Mean Number Of Oocytes Research Articles

P-655 Live birth rate in the fresh cycle associated with number of oocytes in ovarian stimulation with individualised follitropin delta: an individual patient data meta-analysis

Abstract Study question What is the optimum number of oocytes retrieved to achieve a live birth for women undergoing ovarian stimulation with individualised follitropin delta? Summary answer The live birth rate (LBR) in the fresh cycle was highest in the range of 8-14 oocytes retrieved, peaking at 11 oocytes. What is known already The number of oocytes retrieved following ovarian stimulation for assisted reproductive technologies is regarded a prognostic marker of pregnancy outcome, where high numbers increase chances of live birth but also the risk of complications, especially ovarian hyperstimulation syndrome (OHSS). Thus, an optimum range of oocytes retrieved is essential. Still, there is no consensus regarding this range in fresh cycles. Optimum numbers between 6 and 15 oocytes have been suggested, taking the risk of OHSS into consideration. The individualised dosing algorithm for the recombinant follicle-stimulating hormone follitropin delta has a target range of 8–14 oocytes. Study design, size, duration Individual patient data meta-analysis of 1772 patients from 5 randomised controlled trials using individualised dosing of follitropin delta for ovarian stimulation, with fixed daily dosing based on serum anti-Müllerian hormone (AMH) and body weight. The analysis included patients with ≥1 oocyte retrieved. Outcomes of LBR and OHSS in the fresh stimulation cycle were evaluated in relation to number of oocytes retrieved. Subgroup analyses were performed based on age, AMH and number of oocytes retrieved. Participants/materials, setting, methods Participants were women, 18–42 years, undergoing first or second in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle in a GnRH antagonist/long agonist protocol with human chorionic gonadotrophin or GnRH agonist triggering and IVF/ICSI. Single or double embryo/blastocyst transfer was performed on Day 3/5. All pregnancies were followed until birth. Predicted live birth was obtained using a logistic regression analysis with fractional polynomials to assess the association between number of oocytes retrieved and live birth. Main results and the role of chance The studied population (n = 1772) had a mean age of 32.6 years and median AMH of 17.7 pmol/l. Mean number of oocytes retrieved was 10.4, the LBR was 32.1% and the OHSS rate (any grade and onset) was 6.6%. The LBR steadily increased with the number of oocytes retrieved up to a plateau starting at 8 oocytes, with a LBR above 34% in the range of 8-14 oocytes retrieved, peaking at 34.9% for 11 oocytes. Beyond 14 oocytes, LBR gradually declined. By number of oocytes (grouped), the LBR was 27.8%, 33.6% and 30.9% at 1-7, 8-14 and ≥15 oocytes. In patients with embryo transfer, corresponding rates were 32.8%, 37.2% and 38.7%. In the subgroup analyses, LBR decreased with increasing age (32.7%, 30.7% and 23.4% at < 35, 35-37 and 38-42 years) while it was similar for AMH <15 and ≥15 pmol/l (30.4% and 31.3%, respectively). LBR was highest at 8-14 oocytes in patients <35 years (28.0%, 36.2% and 32.4% at 1-7, 8-14 and ≥15 oocytes), while it was consistently low (<26%) in patients 38-42 years, irrespective of number of oocytes retrieved. The OHSS rate (any grade) increased from 2.1% with 1-7 oocytes, to 5.2% with 8-14 oocytes and 17.0% with ≥15 oocytes. Limitations, reasons for caution A limitation of this study is the small number of patients with >20 oocytes retrieved in the studied population. Wider implications of the findings The current individual patient data meta-analysis suggests an optimum range of 8-14 oocytes retrieved to achieve a live birth in fresh cycles with follitropin delta. Furthermore, the analysis demonstrates a marked increase in OHSS rate from 15 oocytes retrieved. The results support the appropriateness of individualised follitropin delta dosing regimen. Trial registration number NCT01956110, NCT03228680, NCT03296527, NCT03564509, NCT03809429

The Covid-19 Infection Effect on Assisted Reproductive Method Outcomes.

COVID-19 can have potential pathogenic effects on the oocyte and embryos, but there is limited data about its impact. This study aimed to investigate the COVID-19 impact on the outcome of Assisted Reproduction Techniques (ART) methods. This case-control study was conducted on 190 infertile women who underwent oocyte retrieval at Yas Hospital in vitro fertilization (IVF) department affiliated to Tehran University of Medical Sciences, from October 2021 to October 2022. The case group was defined as women whose PCR test was positive on puncture day and the control group was women with COVID-19 negative tests on puncture day. The study outcome measurements included the number of oocytes retrieved and the number and quality of embryos. Finally, the data were analyzed by SPSS 24. The mean age of the participants was 32.89 ± 5.58 years with an age range of 18-49 years. No significant difference was observed between the two groups regarding baseline variables. The mean number of oocytes was significantly (p =0.001) lower in the case (6.68±4.25) group versus the control (9.07±4.10) group. While there was no statistically significant difference regarding the mean number of embryos in the study groups, No grade A embryos were observed in more than half (57.5%) of the women in the case group. Furthermore, the frequency of grade C embryos on average was 1.08±1.11 in the case group and 0.57±0.75 in the control group, with a statistically significant difference (p =0.010). The findings of this research highlighted that women infected with COVID-19 on the puncture day have a lower number of oocytes and also good-quality embryos.

IVF outcomes pre- and post-anti-COVID-19 vaccination – Are there any differences?

Since the beginning of the SARS-CoV-2 pandemic, there have been rising concerns about the virus's possible ability to affect male and female fertility. Although effective vaccines were introduced and the vaccination rate of the general population is high, some reproductive-age individuals are still hesitant to receive the vaccine, because of an unestablished belief that the vaccine might impair fertility. In this single-center retrospective study, encompassing data from 387 medical files of in-vitro fertilization (IVF) patients we compared IVF cycle outcomes and sperm characteristics in vaccinated couples before and after vaccination, as well as between vaccinated patients and a control group of individuals who were neither vaccinated nor infected with COVID-19 before or during the cycles. We found no significant differences between vaccinated and non-vaccinated patients concerning the number of retrieved oocytes and the total motile sperm count (TMC). The mean number of retrieved oocytes showed a slight increase in the vaccinated group compared to the non-vaccinated control group (10.8 vs. 9.18, p = 0.14). Additionally, within the vaccinated group, no significant difference was observed in the mean number of oocytes before and after vaccination (9.7 and 10.8, p = 0.14). Other similar cycle outcomes between the groups were the rates of implantation, pregnancy, and ovarian hyperstimulation syndrome. This study emphasized that the mRNA anti-COVID-19 vaccination doesn’t adversely affect ovarian response or sperm quality in IVF patients. These findings contribute valuable insights to the safety profile of anti-COVID-19 vaccines in the context of reproductive-aged populations, aiding decision-making during ongoing virus outbreaks and potential future scenarios.

Detecting partial premature ovulation during follicular aspiration compromises the quantity, but not the quality, of the oocytes retrieved in stimulated in vitro fertilization (IVF) cycles.

To analyze if partial premature ovulation (PPO) detection during oocyte pick-up (OPU) impairs the quality of the retrieved oocyte cohort. The PPO concept refers to the situation when premature ovulation happens only in some of the follicles and it is detected during OPU. This study constitutes a retrospective analysis performed in an infertility clinic (Spain) during 2016-2021 with patients undergoing OPU after controlled ovarian hyperstimulation for an in vitro fertilization (IVF) treatment. Study code: 2110-VLC-091- VG, registered on December 9 2021. Data from women with PPO (n=111) were compared to a matched control sample of cycles without PPO (n=333) at a proportion of 1:3. Cycles were matched for age, body mass index (BMI), treatment year, embryo genetic analysis and stimulation protocol type. The mean numbers of oocytes (6.1 vs. 11.2), mature oocytes (4.7 vs. 8.8), correctly fertilized oocytes (3.6 vs. 6.6) and top-quality blastocysts (0.9 vs. 1.8) were significantly lower in the PPO group than the nonPPO group (p<0.05). However, maturation, fertilization, top-quality blastocyst and pregnancy rates were statistically comparable among groups (p>0.05). Cycles with PPO have fewer available oocytes and, thus, fewer available embryos for transfer, al though their quality is intact, and still offer chances of pregnancy in these cases. Hence cycle cancellation may not be worth associated money, time and morale losses once PPO is detected.

Live birth rates in in vitro fertilization cycles with five or fewer follicles.

To evaluate live birth rates (LBRs) for in vitro fertilization (IVF) cycles with ≤5 follicles at trigger, with the goal of helping patients with low follicle counts decide whether to proceed to retrieval. This is a retrospective cohort study from an urban, university-affiliated fertility center. All IVF cycles that yielded <10 oocytes between 2016 and 2020 were reviewed. Cycles were included if <5 follicles measuring >14 mm were verified on trigger day. The primary outcome was LBR per retrieval after fresh or frozen transfer. Secondary outcomes were number of oocytes, mature oocytes, 2-pronuclear zygotes (2-PNs), blastocysts for transfer/biopsy, and euploid blastocysts (if preimplantation genetic testing for aneuploidy (PGT-A) was used). 1502 cycles (900 with PGT-A) from 972 patients were included. Mean number of oocytes, mature oocytes, 2-PNs, blastocysts for transfer/biopsy, and euploid blastocysts differed by follicle number (p < 0.001). Across all age groups, there were differences in LBR associated with follicle number (p < 0.001). However, within age groups, not all results were significant. For example, for patients <35 years, LBR did not differ by follicle number and among patients 35-37 years; LBR with two or three follicles was lower than with five (p < 0.02). LBR for patients 35-40 years was <20% with 1-3 follicles and 25-40% with 4-5 follicles. LBR for patients >41 years was <5% with 1-3 follicles and <15% with 4-5 follicles. As expected, LBR is higher with more follicles. Providing patients with <5 follicles with specific data can help them weigh the emotional, physical, and financial costs of retrieval.

P-646 The effect of profound LH suppression in GnRH antagonist cycles on IVF/ICSI outcomes-A retrospective study of 400 cycles

Abstract Study question Does low pretrigger LH in GnRH antagonist cycles affect the blastulation rates and cumulative live birth rates? Summary answer Low pretrigger LH in GnRH antagonist cycles does not affect the blastulation rates and cumulative live birth rates in frozen embryo transfer cycles. What is known already • There is conflicting evidence that in GnRH antagonist cycles stimulated with recombinant FSH, low serum LH may effect negatively the pregnancy outcomes in fresh embryo transfer.(Benmachiche et al 2019). • Whether the observed effect of low LH is on the embryo or on the endometrial receptivity is not clear. Study design, size, duration • Retrospective observational single centre study with a study population of 400 undergoing IVF/ICSI in between December 2018- December 2021. • Controlled ovarian stimulation in GnRH Antagonist protocol in unselected population &amp;gt; 21yrs old undergoing IVF/ICSI. • Exclusion Criteria- • Long protocol • Flare protocol • Oocyte cryopreservation cycle • Donor oocyte cycle Participants/materials, setting, methods • Controlled ovarian stimulation is done according to the hospital’s standard operations of practice in flexible antagonist cycle with human menopausal gonadotropins and recombinant/urinary follicle stimulating hormone. • When 3 or more follicles &amp;gt;/=17mm, triggered with GnRH Agonist or dual trigger. • Oocyte pick up scheduled at 35-36hrs following trigger. • Serum LH measured at baseline and at trigger. • Clinical and embryological outcomes are assessed in between low serum LH i.e., &amp;lt;1.5MIU/ML and normal serum LH &amp;gt;/= 1.5 MIU/ML. Main results and the role of chance Demographic variables were comparable between both the arms, except that baseline LH is low in subjects with low pretrigger LH. Mean dose of gonadotropins although not statistically significant, is slightly higher in the low pretrigger LH group. Mean duration of stimulation is higher in low pretrigger LH group and is statistically significant. Mean number of oocytes retrieved, mature oocytes, fertilisation rate, number of blastocysts, day5 and day6 blastocyts, good quality blastocysts and cumulative live birth rates are similar between low pretrigger LH and normal pretrigger LH group. Outcomes between low pretrigger LH and normal pretrigger LH- Mean number of blastocysts- 5.02 +/-3.84 vs 4.72 +/-3.82 (p = 0.44) Mean number of day5 blastocysts- 4 (0-14) vs 3.5(0-20) (p = 0.86) Mean number of day6 blastocysts- 1 (0-8) vs 1 (0-9) (p = 0.4) Mean number of good quality blastocysts- 2(0-19) vs 2 (0-17) (p = 0.68 ) Number of cycles with no blastocysts- 11.1 vs 16.1% (p = 0.35) Cumulative live birth rate 47 vs 48% (p = 0.99) SECONDARY OUTCOMES- Mean dose of gonadotropins- 3282+/- 913 iu vs 3119 vs 926iu (p = 0.07) Mean duration of stimulation- 11.67 +/- 1.87days vs 11.09 +/- 2days (p = 0.01) Mean number of oocytes retrieved-14.98+/- 7.14 vs 13.9+/-7.9 (p = 0.15) Mean number of mature oocytes-11.19+/- 5.64 vs 10.43+/-6.44 (p + 0.21) Mean fertilisation rate-10.7+/- 5.47 vs 9.81+/-6.08 (p = 0.12) Limitations, reasons for caution Retrospective design. Outcomes are assessed in frozen embryo transfer cycles, bur are not compared with fresh embryo transfer cycles. Wider implications of the findings The study provides reassuring data that low serum LH on the day of trigger does not affect the blastulation rates, quality of blastocysts and cumulative live birth rates in frozen embryo transfer cycles. Whether frozen embryo transfer can negate the effect of low pretrigger LH, further studies are needed. Trial registration number Not applicable

O-224 Effect of intraovarian injection of platelet rich plasma on ovarian response in poor responder women

Abstract Study question Does intraovarian administration of platelet rich-plasma (PRP) increase ovarian response in women with poor ovarian response (POR) undergoing IVF treatment? Summary answer In patients with low ovarian response, the number of oocytes and embryos is higher in the 4 cycles after PRP administration compared to pre-PRP cycles. What is known already The number of oocytes after controlled ovarian stimulation is a crucial factor in IVF outcomes. For this reason, different approaches have been investigated for the management of patients with POR, such as the administration of adjuvant treatments, or the change of protocol, dose or type of gonadotropin. However, none of these strategies has proven to be fully effective in improving oocyte yield. More recently, innovative treatments aimed at activating preantral follicles have emerged, such as intraovarian administration of autologous platelet rich plasma (PRP). Although the evidence is still limited, some studies suggest an improvement in ovarian response following PRP treatment. Study design, size, duration Retrospective study of 83 patients diagnosed with low ovarian reserve according to Bologna criteria who underwent intraovarian PRP between July 2021 and December 2022. 111 stimulation cycles after PRP were compared with the cycles immediately prior to PRP administration. Participants/materials, setting, methods Patients with POR were presented with an oocyte or embryo preservation strategy, which included the option of administering intraovarian platelet-rich plasma (PRP) either during the initial oocyte retrieval or in the follicular phase of the cycle preceding stimulation. A 2 ml dose of PRP was administered into each ovary. The ovarian response was analyzed in terms of the number of oocytes, MII, and embryos, and was further evaluated based on different age groups. Main results and the role of chance 83 women (age: 38,68 ± 3,54, range 28-46 years) underwent a PRP injection. The patients had low ovarian reserve markers (AMH 2,90 ± 2,76 pmol/l, AFC 4,74 ± 2,70). Of the cycles after PRP, 48 were performed in the luteal phase of the same cycle, 28 in the follicular phase of the first post-PRP cycle and 35 between the 2nd and 4th cycle post PRP. The overall mean number of oocytes (2,38 ± 2,09 vs. 3,19 ± 2,70; p = 0,002) and MII (1.84 ± 1.77 vs. 2.54 ± 2.25, p = 0.0008) was significantly higher after PRP. There was also a statistically significant difference in the number of blastocysts pre and post PRP (0,85 ± 1,12 vs. 1,77 ± 1,89; p = 0,0005). There were no differences in the blastulation or euploidy rates. Differences in the number of oocytes were not observed in the luteal phase cycle (2.97 ± 2.35 vs. 3.45 ± 2.66, p = 0.2) compared to the subsequent 1st-4th cycles (1.88 ± 1.77 vs. 2.95 ± 2.73, p = 0.003). Improvement in response was observed in patients younger than 40 years (2 ± 1.52 vs 3.3 ± 2.62 oocytes; p = 0.0002), but not in patients aged ≥ 40 years (2.9 ± 2.58 vs 3.02 ± 2.77 oocytes; p = 0.7). Limitations, reasons for caution The retrospective nature of the study is a significant limitation. As this research is based on real-world clinical practice, the patientś stimulation protocols were diverse which may have impacted the results. To verify our findings, further studies with a uniform control group are required. Wider implications of the findings We observed improved response to intraovarian platelet-rich plasma administration in patients with POR under 40 years of age. This enhancement was observed from the initial follicular cycle following administration. Our findings suggest that intraovarian PRP may be a valuable supplementary treatment for this patient population. Trial registration number not applicable

P-285 Analysis, including morphokinetic data, of IVF/ICSI cycles with oocytes containing aggregates of smooth endoplasmic reticulum (SER)

Abstract Study question Is there a difference in ART outcomes and morphokinetic parameters for SER+ and SER- cycles and oocytes? Summary answer Fertilisation and blastulation rates are lower in the SER+ group but no difference was seen in pregnancy or live birth rates. What is known already The SER is an organelle found in eukaryotic cells, including oocytes. SERs synthesize lipids and steroids, and store and metabolise calcium ions, needed for fertilization and early embryonic development. SERs can aggregate in the oocyte, forming an intracytoplasmic dimorphism, thought to interfere with reproductive outcomes. It is suggested that SER aggregates in an oocyte may negatively effect embryo development and implantation. Oocytes without SERs, but which arise from the same oocyte cohort as SER+ oocytes may also affect outcomes. Evidence around the safety and use of these SER+ and SER- oocytes is conflicting, with widespread variations in clinical practice. Study design, size, duration A retrospective review was conducted of all IVF/ICSI[MW1] cycles between January 2019 and December 2020 at Merrion Fertility Clinic, Dublin. Cycles containing SER+ oocytes were identified, and their outcomes were compared with those of a matched control group of SER- cycles. Within the SER+ group, results were compared for SER+ and SER- oocytes within the same cohort. Participants/materials, setting, methods Once participants had been identified, a chart review was undertaken noting demographics, IVF protocol used, duration of stimulation, ART and neonatal outcomes and morphokinetic parameters in the embryoscope. Statistical analysis was performed using PRISM. Main results and the role of chance There were 77 SER+ cycles with a total of 135 SER+ oocytes and 645 SER- oocytes, accounting for 8% of total cycles for the study period. These were matched to 64 control cycles with 528 SER- oocytes. 12 embryo transfers occured using blastocysts derived from SER+ oocytes. SER+ cycles had a higher mean oocyte number than controls (9.3 vs 7.3) and 92% of oocytes were mature compared to 88% of the control group. Fertilisation rates were significantly lower in the study group (60% SER+cycle; 68% in SER-cycle), related to the SER+ oocytes in that cohort. Good/top quality blastocyst rates differed (SER+ cycle 28%, SER- cycle 36%) but pregnancy(SER+ cycle 53%, SER- cycle 51%) and livebirth (SER+31%, SER- 32% ) rates were similar, even when blastocysts derived from SER+ oocytes were transferred. 5 morphokinetic variables were studied – time to 2-cell (t2), 3 cell (t3) 4 cell (t4), 5 cell (t5) and time to blastulation (tB). T5 appears to be shorter in embryos derived from SER+ oocytes than in controls, with the other parameters being comparable. In terms of neonatal outcomes there were no congenital malformations reported in the SER+ groups and one case of upper limb amelia in the control group. Limitations, reasons for caution This study is limited by its retrospective nature. We only have embryoscope data on 46 out of 77 patients with SERs, limiting numbers. Embryos transferred which derived from SER+ve oocytes were limited by the clinic policy to only transfer these embryos if no other embryos available. PGT was not performed. Wider implications of the findings This preliminary study shows that, while SER+ cycles have lower fertilisation rates than SER- cycles, pregnancy rates and live birth rates are comparable. Neonatal outcomes are reassuring. Initial analysis of morphokinetic data shows little effect. Larger numbers and further analysis are needed to fully understand the importance of these aggregates. Trial registration number n/a

Live birth rates following individualized dosing algorithm of follitropin delta in a long GnRH agonist protocol

PurposeTo explore the efficacy and safety of individualized follitropin delta dosing, based on serum anti-Müllerian hormone (AMH) concentration and bodyweight, in a long gonadotropin-releasing hormone (GnRH) agonist protocol.MethodsClinical outcomes after one treatment cycle are reported in women with AMH: 5–35 pmol/L. Oocytes were inseminated by intracytoplasmic sperm injection, blastocyst transfer was on Day 5 and remaining blastocysts were cryopreserved. Data collection included live births and neonatal health follow-up for all fresh/frozen transfers performed within one year after treatment allocation.ResultsIn total, 104 women started stimulation, of whom 101 had oocyte recovery and 92 had blastocyst transfer. The average daily dose of follitropin delta was 11.0 ± 1.6 µg and the duration of stimulation was 10.3 ± 1.6 days. The mean number of oocytes was 12.5 ± 6.4, the mean number of blastocysts was 5.1 ± 3.4, and 85% had at least one good-quality blastocyst. Following mostly single blastocyst transfer (95%), the ongoing pregnancy rate was 43%, the live-birth rate was 43%, and the cumulative live-birth rate was 58% per started stimulation. There were 6 cases of early OHSS (5.8%) graded as mild (n = 3) and moderate (n = 3) and 6 cases of late OHSS (5.8%) graded as moderate (n = 3) and severe (n = 3).ConclusionIn this first evaluation of the individualized follitropin delta dosing in a long GnRH agonist protocol, the cumulative live-birth rate was high. A randomized trial comparing follitropin delta in a long GnRH agonist protocol versus in a GnRH antagonist protocol should provide further insight into the efficacy and safety of this treatment option.Trial registration numberNCT03564509; June 21, 2018.

Transabdominal ultrasound-guided oocyte retrieval for oocyte cryopreservation using a vaginal probe: a comparison of applicability, effectiveness, and safety with conventional transvaginal approach.

We aimed to compare the feasibility, effectiveness, and safety of transabdominal ultrasound-guided oocyte retrieval (TUGOR) using a vaginal probe and traditional vaginal approach in virgin patients undergoing oocyte cryopreservation. A total of 116 virgin patients who underwent transabdominal ultrasound-guided oocyte retrieval using a vaginal ultrasound probe and 33 patients matched for BMI, antral follicle count, age, day 3 FSH, estradiol, and AMH who underwent vaginal approach were enrolled. Mean number of total oocytes collected, mean number of cryopreserved MII oocytes, duration of the procedure, duration of stimulation, mean gonadotropin consumption, mature oocyte ratio, and a modified follicle-oocyte index were compared between the groups. No statistical difference was found between the groups in mean number of follicles > 12mm (4.62 ± 4.54 vs. 5.44 ± 4.52), mean number of oocytes collected (4.44 ± 4.14 vs. 5.33 ± 4.52), mean number of cryopreserved MII oocytes (4.01 ± 3.67 vs. 4.53 ± 4.13), mean duration of the procedure (12.4 ± 1.2 vs. 13.4 ± 1.6min), mean days of stimulation (8.05 ± 1.91 vs. 8.35 ± 1.72days), mean gonadotropin consumption (1507.9 ± 475.3 vs. 1571.74 ± 404.6 units), mature oocyte ratio (0.78 ± 0.24 vs. 0.82 ± 0.26), and modified follicle oocyte index (0.86 ± 0.63 vs. 0.84 ± 0.19). In the TUGOR group, superficial epigastric artery injury occurred in two patients and resolved spontaneously. Transabdominal oocyte retrieval using a vaginal ultrasound is a safe, effective, and feasible method of oocyte retrieval in some selected patient groups.

Treatment safety of ART cycles with extremely high oestradiol concentrations using GnRH agonist trigger

Research questionAre IVF treatments with extremely high peak oestradiol levels and gonadotrophin releasing hormone (GnRH) agonist trigger associated with higher complication rates? DesignA retrospective cohort study including patients from two large medical centres treated between 2019 and 2021. A study group with extremely high peak oestradiol levels (≥20,000 pmol/l on the day of ovarian stimulation, or ≥15,000 pmol/l on the previous day) and a control group with normal range oestradiol levels (3000–12000 pmol/l) that received GnRH agonist triggering. Patients were surveyed about complaints and medical care related to ovum retrieval and medical files were reviewed. Major complication rates and the need for medical assistance were compared. ResultsSeveral differences between the study and control group were observed because of the study design: mean age was 33.01 ± 5.14 versus 34.57 ± 4.52 (P < 0.001), mean peak oestradiol levels was 26645.34 ± 8592.57 pmol/l versus 7229.75 ± 2329.20 pmol/l (P < 0.001), and mean number of oocytes were 27.55 ± 13.46 versus 11.67 ± 5.76 (P < 0.001) for the study and control group, respectively. Major complications and hospitalization rates were similar between the study and control groups (three [1.25%] versus one [0.48%]; P = 0.62 and three [1.25%] versus two [0.96%]; P = 1.0, respectively). Thirty-six patients (15.1%) in the study group and 11 (5.3%) in the control group sought medical care after retrieval, mostly due to abdominal pain, without the need for further workup or hospitalization (P < 0.001). ConclusionsExtremely high oestradiol levels were not associated with thromboembolic events, higher major complication or hospitalization rates, and therefore may be considered safe. Nevertheless, patients may be informed of possible higher rates of discomfort, mostly abdominal pain. Larger studies are warranted to confirm our results.

Does follicular flushing increase oocyte number in poor responders? An update of a systematic review

Research questionDoes flushing of the follicles at ovum retrieval increase the number of retrieved oocytes in poor-response IVF patients? DesignAn update of an electronic literature search was performed to identify randomized controlled trials (RCT) investigating follicular flushing versus no flushing in women with a poor response to IVF treatment. No exclusion criteria for type of needle, stimulation or protocol were applied. A meta-analysis was conducted using the software RevMan 5.4. ResultsSix RCT were identified that had the primary objective of testing for an increase in mean number of cumulus–oocyte complexes or/and metaphase II oocytes between flushing and no flushing. A double-lumen needle was used in five trials, one study investigated a pseudo-double-lumen needle, and a conventional single-lumen needle was used in all the control groups. The main risk of bias in all the included studies is a lack of blinding of the physicians performing the puncture and incomplete data in four trials. A heterogeneity of direction and size of effect of follicular flushing on mean oocyte number retrieved was detected (I2 = 80, P = 0.0001), which precludes a synthesis of the data. Two studies showed a decrease or tendency towards a decrease in oocyte numbers, one study showed similar oocyte numbers, and one study showed a strong tendency towards increased oocyte numbers with flushing. A similar picture was seen for metaphase II oocytes (I2 = 73, P = 0.002). ConclusionsIt is uncertain whether follicular flushing in poor-response IVF patients affects the number of retrieved oocytes. Larger pragmatic trials are warranted to clarify the effect of flushing on oocyte numbers and clinical outcomes in poor responders and monofollicular patients.

"Short agonist stop" protocol, an ovarian stimulation for poor responders in in vitro fertilization (IVF): A pilot study.

Poor responder patients remain a challenge in assisted reproductive technologies. The "short agonist stop" (SAS) stimulation protocol uses a double stimulation (flare up effect with the gonadotropin-releasing hormone (GnRH) agonist (GnRH-a) then gonadotropins) associated with a less strenuous blockage (discontinuation of GnRH-a) to favor follicular recruitment in order to obtain a better ovarian response. This study aims to compare the number of oocytes obtained after a SAS stimulation protocol with those obtained after the previous stimulation protocol, in the same women, with poor ovarian response (POR) diagnosed according to the POSEIDON criteria. This therapeutic observational retrospective cohort from 2018 to 2022, with a case-control evaluation compared with the same patients' previous performance, included women with POR undergoing IVF with SAS stimulation protocol. The primary outcome was the number of total oocytes recovered and secondary outcomes were the numbers of mature oocytes, total embryos observed at day 2 and usable cleaved embryos and blastocysts (day 5/6). 63 patients with SAS and previous cycles were included. In the SAS group, the mean number of oocytes was significantly higher: 7.3 vs 5.7, p=0.018 in comparison with the previous attempt. So was the number of mature oocytes (5.8 vs 4.1, p=0.032) and the total mean number of embryos obtained at day 2 (4.1 versus 2.7, p=0.016). The SAS stimulation generated 84 usable embryos: 57 cleaved embryos and 27 blastocysts. The mean number of usable embryos was similar in both groups (1.64 vs 1.31, respectively, p=0.178). In total, out of 63 patients, after the SAS protocol, and subsequent embryo transfers (fresh and frozen, n=54), 9 patients had ongoing pregnancies and no miscarriage occurred. The cumulative ongoing pregnancy rate (cOPR) after the SAS protocol was 14.3% (9/63) per oocyte pick-up and 16.7% (9/54) per transfer. SAS stimulation is a short and original protocol strengthening the therapeutic arsenal of poor responders, that may offer promising results for those patients with low prognosis and previous failed IVF. Results must be confirmed with a randomized controlled trial.

The earlier the initiation of gonadotropin in poor responders in luteal phase stimulation protocols, the better.

Luteal-phase ovarian stimulation has been proved to be feasible for producing competent oocytes/embryos and achieving live births, yet there is no standardized stimulation protocol for luteal-phase ovarian stimulation (LPS). The aim of this study was to explore the optimal timing of gonadotropin initiation in the LPS protocol for poor ovarian responders. This was a retrospective cohort study conducted in the reproductive medicine center of a tertiary hospital. A total of 327 poor responders fulfilling Bologna criteria underwent LPS with IVF/ICSI treatment. HMG and letrozole were administrated after ovulation. Patients were stratified into three groups according to the gonadotropin start day: early, early-mid, and mid-late luteal phase. A freeze-all strategy was performed for all cycles. The duration of ovarian stimulation, total gonadotropin dose, number of oocytes retrieved, implantation rate, clinical pregnancy rate, and live birth rate after frozen/thawed embryo transfer cycles were included for evaluation. The group accepted ovarian stimulation in the earlier phase tended to have a shorter duration of ovarian stimulation [8 (7,10) in early luteal group, 9 (8,10.25) in early-mid luteal group, and 11 (10,12) in mid-late luteal group; P <0.001] and lower gonadotropin consumption [1993.35 ± 720.31, 2282.73 ± 703.38, and 2764.83 ± 722.26, respectively; P <0.001]. Logistic regression and multiple linear regression were used to assess the associations between the phase of gonadotropin initiation and duration of ovarian stimulation (or total gonadotropin dose) by adjusting for confounding factors. Compared with the early luteal group, longer ovarian stimulation(>9 days) was more likely to occur in the early-mid and mid-late luteal groups, with the adjusted odds ratios 0.584 (0.327-1.042) and 0.116 (0.049-0.271), respectively (P-trend<0.001). Delayed gonadotropin initiation showed an 113.200 IU increase (95%CI: 70.469, 155.930) per-day in the total gonadotropin dosage. Meanwhile, there were no significant differences in the mean number of oocytes, utilizable embryos, pregnancy outcomes among three groups. Although the timing of gonadotropin initiation is not associated with pregnancy outcomes, earlier initiation of gonadotropin therapy after ovulation was associated with a shorter duration of ovarian stimulation and lower gonadotropin consumption in poor responders in LPS.

Comparison of blastocyst euploidy rates following luteal versus follicular phase stimulation in a GnRH antagonist protocol: a prospective study with repeated ovarian stimulation cycles.

Is there any difference in the mean number of euploid embryos following luteal phase start (LS) and follicular phase start (FS) of ovarian stimulation? The mean number of euploid blastocysts is equivalent independent of whether the inseminated oocytes are derived from FS or LS. Starting ovarian stimulation at any time of the cycle ('random-start') is commonly used for emergency fertility preservation in cancer patients. A few retrospective studies have been published evaluating LS in women undergoing ovarian stimulation in the context of IVF, but there is a lack of robust data on the comparative efficacy of LS versus FS.Although 'random start' is commonly used in cancer survivors, few retrospective and uncontrolled studies have been published evaluating luteal phase stimulation in women undergoing ovarian stimulation in the context of IVF. Owing to this evident lack of robust data on the efficacy of LS, guidelines typically recommend the LS approach only for medical reasons and not in the context of IVF. This is a prospective, equivalence study, with repeated stimulation cycles, conducted between May 2018 and December 2021. Overall, 44 oocyte donors underwent two identical consecutive ovarian stimulation cycles, one initiated in the FS and the other in the LS. The primary outcome of the study was to evaluate whether FS and LS in the same patient would result in equivalent numbers of euploid embryos following fertilization of oocytes with the same sperm sample. Overall, 44 oocyte donors underwent two consecutive ovarian stimulation protocols with 150 μg corifollitropin alpha followed by 200 IU recombinant FSH (rFSH) in a fixed GnRH antagonist protocol. The only difference between the two cycles was the day of initiation of ovarian stimulation, which was in the early follicular phase (FS) in one cycle, and in the luteal phase (LS) in the other. Forty-four oocyte recipients participated in the study receiving a mean of six metaphase II (MII) oocytes from each stimulation cycle (FS and LS). All MIIs were inseminated with the corresponding recipient's partner sperm (which had been previously frozen) or donor sperm, in order to safeguard the use of the same sample for either the FS or LS. Following fertilization and blastocyst culture, all generated embryos underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuploidy). FS resulted in a significantly shorter duration of ovarian stimulation (difference between means (DBM) -1.05 (95% CI -1.89; -0.20)) and a lower total additional dose of daily rFSH was needed (DBM -196.02 (95% CI -319.92; -72.12)) compared with LS. The donors' hormonal profile on the day of trigger was comparable between the two stimulation cycles, as well as the mean number of oocytes (23.70 ± 10.79 versus 23.70 ± 8.81) (DBM 0.00 (95% CI -3.03; 3.03)) and MII oocytes (20.27 ± 9.60 versus 20.73 ± 8.65) (DBM -0.45 (95% CI -2.82; 1.91)) between FS and LS cycles, respectively. Following fertilization, the overall blastocyst formation rate was 60.70% with a euploid rate of 57.1%. Comparisons between the two stimulation cycles did not reveal any significance differences in terms of fertilization rates (71.9% versus 71.4%), blastocyst formation rates (59.4% versus 62%) and embryo euploidy rates (56.9 versus 57.3%) for the comparison of FS versus LS, respectively. The mean number of euploid blastocysts was equivalent between the FS (1.59 ± 1.30) and the LS (1.61 ± 1.17), (DBM -0.02 (90%CI -0.48; 0.44)). The study was performed in young, potentially fertile oocyte donors who are patients with high blastocyst euploidy rates. Although results may be extrapolated to young infertile women with good ovarian reserve, caution is needed prior to generalizing the results to infertile women of older age. The current study provides evidence that initiation of ovarian stimulation in the luteal phase in young potentially fertile women may result in a comparable number of oocytes and comparable blastocyst euploidy rates compared with follicular phase stimulation. This may imply that in case of a freeze-all protocol in young patients with good ovarian reserve, clinicians may safely consider initiation of ovarian stimulation during the luteal phase. This research was supported by an unrestricted grant from MSD/Organon. N.P.P. has received Research grants and honoraria for lectures from: Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins Intenational, Roche Diagnostics, IBSA, Theramex, Gedeon Richter. F.M., E.C., M.R. and S.G. declared no conflict of interests. The study was registered at Clinical Trials Gov (NCT03555942).

Myo-inositol effect on pregnancy outcomes in infertile women undergoing in vitro fertilization/intracytoplasmic sperm injection: A double-blind RCT.

BackgroundMyo-inositol is an intracellular mediator which is involved in various aspects of reproduction in women.Objective This study aimed to evaluate the impact of Myo-inositol on the outcomes of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles in infertile women.Materials and MethodsThis double-blind randomized controlled trial was conducted on 70 infertile women referred to the Infertility Treatment Center, Besat hospital, Sanandaj, Iran from May 2019 to September 2019 for IVF/ICSI cycles. The participants were randomly divided into 2 intervention (n = 36) and control (n = 34) groups. The intervention group received 2000 mg of Myo-inositol and 200 mcg folic acid twice a day for 2 months and the control group received 200 mcg of folic acid twice a day for 2 months in the IVF/ICSI cycles (from the third day of cycle until the end of the second month). Finally, the number of oocytes, the quality of embryos, and the IVF/ICSI outcomes were compared between the 2 groups.ResultsThe mean numbers of oocytes, MII oocytes, and 2 pronuclear embryos were significantly higher in the intervention group than the control group. Also, the clinical pregnancy and live birth rates in the intervention group were significantly higher than in the controls (p = 0.04).Conclusion The administration of Myo-inositol may increase clinical pregnancy and live birth rates by increasing the number of total and meiosis II oocytes in infertile women undergoing IVF/ICSI.

P-650 Partial premature ovulation detection during follicular aspiration compromises the quantity but not the quality of the retrieved oocytes in stimulated fresh IVF cycles

Abstract Study question Is partial premature ovulation (PPO) detection during the oocyte pick-up (OPU) a sign of poor prognosis in in vitro fertilization (IVF) cycles with own oocytes? Summary answer PPO halves the number of metaphase II oocytes available for an IVF treatment without reducing their quality, demonstrated by unaltered fertilization and top-quality blastocyst rates. What is known already PPO detected during the OPU procedure has not been extensively studied in the literature. This phenomenon may result in a reduction in the number and/or competence of the oocytes retrieved, due to the potential loss of the already expelled oocytes, as well as the likely dominance exerted by the ruptured follicle/s in the rest of the cohort. Despite this, several authors have demonstrated that competent oocytes can be retrieved from these already ruptured follicles, suggesting that oocyte extrusion frequently does not occur after follicle rupture. The potential negative effect exerted in the rest of sibling oocytes remains unknown. Study design, size, duration Retrospective cohort analysis performed in IVIRMA Valencia (Spain), including 8994 cycles of controlled ovarian stimulation (COS) for an IVF treatment with fresh own oocytes, between January 2016 and May 2021. OPU procedures for oocyte cryopreservation, as well as mixed cycles with both fresh and frozen oocytes, were discarded. PPO diagnosis was based on ultrasound visualization of any already formed corpus luteum structure/s, a lower follicular count than expected, and/or free fluid. Participants/materials, setting, methods Female patients undergoing OPU after COS for a fresh IVF treatment. Cycles in which PPO has been detected will be compared with a random, and of the same size, sample without PPO. Mean number of oocytes, metaphase II, fertilized oocytes and top-quality embryos, as well as IVF success rates, will be compared between both groups. Patients’ basal characteristics and COS parameters will be analyzed in order to detect any potential early indicator of PPO. Main results and the role of chance PPO was detected in 123 of the 8994 cycles (1.37%) performed. A random control group of 123 cycles without PPO was selected. Patients’ mean age was 37.6±3.6, with a BMI of 23.3±4.1 kg/m2 and an anti-mullerian hormone of 1.62±1.3 ng/mL. Patient’s basal characteristics and COS parameters were statistically comparable among groups (p &amp;gt; 0.05), except for lower serum estradiol levels (2037.64 vs. 1582.24 pg/mL; p = 0.004) in the PPO group on the last ultrasound prior to OPU. Patients with PPO showed lower aspiration rates (88.95% vs. 55.78% in the PPO gr.), as well as a reduced mean number of oocytes (10.69 vs. 5.68 in the PPO gr.), metaphase II (8.41 vs. 4.33 in the PPO gr.), fertilized oocytes (6.23 vs. 3.26 in the PPO gr.) and top-quality blastocysts (2.77 vs. 1.35 in the PPO gr.) (p = 0.000). In contrast, maturation (80.72% vs. 76.57% in the PPO gr.), fertilization (73.52% vs. 75.18% in the PPO gr.) and top-quality blastocyst rates (44.03% vs. 38.68% in the PPO gr.) were statistically similar between both groups (p &amp;gt; 0.05). Limitations, reasons for caution The main limitations of the present study are its retrospective design and its small sample size, derived from the low frequency of the PPO phenomenon in our clinic. Larger prospective studies should be proposed in order to accurately define the negative impact of PPO in IVF success rates. Wider implications of the findings PPO clearly reduces the number of oocytes available for an IVF treatment, although it does not seem to impair the competence of the remaining cohort. Once PPO is detected, cycle cancellation may not be worth the associated loss of money, time and morale, especially given its low prevalence (around 1%). Trial registration number Not applicable

O-013 The individualised dosing algorithm of follitropin delta, developed in a GnRH antagonist protocol, shows to be highly effective in a long GnRH agonist protocol

Abstract Study question Is the individualised follitropin delta regimen based on serum anti-Müllerian hormone (AMH) concentration and body weight effective and safe in a long GnRH agonist protocol? Summary answer Per started stimulation, the live birth rate following fresh transfer was 43% and the cumulative live birth rate following fresh and frozen transfers was 58%. What is known already Individualised follitropin delta treatment in a GnRH antagonist protocol reduces the incidence of OHSS and/or preventive interventions without compromising live birth rates. In a multinational, double-blind, randomised trial (RAINBOW, NCT03564509) exploring the efficacy and safety of choriogonadotropin beta in women undergoing ovarian stimulation in a long GnRH agonist protocol, the control group was treated with the same individualised follitropin delta regimen based on AMH (Elecsys AMH Plus Immunoassay) and body weight. Women had one stimulation cycle and were followed up to live birth following the fresh and all frozen blastocyst transfers performed within one year after start of stimulation. Study design, size, duration Analysis of fresh and cumulative live birth rates in 104 women (30–42 years, AMH 5-35 pmol/L) down-regulated with 0.1 mg/day triptorelin and stimulated in one cycle with a fixed individualised daily dose of follitropin delta. Triggering was performed when 3 follicles ≥17 mm. Oocytes were inseminated by ICSI; blastocyst transfer was on day 5 and remaining blastocysts were cryopreserved on day 5/6 and subsequently used for frozen transfers. Participants/materials, setting, methods Data collection included live birth and neonatal health follow-up for all transfers of fresh or frozen embryos performed within one year after the start of stimulation. The data presented are based on all women who were down-regulated and started stimulation. The cumulative live birth rate was calculated as the percentage of women starting stimulation that had at least one live born neonate. Main results and the role of chance Of 104 women starting stimulation, 101 had triggering. Two subjects were cancelled due to poor response and one due to adverse event. Nine subjects had transfer cancellations; six due to no day 5 blastocyst available, and one each due to risk of OHSS, adverse event, and other reason. The average daily dose of follitropin delta was 11.0±1.6 and the duration of stimulation was 10.3±1.6 days. The mean number of oocytes was 12.5±6.4; the mean number of blastocysts was 5.1±3.4; and 85% had at least one good-quality blastocyst. Following mostly single blastocyst transfer (95%), the ongoing pregnancy rate (10–11 weeks after transfer) was 43% per started stimulation. There were six cases of early OHSS (5.8%) graded as mild (3) and moderate (3) and six cases with late OHSS (5.8%) graded as moderate (3) and severe (3). In total, 92% of women had at least one fresh or frozen transfer and 150 blastocyst transfers were performed (92 fresh and 58 frozen transfers). Per started stimulation, the live-birth rate following fresh transfer was 43% and the cumulative live-birth rate following fresh and all frozen transfers was 58%. There were three neonates with congenital anomalies following fresh transfer and none following frozen transfer. Limitations, reasons for caution This is the first clinical trial investigating the individualised follitropin delta regimen in a long GnRH agonist protocol. A final evaluation of this regimen requires comparative data. Accordingly, a randomised trial comparing follitropin delta in a long GnRH agonist protocol vs. in a GnRH antagonist protocol is currently ongoing (NCT03809429). Wider implications of the findings The use of individualised follitropin delta dosing based on AMH and body weight in a long GnRH agonist protocol resulted in high fresh and cumulative live birth rates, and with an incidence of OHSS similar to previously reported for other FSH products in long GnRH agonist protocols. Trial registration number NCT03564509

P-634 Safety of ART cycles with extremely high estradiol levels - A retrospective cohort study

Abstract Study question Are IVF treatments with extremely high peak estradiol levels during ovarian hyperstimulation associated with higher complication rates? Summary answer Extremely high estradiol levels were not associated with higher major complication rates, but patients were more likely to seek medical care following retrieval. What is known already The freeze-all policy and the increasing popularity of social oocyte freezing, have led to an increase in gonadotropin doses and number of oocytes retrieved and, as a direct effect, higher estradiol levels. Studies reporting major ART complications (OHSS, bleeding, infection, torsion, thromboembolic events) are based on heterogeneous patient populations without stratification by oocyte number or estradiol levels, except for a single study reporting an association between peak estradiol levels and the risk of ovarian torsion. Extreme estradiol levels, are associated with larger ovaries, repeated ovarian punctures, and possibly a thrombogenic effect. Therefore, higher complication rates can be expected. Study design, size, duration A retrospective cohort study including patients from two large medical centers treated between 2019-2021. Participants/materials, setting, methods A study group (239 patients) with extremely high peak estradiol levels (&amp;gt;20,000 pmol/L on the day of ovulation induction, or &amp;gt; 15,000 pmol/L on the previous day) and a control group (208 patients) with normal range estradiol levels (3000-12000pmol/L), treated at two large units were included. Patients were surveyed about complaints and medical care related to ovum pick up (OPU), and medical files were reviewed. Complication rates and the need for medical assistance were compared. Main results and the role of chance Several differences between the study and control group were observed as a consequence of the study design: Mean age was 33.01±5.14 vs. 34.57±4.52 (p = 0.01), Mean peak estradiol levels was 26645.34±8592.56 vs.7229.750±2329.20 (p &amp;lt; 0.001), mean number of oocytes were 27.55±13.46 vs. 11.63±5.77 (p &amp;lt; 0.001) for the study and control group respectivly. More patients in the control group underwent fertility preservation. Mean FSH levels and total gonadotropin dosage were higher in the control group. Major complications [3 (1.25%) in the study group vs. 1 (0.96%) in the control group] were similar between groups (p = 0.62). In the study group Two patients were diagnosed with ovarian torsion (0.83%), and one (0.41%) with early severe OHSS as a result of a positive BhCG related to an undiagnosed pregnancy prior to OPU. All three were admitted (1.25%). In the control group one patient was diagnosed with PID requiring inpatient IV antibiotic treatment (0.48%). One more patient was admitted with severe abdominal pain following OPU, for a total of 2 admissions (0.96%) (p = 1). 33 patients (13.8%) in the study group and 10 (4.8%) in the control group sought medical care after OPU, mostly due to abdominal pain, without further workup or hospitalization (p = 0.001). Limitations, reasons for caution A retrospective study with possible recall bias. Major adverse events are rare in IVF and may not be fully captured in the study population. Wider implications of the findings Based on our results, extremely high estradiol levels during ovarian hyperstimulation were not associated with thromboembolic events, higher major complication or hospitalization rates, thus may be considered safe. Nevertheless, patients may be informed of possible higher rates of discomfort, mostly abdominal pain. Larger studies are warranted to confirm our results. Trial registration number 0090-21-ASF

Is letrozole during ovarian stimulation useful in breast cancer patients undergoing fertility preservation to reduce early luteal progesterone levels following GnRH-agonist trigger?

BackgroundIn absence of contraindication, breast cancer patients of reproductive age can undergo fertility preservation with controlled ovarian stimulation for oocyte/embryo cryopreservation before the administration of potentially gonadotoxic treatments. High hormonal levels induced by ovarian stimulation might have an adverse impact on hormone-positive breast cancer. Whether letrozole supplementation during ovarian stimulation (COSTLES) reduces serum progesterone levels after GnRHa trigger remains unknown. We aimed to determine whether COSTLES might be useful for breast cancer patients undergoing fertility preservation to reduce early luteal progesterone levels following GnRH-agonist (GnRHa)trigger.MethodsAll women who underwent COS with GnRH antagonist protocol with GnRHa trigger were included. Serum progesterone level measured 12 h after GnRHa trigger was compared between patients undergoing COS with letrozole supplementation (COSTLES group) and patients undergoing COS without letrozole (Control group) for fertility preservation purposes.ResultsA total of 246 patients were included, of which 84 patients (34.1%) in the COSTLES group and 162 patients (65.6%) in the Control group. All patients in the COSTLES group were BC patients (n = 84, 100%), while the Control group included 77 BC patients (47.5%). Patients in the two groups were comparable. The mean number of oocytes recovered and vitrified at metaphase 2 stage did not significantly differ between the two groups. Serum progesterone levels on the day after GnRHa trigger were significantly lower in the COSTLES group (8.6 ± 0.7 vs. 10.5 ± 0.5 ng/mL, respectively, p < 0.03), as well as serum E2 levels (650.3 ± 57.7 vs. 2451.4.0 ± 144.0 pg/mL, respectively, p < 0.01). However, the GnRHa-induced LH surge was significantly higher in in the COSTLES group (71.9 ± 4.6 vs. 51.2 ± 2.6 UI/L, respectively, p < 0.01).ConclusionsOur results show that COSTLES for fertility preservation in breast cancer patients using GnRHa trigger reduces serum progesterone levels compared to ovarian stimulation without letrozole. These findings encourage the use of COSTLES in this context to decrease the potential deleterious effect of elevated hormonal levels on hormone-positive breast cancer.