Baseline Antral Follicle Count Research Articles

Risk factors for empty follicle syndrome in diminished ovarian reserve patients undergoing intracytoplasmic sperm injection cycles: A retrospective observational analysis.

The aim of this study is to evaluate the risk factors for empty follicle syndrome (EFS) in patients with diminished ovarian reserve (DOR) undergoing an intracytoplasmic sperm injection cycle. In this retrospective study, patients with DOR were divided into 2 groups according to the presence of empty follicles on the day of oocyte retrieval. Patient age, body mass index (BMI), anti-Müllerian hormone (AMH), baseline follicle stimulating hormone (FSH) and estradiol (E2) levels, basal antral follicle count (AFC), total gonadotropin dose, and day of stimulation were recorded as risk factors. The association between EFS and these variables was assessed using the logistic regression method and ROC curve analysis. Increased BMI, low AMH, higher baseline FSH, low baseline AFC, higher gonadotropin dose, and longer day of ovulation induction were independent risk factors for EFS in patients with DOR. ROC curve analysis showed that BMI, AMH, baseline FSH, baseline AFC, higher gonadotropin dose, and longer ovulation induction days were predictive parameters in this group. According to the current study, higher BMI, lower AMH, higher baseline FSH, lower baseline AFC, higher gonadotropin dose and longer ovulation induction days were independent risk factors for EFS in patients with reduced ovarian reserve.

P-623 Post-market analysis of an AI-powered clinical decision support tool for ovarian stimulation

Abstract Study question How do treatment decisions and patient outcomes change with physician utilization of artificial intelligence (AI) to help determine FSH starting dose and trigger injection timing? Summary answer With physician use of an AI platform, patients were treated with significantly less starting and total FSH without statistically significant changes in outcomes. What is known already Stim Assist is an AI clinical decision support software providing physicians with adjunctive information for the prediction of the number of mature (MII) oocytes that may be retrieved from an ovarian stimulation cycle. The software is intended to assist with the selection of the starting dose of FSH as well as the decision of when to administer the trigger injection. Prior studies have retrospectively estimated the benefit of using AI for treatment decisions during ovarian stimulation, but there is a lack of post-market analyses evaluating the true efficacy of these tools when integrated in clinical practice. Study design, size, duration This study was conducted by multiple physicians at a single IVF clinic in the U.S. The treatment arm consisted of 292 patients seen by physicians using Stim Assist between December 2022 - December 2023. The control arm consisted of 292 matched historical control patients, treated between May 2019 - May 2022 at the same clinic without use of Stim Assist. Participants/materials, setting, methods Matching for each patient was performed for each physician individually, comparing each treatment-arm patient to a historical control-arm patient who was seen by the same physician. Patients were matched 1-to-1 based on age, baseline AMH, and baseline antral follicle count. The primary endpoints were the starting FSH and total FSH prescribed to the patient, as well as MIIs retrieved at the end of stimulation. Main results and the role of chance Comparing the treatment arm to the control arm, the average MIIs were 11.17 vs. 11.45 (p = 0.68), the average starting FSH was 397.09 vs. 443.58 (p < 0.01), and the average total FSH was 4181.77 vs 4601.8 (p < 0.01). The results were stratified by age groups of < 35, 35-40, and >40. For patients in the <35 group (N = 122), the average MIIs were 13.99 vs. 16.06 (p = 0.06), the average starting FSH was 346.72 vs. 380.53 (p < 0.01), and the average total FSH was 3525.84 vs. 3927.25 (p < 0.01). For patients in the 35-40 group (N = 129), the average MIIs were 9.46 vs. 8.71 (p = 0.34), the average starting FSH was 420.35 vs. 486.05 (p < 0.01), and the average total FSH was 4568.6 vs. 5063.37 (p < 0.01). For patients in the >40 group (N = 41), the average MIIs were 8.17 vs. 6.34 (p = 0.12), the average starting FSH was 473.78 vs. 497.56 (p = 0.16), and the average total FSH was 4916.46 vs. 5156.71 (p = 0.34). Limitations, reasons for caution This preliminary post-market analysis was performed at a single clinic in the U.S. We could not calculate live birth outcomes. Due to the limited sample size, differences in outcomes were not statistically significant. Wider implications of the findings These findings suggest that physician use of Stim Assist helped significantly reduce the starting and total FSH prescribed to patients. Additionally, MII outcome differences showed a trend towards an increase in MIIs for patients >35 years old, and a slight reduction in MIIs for younger, better prognosis patients. Trial registration number not applicable

P-694 Desogestrel did not affect Follicular Output Rate (FORT) during controlled ovarian stimulation for oocyte vitrification: prospective cohort study

Abstract Study question Does desogestrel an option for LH suppression during controlled ovarian stimulation for oocyte vitrification? Summary answer This new option for LH suppression did not affect FORT and, consequently, the number of collected oocytes for vitrification. What is known already Traditionally, LH suppression is achieved by using a gonadotropin-releasing hormone (GnRH) analogue. However, improved cryopreservation techniques and freeze-all strategies are introducing new concepts, including the possibility of using progesterone instead of GnRH analogues. Progesterone compounds are currently wide-used during ovarian stimulation for oocyte freezing for LH suppression. The use of oral medroxyprogesterone was previously shown to effectively prevent the LH surge, without impacting embryo development or pregnancy rates after frozen embryo transfer. The use of dydrogesterone with the same purpose was also effective. Desogestrel is a progesterone broadly known and accepted, and has good tolerability and low cost. Study design, size, duration A prospective cohort study was performed during the period of 2019-2021 including 75 patients submitted to oocyte freezing and 173 women matched by age as the controls (patients submitted to IVF for the first time). Participants/materials, setting, methods Patients from the control group used a flexible GnRH antagonist for LH suppression, and patients in the desogestrel group utilized desogestrel 75 mcg oral twice a day (starting from the beginning of gonadotropin to hCG/agonist day). All patients received the same gonadotropin regimen (recombinant FSH). The final oocyte maturation was equal for both groups (recombinant hCG and GnRH analogue agonist). The primary endpoint was the antral follicle responsiveness to follicle-stimulating hormone, measured by FORT. Main results and the role of chance Age [control group= 36 years (median 28-45); desogestrel group= 36 years (median 23-43); p = 0.793; Mann Whitney U test], baseline antral follicle count [control group= 8 (2-23); desogestrel group= 9 (2-21); p = 0.741; Mann Whitney U test] and anti-Mullerian hormone [control group= 1.5 (0.05-7.95); desogestrel group= 1.00 (0.01-16.00); p = 0.540; Mann Whitney U test] were similar between both groups. However, the controlled ovarian stimulation length was shorter in the control group [10.4±1.6 vs. 11.0±1.6; p = 0.044; t-student test,] and those patients utilized less gonadotropin than the desogestrel group [2736 UI ± 745 vs. 2933 UI ± 785; p = 0.047; t-student test,]. Finally, Follicular Output Rate (FORT) [control group= 45%; desogestrel group= 52%; p = 0.217; t-student test], number of collected oocytes [control group= 6 (1-33); desogestrel group= 8 (1-20); p = 0.293; Mann Whitney U test] and MII [control group= 5 (1-27); desogestrel group= 6 (1-19); p = 0.156, Mann Whitney U test] were the same between both groups. Limitations, reasons for caution The small sample size and the absence of randomization are the main limitations of our study. Since the first results were encouraging, a randomized study should be performed. Wider implications of the findings Desogestrel is a cheap and easy option to be used during controlled ovarian stimulation for oocyte vitrification, since the final results are the same. This is the first scientific report showing the use of desogestrel did not affect FORT and, consequently, the number of collected oocytes for vitrification. Trial registration number Not applicable

P-532 Understanding the utility of hysteroscopic endometrial peeling in women with implantation failure

Abstract Study question Does hysteroscopic endometrial peeling improve reproductive outcomes in women with implantation failure (IF) undergoing a single euploid embryo transfer (SEET)? Summary answer Women with IF may benefit from intraoperative endometrial peeling prior to a SEET. What is known already Preimplantation genetic testing for embryonic aneuploidy (PGT-A) has been suggested as a strategy to improve implantation rates in women with IF. However, after controlling for the genetic status of the embryo, implantation rates still vary from 40-70%, suggesting that other factors aside from the ploidy of the embryo contribute with the cause of IF. We previously demonstrated that hysteroscopic endometrial peeling enhances implantation in women with IF. However, our study was limited by only including frozen embryo transfers of unscreened embryos. We aim to analyze the clinical utility of hysteroscopic endometrial peeling in women who underwent a SEET. Study design, size, duration A retrospective, cohort study included infertile patients with IF diagnosis who underwent endometrial peeling through hysteroscopy and subsequently a SEET from January 2016 to December 2022. Only the first transfer after the hysteroscopic endometrial peeling was included in the analysis. Participants/materials, setting, methods Women <41 years, with IF, normal saline sonogram, and no previous uterine surgeries were segregated into two groups: A) 66 patients underwent hysteroscopic endometrial peeling, which consists of removing the superficial endometrial layer of the whole uterine cavity with hysteroscopic biopsy forceps, and B) 38 controls who did not undergo surgical endometrial peeling. All patients underwent a subsequent SEET. Main results and the role of chance In total 104 women were included in the cohort. No differences were found in age, body mass index, baseline FSH, AMH, baseline antral follicle count, previous number of stimulation/IVF cycles, number of embryos transferred, and, embryonic quality among cohorts. Evaluating the endometrium, no differences were observed in the endometrial pattern, however, the endometrial thickness was thicker in group B (8.4±1.5mm vs 9.2±1.3mm, p = 0.02). When analyzing the subsequent SEET cycle, women in group A had higher implantation (51.8% vs 40.6%, p = 0.001) and clinical pregnancy rates (63.5% vs 31.4%, p = 0.009). No difference was found in clinical loss rates (9.4% vs 10.1%, p = 0.06) among cohorts. Of the patients who underwent surgical endometrial peeling, 18.1% (12/66) had the following incidental intraoperative findings: mild intrauterine and/or cervical adhesions (5/66, 0.07%), endometrial polyps (10/66, 15.1%), polypoid endometrium (8/66, 12.1%). 64.3% of the patients with incidental findings became pregnant. Limitations, reasons for caution This study is limited by its retrospective nature. Additionally, in patients with noted uterine pathology, appropriate surgical management was administered in the same setting, this could have biased the results. Future randomized controlled trials are needed. Wider implications of the findings This study continues to support the possible benefit of mechanically peeling the superficial endometrial layer through hysteroscopy to increase implantation rates in women with IF who undergo a SEET. Trial registration number NA

O-014 An expected benefit analysis of using an interpretable machine learning model for gonadotropin starting dose selection during ovarian stimulation

Abstract Study question What is the expected benefit of using a machine learning model for predicting the optimal starting dose of gonadotropin during ovarian stimulation? Summary answer Patients who had an optimal starting gonadotropin dose had improved outcomes and used significantly less total FSH compared to propensity matched patients who did not. What is known already The relationship between the starting dose of follicle-stimulating hormones (FSH) and ovarian response is complex. In general, too little starting FSH may lead to inadequate follicle recruitment, while too much may lead to excessive response. In completed cycles, there exists conflicting evidence of whether higher doses are beneficial or detrimental to the number of oocytes retrieved. The field of assisted reproduction has begun to apply machine learning techniques to clinical decision support for ovarian stimulation, but no studies have specifically investigated optimizing starting FSH dose selection. Study design, size, duration We performed a retrospective analysis of patients undergoing autologous, non-cancelled IVF cycles from 2014 - 2020 (n = 18,591) at three different IVF clinics in the United States. The primary outcomes were the average number of MIIs, 2PNs, and usable blastocysts in relation to starting and total doses of FSH. Participants/materials, setting, methods A K-nearest neighbor similarity model was trained on all cycles and used to identify the 100 most similar patients to a patient-of-interest using age, BMI, baseline anti-mullerian hormone (AMH), and baseline antral follicle count (AFC). For each patient, a patient-specific dose response curve was created by fitting a constrained second order polynomial to the number of MII oocytes relative to the starting dose of FSH across all of the neighbors. Main results and the role of chance For each patient, their individual dose response curve was used to determine if there was an optimal dose that maximizes the prediction of MIIs (called dose-responsive patients), or if the dose response curve shows no optimal dose (called non-responsive patients). 30% of cycles were identified as dose-responsive, 64% were identified as non-responsive, and 6% were inconclusive and excluded from analysis. Dose-responsive patients who received an optimal starting dose had, on average, 1.5 more MIIs, 1.0 more 2PNs, and 0.5 more usable blastocysts using 10 IU’s less of starting FSH and 195 IU’s less of total FSH compared to propensity-matched patients with non-optimal doses. Non-responsive patients who received a low starting dose had, on average, 0.3 more MIIs, 0.4 more 2PNs, and 0.3 more usable blastocysts using 150 IU’s less of FSH and 1375 IU’s less of total FSH compared to propensity-matched patients with a high starting dose. Limitations, reasons for caution The primary limitation is the retrospective nature of this study. Further, our calculations of starting FSH combined the contribution of pure FSH plus the FSH component of FSH/LH medication, rather than evaluating each separately. We also did not differentiate between types of protocols, as the majority were antagonist cycles. Wider implications of the findings Our results suggest that a patient similarity model for selecting starting FSH can help increase MII outcomes while reducing the amount of FSH given to a patient. Future work will include continuing to increase the diversity of our dataset and performing validation studies to show improved outcomes with model use. Trial registration number Not applicable

P-704 Post trigger progesterone levels as a predictor of oocyte recovery rate

Abstract Study question Do progesterone (P) levels the day after trigger for oocyte maturation impact the oocyte recovery rate? Summary answer A progesterone cutoff value of ≤ 5.0 ng/ml the day after trigger for oocyte maturation is associated with a lower oocyte recovery rate. What is known already Oocyte maturation and embryo development are controlled by intra-ovarian factors such as steroid hormones. P exists in the follicular fluid, and it is known to mediate some luteinizing hormone (LH)- initiated periovulatory events through autocrine/paracrine mechanisms that help mediate granulasa cell luteinization and oocyte maturation. More importantly, a rise in P levels is associated with an adequate follicular rupture. To date, no study has evaluated if lower P levels after oocyte maturation induction are a reflection of impaired physiological periovulatory mechanisms required for the oocyte release from the follicular wall. Study design, size, duration This monocentric retrospective analysis from January 2017 to December 2021 included 435 controlled ovarian hyperstimulation cycles for in vitro fertilization (IVF)/ egg freezing. Serum P, estradiol (E2), bHCG, and LH levels were measured the day after trigger for oocyte maturation to assure adequate luteinization. Participants/materials, setting, methods Women <4O years, that underwent controlled ovarian hyperstimulation with a GnRH antagonist protocol and final oocyte maturation (when ≥2 follicles reached ≥18 mm in diameter) induction with dual trigger (Leuprolide acetate and hCG) were segregated into two groups: Group 1: progesterone cutoff value of ≤ 5.0 ng/ml the day after trigger; Group 2: progesterone cutoff value of ≥ 5.1 ng/ml the day after trigger. Main results and the role of chance 147 cycles in Group 1 were compared with 288 cycles on Group 2. No significant differences were noted in mean patient’s age, BMI, baseline FSH, AMH, baseline antral follicle count, serum P and E2 levels the day of trigger, total dose of gonadotropins, day of trigger as well as serum E2, LH, and bHCG levels the day after trigger among cohorts. A total of 5765 oocytes were retrieved: 1703 corresponding to group 1 and 4692 to group B. Women with progesterone levels higher than ≥5.1 ng/ml the day after trigger had a greater number of oocytes retrieved compared to women with a progesterone cutoff value of ≤ 5.0 ng/ml (16.3 ± 9.1 versus 11.5 ± 7.4, p = < 0.0001). The oocyte/follicle rate was also significantly higher in women in Group 2 vs Group 1 (80.3% vs 63.7%, p = 0.003) However, the mature oocyte (MII) rate was comparable among cohorts (Group 1: 78.0 ± 20.2% vs Group 2: 78.8 ± 17.7%, p = 0.38). Limitations, reasons for caution The retrospective nature of the study, small sample size, selected progesterone cutoff value, and progesterone assay techniques compared to other ART centers may limit the external validity of our findings. Wider implications of the findings Our findings suggest for the first time that lower progesterone levels after final oocyte maturation induction may be a result of compromised mechanisms associated with the release of the oocyte from the follicular wall as demonstrated by a lower oocyte recovery rate. Trial registration number NA

P-366 Tumor necrosis factor-alpha and milk fat globule-epidermal growth factor 8: novel biomarkers to predict implantation failure and pregnancy loss

Abstract Study question Can implantation failure (IF) and pregnancy loss be predicted in serum prior to in vitro fertilization (IVF)? Summary answer Tumor necrosis factor (TNFα) and milk fat globule-epidermal growth factor 8 (MFG-E8) levels may serve as serum markers to predict IF and pregnancy loss. What is known already In a normal pregnancy, mediators such as TNFα are released creating a physiological inflammatory response. However, an exaggerated release of TNFα has been associated with IF and recurrent pregnancy loss (RPL). Recent studies demonstrated that TNFα up-regulates the expression of inflammatory factors such as MFG-E8. MFG-E8 is known to modulate implantation by acting at various levels of the trophoblast and endometrial compartments. Hence an overexpression of this protein may result in apoptosis, endometrial damage, and impaired implantation. Study design, size, duration This multicentric prospective controlled pilot clinical study was conducted from January 2016 to January 2020 and included 30 women in their natural cycle in which serum MFG-E8, TNFα, estradiol (E2), and progesterone (P4) levels were quantified in the early proliferative (cycle day 2) and secretory phases (urinary LH + 7 days). Additionally, an endometrial biopsy was obtained on urinary LH + 7 days for MFG-E8 and TNF α protein and gene expression analysis. Participants/materials, setting, methods Women ages 21-35y were recruited from 3 groups: fertile controls (C), unexplained IF (following 3 failed good quality embryo transfers), and RPL (at least 2 unexplained first trimester miscarriages). Patients with history of uterine surgery, abnormal uterine cavity (fibroids, endometrial polyps, adhesions, adenomyosis, and congenital uterine abnormalities), hydrosalpinx, diminished ovarian reserve, harboring chromosomal rearrangements, thrombophilia, or autoimmune diseases were excluded. Main results and the role of chance Ten women were included in each group. No statistical differences were found in age, BMI, AMH, baseline FSH, and baseline antral follicle count among cohorts. Mean serum E2 and P4 levels were similar among all groups in both the proliferative and secretory phases: E2 proliferative (C 69.19±26.64 pg/ml, IF 64.19±32.56 pg/ml, RPL proliferative 57.44±38.51; p = 0.55), E2 secretory (C 164.10±52.57 pg/ml, IF 172.57±121, RPL 173.81±.97.35; p = 0.25), P4 proliferative (C 0.45±0.15 ng/ml, IF 0.45±0.19 ng/ml, RPL 0.53±0.18 ng/ml; p = 0.85), P4 secretory (C 7.42±4.06 ng/ml, IF 7.8±4.56 ng/ml, RPL 8.05±4.38 ng/ml; p = 0.74). Mean serum TNFα levels were significantly higher in both, the proliferative and secretory phases for the RPL group (proliferative RPL 9.98±4.47 pg/ml, IF 4.73±2.56 pg/ml, C 3.42±1.01 pg/ml; p = 0.001 vs secretory RPL 8.67±4.45 pg/ml, C 3.35±0.94 pg/ml, IF 3.85±1.01 pg/ml; p = 0.03). Mean serum MFG-E8 levels were significantly higher in the IF group during the proliferative phase (IF 373±201 pg/ml, RPL 201±115 pg/ml, C 225.58±109.73pg/ml; p = 0.03), but not in the secretory phase (IF 237±101 pg/ml, RPL 189±116 pg/ml, C 199.41±112.43 pg/ml; p = 0.15). Endometrial MFG-E8 mRNA levels were significantly lower in the IF and RPL group compared to C (p = 0.03). TNFα mRNA levels were not statistically significant among groups (p = 0.12). Limitations, reasons for caution This is a pilot study to assess feasibility. Due to the small sample size, the effects of more subtle covariates would not have been detected. Future larger studies are warranted. Wider implications of the findings These novels differentially expressed serum and endometrial markers may provide information on the physiology of implantation and could generate the basis for non-invasive diagnostic tools and therapeutic use of MFG-E8/TNFα antagonists in women with IF and RPL. Trial registration number IIT-2014-100366

Breast cancer grade and stage do not affect fertility preservation outcomes.

To investigate if breast cancer stage and grade affect fertility preservation outcomes. We performed a retrospective cohort study that included premenopausal women with breast cancer undergoing fertility preservation diagnosed between January 2011 and January 2019. The primary outcome measure was the number of mature oocytes (MII) per antral follicle count (AFC). Secondary outcome measures included total oocytes retrieved, total mature oocytes retrieved, and greater than 10 mature oocytes preserved. Univariate and multivariate models were used to assess the association of low vs. high stage (low stage I-II and high stage III-IV) and grade I vs. grade II/III with each outcome, with adjustment for confounders. A total of 267 premenopausal breast cancer patients undergoing fertility preservation were included in our study, with the majority presenting with low stage (N = 215, 80.5%), grade II/III (N = 235, 88.1%) disease. Baseline AFC, total gonadotropin dose, days of stimulation, and follicles [Formula: see text] 13mm on the day of trigger did not differ by stage or grade. After adjusting for age, BMI, and baseline AFC, we found that the mean MII per AFC did not differ by stage (1.0 vs. 1.1, P = 0.3) or grade (1.0 vs. 1.0, P = 0.92). Similarly, total oocytes retrieved, total MII retrieved, and percentage of patients who were able to preserve greater than 10 MII did not differ by breast cancer stage or grade (all P > 0.2). Breast cancer grade and stage do not impact ovarian stimulation or fertility preservation outcome.

SERUM ANTI-MÜLLERIAN HORMONE CONCENTRATIONS IMPACTS NOT ONLY THE QUANTITY, BUT ALSO THE QUALITY OF THE OVARIAN RESERVE: THE IMPORTANCE OF TIME-LAPSE IMAGING SYSTEM

Serum anti-müllerian hormone (AMH) concentration has been implicated as the most valuable marker of the ovarian reserve, as it correlates highly with the baseline antral follicle count. The AMH has been assigned as a marker of ovarian function mainly in the assessment of the quantitative aspect of the ovarian reserve. On the other side, the predictive value of AMH on oocyte quality and embryo developmental competence is controversial. Time-lapse imaging (TLI) systems allow for the assessment of morphological changes with the exact time-point of occurrence, and may be a valuable tool to evaluate the correlation between serum AMH concentration and the competences of both oocyte and developing embryo. The goal for the present study was to evaluate whether the serum AMH concentration impacts morphokinetic events in a TLI system. This retrospective cohort study was performed in a private university-affiliated IVF center from March 2019 to December 2020 and included 902 injected oocytes from 114 ICSI cycles, cultured in a TLI incubator until the fifth day of development. The effects of serum AMH concentrations on morphokinetic events and ICSI outcomes were evaluated by taking into account clustering of data (multiple embryos per cycle), using generalized mixed models. Evaluated kinetic markers were: pronuclei appearance (tPNa), timing to pronuclei fading (tPNf), timing to two (t2), three (t3), four (t4), five (t5), six (t6), seven (t7), and eight cells (t8), and timing to blastulation (tB). Durations of the second (t3-t2) and third (t5-t3) cell cycles (cc2 and cc3, respectively) and timing to complete synchronous divisions s1 (t2-tPNf), s2 (t4-t3), and s3 (t8-t5) were also evaluated. The post hoc achieved power was > 98.0%. Inverse relationships were observed between serum AMH concentrations and faster tPNf (B: -0.047, CI: -0.071 – -0.024, p<0.001), t3 (B: -0.070, CI: -0.102 – -0.039, p<0.001), t4 (B: -0.080, CI: -0.114 – -0.046, p<0.001), t5 (B: -0.075, CI: -0.123 – -0.028, p=0.002), t6 (B: -0.105, CI: -0.147 – -0.064, p<0.001), t7 (B: -0.120, CI: -0.165 – -0.075, p<0.001), t8 (B: -0.170, CI: -0.220 – -0.119, p<0.001), and tB (B: -0.153, CI: -0.224 – -0.082, p<0.001), cc2 (B: -0.041, CI: -0.062 – -0.019, p<0.001), and s3 (B: -0.086, CI: -0.129 - -0.044, p<0.001). There was a positive association between serum AMH concentration and implantation rate (B: -19.11, CI: -29.12 - -9.11, p<0.001). No significant associations were found between serum AMH concentrations and other morphokinetic parameters or clinical outcomes. Increased serum AMH concentrations correlate with faster embryo development in a TLI incubator and implantation rates.

P–685 Luteinization after final oocyte maturation induction is not compromised in women that receive double dose of Gonadotrophin-releasing hormone antagonists during controlled ovarian hyperstimulation

Abstract Study question Does the use of double dose of GnRH antagonists during COH in women with risk of premature LH surge alter luteinization after final oocyte maturation induction? Summary answer The use of double dose of GnRH antagonist in women with risk of premature luteinizing hormone surge dosent affect luteinization after final oocyte maturation induction. What is known already GnRH antagonists are used to prevent a premature LH surge during controlled ovarian hyperstimulation. The antagonists directly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors, producing a rapid suppression of LH and FSH, with no initial flare effect. In women with diminished ovarian reserve (DOR) it is not uncommon that premature luteinization cannot be completely prevented using a daily dose GnRH antagonist. To date, no study has evaluated the effects of using a daily double dose of GnRH antagonists to prevent a premature LH surge and its effect on luteinization after final oocyte maturation induction. Study design, size, duration This monocentric retrospective analysis evaluated the effect on luteinization after final oocyte maturation induction in twenty women during COH who received a daily double dose of GnRH antagonists (Cetrotide 0.25 mg/mL, Merck) from January 2020 to December 2020. Participants/materials, setting, methods Women with severe DOR and history of premature luteinization during COH received a double dose of GnRH antagonist when the leading follicle reached 12–14 mm (am and pm). When two follicles reached ≥18 mm in diameter, final oocyte maturation was induced with dual trigger using Leuprolide acetate and hCG. Progesterone, estradiol, bHCG, and LH levels were measured the day after final oocyte maturation induction to assure adequate luteinization. Main results and the role of chance In total twenty women were included in the analysis. Mean age 36.8± 4.2, AMH 0.65± 0.32 ng/ml, baseline antral follicle count 4± 2.3, serum hormone levels the day of ovulation induction trigger: progesterone 0.89± 0.34 ng/ml, LH 1.6± 2.1 ng/ml, estradiol 1235 ± 1420 pg/ml. Post-surge serum hormone levels average reached adequate levels: estradiol 1645 ± 1116 pg/ml, progesterone 20.4 ±2.2 ng/ml, LH 62.66± 10.5 IU/ml and, bHCG 247±115 IU/ml. A total of 76 oocytes were retrieved (3.8± 0.8 oocytes per patient), 63.1% (48/76) MII, 22% (17/76) MI, 14% (11/76) GV. Limitations, reasons for caution The retrospective nature of the study, small sample size, and potential variability in the study center’s laboratory protocol(s) compared to other reproductive treatment centers may limit the external validity of our findings. Wider implications of the findings: The daily use of double dose of GnRH antagonists during COH offers the possibility of preventing a premature LH surge in women with DOR with high risk of early ovulation, without compromising luteinization after final oocyte maturation induction. Trial registration number NA

Comparison of antral follicle count and serum anti Müllerian hormone level for determination of gonadotropin dosing in in-vitro fertilization: randomized trial.

To compare the proportion of women achieving a desired ovarian response following ovarian stimulation when gonadotropin dosing was determined based on antral follicle count (AFC) vs serum anti-Müllerian hormone (AMH) level, in women undergoing in-vitro fertilization (IVF) using the gonadotropin-releasing hormone (GnRH) antagonist protocol. This was a randomized double-blind trial carried out in a university-affiliated assisted reproduction unit. A total of 200 women undergoing their first IVF cycle using the GnRH-antagonist protocol between April 2016 and February 2018 were randomized to determination of gonadotropin dosing based on either AFC or serum AMH level measured in the pretreatment cycle 1 month before the IVF cycle. Patients underwent IVF as per our center's standard protocol. The proportion of subjects achieving a desired ovarian response, defined as retrieval of six to 14 oocytes, was compared between the two study arms. Subgroup analysis of patients with baseline AFC > 5 and those with baseline AFC ≤ 5 was performed. Concordance in AFC and AMH categorization between the pretreatment cycle and the ovarian-stimulation cycle was assessed using Cohen's kappa (κ). There was no significant difference in the proportion of patients achieving a desired ovarian response between the AFC (54%) and AMH (49%) groups (P = 0.479). The median number of oocytes retrieved was nine vs seven (P = 0.070), and the median follicular output rate was 0.54 vs 0.55 (P = 0.764) in the AFC and AMH groups, respectively. Similar findings were observed on subgroup analysis of subjects with AFC ≤ 5 and AFC > 5 at the start of ovarian stimulation (P > 0.05 for all comparisons). There was moderate concordance between AFC and AMH measured in the pretreatment cycle and the stimulation cycle (κ = 0.478 and 0.587, respectively). The proportion of women achieving a desired ovarian response following ovarian stimulation using the GnRH-antagonist protocol is similar when the gonadotropin-dosing algorithm used is based on AFC or serum AMH level. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Serum Anti-Müllerian Hormone Is Significantly Altered by Downregulation With Daily Gonadotropin-Releasing Hormone Agonist: A Prospective Cohort Study.

Research Question: What is the effect of gonadotropin-releasing hormone (GnRH)-agonist treatment on serum anti-Müllerian hormone (AMH)?Design: This prospective cohort study conducted in a tertiary university hospital comprised patients (n = 52) who self-administered daily triptorelin (0.1 mg/0.1 mL) subcutaneously for 14 days from menstrual cycle day 21 ± 3, between July 2015 and March 2016. Enrolled women were 18–43 years old, considered normal ovarian responders, with a planned GnRH agonist controlled ovarian stimulation protocol. The primary endpoint was to evaluate the effect of GnRH agonist on serum AMH levels after 7 and 14 days of treatment.Results: Under GnRH agonist treatment, serum AMH was significantly decreased vs. baseline on day 7 (mean change from baseline: −0.265 ng/mL; 95% confidence interval [CI], −0.395 to −0.135 ng/mL; p < 0.001). On day 14, serum AMH was significantly increased (mean change from baseline: 0.289 ng/mL; 95% CI, 0.140–0.439 ng/mL; p < 0.001). Although the median change in AMH from baseline was only −14.9% on day 7 and +17.4% on day 14, from day 7 to 14 AMH significantly increased by 0.55 ng/mL (43.8%; p < 0.001), which is of paramount clinical importance. A linear, mixed-effect model demonstrated that GnRH agonist treatment for 7 and 14 days had a highly significant effect on serum AMH concentration after adjustment for confounding factors (age, body mass index, baseline antral follicle count, and visit). AMH assay precision was excellent (four aliquots/sample); coefficient of variation was 1.2–1.4%.Conclusions: GnRH agonist treatment had a clinically significant effect on serum AMH, dependent on treatment duration. The clear V-shaped response of AMH level to daily GnRH agonist treatment has important clinical implications for assessing ovarian reserve and predicting ovarian response, thus AMH measurements under GnRH agonist downregulation should be interpreted with great caution.

Prevalence of diminished ovarian reserve in Chinese women with polycystic ovary syndrome and sensitive diagnostic parameters

Objectives: To assess the prevalence of diminished ovarian reserve (DOR) in patients with polycystic ovary syndrome (PCOS) in China, and to search for sensitive diagnostic parameters.Methods: Three hundred and thirty eight PCOS women aged 20–39 years were recruited. Basic characteristics, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone and anti-Müllerian hormone (AMH) were measured. The best indices to diagnose PCOS with DOR were assessed.Results: The prevalence of DOR in our Chinese PCOS patients was 16.9%. The level of E2 and FSH and the FSH/LH ratio had a positive correlation with PCOS and DOR (OR > 1, p < 0.05) independent of age and testosterone, while AMH and baseline antral follicle count had a negative correlation (OR < 1, p < 0.05). AMH was a good parameter to diagnose PCOS with DOR, the cutoff was 2.53 ng/ml, with sensitivity 92.5%, specificity 73.7% and area under curve 0.932. AMH had a significant positive correlation with LH (r = 0.016, p < 0.05) and testosterone (r = 0.209, p < 0.01), while had significant negative correlation with age (r=–0.140, p < 0.05), FSH (r=–0.229, p < 0.01) and FSH/LH ratio (r=–0.240, p < 0.01).Conclusions: In our study, AMH was a sensitive parameter to diagnose PCOS with DOR, but to improve the accuracy it will still need further studies.

Response to ovarian stimulation is not impacted by a breast cancer diagnosis.

Does a breast cancer diagnosis impact ovarian function in the setting of fertility preservation? Ovarian reserve and ovarian stimulation outcomes are similar in patients with a new diagnosis of breast cancer and patients undergoing elective fertility preservation. Prior studies, with small study populations, lack of controlling for individual differences in ovarian reserve and infertile controls, have reported conflicting outcomes for cancer patients undergoing ovarian stimulation for fertility preservation. This retrospective cohort analysis included 589 patients undergoing ovarian stimulation for fertility preservation between 2009 and 2015. Women with a recent breast cancer diagnosis (n = 191) and women desiring elective fertility preservation (n = 398) underwent ovarian stimulation with an antagonist protocol at an academic medical center. The aromatase inhibitor letrozole was administered to breast cancer patients with estrogen-sensitive disease. Baseline antral follicle count (AFC) was not different between the breast cancer patients and controls (15.4 ± 10.4 [mean ± SD] vs 15.4 ± 10.0, P = NS), even after categorization by age. Total (19.4 ± 0.9 [mean ± SEM] vs 17.0 ± 0.5, P = NS) and mature (MII) oocytes retrieved (13.7 ± 0.7 vs 13.2 ± 0.4, P = NS), adjusted for age, BMI and total gonadotropin dose, were also similar between the two groups. Letrozole use was associated with a decreased maturity rate (MII/total oocytes retrieved) compared to elective cryopreservation (0.71 ± 0.01 vs 0.77 ± 0.01, P < 0.001), although the mature oocyte yield [MII/AFC] was comparable (1.01 ± 0.06 vs 0.93 ± 0.03, P = NS). The single center design may impact generalizability. Additionally, the lack of subsequent embryo and pregnancy data is an inherent weakness. In females, a breast cancer diagnosis does not impact gonadal function as measured by AFC or ovarian stimulation outcomes. Breast cancer patients should be counseled that their response to ovarian stimulation for fertility preservation is similar to that of patients undergoing elective oocyte cryopreservation. None. N/A.

Comparison of pregnancy outcomes between obese and non-obese polycystic ovary syndrome (PCOS) patients undergoing in vitro fertilization (IVF) cycles

PCOS is commonly associated with metabolic abnormalities and obesity. Obesity has been shown to have adverse effects on both assisted reproductive technology (ART) cycles and pregnancy outcomes. The primary objective of this study was to determine whether there was a difference in reproductive outcomes between obese and non-obese PCOS patients undergoing IVF. A secondary objective was to determine demographic and clinical factors that may predict clinical pregnancy among women with PCOS. Historical cohort study in an academic setting. Women (n=79) meeting the Rotterdam PCOS criteria and undergoing IVF from 2007 to 2016 were included in the study. Data collected included baseline demographics, clinical parameters, and treatment outcomes. Obesity was defined as BMI>=30kg/m2. Clinical pregnancy was defined as the presence of fetal heart beat on ultrasound. Bivariate analysis was done using Student’s t, Pearson’s chi-squared, and Wilcoxon rank sum tests as appropriate. Logistic regression and generalized estimating equations (GEE) were performed to control for confounding variables and to account for multiple cycles from the same patients. A total of 108 IVF cycles (obese group n=63 and non-obese group n=45) were included in the analysis. Baseline demographics and clinical parameters were similar when examining pregnant versus non-pregnant women except for age (32.3 vs. 35 years old, p=0.007), baseline antral follicle count (AFC) (24.1 vs. 17.7, p=0.003), and progesterone level on day of trigger (0.6 vs. 0.8 ng/mL, p=0.06). The obese group had lower serum peak estradiol level (1898 vs. 2623 pg/mL, p=0.001), required more total gonadotropins (2907 vs. 2187 units, p<0.001), and needed a longer stimulation course (11.7 vs. 10.6 days, p=0.02) compared to the non-obese group. After adjusting for confounding variables, the pregnancy rates were similar in the obese (37.5%) compared to the non-obese group (41.7%) (p=0.7). After adjusting for age and serum progesterone level on day of trigger, AFC was the only significant predictor of clinical pregnancy (OR 2.1, 95% CI 1.1-4.1; p=0.02). Obesity does not affect clinical pregnancy rates in PCOS patients undergoing IVF. On the other hand, AFC seems to be associated with clinical pregnancy in PCOS patients. Further investigation is needed to determine if AFC is an accurate predictor of clinical pregnancy in women with PCOS.

Do diminished ovarian reserve markers necessarily reflect lower oocyte quality in young patients? the effect of antral follicle count

To compare clinical pregnancy rates of single blastocyst transfers in young patients (age ≤35) with low ovarian reserve markers (baseline antral follicle count (AFC) <7) and controls with normal ovarian reserve (baseline AFC of 10-15).

Predictors of treatment failure in young patients undergoing in vitro fertilization.

The purpose of the study was to evaluate whether routinely collected clinical factors can predict in vitro fertilization (IVF) failure among young, "good prognosis" patients predominantly with secondary infertility who are less than 35years of age. Using de-identified clinic records, 414 women <35years undergoing their first autologous IVF cycle were identified. Logistic regression was used to identify patient-driven clinical factors routinely collected during fertility treatment that could be used to model predicted probability of cycle failure. One hundred ninety-seven patients with both primary and secondary infertility had a failed IVF cycle, and 217 with secondary infertility had a successful live birth. None of the women with primary infertility had a successful live birth. The significant predictors for IVF cycle failure among young patients were fewer previous live births, history of biochemical pregnancies or spontaneous abortions, lower baseline antral follicle count, higher total gonadotropin dose, unknown infertility diagnosis, and lack of at least one fair to good quality embryo. The full model showed good predictive value (c = 0.885) for estimating risk of cycle failure; at ≥80% predicted probability of failure, sensitivity = 55.4%, specificity = 97.5%, positive predictive value = 95.4%, and negative predictive value = 69.8%. If this predictive model is validated in future studies, it could be beneficial for predicting IVF failure in good prognosis women under the age of 35years.

Impact of pituitary suppression on antral follicle count and oocyte recovery after ovarian stimulation

To investigate the potential influence of short-term pituitary suppression on antral follicle count (AFC) and correlate the AFC with the number of oocytes retrieved after ovarian stimulation. Retrospective study. University fertility center. A total of 1,479 infertile patients. Patients had baseline AFC, when they were not on any medications known to cause pituitary suppression, and follow-up AFC (suppressed AFC) while on E2, GnRH agonist (GnRH-a), oral contraceptive (OC) pills, or OC pills/GnRH-a in preparation for ovarian stimulation, performed within 6 months of initial baseline AFC. The AFC at baseline, AFC during pituitary suppression, and the number of oocytes retrieved. Although there was an average unadjusted decline of 0.4, 0.9, 2.2, and 3.0 in AFC while patients were on E2, GnRH-a, OC pills, and OC pills/GnRH-a, respectively, this decline was driven by age, baseline AFC, and the hormones used. Although baseline and suppressed AFC were found to be good predictors of the number of oocytes retrieved after ovarian stimulation, statistically, suppressed AFC was found to be a marginally better predictor. Short-term pituitary suppression has a negative impact on AFC. This decline in AFC may influence the number of oocytes retrieved, suggesting the suppressive impact of exogenous hormones on the biological capacity of the ovary during stimulation.

Role of baseline antral follicle count and anti-Mullerian hormone in the index stimulation cycle of IVF treatment in predicting outcome of subsequent frozen-thawed embryo transfers

This retrospective cohort study aims at determining whether baseline antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) level in the index stimulation cycle predict live-birth outcome in subsequent frozen-thawed embryo transfer (FET) cycles. We studied 500 women undergoing the first IVF cycle who had embryo(s) cryopreserved. The main outcome measures were live-birth in the first FET cycle and cumulative live-birth in all the FETs combined after the same stimulation cycle. Our results showed that baseline AFC and AMH level on the day before ovarian stimulation showed significant correlation. In the first FET cycle, AFC and AMH level were significantly higher in subjects attaining live-birth in the first FET cycle or cumulative live-birth from all FETs than those who did not. Both AMH and AFC were insignificant predictors of live-birth in the first FET cycle or cumulative live-birth after adjusting for age. The areas under the ROC curves for AMH, AFC and age were 0.654, 0.625 and 0.628, respectively, for predicting cumulative live-birth. In conclusion, we reported for the first time that baseline AFC and AMH in the index stimulation cycle have only modest predictive performance on cumulative live-birth in subsequent FET cycles.

Fertility preservation in patients with haematological disorders: a retrospective cohort study

This study investigated the factors associated with utilization of fertility preservation and the differences in treatments and outcomes by prior chemotherapy exposure in patients with haematological diseases. This study included all 67 women with haematological diseases seen for fertility preservation consultation at two university hospitals between 2006 and 2011. Of the total, 49% had lymphoma, 33% had leukaemia, 7% had myelodysplastic syndrome and 4% had aplastic anaemia; 46% had prior chemotherapy; and 33% were planning for bone marrow transplantation, 33% pursued ovarian stimulation and 7% used ovarian tissue banking; and 48% of patients did not pursue fertility preservation treatment. All five cycle cancellations were in the post-chemotherapy group: three patients with leukaemia and two with lymphoma. Patients with prior chemotherapy had lower baseline antral follicle count (10 versus 22) and received more gonadotrophins to achieve similar peak oestradiol concentrations, with no difference in oocyte yield (10.5 versus 10) after adjustment for age. Embryo yield was similar between those who had prior chemotherapy and those who had not. Half of the patients with haematological diseases who present for fertility preservation have been exposed to chemotherapy. While ovarian reserve is likely impaired in this group, oocyte yield may be acceptable.Women with haematological diseases, particularly haematological cancers, may need therapies that can impact fertility. In this study, women with haematological diseases who presented for fertility preservation consultation were evaluated to assess what factors were associated with the fertility preservation treatments chosen and the outcomes of ovarian stimulation for egg or embryo banking. Of the total patients, 46% had already had prior chemotherapy at the time of consultation, and one-third elected to pursue ovarian stimulation. Women who had prior chemotherapy had lower antral follicle counts and received more gonadotrophins to achieve similar peak oestradiol concentrations suggesting that ovarian reserve is likely impaired after chemotherapy in these women, consistent with the findings of other studies. However, there was no difference in oocyte or embryo yield in women undergoing ovarian stimulation before chemotherapy compared with those undergoing stimulation after chemotherapy, after adjusting for age. Thus while ovarian reserve may be impaired, response to ovarian stimulation and IVF may be acceptable for these women.