL). A total of 96 COS cycles were retrospectively analyzed. Supraphysiologic level of serum estradiol was found in 21.9% of the patients. Mean age, AMH, duration of stimulation, total dose of gonadotropins administered were not different between the two groups. However, early monitoring serum estradiol level was significantly higher in the supraphysiologic estradiol group (67.1±47.9 vs. 115.6±78.1, p = 0.001) and was associated with the occurrence of supraphysiologic elevation of serum estradiol on hCG triggering day. Patients with early monitoring serum estradiol ≥84.5 pg/mL had an odds ratio of 5.376 [95% CI, 1.613-17.913] for supraphysiologic elevation of serum estradiol compared to those with early monitoring serum estradiol below 84.5 pg/mL. In conclusion, early monitoring serum estradiol is an independent predicting factor for supraphysiologic level of serum estradiol on hCG triggering day in the COS cycles using letrozole and gonadotropins.

Is intrauterine insemination a viable treatment option for women over 43 years old? An analysis by ovarian stimulation protocol and sperm source.

PURPOSE: The aim of this study was to determine how female age at the end of the reproductive spectrum effects success of natural cycle intrauterine insemination (IUI) or IUI in combination with ovarian stimulation. METHODS: We performed a retrospective cohort study of women 43 years of age and older at the time of IUI in a single academic fertility center between January 2011 and March 2018. Primary outcomes were both pregnancies and live births per cycle of IUI. Data are presented as percentage or mean ± SD. Fisher exact and chi-squared analyses were performed. RESULTS: There were 9334 IUI cycles conducted during the study period. Of these cycles, 325 IUIs (3.5%) were for women aged 43 years and over at the time of insemination (43.6 ± 0.8, range 43 to 47 years). Analysis of these 325 IUI cycles revealed 5 biochemical pregnancies (1.5%) and only 1 live birth (0.3%). The pregnancy rate did not differ between IUIs using donor sperm (N = 1/49, 2.0%) compared to IUIs with partner sperm (N = 4/276, 1.4%). The pregnancy rate did not differ between IUIs with gonadotropins (N = 2/211, 0.9%), clomiphene or letrozole (N = 2/78, 2.6%), or natural cycle (N = 1/36, 2.8%). CONCLUSIONS: The use of intrauterine inseminations in women 43 years of age and older is an ineffective treatment strategy. This is irrespective of the use of ovarian stimulation or donor sperm. Costly gonadotropin injections did not increase the chance of pregnancy nor did oral medication when compared to natural cycle IUIs.

Intrauterine insemination cycles: prediction of success and thresholds for poor prognosis and futile care.

PURPOSE: We aimed to define intrauterine insemination (IUI) cycle characteristics associated with viable birth, identify thresholds below which IUI treatments are consistent with very poor prognosis and futile care, and develop a nomogram for individualized application. METHODS: This retrospective cohort study evaluated couples using fresh partner ejaculate for IUI from January 2005 to September 2017. Variables included female age, semen characteristics, and ovarian stimulation type. Using cycle-level data, we evaluated the association of these characteristics with the probability of viable birth by fitting generalized regression models for a binary outcome with a logit link function, using generalized estimating equation methodology to account for the correlation between cycles involving the same patient. RESULTS: The cohort consisted of 1117 women with 2912 IUI cycles; viable birth was achieved in 275 (9.4%) cycles. Futile care (viable birth rate < 1%) was identified for women age > 43, regardless of stimulation type or inseminate motility (IM). Very poor prognosis (viable birth rate < 5%) was identified for women using oral medications or Clomid plus gonadotropins who were (1) age < 35 with IM < 49%, (2) age 35-37 with IM < 56%, or (3) age ≥ 38, and (4) women age ≥ 38 using gonadotropins only with IM < 60%. A clinical prediction model and nomogram was developed with an optimism-corrected c-statistic of 0.611. CONCLUSIONS: The present study highlights the impact of multiple clinical factors on IUI success, identifies criteria consistent with very poor prognosis and futile care, and provides a nomogram to individualize counseling regarding the probability of a viable birth.

A comparison of IVF outcomes transferring a single ideal blastocyst in women with polycystic ovary syndrome and normal ovulatory controls.

PURPOSE: To assess the effects PCOS on live birth rates when transferring a single fresh ideal blastocyst. METHODS: A retrospective cohort study performed at the university-affiliated reproductive center. Women with PCOS and a control group of normal ovulatory women who underwent their first fresh embryo transfer with single ideal grade blastocyst were included in the study. Demographic, stimulation information and pregnancy outcomes were collected and analysed. The primary outcome was live birth rates, and secondary outcomes included pregnancy and clinical pregnancy rates. RESULTS: 71 Women with PCOS and 272 normal ovulatory controls underwent their first embryo transfer and met the inclusion and exclusion criteria. PCOS patient were younger (31.0 ± 3.7 vs. 33.1 ± 3.2, p = 0.0001), with higher AFC (40.0 ± 9.3 vs. 13.3 ± 4.6, p = 0.0001), required lower dose of gonadotropins to stimulate (1198 ± 786 vs. 1891 ± 1224, p = 0.0001), and had higher serum testosterone levels (2.3 ± 0.7 vs. 1.1 ± 0.3, p = 0.0001). No significant difference was found between the two groups regarding the number of previous pregnancies, the number of previous full-term pregnancies, the level of basal serum FSH, estradiol level at triggering and the BMI. When compared by Chi squared testing pregnancy rates, clinical pregnancy rates and live birth rates did not differ. However, when controlling (with multivariate stepwise logistic regression) for confounders, live birth rates were lower among the women with PCOS (p = 0.035, CI: 0.18-0.92). CONCLUSION: After controlling for confounders, when transferring a fresh single ideal blastocyst, live birth rates were lower among the women with PCOS than normal ovulatory controls.

[Effect of exogenous gonadotropin dosage on embryo aneuploidy rate and pregnancy outcome in patients of preimplantation genetic test].

Objective: To investigate the effect of gonadotropin (Gn) on embryo aneuploidy rate and pregnancy outcome during preimplanptation genetic testing for aneuploidy (PGT-A) cycles. Methods: The clinical data of patients undergoing PGT-A cycle at the First Medical Center of the PLA General Hospital from January 1, 2013 to May 31, 2019 were retrospectively analyzed. Patients were divided into younger patient group (<35 years old) and elder patient group (≥35 years old) by maternal age, then divided into two groups in line with Gn dosage (≤2 250 U, >2 250 U), and into four groups by number of oocytes retrieved (1-5, 6-10, 11-15 and ≥16 oocytes). The embryo aneuploidy rate and pregnancy outcome between the groups were compared. Logistic regression was used to analyze the relationship between the cumulative amount of Gn, embryo aneuploidy rate and live-birth rate. Results: A total of 402 cycles (338 patients) and 1 883 embryos were included in the study. (1) In the younger patients, the aneuploidy rate was 52.5% (304/579) in the group of Gn≤2 250 U and 48.6% (188/387) in the group of Gn>2 250 U, with no significant difference between them (P=0.232). In the elderly patients, the difference in embryo aneuploidy rate between the two Gn group [57.9% (208/359) versus 60.6% (319/526)] was not statistically significant (P=0.420). (2) The embryonic aneuploidy rate in different protocol of ovary stimulation was analyzed,in the younger group, the embryonic aneuploidy rate in patients using antagonist long protocol was 50.3% (158/314), it was 50.0% (121/242) in agonist long protocol, 52.1% (207/397) in agonist short protocol and 6/13 in luteal phase protocol, no statistical difference was found in above groups (P=0.923); in the elder group, embryonic aneuploidy rate was 60.8% (191/314) in antagonist protocol, 58.4% (132/226) in agonist long protocol, 59.2%(199/336) in agonist short protocol, 5/9 in luteal phase protocol, respectively,no significant difference was found (P=0.938). (3) In the younger patients, the aneuploidy rate in 1-5 oocytes group, 6-10 oocytes group, 11-15 oocytes group and ≥16 oocytes group was 37.9% (11/29), 54.0% (94/174), 52.5% (104/198) and 50.1% (283/565) respectively, no significant difference was found between the groups (P=0.652); while in the elder patients, the difference between aneuploidy rate in each retrieved oocytes group [73.6% (89/121), 57.5% (119/207), 56.3% (108/192), 57.8% (211/365)] was statistically significant (P=0.046). (4) Logistic regression analysis of age, cumulative dosage of Gn, number of oocytes obtained, and embryo aneuploidy rate showed that there was no association between the amount of Gn and embryo aneuploidy rate (P>0.05); the increase in maternal age would increase the risk of aneuploidy rate of embryos, which was statistically significant (OR=1.031, 95%CI: 1.010-1.054, P=0.004); the increase in oocytes retrived would significantly decrease the risk of aneuploidy (OR=0.981, 95%CI: 0.971-0.991, P<0.01). (5) There was no significant difference in biochemical pregnancy rate [55.6% (80/144) versus 52.1% (63/121)], clinical pregnancy rate [50.0% (72/144) versus 47.9% (58/121)] and live-birth rate [46.5% (67/144) versus 40.5% (49/121)] between different Gn dosage groups (P=0.613, P=0.738, P=0.324). The logistic regression analysis showed that the maternal age, the cumulative dosage of Gn, the number of oocytes obtained, and the ovarian stimulation protocol had no effect on the live-birth rate (all P>0.05). Conclusions: In PGT-A cycle, the dosage of Gn has no association with the embryo aneuploidy rate and pregnancy outcome. In the patients ≥35 years old, the increase in number of oocytes obtained may decrease the risk of aneuploidy. Age is an important factor affecting the embryo aneuploidy in PGT-A cycle.

High serum Antimullerian hormone levels are associated with lower live birth rates in women with polycystic ovarian syndrome undergoing assisted reproductive technology.

INTRODUCTION: Antimullerian hormone (AMH) strongly correlates with ovarian reserve and response to controlled ovarian stimulation. Emerging data suggests that serum AMH level may also predict ART outcomes. However, AMH is characteristically elevated in PCOS women and it is unknown whether it may predict live birth outcomes in this population. METHODS: This was a retrospective cohort study of 184 PCOS women (Rotterdam criteria) who underwent their first fresh IVF/ICSI cycle. Women were divided into 3 groups according to the <25th (low), 25 to 75th (average), or > 75th (high) percentile of serum AMH concentration. Cycle stimulation parameters and reproductive outcomes were compared between groups. RESULTS: Women in the low serum AMH group were older than those in the average or high AMH (p < 0.05), and required greater gonadotropin dose for stimulation compared to the high AMH group (p < 0.05). Women with high AMH had greater testosterone level compared to women in the low or average AMH groups. No differences were noted between groups in terms of maximal E2, oocytes retrieved and fertilization rate. However, low serum AMH women had significantly greater live birth rates (p < 0.05) and showed a trend towards greater clinical pregnancy rates compared to women in the average and high AMH groups (p = 0.09). The significant association of AMH with live birth rate remained after adjusting for age, BMI, day of transfer and number of embryos transferred. CONCLUSIONS: In PCOS women, elevated AMH concentrations are associated with hyperandrogenism and lower live birth rates.