Luteal-phase Ovarian Stimulation Research Articles

Comparison of luteal phase stimulation with follicular phase stimulation in poor ovarian response: a single-blinded randomized controlled trial

BackgroundIn the last decade, luteal-phase ovarian stimulation (LPOS) has been suggested as an alternative controlled ovarian stimulation (COS) protocol for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles mainly in women with a history of poor ovarian response (POR). The present randomized controlled trial study aimed to compare the outcomes of follicular phase ovarian stimulation (FPOS) and LPOS protocols in POR cases undergoing ICSI cycles.MethodsSeventy-eight POR patients who met the Bologna criteria and underwent an ICSI cycle were included. In this study, 39 POR cases were allocated to the FPOS group, and 39 POR cases were allocated to the LPOS group. The primary outcome was the number of metaphase II (MII) oocytes. In addition, the total number of oocytes, number of top-quality day 3 embryo, day 3 embryo development rate, chemical pregnancy and clinical pregnancy rates were defined as secondary outcomes.ResultsThe obtained results demonstrated that the number of MII oocytes significantly increased in the LPOS group compared to the FPOS group (P = 0.007). However, there was no significant difference between the two groups regarding the number of GV and MI oocytes, number of top-quality day 3 embryos and day 3 embryo development rate among both categories of patients. Also, the number of total and MII oocytes was significantly higher in the LPOS group (P = 0.016).ConclusionThese results suggest that LPOS protocol effectively increases the number of mature oocytes in women with a history of POR.Trial registrationIRCT20210405050852N1 (Registered at Iranian registry of clinical trials; available at https://en.irct.ir/trial/55402).

Ovarian follicular waves in ovulation induction in assisted reproduction techniques

Background: A greater understanding of the menstrual cycle and multiple waves of antral ovarian follicular development has challenged traditional concepts of female reproductive physiology and the foundations of assisted reproductive technologies (ART). Approximately two-thirds of women develop two follicle waves throughout an interovulatory interval, and the remainder exhibit three waves of follicle development. Major and minor waves of follicle development have been observed. Major waves are those in which a dominant follicle develops; dominant follicles either regress or ovulate. In minor waves, the physiological selection of a dominant follicle is not manifested. Knowledge of the waves of antral follicular development has led to the global adoption of novel ovarian stimulation strategies in which stimulation can be initiated at various times throughout the cycle. Random-start and luteal-phase ovarian stimulation regimens have important clinical applications in women requiring urgent oocyte or embryo cryopreservation for fertility preservation before chemotherapy.
 Objective:  To evaluate the role of multiple waves of the antral ovarian follicular in the menstrual cycle in ovulation induction in ART.
 Methods: A literature search using the keywords “multiple waves of antral ovarian follicular development,  In Vitro Fertilization, Ovarian stimulation ” was performed in the PubMed database.
 Outcome: Random start and luteal phase of ovulation induction in ART offer the same results in fertilization and pregnancy rates as conventional early follicular phase start.
 Conclusion: The primary benefits of the random-start protocol include a patient-oriented approach to care, timely and efficient treatment, and a lower dropout rate.  Women with poor ovarian reserve and those diagnosed with cancer will have a greater chance of successful assisted reproduction with the use of these strategies.

The cumulative live birth rates of 18 593 women with progestin-primed ovarian stimulation-related protocols and frozen-thawed transfer cycles.

What are the odds of achieving pregnancy when adopting progestin-primed ovarian stimulation (PPOS)-related protocols combined with repetitive frozen-thawed transfer (FET) cycles in patients with different clinical characteristics? The cumulative live birth rates (CLBRs) of women undergoing different PPOS-related protocols can be significantly and consistently enhanced within six FET cycles when the female age is <40 years (or even <45 years) and when >5 oocytes are retrieved, regardless of antral follicle count (AFC). There have been numerous studies on the live birth rate of the first FET cycle in patients with PPOS-related protocols. These studies have focused mainly on comparing pregnancy outcomes with those of other stimulation protocols. However, owing to the unique features of the PPOS-related strategy, such as its flexible timing of oocyte retrieval and repeated transfer of frozen embryos, studies using the CLBR as an overall indicator of success and investigating which types of patients would benefit from this protocol are lacking. This retrospective cohort study included 18 593 women who underwent PPOS-related protocols (dydrogesterone + hMG, medroxyprogesterone acetate + hMG, micronized progesterone + hMG treatment, and luteal-phase ovarian stimulation protocol) from 1 March 2011 to 31 September 2022 in our centre. The population was categorized by female age, number of oocytes retrieved, and AFC in the analysis of CLBR within six FET cycles. The age groups (Groups 1-5, respectively) were <30, 30-34, 35-39, 40-44, and ≥45 years. The number of oocytes retrieved was grouped as 1-5, 6-10, 11-15, 16-20, and >20. AFC was grouped as <5, 5-10, 11-15, and >15. The Kaplan-Meier analysis (optimistic method), which hypothesized that patients who did not continue treatment had the same chance of achieving a live birth as those who continued, and the competing risk method (conservative method) which hypothesized they had no chance of achieving a live birth, were applied. In further analyses, the Cox model and Fine-Gray model were adopted: the former corresponds to the optimistic scenario, and the latter corresponds to the pessimistic scenario. CLBR had a declining trend with female age over six FET cycles (Groups 1-5, respectively: optimistic: 96.9%, 96.6%, 91.4%, 67.3%, and 11.7%; conservative: 87.3%, 85.0%, 74.0%, 41.3%, and 7.5%), requiring more FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 4, and >6 cycles; conservative: 2, 2, 2, >,6 and >6 cycles). CLBR showed an increasing trend with the number of oocytes retrieved (Groups 1-5, respectively: optimistic: 93.8%, 94.3%, 95.8%, 96.0%, and 95.6%; conservative: 66.2%, 78.3%, 85.6%, 88.9%, and 91.0%). All groups needed the same number of FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 2, and 2 cycles; conservative: 2, 2, 2, 2, and 2 cycles). Furthermore, the CLBR within six FET cycles had an increasing trend with AFC number (Groups 1-4, respectively: optimistic: 89.2%, 94.8%, 95.9%, and 96.3%; conservative: 67.4%, 78.2%, 83.9%, and 88.1%), with all four groups achieving a success rate of at least 50% by the second FET cycle. The current research is limited by its retrospective design and single-centre nature, which may restrict the generalizability of our findings. This work describes two models (the Kaplan-Meier analysis and the competing risk method) to evaluate the clinical outcome of patients using PPOS-related protocols, which are especially useful for patients of advanced age or those with diminished ovarian reserve. Our findings encourage patients below 45 years old, especially younger than 40 years, and patients with lower AFCs and fewer retrieved oocytes to try this new protocol. Moreover, this study demonstrates the degree of improvement in the CLBR within six FET cycles for patients with different clinical characteristics, providing a valuable point of reference to determine whether to continue ART after a transfer failure. The study was supported by grants from the National Natural Science Foundation of China (82071603 to L.W., 82001502 to Y.L.). There are no conflicts of interest to declare. N/A.

Luteal phase stimulation in double ovarian stimulation cycles is not affected by the follicle-stimulating hormone (FSH) receptor genotype: double ovarian stimulation is beneficial independently of the genotype at position 680 of the follicle-stimulating hormone receptor.

To determine whether follicle-stimulating hormone receptor (FSHR) genotype influences the outcome of ovarian stimulation treatment in luteal phase. A total of 299 patients were included in a retrospective study between July 2017 and December 2021. These patients carried out a double stimulation protocol and the variant Asn680Ser (rs6166; c.2039A>G) of FSH receptor was genotyped either as part of the pre-treatment fertility tests or for the current study. Patients undergoing a double stimulation treatment who could not be genotyped were excluded from this analysis. The results obtained from ovarian stimulation in luteal phase were better than those obtained in conventional follicular phase. Statistically significant differences ( P  < 0.001) were found in the number of retrieved oocytes (5.47 vs. 4.18), retrieved MII (4.52 vs. 3.29) and fertilised oocytes (3.81 vs. 2.20). Furthermore, these differences remained regardless of the FSH receptor genotype for the 680 position in all groups ( P  < 0.05). In addition, stimulation in luteal phase lasts longer and requires more gonadotropins than in follicular phase. This is especially noteworthy in patients with Ser/Ser genotype, who required a slightly higher dose of gonadotropins compared to other genotypes in luteal phase, as previously observed in the follicular phase for this genotype. No significant differences in age, anti-Müllerian hormone levels, antral follicle count, BMI and type of trigger used in luteal phase were observed among groups of patients with different FSH receptor genotypes. All patients undergoing IVF seem to benefit from luteal phase ovarian stimulation, regardless of their FSHR genotype.

P-211 “Survival rates after vitrification of oocytes obtained after luteal phase vs follicular phase ovarian stimulation”

Abstract Study question Do the oocytes retrieved after luteal phase ovarian stimulation (OS) have the same survival rate as those retrieved after follicular phase (OS)? Summary answer Oocyte survival rate after vitrification is similar in oocytes retrieved in a follicular phase OS compared to those in luteal phase. What is known already Oocytes retrieved in luteal phase have recently captured scientific interest as dual stimulation is gaining popularity. Oocytes obtained in luteal phase OS added to those obtained in follicular phase shorten time to pregnancy per intention to treat in poor responders. Embryos obtained with these oocytes show similar ploidy rates, as well as clinical outcomes. Study design, size, duration We analyzed data from a randomized, non-inferiority Duo Stim Preimplantation Genetic Testing for aneuploidies (PGT-A) trial performed from 2017 to 2021 in women &amp;gt;38 years old. Only cycles with at least one oocyte retrieved in both follicular and luteal were included. We compared survival rates from oocytes obtained in after follicular phase OS (n = 154 oocytes) versus luteal phase OS (n = 201 oocytes) within the same patient. Participants/materials, setting, methods A subtotal of 38 patients were included who underwent 2, 3, or 4 OS cycles to accumulate oocytes for subsequent ICSI with PGT-A. After retrieval and decumulation, oocyte vitrification was performed with Kitazato vitrification protocol (Kitazato, Japan) and Cryotop device, same as subsequent thawing. Main results and the role of chance Mean of age in the selected patients was 39,7 years. In total, 195 cumulus-oocyte complexes were retrieved after follicular phase OS vs 245 in luteal phase. From this group of oocytes, 145/195 were mature (78.97%) vs 201/245 (82.04%), respectively. No statistically significant differences were observed in survival rate whether oocytes came from a follicular phase OS 81.16 % (125/154) versus luteal phase 87.06% (175/201) (p = 0.3312). Our results confirm that survival rate of oocyte obtained in a luteal phase OS is comparable to conventional follicular phase OS, validating oocyte accumulation strategy in a Duo Stim protocol. Limitations, reasons for caution The limited sample size was due to the nature of the randomized, controlled trial. Our results need to be replicated in larger series for validation. Wider implications of the findings Luteal phase OS oocytes showed similar survival rates after thawing than conventional OS cycles, opening a new venue for oocyte vitrification in oncological patients or poor responders accumulating oocytes. This approach might be of interest as well in patients or countries where ethical/legal limitations may limit embryo accumulation. Trial registration number not applicable

Retrospective study of influencing factors on the outcomes of luteal phase stimulation in patients with dual stimulation.

Dual/double stimulation (DS) is an ovarian stimulation strategy that has emerged in recent years; it is characterized by two rounds of ovarian stimulation and oocyte retrieval in the same menstrual cycle. DS can greatly shorten the time required to obtain valid embryos in assisted reproduction. For fertility preservation, DS can speed up oocyte storage process. However, factors influencing luteal phase ovarian stimulation (LPS) outcomes in DS have not been elucidated. A total of 156 cycles from 78 cases were studied. Patients were grouped and analyzed according to their follicular phase ovarian stimulation (FPS) types. Female ages, ovarian stimulation protocols, number of oocytes retrieved, embryo quality were recorded. Comparisons of outcomes were conducted between different groups. Our study found that LPS obtained similar outcomes to follicular phase stimulation (FPS), and that the choice of FPS protocol affected the efficiency of LPS, the antagonist protocol and progestin-primed ovarian stimulation (PPOS) protocol resulted in better embryo outcomes in LPS. In LPS of DS, sufficient stimulation duration was the guarantee of embryo quality (number of available embryos: β = 0.145, 95% CI [0.078-0.211], P = 0.000; number of high-quality embryos: β = 0.114, 95% CI [0.057-0.171], P = 0.000). This study provided ideas for the precise use of DS. We suggest to further expand the sample size of DS in the future, conduct prospective controlled studies, unify the sample size of each subgroup, include the ovarian reserve of patients in the grouping basis, and exclude the influence of male factors. We hope that this study will help further refinement of DS so as to maximize patient benefits from it. When the DS strategy is considered in the follicular phase, the antagonist protocol and PPOS protocol are more recommended for better embryo outcomes in LPS. During LPS, adequate ovarian stimulation duration is the most important guarantee for LPS efficiency.

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.

Intraovarian Injection of Recombinant Human Follicle-Stimulating Hormone for Luteal-Phase Ovarian Stimulation during Oocyte Retrieval Is Effective in Women with Impending Ovarian Failure and Diminished Ovarian Reserve

It is a challenge to obtain sufficient eggs during in vitro fertilization (IVF) in women with impending ovarian failure (IOF)/diminished ovarian reserve (DOR). Although studies have suggested that more than one wave of follicle growth exists, the efficacy of controlled ovulation stimulation (COS) in both follicular and luteal phases of the same ovarian cycle (DuoStim) is not established in women with IOF/DOR. We investigated the efficacy of DuoStim using the intraovarian injection of recombinant human follicle-stimulating hormone (rhFSH) during oocyte retrieval in women with DOR. For luteal-phase stimulation, intraovarian (Group A, N = 28) or superficial subcutaneous (Group B, N = 18) injection of 300 IU rhFSH immediately after oocyte retrieval was administered as the first dose, and intermittent superficial subcutaneous addition of gonadotropins was employed accordingly for further COS in both groups. In Group A, significantly lower Gn doses, a shorter duration of COS, a greater number of antral follicle counts, and an increased number of retrieved mature and total oocytes were noted. Compared with the clinical outcomes of luteal-phase COS, the average daily doses of rhFSH used in Group A were significantly lower. In summary, the novel approach using intraovarian rhFSH injection provides an efficient treatment regimen in women with IOF/DOR.

P–588 Follicle-stimulating hormone receptor genotype and its influence on the results of double ovarian stimulation in IVF cycles

Abstract Study question Does the follicle-stimulating hormone receptor (FSHR) genotype influence the results of the ovarian stimulation treatment in the luteal phase? Summary answer All patients undergoing in-vitro fertilization benefit from luteal phase ovarian stimulation, regardless of their follicle-stimulating hormone receptor genotype. What is known already Previous studies suggest that FSH receptor polymorphism in position 680 influences the response to ovarian stimulation in the luteal phase. It was observed that patients with SS genotype seems to require a higher dose to obtain an optimal ovarian response. Later, it was reported that, in patients with SS genotype, a better performance seems to be obtained by administering highly purified urinary FSH while, in SN patients, better results were obtained with recombinant FSH. In patients with NN genotype, no differences were found. Our aim was to test whether this concept is applicable to ovarian stimulation in the luteal phase. Study design, size, duration One hundred and thirty-four patients were included in a retrospective study between July 2017 and September 2020. In these patients, a double stimulation protocol was carried out and the FSH receptor was genotyped either as part of the pre-treatment fertility tests or for the current study. Patients with a double stimulation treatment who could not be genotyped were excluded from the analysis. Participants/materials, setting, methods To genotype the 680 position of the FSH receptor, a real-time PCR for allelic discrimination was carried out using StepOnePlus™ Real-Time PCR System (Applied Biosystems™. Ref: 4376600). Non-parametic tests were used to study the differences between the groups. They were performed with the software R Statistical Software, version 4.0.3. Main results and the role of chance The results of ovarian stimulation in the luteal phase were better compared to the conventional follicular phase. Statistically significant differences (p &amp;lt; 0.001) were found in the number of retrieved oocytes (5.06 versus 3.51), retrieved MII (4.13 versus 2.91), fertilized oocytes (3.22 versus 1.81) and blastocysts formed (1.79 versus 0.62). Furthermore, these differences remained regardless of the genotype for the 680 position of the FSH receptor in all groups (p &amp;lt; 0.05). In addition, better results were obtained in the luteal phase in patients who have been stimulated with the type of gonadotropin that already had better performance in the follicular phase for its genotype, that is, highly purified urinary FSH in SS patients and recombinant FSH in SN patients, compared to other types of gonadotropin (p &amp;lt; 0.05). We also observed that stimulation in the luteal phase lasts longer and consume more gonadotropins than in the follicular phase. This is especially notable in the case of patients with SS genotype, who required slightly higher consumption of gonadotropins compared to the other genotypes in the luteal phase, as had previously been observed in the follicular phase for this genotype. Limitations, reasons for caution The retrospective study design and the sample size could be a limitation. Furthermore, we cannot determine whether the improvement in luteal phase performance is related to differences in the physiological environment between phases of the cycle or is caused by a possible activation of the ovary from the previous stimulation. Wider implications of the findings: All patients undergoing in-vitro fertilization seems to benefit from luteal phase ovarian stimulation, regardless of their genotype for FSHR. In addition, the pharmacogenetic recommendation when choosing the type of FSH for ovarian stimulation should be the same both in the follicular phase and in the luteal phase. Trial registration number Not applicable

O-111 The DuoStim strategy shortens the time to obtain an euploid embryo in poor prognosis patients: a non-inferiority, randomized controlled trial

Abstract Study question Is there any difference in the time to obtain euploid embryos from poor prognosis patients who performed two conventional cycles versus double stimulation (DuoStim) in the same cycle? Summary answer DuoStim showed similar ovarian response and in vitro fertilization (IVF) laboratory outcomes while shortening the time to obtain an euploid embryo in poor prognosis patients. What is known already Several waves of cyclic development of antral follicles within the same menstrual cycle have been demonstrated. Likewise, it has been shown that oocytes obtained from luteal phase ovarian stimulation (OS) have similar competence than those obtained in the follicular phase OS. Often, some patients require sequential OS in order to obtain more oocytes and increase their chances to reach embryo transfer. Thus, the DuoStim strategy could be an attractive alternative to reduce the time-to-pregnancy. However, prospective data and randomized trials that validate this strategy are lacking. Study design, size, duration We conducted a prospective, randomized controlled trial at our institution from[MCM1] [JAGV2] January 2017 to December 2020. A total of 80 poor prognosis patients aged over 38 years undergoing PGT-A were enrolled in two groups: 39 patients did two OS in consecutive cycles (control) whereas 41 women underwent two OS in the same menstrual cycle (DuoStim). Participants/materials, setting, methods Poor prognosis was defined as suboptimal responders. The primary outcome was the time needed to obtain an euploid embryo. The secondary outcomes were duration of stimulation, dose of gonadotropins, oocyte maturity rate, fertilization and blastocyst formation rates. Variables were expressed as mean ± standard deviation. Statistical analyses was performed by ANOVA and Chi-square tests, as appropriate. Differences were considered significant when p-value &amp;lt; 0.05. Main results and the role of chance The patients’ baseline characteristics were similar between groups. We did not find any difference in the mean days of stimulation between the control and the DuoStim group (21.3 ± 1.6 vs. 23 ± 1.4, p = 0.105), nor in the amount of gonadotropin required (4005 ± 450 vs. 4245 ± 430, p = 0.43), number of MII oocyte (8.7 ± 1.8 vs. 6.8 ± 1.7, p = 0.159), blastocyst rate (51.4% vs. 34.8%, p = 0.113) and the number of euploid embryos (0.8 ± 0.4 vs. 0.6 ± 0.4, p = 0.45). However, there was a significant difference in the average number of days until reaching an euploid blastocyst, favoring the DuoStim group (44.1 ± 2 vs. 23.3 ± 2.8, p &amp;lt; 0.001). Comparing the follicular versus the luteal phase within the DuoStim group, the only difference detected concerns to the mean days of stimulation (10.3 ± 0.8 vs. 12.7 ± 0.9, p &amp;lt; 0.001). We also observed a trend towards a higher fertilization (38.1% vs. 61.8%, p = 0.02) and blastulation rate (23% vs. 53%, p = 0.03) in the luteal phase of the DuoStim cycle. Limitations, reasons for caution The major limitation is related to the limited sample size, as it limits our power analysis (70%). On the other hand, it is one of the first randomized prospective pilot trial that compared the efficiency of performing two consecutive ovarian stimulation in different menstrual cycles with the DuoStim strategy. Wider implications of the findings This study clearly showed that the DuoStim protocol is not inferior to the conventional stimulation in terms of ovarian response and laboratory outcomes. Moreover, the DuoStim reduces the time to obtain an euploid embryo in poor prognosis patients, which is of great clinical utility. Trial registration number NCT03291821

P-643 Pre-selected for an award: Is Euploid blastocyst number higher in luteal versus follicular phase? A case-control study of IVF outcomes of follicular versus luteal phase ovarian stimulation

Abstract Study question Is there a difference between IVF outcomes in patients undergoing follicular versus luteal phase ovarian stimulation in different menstrual cycles? Summary answer Number of euploid blastocyst were higher in luteal phase ovarian stimulation IVF cycles. All other outcomes were similar between follicular and luteal phase IVF cycles. What is known already It has been published that human beings can have two or three follicular recruitment waves as observed in animals studies a long time ago. From these findings, several recent studies showed that two egg retrievals at the same menstrual cycle, named as Duo Stim, optimize time and IVF outcomes in women with low ovarian reserve due to more eggs retrieved in a shorter period with consequently higher probability of having good embryos to transfer. However, there is no knowledge about diferences concerning IVF outcomes between folicular and luteal ovarian stimulation, performed at the same women in different menstrual cycles. Study design, size, duration Retrospective, case-control study in a single IVF center. One-hundred-two patients who had two IVF treatments – the first cycle initiating ovarian stimulation at follicular phase (FPS) and the second cycle initiating after a spontaneous ovulation at luteal phase (LPS) – in different menstrual cycles (until 6 months apart) between 2014 and 2020, were included. Statistical analysis was performed with Mann-Whitney test and was considered significant when p ≤ 0.05. Data is represented as mean±SD. Participants/materials, setting, methods Patients underwent two IVF treatments in different menstrual cycles; the FPS IVF treatment was initiating at D2/D3 of menstrual cycle and the LPS treatment started three or four days after spontaneous ovulation, if at least 4 antral follicles were detected. Both IVF treatments were performed with and antagonist protocol and freeze all strategy. The majority of patients presents low ovarian reserve/Ovarian age as primary infertility factor (84.3%). Main results and the role of chance Patient’s mean age was 39.30±3.15 years, BMI (22.66±3.16) and AMH levels (0.85±0.85 ng/mL). Comparison of hormonal levels at the beginning of ovarian stimulation showed differences for FPS vs LPS, as expected: E2 (39.69±31,10 pg/mL vs 177.33±214.26 pg/mL, p &amp;lt; 0.0001) and P4 (0.76±2.47ng/mL vs 3,00±5.00 ng/mL,p &amp;lt; 0.0001). However, E2 and P4 at the day of oocyte maturation trigger were not different between FPS and LPS (1355.24±895.73 pg/mL vs 1133.14±973.01 ng/mL,p = 0.0883 and 1.12±1.49 ng/mL vs 2.94±6.51,p = 0.0972 respectively). There was no difference for total dose of gonadotrofins (FPS 2786.43±1102.39.01UI vs LPS 2824.12±1188.87UI, p = 0,8578), FSH (FPS 9.50±4.98 vs LPS 11.90±12.99, p = 0.7502) and AFC (FPS 7.13±4.25 vs LPS 6.42±4.65,p = 0,0944). From 102 patients that started ovarian stimulation, 78 had 1 or more oocyte collect in FPS group and 75 in LPS group: OPU (FPS 4.78±4.93 vs LPS 4.65±5.54,p = 0.7889), number of MII (FPS 3.21±3.52 vs LPS 3.40±4.53,p = 0.7889). From those, 52 patients performed ICSI in both cycles; fertilization rate 64.9%±28.6% for FPS vs 62.1%±32.4% for LPS,p = 0.7899) and blastocyst formation 2.15±2.15 for FPS vs 2.54±2.35,p = 0.3496). Data from 25 patients who had embryo biopsy for PGT-A showed similar number of blastocyst biopsed (2.12±1.72 FPS vs 2.48±1.71 LPS,p = 0.3101) and a statistically significant difference regarding number of euploid blastocyst (0,20±0,41 FPS vs 0,96±0,93 LPS,p = 0,0008). Limitations, reasons for caution This is a retrospective study in a limited number of patients. Therefore, it is not possible to make a definitive conclusion that LPS proportionate higher number of euploid than FPS. More studies are necessary to investigate not only IVF outcomes but also the impact on pregnancy rates. Wider implications of the findings In our study, LPS protocol after spontaneous ovulation, presents similar IVF outcomes compared to routinely FPS protocol. Intriguingly, the number of euploid blastocyst was significant higher in LPS, which may be further investigated. In this way, LPS is another option of IVF treatment, and may optimize time and treatment results. Trial registration number Not Applicable

P–643 Is Euploid blastocyst number higher in luteal versus follicular phase? A case-control study of IVF outcomes of follicular versus luteal phase ovarian stimulation

Abstract Study question Is there a difference between IVF outcomes in patients undergoing follicular versus luteal phase ovarian stimulation in different menstrual cycles? Summary answer Number of euploid blastocyst were higher in luteal phase ovarian stimulation IVF cycles. All other outcomes were similar between follicular and luteal phase IVF cycles. What is known already It has been published that human beings can have two or three follicular recruitment waves as observed in animals studies a long time ago. From these findings, several recent studies showed that two egg retrievals at the same menstrual cycle, named as Duo Stim, optimize time and IVF outcomes in women with low ovarian reserve due to more eggs retrieved in a shorter period with consequently higher probability of having good embryos to transfer. However, there is no knowledge about diferences concerning IVF outcomes between folicular and luteal ovarian stimulation, performed at the same women in different menstrual cycles. Study design, size, duration Retrospective, case-control study in a single IVF center. One-hundred-two patients who had two IVF treatments – the first cycle initiating ovarian stimulation at follicular phase (FPS) and the second cycle initiating after a spontaneous ovulation at luteal phase (LPS) – in different menstrual cycles (until 6 months apart) between 2014 and 2020, were included. Statistical analysis was performed with Mann-Whitney test and was considered significant when p ≤ 0.05. Data is represented as mean±SD. Participants/materials, setting, methods Patients underwent two IVF treatments in different menstrual cycles; the FPS IVF treatment was initiating at D2/D3 of menstrual cycle and the LPS treatment started three or four days after spontaneous ovulation, if at least 4 antral follicles were detected. Both IVF treatments were performed with and antagonist protocol and freeze all strategy. The majority of patients presents low ovarian reserve/Ovarian age as primary infertility factor (84.3%). Main results and the role of chance Patient’s mean age was 39.30±3.15 years, BMI (22.66±3.16) and AMH levels (0.85±0.85 ng/mL). Comparison of hormonal levels at the beginning of ovarian stimulation showed differences for FPS vs LPS, as expected: E2 (39.69±31,10 pg/mL vs 177.33±214.26 pg/mL,p&amp;lt; 0.0001) and P4 (0.76±2.47ng/mL vs 3,00±5.00 ng/mL,p&amp;lt; 0.0001). However, E2 and P4 at the day of oocyte maturation trigger were not different between FPS and LPS (1355.24±895.73 pg/mL vs 1133.14±973.01 ng/mL,p=0.0883 and 1.12±1.49 ng/mL vs 2.94±6.51,p=0.0972 respectively). There was no difference for total dose of gonadotrofins (FPS 2786.43±1102.39.01UI vs LPS 2824.12±1188.87UI, p = 0,8578), FSH (FPS 9.50±4.98 vs LPS 11.90±12.99,p=0.7502) and AFC (FPS 7.13±4.25 vs LPS 6.42±4.65,p=0,0944). From 102 patients that started ovarian stimulation, 78 had 1 or more oocyte collect in FPS group and 75 in LPS group: OPU (FPS 4.78±4.93 vs LPS 4.65±5.54,p=0.7889), number of MII (FPS 3.21±3.52 vs LPS 3.40±4.53,p=0.7889). From those, 52 patients performed ICSI in both cycles; fertilization rate 64.9%±28.6% for FPS vs 62.1%±32.4% for LPS,p=0.7899) and blastocyst formation 2.15±2.15 for FPS vs 2.54±2.35,p=0.3496). Data from 25 patients who had embryo biopsy for PGT-A showed similar number of blastocyst biopsed (2.12±1.72 FPS vs 2.48±1.71 LPS,p=0.3101) and a statistically significant difference regarding number of euploid blastocyst (0,20±0,41 FPS vs 0,96±0,93 LPS,p=0,0008). Limitations, reasons for caution This is a retrospective study in a limited number of patients. Therefore, it is not possible to make a definitive conclusion that LPS proportionate higher number of euploid than FPS. More studies are necessary to investigate not only IVF outcomes but also the impact on pregnancy rates. Wider implications of the findings: In our study, LPS protocol after spontaneous ovulation, presents similar IVF outcomes compared to routinely FPS protocol. Intriguingly, the number of euploid blastocyst was significant higher in LPS, which may be further investigated. In this way, LPS is another option of IVF treatment, and may optimize time and treatment results. Trial registration number Not applicable

ART outcomes following ovarian stimulation in the luteal phase:a systematic review and meta-analysis.

This study aimed to evaluate the impact of luteal phase ovarian stimulation (LPS) on the outcomes of assisted reproductive technology (ART) for infertile couples and patients desiring non-urgent egg cryopreservation. We included all studies reported patients who received LPS and that used follicular phase ovarian stimulation (FPS) as a comparison group until January 2021. Prior meta-analysis regarding the outcomes of LPS in double stimulation and fertility preservation have already been published, so these studies were excluded. Risk of Bias in Non-randomized Studies of Interventions was used to assess the study quality. The study was registered in the International Prospective Register of Systematic Reviews database (CRD42020183946). Twelve studies with a total of 4433 patients were included. The regimen employed can be categorized into two groups, but there is currently no evidence to support one over the other. After we excluded the largest study, the clinical pregnancy rate and live birth rate were similar after FPS and LPS. There were significantly more stimulation days and total gonadotropins used in the LPS group. After subgroup analysis, we found that poor responders received significantly more cumulus oocyte complexes (+0.64) in the LPS group. Current evidence indicates that patients in the LPS group could achieve pregnancy outcomes non-inferior to those in the FPS group. Because of current debate over freeze-all policy and the limited data about live birth rate, the universal use of LPS is considered controversial. In the future, more well-designed studies are necessary to investigate the indications for LPS and its cost-effectiveness.

Dual stimulation in unexpected poor responder POSEIDON classification group 1, sub-group 2a: A cross-sectional study.

BackgroundPoor ovarian response management is a complex and controversial issue in the field of reproductive medicine.Objective The aim of this study was to apply double stimulation in the same cycle in unexpected poor responders in POSEIDON classification group 1, sub group 2a and compare assisted reproductive technology outcomes between luteal phase and follicular phase ovarian stimulation.Materials and MethodsIn this cross-sectional study, 10 women with age 35 yr, antral follicle count 5, and anti-müllerian hormone 1.2 ng/mL were enrolled. All participants received conventional antagonist protocol in the follicular phase and only the cycles with retrieved oocytes 4 in this phase included. The luteal phase ovarian stimulation was initiated from the day of first oocytes retrieval by 300 IU of human menopausal gonadotropin / day. When dominant follicles amounted to 14 mm in mean diameter, 0.25 mg/day of gonadotropin-releasing hormone antagonist was initiated and 10,000 IU human chorionic gonadotropin was injected when at least two follicles with a mean diameter of 17 mm were observed. Oocyte retrieval was carried out 34-36 hr following human chorionic gonadotropin injection. Finally, a comparison was made between the two phase in terms of the number of retrieved oocytes as well as the number of obtained embryos and fertilization rates.Results Numbers of retrieved oocytes (p = 0.004), mature oocytes (p = 0.016), and embryos (p = 0.013) was significantly higher in luteal phase in compared with follicular phase. Quality of embryos was similar in two phases.ConclusionDouble stimulation protocol can increase number of retrieved oocytes in unexpected PORs

Luteal phase stimulation versus follicular phase stimulation in poor ovarian responders: results of a randomized controlled trial

BackgroundIn young women with poor ovarian response, luteal-phase ovarian stimulation (LPOS) is a potential method for collecting competent oocytes. The aim of this study was to assess the efficacy of LPOS compared with follicular phase ovarian stimulation (FPOS) in young women with poor ovarian response (POR).MethodsThis single-center, prospective, randomized pilot study compared LPOS and FPOS in women with POR fulfilling Bologna criteria who underwent in vitro fertilization at the Instituto Bernabeu. The primary outcome was the number of metaphase II (MII) oocytes obtained by follicular puncture.ResultsSixty women were included in the study, with 27 women completing LPOS and 30 undergoing FPOS. There was no statistically significant difference in the number of MII oocytes obtained between the LPOS group and the FPOS group (2.1 ± 2.0 vs. 2.6 ± 2.2, p = 0.31). Length of stimulation was also similar in both groups (8.35 ± 2.8 vs. 8.15 ± 4.1 days, p = 0.69). Similarly, there was no significant difference in the follicle-stimulating hormone total dose, number of cumulus-oocyte complexes, survival rate, fertilization rate, or cancellation rate between groups. A significantly higher Ovarian Sensitivity Index was observed in the LPOS group versus the FPOS group (0.96 vs. 0.57, p = 0.037).ConclusionLPOS was comparable with FPOS in terms of efficacy and may improve ovarian responsiveness in young women with POR.Trial registrationClinicalTrials.gov identifier: NCT02625532; EudraCT identifier: 2015–003856-31.

The Ovarian Response After Follicular Versus Luteal Phase Stimulation with a Double Stimulation Strategy

The double-ovarian stimulation strategy has been proposed to optimize the number of oocytes retrieved within the shortest possible timeframe. The objective of this study is to explore the effectiveness of luteal phase (LP) ovarian stimulation as compared to the previous follicular phase (FP) stimulation in a double stimulation strategy. We conducted an observational cohort study of women scheduled for a double stimulation protocol between March 2014 and June 2017, who had completed the FP controlled ovarian stimulation (COS 1) and started the LP stimulation (COS 2) in the same cycle. Women received equivalent daily doses of gonadotropins in combination with GnRH-antagonist protocol for both the COS 1 and the COS 2 performed during the same cycle. Ovulation was triggered using GnRH-agonist in the two stimulations. The primary outcome was the number of oocytes retrieved. A total of 77 patients were included in the analysis. The number of oocytes retrieved after COS 1 was significantly higher than after the COS 2 (5.25 ± 3.38 for COS 1 versus 3.83 ± 3.14 for COS 2; p = 0.001). The duration of the stimulation was significantly shorter, the total dose of injected gonadotropins was significantly lower, and the estradiol level on the trigger day was significantly higher with COS 1 as compared to COS 2. Stimulation during the LP in a double-successive stimulation strategy results in a lower ovarian response as compared to the FP equivalent daily dose stimulation.

Analysis of embryo quality with luteal phase ovarian stimulation after failed in vitro fertilization-embryo transfer with long or ultra-long protocol

ObjectiveTo investigate the effect of luteal phase ovarian stimulation on embryo quality after failed in vitro fertilization-embryo transfer with long or ultra-long protocol. MethodsIn patients who underwent luteal phase ovarian stimulation after failed in vitro fertilization-embryo transfer with long or ultra-long protocol in the reproductive center between January 2015 and October 2017, self-control observations and statistical analyses were carried out for the number of oocytes retrieved, the rate of fertilization, the rate of D3 high-quality embryos, the rate of transplantable blastocyst formation, and the pregnancy rate of transfer cycle between long or ultra-long protocol and luteal phase ovarian stimulation. ResultsThe rate of fertilization and blastocyst were significantly increased after luteal phase ovarian stimulation (P < 0.05). However, the difference of the number of oocytes retrieved and the rate of D3 high-quality embryos was not statistically significant (p > 0.05). ConclusionsThe patients who failed with long protocol or ultra-long protocol due to low quality embryos, the protocol changed over to luteal phase ovarian stimulation. Can significantly improve the rate of fertilization oocytes and the transplantable blastocyst, and improve the outcome of clinical pregnancy. It provides an alternative ovarian stimulation protocol in patients with IVF-ET failure.

Random-start ovarian stimulation with aromatase inhibitor for fertility preservation in women with Japanese breast cancer.

PurposeFertility preservation is an important issue for young cancer patients. Random‐start controlled ovarian stimulation and double ovarian stimulation have been proposed for efficient oocyte retrieval within the limited time before cancer therapy. We aimed to clarify the efficacy of these new protocols within the Japanese population.MethodsWe performed a retrospective observational study at a multicenter from February 2012 to August 2017. The study entailed 50 cycles with 34 patients who underwent fertility preservation due to breast cancer. Follicular phase or luteal phase ovarian stimulation with aromatase inhibitor was performed. A second ovarian stimulation was started with or without waiting until the next menstruation. We measured the number of retrieved oocytes and cryopreserved oocytes/embryos, the ratio of mature oocytes, and the fertilization rate.ResultsThe numbers of retrieved oocytes and frozen oocytes/embryos were not significantly different between follicular phase and luteal phase ovarian stimulation. The number of retrieved oocytes was not reduced at the second ovum pick up compared to the first ovum pick up in the double ovarian stimulation.ConclusionsRandom‐start controlled ovarian stimulation and double ovarian stimulation with aromatase inhibitor for breast cancer patients were effective protocols for retrieving a greater number of oocytes within the limited time.

Can we perform flexible antagonist protocol for luteal phase ovarian stimulation for breast cancer patients seeking fertility preservation?

Can we perform flexible antagonist protocol for luteal phase ovarian stimulation for breast cancer patients seeking fertility preservation?

Luteal phase ovarian stimulation for poor ovarian responders.

ObjectiveTo compare the clinical outcomes of follicular versus luteal phase ovarian stimulation in women with poor ovarian response (Bologna criteria) undergoing IVF.MethodsThis retrospective study investigated 446 patients submitted to 507 cycles in three groups. First, the two larger cohorts were examined: 154 patients treated with luteal phase ovarian stimulation (Group Lu); and 231 patients administered follicular phase ovarian stimulation (Group Fo). Then the clinical outcomes of 61 patients submitted to double ovarian stimulation were analyzed. Clinical outcomes included number of retrieved oocytes, fertilization rate, cleavage rate, top-quality embryo rate, clinical pregnancy rate (CPR), and live birth rate (LBR).ResultsLonger stimulation, higher dosages of HMG, and higher MII oocyte rates were achieved in Group Lu (p<0.001). There were no significant differences in CPR and LBR between the two groups offered frozen-thawed embryo transfer (28.4% vs. 33.0%, p=0.484; 22.9% vs. 25.5%, p=0.666). In the double ovarian stimulation group, the number of oocytes retrieved in the luteal phase stimulation protocol was higher (p=0.035), although luteal phase stimulation yielded a lower rate of MII oocytes (p=0.031). CPR and LBR were not statistically different (13.8% vs. 21.4%, p=0.525; 10.3% vs. 14.3%, p=0.706).ConclusionLuteal phase ovarian stimulation may be a promising protocol to treat women with POR, particularly for patients unable to yield enough viable embryos through follicular phase ovarian stimulation or other protocols.