Ovarian Stimulation In Women Research Articles

Comparison of fixed and flexible progestin-primed ovarian stimulation in women classified in patient-oriented strategies encompassing individualized oocyte number (POSEIDON) group 4.

This study aimed to compare the fixed and flexible protocols for progestin-primed ovarian stimulation (PPOS) in poor ovarian responders. This retrospective study included 95 poor ovarian responders classified using the Patient-Oriented Strategies Encompassing Individualized Oocyte Number group 4 criteria. Treatment involved assisted reproductive medicine using fixed and flexible PPOS protocols at Shiga University of Medical Science between July 2019 and August 2023. PPOS cycles were assigned to the fixed and flexible groups at the discretion of attending physicians. The results of assisted reproductive medicine were compared between groups. The fixed and flexible groups included 68 and 27 patients, respectively. The flexible group obtained more retrieved oocytes and two pro-nuclei than the fixed group, without an early luteinizing hormone surge. Multiple linear regression analysis demonstrated that differences in protocols and anti-müllerian hormone (AMH) levels were related to the number of retrieved oocytes. The differences in protocols were more strongly correlated with the number of oocytes than with the AMH levels. Among poor ovarian responders, the flexible PPOS protocol provided more retrieved oocytes than the fixed PPOS protocol, possibly because the total dosage of progestins was lower in the flexible group and progestins were not administered at the time when ovarian stimulation was initiated.

Controlled ovarian stimulation leads to cardiovascular changes in patients undergoing in vitro fertilization

ObjectiveTo study hemodynamic changes along controlled ovarian stimulation in women undergoing in vitro fertilization. Study designProspective observational cohort study conducted at Mother and Child Department of University Hospital Federico II, in Naples, Italy, between April 2021 and July 2022. Sixty-eight infertile patients undergoing controlled ovarian stimulation with gonadotropin, antagonist protocol and a fresh embryo transfer were included. Haemodynamic assessment was carried out using UltraSonic Cardiac Output Monitor at baseline (T1), estradiol peak (T2), fresh embryo-transfer day (T3). To evaluate relationships between quantitative variables and groups a Student T test for independent data was assessed. One-way analysis of variance (ANOVA) was used to determine the differences between the means of three time points (T1, T2 and T3) for quantitative variables. A mixed-model analysis of variance (ANOVA) was used to determine the differences between groups, among time points (T1, T2 and T3). ResultsSixty-eight patients were included. Significant differences over the three time points have been observed for CO (f = 3.78 l/min; p = 0.025), SVI (f = 3.56 ml/m2;p = 0.013), and RSVI (f = 4.84 dscm-5 m2; p = 0.009). No significant differences in trends have been found between beta hCG positive and beta hCG negative groups. There were no significant differences in maternal hemodynamic parameters at time-point T3 between patients treated with hCG 10,000 UI and with Triptorelin. Patients considered at increased risk of hyperstimulation reported a significant increase in SVI at baseline (26.9 ± 9.0 mL/m2 vs 21.9 ± 7.0 mL/m2; p = 0.010). ConclusionAccording to the results of our study, during controlled ovarian stimulation with antagonist protocol, patients undergo significant changes in maternal cardiovascular parameters over a very short period.

A heatmap for expected cumulative live birth rate in preimplantation genetic testing for monogenic disorders and chromosomal structural rearrangements

PurposeOur objective is to predict the cumulative live birth rate (CLBR) and identify the specific subset within the population undergoing preimplantation genetic testing for monogenic disorders (PGT-M) and chromosomal structural rearrangements (PGT-SR) which is likely to exhibit a diminished expected CLBR based on various patient demographics.MethodsWe performed a single-centre retrospective cohort study including 1522 women undergoing 3130 PGT cycles at a referral centre for PGT. A logistic regression analysis was performed to predict the CLBR per ovarian stimulation in women undergoing PGT-M by polymerase chain reaction (PCR) or single-nucleotide polymorphism (SNP) array, and in women undergoing PGT-SR by SNP array, array comparative genomic hybridization (CGH) or next-generation sequencing (NGS).ResultsThe mean age of women was 32.6 years, with a mean AMH of 2.75 µg/L. Female age and AMH significantly affected the expected CLBR irrespective of the inheritance mode or PGT technology. An expected CLBR < 10% was reached above the age of 42 years and AMH ≤ 1.25 µg/L. We found no significant difference in outcome per ovarian stimulation between the different PGT technologies, i.e. PCR, SNP array, array CGH and NGS. Whereas per embryo transfer, we noticed a significantly higher probability of live birth when SNP array, array CGH and NGS were used as compared to PCR.ConclusionIn a PGT-setting, couples with an unfavourable female age and AMH should be informed of the prognosis to allow other reproductive choices. The heatmap produced in this study can be used as a visual tool for PGT couples.

COMMENTARY PART 2: WEIGHT LOSS INTERVENTIONS FOR IMPROVING FERTILITYA SYNTHESIS OF CURRENT EVIDENCE

Infertility is a widespread issue which is estimated to affect up to 17.5% of the global population. Evidence suggests that the most common causes of female infertility are ovulation disorders. That said, lifestyle factors such as dietary patterns, alcohol consumption, smoking and obesity are key determinants which have been shown to impact female physiology and significantly decrease the chances of conception. Obesity has been widely recognised as a significant factor that negatively impacts ovarian stimulation in women and is associated with several reproductive disorders. Despite improvements in fertility treatments, obesity remains a challenge particularly for fertility clinics because of the poorer pregnancy outcomes observed within the population. In this article, we will explore the effects of weight loss on female fertility and review the various strategies that have been shown to be effective in reducing obesity and improving reproductive outcomes.

Letrozole cotreatment progestin-primed ovarian stimulation in women undergoing controlled ovarian stimulation for in vitro fertilization.

To investigate the impact of letrozole cotreatment progestin-primed ovarian stimulation (PPOS) (Le PPOS) in controlled ovarian stimulation (COS) and the pregnancy outcomes in frozen-thawed embryo transfer cycles. This retrospective cohort study included women who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). A total of 2575 cycles were included (1675 in the Le PPOS group and 900 in the PPOS group). The primary outcome was the clinical pregnancy rates. The secondary outcome was the live birth rates. In this study, propensity score matching (PSM) was performed to create a perfect match of 379 patients in each group. After matching, the numbers of oocytes retrieved, mature oocytes, fertilization, and clinical pregnancy rates were more favorable in the Le PPOS group than in the PPOS group (all p < 0.05). The multivariable analysis showed that the clinical pregnancy rate was higher in the Le PPOS than in the PPOS group (odds ratio = 1.46, 95% confidence interval: 1.05-2.04, p = 0.024) after adjusting for potentially confounding factors (age, anti-Müllerian hormone levels, antral follicular count, the type of embryo transferred, number of transferred embryos, body mass index, and follicular stimulating hormone and estradiol levels on starting day). This retrospective study with a limited sample size suggests that the Le PPOS protocol might be an alternative to the PPOS protocol in women undergoing COS and could lead to better pregnancy outcomes. The results should be confirmed using a formal randomized controlled trial.

SPERM PARAMETERS' PREDICTIVE VALUE IN INTRAUTERINE INSEMINATION SUCCESS: A SINGLE-CENTER EXPERIENCE

Although intrauterine insemination is a widely used assisted reproductive technique there is no consensus on sperm parameters that affect the probability of pregnancy. Therefore, the purpose of this study was to determine whether semen parameters affect intrauterine insemination success. A total of 403 couples (345 negative pregnancies, and 58 positive pregnancy) that underwent 549 intrauterine insemination treatment cycles for heterogenous indications were included in the study. Clomiphen citrate, letrazole and/or gonadotropins were used for ovarian stimulation in women in this study. The spermiogram tests of the spouse of receiving IUI tretment were examined. Clinical pregnancy occurred in 58 of 549 intrauterine insemination (10.56%). Unexplained infertility, polycystic ovary syndrome, and cervical-tubal factors were higher in positive pregnancy group compared to negative pregnancy group while male factor was more prevalant in negative pregnancy group comparison to positive pregnancy group (p=0.03). There was no statistical difference between women with positive and negative pregnancy in terms of age (≤ 35 and &gt; 35), body mass index, infertility type, infertility time, endometrial thickness on HCG day, stimulation protocol, cycle numbers, number of insemination, estradiol, prolactin, LH, FSH, and TSH levels (p&gt;0.05). The sperm characteristics in males [ejaculate volum, sperm concentration, total sperm count, motility, immotility, and total progressive motile sperm count] did not significantly differed between positive and negative pregnancy groups (p&gt;0.05).&#x0D; Briefly, the present study found that the conception probability of intrauterine insemination did not correlate with the spermiogram parameters.

#317 : The Clinical Outcome of Ovarian Stimulation Undergoing Intrauterine Insemination with Follitropin Delta in Indonesian Women

Background and Aims: Intrauterine insemination (IUI) has been widely used as a common treatment for infertile couples due to its simplicity and low cost. Numerous studies have shown that IUI cycles with controlled ovarian stimulation (COS) result in higher pregnancy rates compared to those without COS. Follitropin delta, a novel recombinant FSH (rFSH) can be used for controlled ovarian stimulation in women undergoing assisted reproductive technologies (ART) and was dosed individually based on serum anti-Müllerian hormone (AMH) concentration and body weight. In this study, we used a simplified dosage equivalent method. The aim of this study was to compare the efficacy and safety of follitropin delta in its simplified dosage equivalent regimen with follitropin alfa in a conventional dose regimen in Indonesian women undergoing intrauterine insemination. Method: A single-center, retrospective observational study from January 2020 to December 2022 was performed in 228 IUI cycles in Halim Fertility Center, Indonesia. Controlled Ovarian Stimulation was performed during IUI cycles and divided into two groups: group I received follitropin delta with a simplified dosage equivalent regimen, and group II received follitropin alfa with a conventional dose. The baseline characteristics, cycle parameters, and IUI outcomes of both groups were compared. Results: Our study included 228 IUI cycles with the follitropin delta group (114 IUI cycles) and the follitropin alfa group (114 IUI cycles). The clinical pregnancy rate was higher in the follitropin delta than the follitropin alfa but there was no significant difference between the groups (p&gt;0.05). The multiple pregnancy rate and Ovarian Hyperstimulation Syndrome (OHSS) rates were lower in follitropin delta than follitropin alfa but there was no significant difference between the groups (p&gt;0.05). Conclusion: Follitropin delta with a simplified dosage equivalent regimen showed higher efficacy and similar safety compared with follitropin alfa in conventional dosing regimen in Indonesian women undergoing Intrauterine insemination.

Growth hormone supplementation during ovarian stimulation in women with advanced maternal age undergoing preimplantation genetic testing for Aneuploidy

BackgroundStudies have shown that supplementation with recombinant human GH (rh-GH) during ovarian stimulation (OS) may improve the ovarian response and clinical outcomes of IVF. However, it remains unclear whether GH is associated with the ploidy status of embryos, and therefore, is unable to explain the underlying reason for the effect of GH on IVF outcomes. This study aimed to investigate whether GH supplementation in women with advanced maternal age (AMA) during OS is related to an increased probability of obtaining euploid blastocysts.MethodsThis was a single center retrospective cohort study. The data of all women aged 38–46 years who underwent their first preimplantation genetic testing for aneuploidy (PGT-A) cycle between January 2021 and June 2022 were reviewed. Patients in the GH group received 4 IU/day subcutaneous GH supplementation from the beginning of OS to the trigger day, and patients in the control group did not. A total of 140 patients in the GH group and 272 patients in the control group were included after 1:2 propensity score matching.ResultsThe baseline and cycle characteristics between the two groups were similar. The proportion of cycles which obtained euploid blastocysts was significantly higher in the GH group than that in the control group (41.43% vs. 27.21%, P = 0.00). The GH group had a significantly higher euploid blastocyst rate per cohort (32.47% vs. 21.34%, P = 0.00) and mean euploid blastocyst rate per cycle (per biopsy cycle 0.35 ± 0.40 vs. 0.21 ± 0.33, P = 0.00; per OS cycle 0.27 ± 0.38 vs. 0.16 ± 0.30, P = 0.02). However, the benefit of GH was more significant in patients aged 38–40 years, but not significant in patients aged 41–46 years. Pregnancy outcomes were similar between the two groups after embryo transfer.ConclusionsGH supplementation during OS is associated with a significantly increased probability of obtaining euploid blastocysts in women aged 38–40 years, but this benefit is not significant in women aged 41–46 years. Our results explained the underlying reason for the effect of GH on IVF outcomes in existing studies, and might be helpful for AMA patients undergoing PGT-A cycles to obtain a better outcome meanwhile to avoid over-treatment.Trial registrationNCT05574894, www.clinicaltrials.gov.

A-055 Clinical Performance Evaluation of the ADVIA Centaur AMH Assay

Abstract Background Anti-Müllerian hormone (AMH) is a transforming growth factor beta protein synthesized by granulosa cells of small growing follicles in ovaries in females and by Sertoli cells of the testes in males. AMH measurements are increasingly being used in the assessment of ovarian reserve, prediction of response to controlled ovarian stimulation in women undergoing assisted reproductive technologies, as an aid in the diagnostic evaluation of polycystic ovary syndrome, and prediction of menopause. The objective of this study was to evaluate the clinical performance of the ADVIA Centaur® AMH assay in the assessment of ovarian reserve and compare performance to the Beckman ACCESS 2 AMH assay. In addition, an exploratory analysis evaluated ADVIA Centaur AMH assay performance in distinguishing women with expected poor ovarian response per published criteria. Methods Clinical specimens were collected from 577 women at 11 U.S. fertility centers. Women enrolled were 22–45 years old and possessed both ovaries. They underwent blood draw and transvaginal ultrasound to measure the antral follicle count on days 2–4 of menstrual cycle. Women with BMI ≥40; pregnancy within 3 months; on contraceptives, hormonal medications; undergoing treatment for malignancy, ovarian abnormalities, surgery in the past 6 months; or with endocrine or metabolic disorders (including PCOS) were excluded. Results Results were considered positive (high ovarian reserve) if the AMH concentration was &amp;gt;1.77 ng/mL and AFC was &amp;gt;15 and negative (normal-to-diminished ovarian reserve) if the AMH concentration was ≤1.77 ng/mL and AFC was ≤15. The estimated sensitivity, specificity, and two-sided 95% Wilson score confidence intervals (CI) of each parameter were determined to be 90.76% (86.97–93.53) and 52.19% (46.29–58.03) using the ADVIA Centaur AMH assay, and 90.10% (86.22–92.98) and 52.19% (46.29–58.03) with the ACCESS 2 AMH assay, respectively.A secondary analysis was completed to investigate poor ovarian response (POR) according to the Bologna criteria, published by the ESHRE. These criteria define poor ovarian response as an AMH measurement of less than 1.1 ng/mL and AFC of less than 7. Of the 577 women included in the study, 32 women had an antral follicle count less than 7, of whom 26 also had a AMH concentration of less than 1.1 ng/mL. Of the 545 women with an antral follicle count greater than or equal to 7, 480 also had AMH measurements of greater than or equal to 1.1 ng/mL. Using the Bologna criteria, the ADVIA Centaur AMH assay performs with a sensitivity of 81.25% and specificity of 88.07%. Conclusions In this clinical population, the sensitivity and specificity of AMH assays on the ADVIA Centaur XP and Beckman ACCESS 2 systems were almost identical when using an AMH cutoff ≤1.77 ng/mL and AFC ≤15 to identify normal-to-diminished ovarian reserve. Using published criteria for POR resulted in a sensitivity and specificity of 81.25% and 88.07% for the ADVIA Centaur AMH assay. Not available for sale in the U.S. Future availability cannot be guaranteed. Product availability varies by county. HOOD#05162003331923

Efficacy of progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing in vitro fertilization: a systematic review and meta-analysis.

NPLASY (202340059). https://inplasy.com/inplasy-2023-4-0059/.

The therapeutic effects of rFSH versus uFSH/uHMG on ovarian stimulation in women undergoing assisted reproductive technology: a meta-analysis of randomized controlled trials.

This systematic review and meta-analysis aimed to compare the therapeutic effects of rFSH versus uFSH/uHMG on ovarian stimulation in women undergoing assisted reproductive technology. The databases of PubMed, Embase, and the Cochrane Library were systematically searched to retrieve data on eligible trials from inception until July 2022. The relative risks (RRs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs) were applied to assess categorical and continuous outcomes, and the pooled results were calculated using the random-effects model. Sensitivity, subgroup, and publication bias analyses were also performed. Forty-eight trials that enrolled 10,127 women were included in this quantitative meta-analysis. There were no significant differences between rFSH and uFSH/uHMG in the clinical pregnancy rate (RR: 1.01; 95% CI 0.95-1.07; P = 0.760), live birth rate (RR: 0.98; 95% CI 0.91-1.06; P = 0.665), multiple pregnancy rate (RR: 0.92; 95% CI 0.77-1.09; P = 0.320), miscarriage rate (RR: 1.17; 95% CI 0.94-1.46; P = 0.151), and the incidence of ovarian hyperstimulation syndrome (RR: 1.25; 95% CI 0.91-1.70; P = 0.164). In addition, the administration of rFSH was associated with a higher number of oocyte retrieval compared with that of uFSH/uHMG (WMD: 0.61; 95% CI 0.03-1.20; P = 0.038), while no significant differences were found between rFSH and uFSH/uHMG in the dosage of gonadotrophin (WMD: 14.80; 95% CI -136.97 to 166.57; P = 0.848) and the duration of ovarian stimulation (WMD: -0.26; 95% CI -0.62 to 0.10; P = 0.152). Thus, the exploratory analyses revealed several potential differences in the effects of rFSH versus uFSH/uHMG on ovarian stimulation. The administration of rFSH significantly increased the number of oocytes retrieved, whereas there were no significant differences between the efficacies of rFSH and uFSH/uHMG for pregnancy outcomes.

P-604 Inhibin B in Low Ovarian Reserve Patients: Correlation With Ovarian Reserve Markers and Oocyte Yield

Abstract Study question Is there a correlation between Inhibin B (InhB) serum levels and oocyte yield after ovarian stimulation (OS) in women with low ovarian reserve? Summary answer InhB presents a positive relationship with oocyte yield during OS in women with AMH&amp;lt;1.1ng/mL. What is known already InhB is produced by granulosa cells in the ovary with the goal of suppressing FSH production. Assay and intercycle variability have been the main limitations affecting specificity and reproducibility of InhB as a marker of ovarian reserve or oocyte yield after OS. This fact is attributed to low specific antibodies for the molecule in previous assays, exhibiting cross-reactivity with other glycoproteins in the transforming growth factor beta family. High specific ELISA assay,measuring bioavailable InhB (bio-InhB), may provide more accurate results, specially important in poor responders, as results may involve clinical decisions on whether or not to proceed with OS. Study design, size, duration Prospective observational study measuring bio-InhB in 72 women with low ovarian reserve, performing OS for IVF/ICSI, at a tertiary referral fertility center, from February 2019 to December 2021. Low ovarian reserve was defined as AMH serum levels &amp;lt;1.1ng/ml (Elecsys, Roche), following Bologna criteria. All patients performed OS for IVF/ICSI in a GnRH-antagonist protocol. Participants/materials, setting, methods On day 2/3 of cycle, before starting OS, AFC, FSH, LH, estradiol, progesterone and AMH (Elecsys, Roche) were measured. Extra serum samples were frozen at -20C for subsequent bio-InhB analysis (AnshLabs, Texas). Ethical approval was obtained (Research Ethics Committee-REFA033c) and informed consent was signed for all participants. Main results and the role of chance Patient characteristics were [Median(IQR)]: age: 39(36-42)years, BMI: 28.51(26.1-30.1) Kg/m2, AFC: 5.5(4-7), FSH:8.23(6.4-12.5) mIU/mL, LH: 6.54(4.51-8.91) mIU/mL, Estradiol: 41.18(28.47-56.44) pg/mL, AMH: 0.64(0.29-0.81)ng/mL, InhB: 62.69(33.78-97.92) pg/mL. Stimulation outcomes were: follicle number on day of trigger (Fdot): 5(3-7), cumulus-oocyte-complexes (COC’s): 3(2-4.5) andmetaphase II oocytes (MII): 3(1-4). Inh-B showed significant positive correlation (Spearman correlation) with AMH (rs = 0.35, p = 0.003), although was better with AFC (rs = 0.43, p &amp;lt; 0.001). Moreover, Inh-B serum levels presented positive association with oocyte yield: Fdot (rs = 0.41, p &amp;lt; 0.001), COC’s (rs = 0.36, p = 0.002) and MII (rs = 0.37, p = 0.002). AUROC analysis was performed to investigate which model predicted better a bad outcome (defined as &amp;lt; =3COC’s after OS) in low ovarian reserve women. No significant benefit was observed when Inh-B was added to AMH+AFC model (AUROC AMH+AFC: 0.757; AUROC AMH+AFC+Inh-B: 0.759, p = 0.843). Limitations, reasons for caution Although clinical assessment was performed in the same centre following the same methodology, inter-observer variability for AFC is a limitation. Besides, fresh AMH serum samples were analysed using Elecsys assay, yet frozen serum samples were shipped to Ansh Lab (Texas) for batched Inh-B analysis. Wider implications of the findings Bio-InhB is correlated to oocyte yield during OS. Although no additional benefit for prediction in women with AMH&amp;lt;1.1ng/mL was observed when added to other currently used markers, future research should explore the utility of bio-inhB on other outcomes associated to ovarian reserve, as embryo quality and ploidy. Trial registration number Not applicable

O-274 Influence of breast cancer prognostic factors on ovarian reserve and response to ovarian stimulation in fertility preservation

Abstract Study question Do breast cancer (BC) prognostic factors influence ovarian reserve and response to controlled ovarian hyperstimulation (COH) in the context of fertility preservation (FP)? Summary answer BC prognostic factors do not influence ovarian reserve and response to COH in the context of FP. What is known already Tumor Grade, triple-negative status, overexpression of HER2, as well as high Ki67 expression are all established prognostic factors for BC, influencing patients’ therapeutic management. Yet, there are still concerns about the potential impact of cancer status on ovarian reserve and response to COH. Previous studies analyzing the results of COH in BC patients have shown conflicting findings. However, there is limited data on the potential impact of BC status and prognostic factors on ovarian reserve and response to ovarian stimulation in women undergoing urgent FP. Study design, size, duration Observational, bicentric retrospective study including all BC patients who had vitrified oocytes after COH using a random start GnRH antagonist protocol after measurement of serum AMH levels and antral follicle count (AFC) between November 2013 and August 2021. Participants/materials, setting, methods Three-hundred-fifty-two BC patients having undergone one cycle of COH were analyzed. Number of oocytes recovered, maturation rate (number of mature oocytes/number of oocytes recovered), and Oocyte Retrieval Rate (number of retrieved oocytes/AFC) were studied according to the patients’ general characteristics, ovarian reserve markers, as well as BC diagnostic and prognostic factors: histological type, uni/multifocal character, TNM or UICC stage, hormonal receptors expression, HER2 status, Ki67, Grade, presence of vascular emboli, lymph node and BRCA1/2 status. Main results and the role of chance Overall, mean patients’ age was 33.6 ± 4 years. Mean AFC and serum AMH level were 20.5 ± 13.0 follicles and 2.7 ± 4.6 ng/mL, respectively. After ovarian stimulation, 12.5 ± 8.5 oocytes were recovered and 9.3 ± 6.9 were mature and further vitrified. Mean oocyte maturation rate was 74 ± 23%. As expected, patient’s age was significantly related to the number of mature oocytes recovered. Indeed, the risk of yielding less than 8 oocytes increased significantly after the age of 35 years. In addition, the oocyte maturation rate was also significantly higher before the age of 30 years, with an OR of 0.64 (0.43-0.96) to obtain a maturation rate &amp;lt;60%. Follicular responsiveness to FSH assessed by the follicular output rate (FORT index) as well as OOR were 30 ± 24% and 61 ± 27%, respectively, and both indexes were not influenced by tumor characteristics. However, maturation rate &amp;lt;60% was significantly related to SBR grade (OR = 0.73 (0.54-0.97), p&amp;lt;0.03) and the presence of a BRCA1/2-mutation (OR = 0.64 (0.42-0.99), p&amp;lt;0.03). Limitations, reasons for caution The main weakness is the retrospective nature of the study. Furthermore, the lack of data on reutilization of oocytes after FP prevents drawing reliable conclusions on the fate of these frozen gametes. Wider implications of the findings Our findings indicate that BC prognostic factors do not influence ovarian reserve markers nor the response to ovarian stimulation in the context of FP. Therefore, tumor grade, triple-negative status, overexpression of HER2, and high Ki67 should not modify the FP strategy when COH for oocyte vitrification is considered. Trial registration number N/A

Pregnancy outcomes of intrauterine insemination without ovarian stimulation in couples affected by unilateral tubal occlusion and male infertility

BackgroundInformation available to date regarding the pregnancy outcomes of intrauterine insemination (IUI) without ovarian stimulation (OS) in infertile patients with unilateral tubal occlusion remains scarce. The objectives of this study were to investigate for couples affected by unilateral tubal occlusion (diagnosed via hysterosalpingography (HSG)/transvaginal real-time three-dimensional hysterosalpingo-contrast sonography (TVS RT-3D-HyCoSy)) and male infertility: (1) whether significant differences exist in pregnancy outcomes between IUI with or without OS cycles, and (2) whether the pregnancy outcomes of IUI without OS in women with unilateral tubal occlusion were similar to those of women with bilateral patent tubes.Methods258 couples affected by male infertility completed 399 IUI cycles. The cycles were divided into three groups: group A, IUI without OS in women with unilateral tubal occlusion; group B, IUI with OS in women with unilateral tubal occlusion; and group C, IUI without OS in women with bilateral patent tubes. The main outcome measures, including clinical pregnancy rate (CPR), live birth rate (LBR), and first trimester miscarriage rate, were compared between either groups A and B or groups A and C.ResultsAlthough the number of dominant follicles > 16 mm were significantly higher in group B than that in group A (group B vs. group A: 1.6 ± 0.6 vs. 1.0 ± 0.2, P < 0.001), the CPR, LBR, and first trimester miscarriage rate were comparable between these two groups. When comparing group C to group A, the duration of infertility was significantly longer in group C than that in group A (group A vs. group C: 2.3 ± 1.2 (year) vs. 2.9 ± 2.1 (year), P = 0.017). Except for the first trimester miscarriage rate, which was significantly higher in group A (42.9%, 3/7) than that in group C (7.1%, 2/28) (P = 0.044), no significant differences were observed in the CPR and LBR in these two groups. After adjusting for female age, body mass index, and the duration of infertility, similar results were obtained between groups A and C.ConclusionsIn couples affected by unilateral tubal occlusion (diagnosed via HSG/TVS RT-3D-HyCoSy) and male infertility, IUI without OS might be an alternative treatment strategy. However, when compared to patients with bilateral patent tubes, the patients with unilateral tubal occlusion showed a higher first trimester miscarriage rate following IUI without OS cycles. Further studies are warranted to clarify this relationship.

Normal-high IGF-1 level improves pregnancy rate after ovarian stimulation in women treated with growth hormone replacement therapy.

Growth hormone (GH) and insulin-like growth factors (IGFs) are not mandatory for reproductive life, but data suggest their synergistic action with follicle-stimulating hormone throughout ovarian folliculogenesis. We aimed to evaluate the association of IGF-1 level on clinical pregnancy rate after ovarian stimulation, with or without intrauterine insemination, in women with GH deficiency (GHD) treated with GH replacement therapy (GHRT) at conception. Data from 19 women with both GHD and hypogonadotropic hypogonadism referred to our reproductive medicine department were retrospectively collected. IGF-1 levels were assessed in a single laboratory, and values were expressed in s.d. from the mean. Amongst the seven patients receiving GHRT during ovarian stimulation, higher IGF-1 levels were significantly associated with clinical pregnancy (+0.4 s.d. vs-1.6 s.d., P = 0.03). Amongst the 24 pregnancies obtained by the 19 infertile patients, pregnancy loss was less frequent with the addition of GHRT than without (1 miscarriage out of 8 total pregnancies vs 4 miscarriages out of 16 total pregnancies). This is the first study evaluating the association of IGF-1 level on clinical pregnancy rate in GH-treated women at conception. When taking care of female infertility due to hypogonadotropic hypogonadism, practitioners should enquire about the associated GHD and IGF-1 levels. To ensure higher clinical pregnancy chances, practitioners should aim for IGF-1 values at conception, ranging from 0 s.d. to +2 s.d., and, if necessary, could discuss initiation or increase GH treatment. Prospective studies should help strengthen our results.

Endothelial dysfunction in subfertile women with polycystic ovary syndrome

Research questionIs there an association between post-occlusive reactive hyperaemia (PORH) and ovarian stimulation in women with normoandrogenaemic polycystic ovary syndrome (PCOS)? DesignWomen eligible for IVF at an academic fertility centre were invited to join this prospective study. Microvascular endothelial function was measured as PORH by laser Doppler flowmetry (LDF) before and after ovarian stimulation. Metabolic characteristics, hormone profiles and biochemical markers were analysed. ResultsThirty-four normoandrogenaemic women with PCOS and 36 normoandrogenaemic women without PCOS were included. The PCOS group displayed higher C-reactive protein levels and insulin resistance (P = 0.048 and P = 0.025, respectively). No significant difference was found in microcirculatory function between the groups at baseline. After ovarian stimulation, PORH was enhanced in the control group (slope 7.1 ± 3.3 versus 9.7 ± 4.5; P = 0.007; peak flow 30.7 ± 16.3 versus 43.5 ± 17.3, P = 0.008; however, the PCOS group experienced a blunting response to supraphysiological hormone status (slope 8.2 ± 5.1 versus 7.2 ± 4.3, P = 0.212; peak flow, 38.8 ± 19.4 versus 37.0 ± 21.8, P = 0.895). ConclusionsImpaired microcirculatory function could be found using a non-invasive LDF technique in normoandrogenaemic women with PCOS undergoing IVF, indicating early changes in vascular endothelial dysfunction. Future observational studies should clarify whether PORH measurement might help predict IVF prognosis or obstetric complications.

Letrozole cotreatment with progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing IVF treatment.

Background: Progestin is an alternative to gonadotropin-releasing hormone (GnRH) analogues in the follicular phase to suppress the premature luteinizing hormone (LH) surge in women with polycystic ovary syndrome (PCOS). However, progestin-primed ovarian stimulation (PPOS) is always accompanied by increased pituitary suppression and gonadotropin consumption. Previous studies suggested that letrozole appeared to have the potential to reduce the total gonadotropin dose required for ovarian stimulation. A retrospective cohort study was performed to evaluate the efficacy of PPOS with or without letrozole in infertile women with PCOS. Methods: This retrospective cohort study included 448 women with PCOS who underwent controlled ovarian stimulation (COS) with human menopausal gonadotropin (hMG) and medroxyprogesterone acetate (MPA) (n = 224) or hMG and MPA cotreatment with LE (n = 224) from January 2018 to March 2021 after propensity-score matching. The primary outcome measure was the hMG dose. The secondary outcomes were the durations of ovarian stimulation, the implantation rate, the number of oocytes retrieved and viable embryos, oocyte maturity and fertilization rates, the percentage of women with profound pituitary suppression (luteinizing hormone [LH] <1.0 IU/L on the trigger day). Results: The hMG doses (1949.89 ± 725.03 IU vs 2017.41 ± 653.32 IU, p > 0.05) and durations of ovarian stimulation (9.03 ± 1.79 days vs 9.21 ± 2.18 days, p > 0.05) were similar between the two groups. The implantation rate was significantly higher in the study group (MPA + hMG + LE) than in the control group (MPA + hMG) (42.22 vs 34.69%, p < 0.05). The numbers of oocytes and embryos retrieved were similar between the two groups. Interestingly, letrozole cotreatment was associated with decreased oocyte maturity and fertilization rates in comparison with standard PPOS protocols even though mature and fertilized oocyte yields were comparable. Compared with those in the control group, the LH values on the trigger day were significantly higher in the study group, together with significantly reduced pituitary suppression. Conclusion: Letrozole combined with PPOS cannot reduce hMG consumption in PCOS patients undergoing IVF treatment and shows no beneficial effect on cycle characteristics of COS. However, letrozole supplementation manifests as a superior implantation rate to that of the standard PPOS protocol in women with PCOS.

Influence of endometrioma size on ART outcomes

Research questionDoes endometrioma size affect the number of oocytes retrieved after ovarian stimulation in women with endometriosis-related infertility undergoing IVF/intracytoplasmic sperm injection (ICSI)? DesignCohort study of infertile women with unilateral or bilateral endometrioma(s) associated with deep infiltrating endometriosis, undergoing their first IVF/ICSI cycle between January 2014 and November 2021. A total of 326 women with an adequate imaging work-up with transvaginal ultrasound and/or magnetic resonance imaging performed by senior radiologists before the start of ovarian stimulation was included. Prognostic factors associated with the number of oocytes retrieved were analysed. IVF/ICSI outcomes were compared between five groups defined according to the largest endometrioma diameter (<2, 2 to <4, 4 to <6, 6 to <8 and ≥8 cm). ResultsFactors that significantly reduced the number of oocytes retrieved after adjustment by multiple linear regression were women's age (regression coefficient –0.18; 95% confidence interval [95% CI] –0.31 to–0.06; P = 0.005), smoking habit (–2.02; 95% CI –3.42 to -0.62; P = 0.005), day 3 FSH concentration (–0.20; 95% CI –0.39 to –0.02; P = 0.031) and a previous history of surgery for ovarian endometriosis (–1.32; 95% CI –2.63 to –0.02; P = 0.047). Antral follicle count and oestradiol concentration on the trigger day were positively correlated with the number of oocytes retrieved (0.14; 95% CI 0.08 to 0.19; P < 0.001 and 0.003; 95% CI 0.002 to 0.004; P < 0.001, respectively). The mean number of oocytes retrieved was not significantly different between the five groups (P = 0.413), nor were the cumulative live birth rate, the number of cancelled cycles and perinatal outcomes. ConclusionsNo significant difference in the number of oocytes retrieved was observed according to endometrioma size. This study suggests that ovarian stimulation can be of benefit to women irrespective of the endometrioma size.

Hormonal and genetic causes of poor response to controlled ovarian stimulation in women of late reproductive age

Objectives: to investigate the hormonal and genetic determinants of the poor response to controlled ovarian stimulation (COS) in women of late reproductive age.Materials and methods. 130 patients from assisted reproductive technology programs were examined. The main group of 80 older reproductive aged patients (35 years and older) was divided into 2 subgroups according to the POSEIDON criteria. Subgroup 1 included 34 women with a predicted poor response to COS, subgroup 2 – 46 patients with a predicted normal response to COS. The comparison group consisted of 50 patients under the age of 35 with a predicted normal response to COS.The pituitary hormones (luteinizing, follicle-stimulating hormones, prolactin), steroid hormones (testosterone, estradiol, progesterone), cortisol, anti-Mullerian hormone (AMH) and inhibin B values was determined in blood serum by the ELISA. Blood was taken on the third day of the menstrual cycle. A molecular genetic study of FSHR gene polymorphism (Ala307Thr, Ser680Asn) was performed.Results. AMH decrease, estradiol increase and inhibin B decrease in potentially poor responders to COS may be an additional indication of reduced ovarian reserve. The level of follicle-stimulating hormone increases with age, but does not have high specificity as a marker of ovarian reserve. Elevated levels of cortisol emphasize its role in reproduction and correspond to increased stress value. The effectiveness of IVF if there were 4 or more mature oocytes obtained is associated with higher levels of AMH and inhibin B, and lower estradiol and cortisol values. The multifaceted dependence of the COC effectiveness in women of older reproductive age on the parameters of the hormonal profile, confirmed by correlation analysis, reflects the complexity of the reproductive function implementation with the use of auxiliary reproductive technologies in such patients. The combination of AA/SS genotypes for the Thr307Ala and Asn680Ser polymorphisms of the FSHR gene can be an additional marker of COC inefficiency.Conclusions. Determination of the hormones levels (inhibin B, estradiol and cortisol), the study of Thr307Ala and Asn680Ser polymorphisms of the FSHR gene can provide additional information for predicting the response to COS in women of older reproductive age.

Fertility preservation for women with breast cancer: a multicentre randomized controlled trial on various ovarian stimulation protocols.

Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation? Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer. Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown. This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18-43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration. During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle. No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference -1.13, 95% CI -5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI -4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was -1.11 (95% CI -5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI -4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome. The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation. Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women's future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence. The study was supported by a grant (2011.WO23.C129) of 'Stichting Pink Ribbon', a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work. NTR4108. 6 August 2013. 30 January 2014.