Progestin-primed Ovarian Stimulation Research Articles

The value of LH maximum level in predicting optimal oocyte yield following GnRH agonist trigger.

Risk factors associated with a suboptimal response to Gonadotropin-releasing hormone (GnRH) agonists include a high or low body mass index (BMI), prolonged use of oral contraceptive pills, and low luteinizing hormone (LH) levels on either the start or trigger days of controlled ovarian stimulation (COS). However, this approach may increase the need for a dual trigger and may also result in a higher incidence of ovarian hyperstimulation syndrome (OHSS) in hyper-responders. We aimed to investigate whether the maximum LH level during stimulation can serve as a predictive factor for achieving an optimal oocyte yield using the GnRH agonist trigger alone. We retrospectively reviewed all antagonist protocols or progestin-primed ovarian stimulation (PPOS) protocols triggered with GnRH agonist only between May 2012 and December 2022. Subjects were divided into three groups, depending on basal LH level and LH maximum level. The freeze-all strategy was implemented in all cycles: Group 1, consistently low LH levels throughout COS; Group 2, low basal LH level with high LH max level during COS; Group 3, consistently high LH levels throughout COS. The primary outcome was the oocyte yield rate. The secondary outcome includes the number of collected oocytes, suboptimal response to GnRH agonist trigger, oocyte maturity rate, fertilized rate, clinical pregnancy rate, ongoing pregnancy rate, and live birth rate. The pregnancy outcomes were calculated for the first FET cycle. Following confounder adjustment, multivariable regression analysis showed that Group 1 (cycles with consistently low LH levels throughout COS) remains an independent predictor of suboptimal response (OR: 6.99; 95% CI 1.035-47.274). Group 1 (b = -12.72; 95% CI -20.9 to -4.55) and BMI (b = -0.25; 95% CI -0.5 to -0.004) were negatively associated with oocyte yield rate. Patients with low basal LH but high LH max levels had similar clinical outcomes compared to those with high LH max levels through COS. The maximum LH level during COS may serve as an indicator of LH reserve and could be a more reliable predictor of achieving an optimal oocyte yield when compared to relying solely on the basal LH level. In the case of hyper-responders where trigger agents (agonist-only or dual trigger) are being considered, we propose a novel strategy that incorporates the maximum LH level, rather than just the basal or trigger-day LH level, as a reference for assessing LH reserve. This approach aims to minimize the risk of obtaining suboptimal oocyte yield and improve overall treatment outcomes.

A delayed ovulation of progestin-primed ovarian stimulation (PPOS) by downregulating the LHCGR/PGR pathway

Progestin-primed ovarian stimulation (PPOS) is a new ovulation stimulation protocol, and its role in ovulation and regulatory mechanism is unclear. The clinical PPOS protocol was simulated in mice. The ovulated oocytes, estradiol, progesterone, and luteinizing hormone (LH) levels were analyzed at different hours after trigger. mRNA extraction and real-time PCR, hematoxylin and eosin staining, and immunofluorescence of ovaries were used to explore the involved signaling pathways. The PPOS group had a delayed ovulation at 12.5h after trigger. Its suppressed LH level reduced the expression of luteinizing hormone/choriogonadotropin receptor (LHCGR) on the preovulatory follicles before trigger and significantly decreased the following progesterone synthesis, blood progesterone level, and progesterone receptor (PGR) expression within 4-6h after trigger. Furthermore, the important ovulatory genes regulated by PGR including ADAMTS-1, VEGF-A, and EDN2 were downregulated, ultimately delaying the ovulation. PPOS suppresses the LH level before trigger and decreases the synthesis of progesterone after trigger, thus delaying the ovulation by downregulating the LHCGR-PGR pathway.

P-640 No impact of Progestin Primed Ovarian Stimulation (PPOS) on euploid blastocyst rate per cohort of metaphase-II oocytes during PGT-A cycles: a case-control study

Abstract Study question Can progestins be used to prevent spontaneous LH surge during ovarian stimulation (OS) without affecting the euploid blastocyst rate (EBR) per metaphase-II (MII) oocytes? Summary answer Progestin Primed Ovarian Stimulation (PPOS) (conducted with norethisterone acetate) and conventional-OS with GnRH-antagonist show similar EBR per MII-oocytes What is known already PPOS is a novel OS protocol based exogenous progesterone to inhibit LH surge and spontaneous ovulation as an alternative to GnRH analogues. The rationale of its use is that multiple follicular waves arise during the ovarian cycle and no spontaneous ovulation occurs during the luteal phase. PPOS effectiveness and safety have been supported lately in the literature. A recent study reported similar number of euploid blastocysts after PPOS (conducted with medroxyprogesterone acetate) versus conventional-OS with GnRH-antagonist. Study design, size, duration Case-control study involving advanced-maternal-age women undergoing ICSI with PGT-A at two private IVF centers (May-2017 to February-2020). 80 PPOS women were matched with 160 control based on maternal-age and ovarian reserve markers. Patients with poor-ovarian-reserve (AFC<3), premature-ovarian-failure, III-IV stage endometriosis, ovarian cyst, severe-male-factor, PGT-SR or PGT-M were excluded. EBR per MII-oocytes was the primary outcome. All other embryological and clinical outcomes were reported. Participants/materials, setting, methods Both groups underwent recombinant-FSH OS with GnRH-agonist ovulation trigger; the only difference was that norethisterone acetate 10mg/day was administered orally to PPOS patients starting from the second day of the menstrual cycle until trigger. The control group, instead, underwent conventional antagonist protocol. The laboratory procedures were similar in both groups: ICSI, blastocyst culture, trophectoderm biopsy, comprehensive-chromosome-testing to report non-mosaic aneuploidies and vitrified-warmed euploid single-embryo-transfers (SETs). Main results and the role of chance The mean fertilization rate per MII-oocytes and blastulation rate per 2PN-zygotes were similar among PPOS and control (75.5%±21.8% versus 71.7±20.7%, p = 0.1; and 56.5%±27.7% versus 53.2%±27.5%, p = 0.4, respectively). No difference was reported for the EBR per MII-oocytes among PPOS and control (15.4%±19.8% versus 14.8%±18.2%, p = 0.9). No difference was reported among the biopsied blastocysts in terms of morphological quality and day of development. A total of 47 and 86 SETs were conducted in the two groups. There was no difference in the live-birth-rates (LBR) per SET in the two groups (N = 19/47, 40.4%, 95%CI 26.7-55.7 versus N = 35/86, 40.7%, 95%CI 30.4-51.8, p = 0.9), nor in the miscarriage rate per clinical pregnancy (N = 1/20, 5%, 95%CI 0.3-26.9 versus N = 3/36, 8.3%, 95%CI 2.2-25.6, p = 0.9). At last, the cumulative-LBR among concluded cycles (i.e., LB achieved or no transferable/all transferred euploid blastocysts) was also similar (N = 19/68, 27.9%, 95%CI 18.1-40.3 versus N = 31/132, 22.0%, 95%CI 15.4-30.2, p = 0.4). Limitations, reasons for caution The main limitation is the retrospective and non-randomized design. More data are required, especially for follicle recruitment, oocyte yield, gestational and perinatal outcomes. Wider implications of the findings Norethisterone acetate-based PPOS protocol has no impact on oocyte competence when compared to conventional GnRH-antagonist OS. These promising data support further investigation on PPOS, especially in view of its reduced cost, and putative increase in patient compliance and decrease in discomfort. Trial registration number none

P-611 Progestin-Primed Ovarian Stimulation is a non-inferior alternative to the GnRH Antagonist Protocol in patients undergoing ovarian stimulation: a propensity score weighting analysis

Abstract Study question To evaluate the effectiveness of the progestin-primed ovarian stimulation (PPOS) protocol versus the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol in ovarian stimulation. Summary answer The PPOS protocol with dydrogesterone provided similar embryo outcomes to the GnRH-ant protocol. The serum LH concentration during ovarian stimulation using PPOS was well-controlled. What is known already Since Yanping Kuang's proposal PPOS in 2015, several studies on the effectiveness of this treatment regimen have been published. Although it has been suggested that outcomes of the PPOS regimen were comparable to those of GnRH-ant regimen, the findings were limited due to differences in study design, patient characteristics, dosage and type of progestins. While medroxyprogesterone acetate is often used in PPOS studies, dydrogesterone has seen far less popularity. Additionally, dydrogesterone is a relatively weak LH inhibitor compared to MPA, leading to concern about the increased incidence of unexpected LH surge Study design, size, duration We conducted a retrospective study among women who underwent In Vitro Fertilization at the Assisted Reproduction Center, Tam Anh General Hospital, Vietnam from January 1st, 2022 to October 10th, 2022. Participants/materials, setting, methods We included 804 patients who underwent ovarian stimulation, among which 208 used the PPOS protocol with dydrogesterone (30 mg dydrogesteron per day from the beginning of stimulation until the trigger-day) and 598 women used the GnRH-ant protocol (cetrorelix 0.25 daily, from day 6 of ovarian stimulation until the trigger-day). In addition to unadjusted analysis, we used propensity score weighting to account for confounding that might possibly remain. Main results and the role of chance Baseline characteristics were comparable in both groups. In both unadjusted and adjusted analysis, the mean number of good cleavage embryos in PPOS (6.33) was non-inferior to GnRH-ant (6.44; unadjusted ratio of two means 1.02, 95%CI 0.92, 1.13). The trigger-day estradiol level in patients with PPOS was higher (4,420 vs 3,830 pmol/L in GnRH-ant) despite similar total follicle stimulating hormone dose and fewer days of ovarian stimulation. The overall number of oocytes retrieved, the number of MII oocytes, the number of cleavage embryos, the number of blastocysts, and the number of good blastocysts were comparable between the two protocols. None of the PPOS patients had an unexpected LH surge, and serum LH levels decreased slightly during ovarian stimulation. Limitations, reasons for caution Due to the nature of the retrospective study design, we did not record the progesterone level on the trigger-day in the PPOS regimen; therefore, identifying LH surge based on LH and progesterone levels is not feasible. Furthermore, we did not study the outcomes of embryo transfer. Wider implications of the findings These results supported the use of PPOS with dydrogesterone as a cheap and effective alternative for clinicians in clinical practice. In patients with an indication for freeze-all embryo, the PPOS protocol could be recommended. Trial registration number Not Applicable

P-205 comparison of GnRH antagonist protocol versus progestin-primed protocol in high ovarian responders: a propensity score-matched study

Abstract Study question To compare the clinical outcomes and cost-efficiency between gonadotropin-releasing hormone (GnRH) antagonist and progestin-primed ovarian stimulation (PPOS) protocol in high ovarian responders. Summary answer Comparing with PPOS protocol, GnRH antagonist protocol was associated with shorter time to live birth, higher OHSS rate and less cost in high responders. What is known already For high ovarian responders prone to develop ovarian hyperstimulation syndrome (OHSS), the best option should be the GnRH antagonist, as it has been shown to significantly reduce the incidence of OHSS. By applying ovarian stimulation using the combination of antagonist with agonist trigger and embryos freezing, OHSS can be erased. PPOS protocol in combination with a freeze-all strategy has proved to be a valid alternative to the conventional stimulation protocols. Recent studies showed that comparing with antagonist protocol, a lower cumulative live birth rate (CLBR) was associated with PPOS in general population, with no data available in high responders. Study design, size, duration This was a propensity score-matched retrospective cohort study. From Jan. 2016 to Jan. 2023, 5810 patients with AMH > 3.67ng/ml undergoing IVF treatment with antagonist or PPOS protocol at the Sixth Affiliated Hospital of Sun Yat-sen University were screened. Participants/materials, setting, methods Two-to-one propensity score matching was performed with a caliper of 0.2. After matching, 540 patients in GnRH antagonist group and 270 patients in PPOS group were included. Generalized estimated equation regression was applied to evaluate the impact of independent variables on the CLBR. Main results and the role of chance No significant difference in baseline characteristics was found in two groups. The OHSS (moderate to severe) rate was significantly higher in the GnRH antagonist group than in the PPOS group (7% vs. 3%). The clinical pregnancy rate and live birth rate per transfer were comparable between the two groups. After excluding patients who didn't achieve live birth but had surplus embryos, the CLBR was comparable between the antagonist and PPOS group (67.4% vs. 61.0%; Risk ratio = 1.106; 95% confidence interval [CI], 0.973-1.256, P = 0.109), and the generalized estimated equation regression analysis also showed that protocol selection had no significant impact on CLBR. The average time to live birth (TTLB) in the antagonist group was significantly shorter than the PPOS group (11.45 months vs. 12.13 months, P < 0.05). Besides, the average cost in the antagonist group was about $4933, while it was about $5465 in the PPOS group. Limitations, reasons for caution Although we recruited a large sample size and the sophisticate statistical analysis method, this was a retrospective study with an intrinsic limitation, besides more patients in the PPOS group had surplus embryos than in the antagonist group (24.1% vs. 19.8%). Further prospective RCTs are required to confirm our findings. Wider implications of the findings For infertile patients with high ovarian reserve, the clinical outcomes were comparable between GnRH antagonist and PPOS group. The antagonist group was associated with a shorter TTLB and more cost-effective, while the PPOS was associated with a lower OHSS rate. Trial registration number Not Applicable

P-281 Single-cell RNA sequencing analysis of granulosa cells in preovulatory follicles in normal ovarian reserve patients undergoing progestin-primed ovarian stimulation and GnRH-antagonist

Abstract Study question Could the difference in controlled ovarian stimulation protocol between progestin-primed ovarian stimulation and GnRH-antagonist induce change in the expression genes of human granulosa cells? Summary answer The mitochondrial DNA (mtDNA) gene expression of granulosa cells in patients who underwent progestin-primed ovarian stimulation was significantly higher than the GnRH-antagonist. What is known already The progestin-primed ovarian stimulation (PPOS) protocol has attracted attention and many studies have reported similar pregnancy outcomes for both PPOS and the GnRH-antagonist (GnRH-ant). However, our previous study demonstrated that pregnancy rate was significantly lower in PPOS compared to GnRH-ant (38th Hybrid Annual Meeting of the ESHRE, O-130). In this study, we evaluated the gene expression of granulosa cells (GCs) which affects reproductive outcome. Many studies have shown a close association between the mitochondrial status of GCs and embryo’s quality. To date, the change in gene expression of GCs with different controlled ovarian stimulation protocols have not been investigated. Study design, size, duration From November 2021 to January 2022, all samples were obtained from the patients who provided written informed consent before the inclusion and underwent controlled ovarian stimulation cycles at a single-institution. Single cell RNA-seq (scRNA-seq) was performed on 2,224 cells corresponding to GCs of the MII-oocyte follicles from a total of 16 patients with normal ovarian reserve (aged < 40 years, AMH ≧1.1 ng/mL) undergoing PPOS with chlormadinone acetate (n = 8), or GnRH-ant with cetrorelix (n = 8). Participants/materials, setting, methods The GCs were obtained by follicular aspiration from 16 patients undergoing oocyte retrieval. The follicular fluid (FF) from each follicle was collected and all FF were mixed together in MII-oocyte for sequencing. The GCs were isolated from the blood cells and cellular debris using Percoll gradient centrifugation. Samples for sequencing were prepared using Chromium Next GEM Single Cell V(D)J Reagent Kits. Libraries were sequenced in DNBSEQ-G400, and reads processed with CellRanger and visualized with CellxGene. Main results and the role of chance Two population of GCs were used in this investigation: PPOS and GnRH-ant of MII-oocyte. After the quality control, 1,197 cells for PPOS and 1,027 cells for GnRH-ant, respectively, were analyzed. The GCs of MII-oocyte were clustered into 6 groups based on Leiden algorithm and visualized by UMAP analysis. There was no significant difference in the gene expression and cell distribution in each cluster. In the two population of GCs, we identified 12 differentially expressed genes (DEGs). Interestingly, we observed significant increase in expression of mtDNA genes in PPOS of MII-oocyte as compared to GnRH-ant of MII-oocyte. The data were confirmed by qRT-PCR analysis. Limitations, reasons for caution Our conclusions are limited due to the inclusion of Asian patients at a single-institution. The results need to be validated across different centers and other ethnicities. Due to the small sample size, these results should prompt further study to confirm our findings. Wider implications of the findings These findings describe, for the first time, the DEGs of GCs investigated in different COS protocols at single-cell level. This study suggests that progestin for PPOS induce elevation of the mt DNA gene expression of GCs which may be associated with reproductive outcomes. Trial registration number Not applicable

P-617 Combined oral contraceptive pill (COCP) pre-treatment and progestin-primed ovarian stimulation (PPOS) protocol: a detrimental combination for the oocyte yield in egg donation programs

Abstract Study question Could the use of combined oral contraceptive pill (COCP) pre-treatment before controlled ovarian hyperstimulation (COH) have a negative effect on oocyte yield in normo-responders patients? Summary answer When COH with progestin-primed ovarian stimulation (PPOS) protocol in normo-responders patients is performed, the COCP pre-treatment could have a detrimental effect on oocyte yield. What is known already COCP pre-treatment is widely used to schedule the start of COH and to organize the working week, but its usefulness and efficiency are still not clear. Most of studies on IVF outcomes have shown no effect of COCP on oocyte yield. For oocyte donation only few studies were carried out showing controversial effects on oocyte yield, but all considered short antagonist or long agonist protocols and no one PPOS protocol. COCP leads to long lasting pituitary suppression and lower LH level in follicular phase that could reduce the ability to effectively respond to GnRH-agonist trigger leading to poor oocyte yield. Study design, size, duration The egg donation cycles carried out from January to September 2022 in Next Fertility Valencia were retrospectively analyzed. Two analyses were conducted. Analysis A, comparative retrospective cohort study of 397 COH cycles: 290 with COCP and 107 without COCP. Analysis B, comparative retrospective paired study of 90 COH cycles: 45 with COCP and 45 without COCP, in which, to attempt to eliminate possible bias due to interpersonal differences, every patient was her own control. Participants/materials, setting, methods All donors underwent to COH with FSH monotherapy, PPOS protocol for pituitary suppression and a GnRH-agonist triggering. The oocyte yield was analyzed focusing on: the number of oocytes retrieved, mature (MII) oocytes and useful oocytes (good mature oocytes used for ICSI), the appropriate response to the GnRH-agonist trigger, the stimulation days, the total gonadotropins dose used and the cancellation rate (for low response or low LH level in follicular phase the first day of COH). Main results and the role of chance In both analyses, the data showed no differences in terms of stimulation days, total FSH dose, number of follicles ≥ 15 mm on the trigger day regardless of use of COCP. After conducting the analysis based on the administration or not of COCP, in the Analysis A a higher number of total oocytes retrieved, mature oocytes and useful oocytes were found in the group that did not used COCP. A significant difference in a nominal variable (Pearson's chi-square test) was observed, consisting of a higher proportion of cancellations due to low LH level (< 2,5 mUI/ml) in the group that used COCP (COCP no: 0.7% vs. COCP yes: 3.7% ). While, in the Analysis B (analysis of variance of one factor, Anova test), the variables total oocytes retrieved, total MII oocytes and total useful oocytes showed significant differences consisting of a higher number of oocytes in the group that did not received COCP. These results have statistical significance both before removing the cases in which the values were 0 due to a cancellation (p < 0.01), and after removing the cancelled cases (p < 0.05). Limitations, reasons for caution The main limitation lies in the retrospective nature of the study. However, since each patient is her own control (Paired study), it gives an added value. Wider implications of the findings COCP before COH in PPOS cycles could have detrimental effects on oocyte yield, reducing the efficacy and efficiency of egg donation programs. This could be extended to social freezing programs in normo-responders patients, in which the probability of future pregnancy is closely linked to the number of good oocytes vitrified. Trial registration number Not Applicable

P-630 Comparison of follitropin delta versus follitropin alfa in progestin-primed ovarian stimulation in IVF

Abstract Study question Is there a difference in a clinical outcome between using follitropin delta and follitropin alfa undergoing a progestin primed ovarian stimulation (PPOS) protocol? Summary answer There was no difference between follitropin delta and follitropin alfa in terms of pregnancy rates. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first recombinant human follicle-stimulating hormone (FSH) using the algorithm-based individualized dosing regimen while reducing the risk of ovarian hyperstimulation syndrome (OHSS) as compared with conventional dosing strategies. The efficacy and safety of follitropin delta has been demonstrated in randomized controlled trials (RCTs). Study design, size, duration We performed a retrospective analysis of 645 patients who underwent ovarian stimulation by a PPOS protocol using follitropin delta or follitropin alfa between April 2022 and August 2022. (325 patients using follitropin delta and 320 patients using follitropin alfa, respectively.) Participants/materials, setting, methods 325 cycles of women who used follitropin delta were compared to 320 cycles of women who used follitropin alfa. The following outcomes were analysed; fertilized rate, 2 pronuclear embryo rate, good quality embryo rate, blastocyst rate, good quality blastocyst rate. A total of 499 women who underwent embryo transfer in cryo cycles using natural cycle or hormone replacement cycle were analysed about biochemical pregnancy rate, clinical pregnancy rate. Main results and the role of chance Baseline demographics for 325 women in follitropin delta group and 320 women in follitropin alfa were: age, 35.1±4.3 years and 35.2±4.3 years; number of previous IVF cycles, 1.6±1.6 and 1.7±1.7, respectively. The laboratory data were: fertilization rate, 81.4% and 80.1%, 2 pronuclear embryo rate, 73.9% and 71.5%, good quality cleavage stage embryo rate, 59.4% and 55.9%, blastocyst rate, 58.9% and 55.7%, good quality blastocyst rate, 41.3% and 38.7%, respectively. Only good quality cleavage stage embryo rate and good quality blastocyst rate were significantly higher (P < 0.05) in follitropin delta group. A vitrified-warmed embryo transfer was performed for 257/325 women (79.1%) and 242/320 women (75.6%) and subsequent positive β-human chorionic gonadotropin (βhCG) reported for 218/621 cycles (35.1%) and 194/570 cycles (34.0%), respectively. Ongoing pregnancy rate after embryo transfer were 19.2% (n = 119) and 19.6% (n = 112) and cumulative ongoing pregnancy rate were both 46.3%. Mild OHSS was reported for 131 women (40.3%) and 170 women (53.1%), respectively (P = 0.07). Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings The present study shows that in addition to reducing the OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the quality of embryos although there was no significant difference in clinical outcomes. Trial registration number not applicable

P-603 Viability of home monitoring of estrone-3-glucuronide (E1-3G) urine levels in controlled ovarian stimulation: A pilot study

Abstract Study question Can the regular determination of E1-3G levels in the patient's urine be used for successful monitoring of progestin-primed ovarian stimulation protocol (PPOS)? Summary answer Regular determination of E1-3G levels in urine can be successfully used in ovarian stimulation (OS), significantly reducing patient visits to the clinic. What is known already To reduce direct and indirect costs and to optimize the workload in IVF clinics, innovative approaches are being sought. It has only recently become possible to implement elements of telemedicine in OS monitoring. Patients have begun performing vaginal sonograms on their own. Studies have further shown that there is a close correlation in the growth of E2 in serum and E1-3G in urine during the menstrual cycle and ovarian stimulation. Thus, theoretical models for the use of urinary E1-3G in ovarian stimulation were developed, which are subject to experimental verification and analysis. Study design, size, duration This is a pilot study carried out in a clinic, which aims to establish the growth rate of E1-3G and to determine its upper and lower limits of growth on each consecutive day at which stimulation is adequate and safe. Inclusion criteria were patients aged < 40 years and AMH ≧ 1.1 ng/mL. From September to December 2022, in total 28 first ovarian stimulatiоn cycles from 28 infertility patients were included. Participants/materials, setting, methods A PPOS protocol with fixed doses of gonadotropins was used. From the second day of stimulation, the patients determined the E1-3G levels in their urine every day at home with a portable analyzer. In parallel, a standard ultrasound follow-up protocol was applied, accompanied by determination of E2, LH and P levels, in order to optimally control stimulation. Patients' convenience of this new approach was assessed using a questionnaire developed for the purpose. Main results and the role of chance The average female age was 32,1 years (±4.4), BMI 22,9 kg/m2 (±4,3), AMH 3,9 ng/ml (±2,7), stimulation days 10,1 (±1,2), collected oocytes 12,6 (±8,5), MII oocytes 10,8 (±7,9), fertilization rate 83,4% (±22,7), blastocyst formation 66,9% (±28,6), good quality blastocysts 31,1% (±16,6). The log-linear mixed effect model (LLMM) estimation produced reasonable estimates of 49% average day-to-day growth rates (slope fixed effect), with one standard deviation (SD) range of 25% to 77% across patients (SD of the slope random effect). Moreover, there was a comparatively high correlation of 0.76 between the individual growth rates of E1G estimated over days 3-6 (the slope random effects of the LLMM model) and the E1-3G levels at day 10. In this way, the estimated slope random effects appear to have a prognostic value and may potentially have therapeutic implications, for example, adjustment of the stimulation dose. Moreover, the Spearman correlation between Estradiol and E1-3G was 0.83 After analyzing interviews and questionnaires, patients evaluated the applied method as easy and convenient, with 97% of them preferring OS monitoring to be performed in this manner compared to the standard method, which includes regular ultrasound examinations and determination of serum hormone levels. Limitations, reasons for caution The small statistical sample size is a limitation of this study, which was carried out in a single clinic. The results have to be confirmed in other clinics and with more diverse populations. Wider implications of the findings This is the first study to analyze the dynamics of E1-3G in the PPOS protocol and the limits of its increase during the entire OS. The results confirm our theoretical model for the successful use of urinary E1-3G in OS. The method is easy to apply and well-accepted by patients. Trial registration number N/A

Outcomes and cost-effectiveness comparisons of progestin-primed ovarian stimulation, GnRH antagonist protocol, and luteal phase stimulation for fertility preservation.

To compare the clinical outcomes and cost-effectiveness of progestin-primed ovarian stimulation (PPOS) and the gonadotropin-releasing hormone-antagonist (GnRH-A) protocol in fertility preservation (FP) in cancer patients. The stimulation option when patients were in the luteal phase was also explored. This retrospective study analyzed clinical data from 163 patients who underwent FP. The number of retrieved oocytes and vitrified oocytes/embryos, total dose of gonadotropin, duration of stimulation, number of injections, and cost were compared among the PPOS, GnRH-A, and luteal phase stimulation (LPS) groups. No significant differences were noted in the numbers of retrieved oocytes and vitrified oocytes/embryos among the three groups. In the multiple regression model, age (P = 0.02) and antral follicle count (AFC) (P < 0.001), but not the controlled ovarian stimulation (COS) protocols (P = 0.586), were associated with the number of retrieved oocytes. The number of injections and the cost were all significantly lower in the PPOS and LPS groups than in the GnRH-A group(P < 0.001). PPOS had similar clinical results but was superior medically and economically to GnRH-A. For patients in the luteal phase, LPS was an optional protocol with similar outcomes and costs to PPOS.

Ovarian stimulation methods at a single-assisted reproductive technology institution: a retrospective study of successful outcomes

Aim : to examine an efficacy of various stimulation methods in a group of successful pregnancies. Materials and Methods . In a single center retrospective study 47 pregnancy cases were examined after performing embryo transfers at our institution from the years 2017 to 2021. Patients were divided into four groups: i) clomiphene hyperstimulation (CH), ii) stimulation with gonadotropin-releasing hormone (GnRH) agonist, iii) with GnRH antagonist, and iv) progestin-primed ovarian stimulation (PPOS). Age, anti-Mullerian hormone, presence of chronic disease, number of in-vitro fertilizations prior to conception, dosage of follicle stimulating hormone (FSH), presence of premature luteinizing hormone surge, number of egg retrievals, fertilization rate, and live birth rate were assessed. Results. The number of pregnancies obtained by CH, agonist, antagonist, and PPOS methods comprised 25, 12, 2, and 8 cases, respectively. No significant difference in parameters between CH group and non-CH groups, excepting FSH was observed. The FSH was used in CH group and non-CH group at dose of 1108 ± 468 IU and 1756 ± 394 IU, respectively (p &lt; 0.0001). Conclusion. CH is not commonly used due to potential luteal phase defects, but it is thought to be cost-effective, requiring lower FSH doses, requiring no ovulation suppression antagonists, and exerting no effect on frozen embryos or fetuses. Hence, CH could be a suitable protocol for egg retrieval in Japan.

Comparison of fixed and flexible progestin-primed ovarian stimulation protocols to prevent premature luteinization in patients with diminished ovarian reserve.

Flexible progestin-primed ovarian stimulation (PPOS) protocol is demonstrated to be effective in suppressing premature luteinization in few studies. We aimed to compare fixed and flexible PPOS protocols in preventing premature luteinization in patients with diminished ovarian reserve. This retrospective cohort study included patients with a diminished ovarian reserve who were administered PPOS protocols for pituitary suppression during ovarian stimulation in a tertiary center in between January 2019 and June 2022. At fixed protocol, 20mg/day dydrogesterone was started in cycle day two or three along with gonadotropins and continued until trigger day. In contrast, at flexible protocol, 20mg/day dydrogesterone was commenced when the leading follicle reached 12mm or serum estradiol (E2) level was > 200pg/mL. A total of 125 patients, of whom 83 were administered fixed PPOS protocol and 42 were administered flexible PPOS protocol, were included in the analysis. Both groups had similar baseline characteristics and cycle parameters, including total days of gonadotropin administration and total gonadotropin dose (p > 0.05). Premature luteinization occurred at 7.2% and 11.9% of patients in fixed and flexible PPOS protocols, respectively (p = 0.505). Retrieved oocytes numbers, metaphase II oocyte numbers, and 2PN numbers were also similar (p > 0.05). Clinical pregnancy rates per transfer were 52.5% in fixed and 36.4% in flexible protocols (p = 0.499). Both fixed and flexible PPOS protocols had statistically similar outcomes in preventing premature luteinization and other cycle parameters. The flexible PPOS protocol seems to be as effective as the fixed PPOS protocol for patients with diminished ovarian reserve; however, further prospective studies should be conducted to validate the results of our research.

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.

Medroxyprogesterone acetate: an alternative to GnRH-antagonist in oocyte vitrification for social fertility preservation and preimplantation genetic testing for aneuploidy

Research questionCan medroxyprogesterone acetate (MPA) be used as a pituitary suppressor instead of a gonadotrophin releasing hormone (GnRH) antagonist during ovarian stimulation in elective fertility preservation and preimplantation genetic testing for aneuploidy (PGT-A) cycles? DesignA multicentre, retrospective, observational, cohort study conducted in 11 IVIRMA centres affiliated to private universities. Of a total of 1652 cycles of social fertility preservation, 267 patients were stimulated using a progestin-primed ovarian stimulation protocol (PPOS), and 1385 patients received a GnRH antagonist. In the PGT-A cycles, 5661 treatments were analysed: 635 patients received MPA and 5026 patients received GnRH antagonist. A further 66 fertility preservation and 1299 PGT-A cycles were cancelled. All cycles took place between June 2019 and December 2021. ResultsIn the social fertility preservation cycles, the number of mature oocytes vitrified in MPA was similar to the number of those treated with an antagonist, a trend that was seen regardless of age (≤35 or >35 years). In the PGT-A cycles, no differences were found in number of metaphase II, two pronuclei, number of biopsied embryos (4.4 ± 3.1 versus 4.5 ± 3.1), rate of euploidy (57.9% versus 56.4%) or ongoing pregnancy rate (50.4% versus 47.1%, P = 0.119) between the group receiving MPA versus a GnRH antagonist, whereas the clinical miscarriage rate was higher in the antagonist group (10.4% versus 14.8%, P = 0.019). ConclusionsAdministration of PPOS yields similar results to GnRH antagonists in oocytes retrieved, rate of euploid embryos and clinical outcome. Hence, PPOS can be recommended for ovarian stimulation in social fertility preservation and PGT-A cycles, as it allows greater patient comfort.

Nomogram to predict FSH starting dose in poor ovarian response women in progestin primed ovarian stimulation protocol

Prediction of individual ovarian response to exogenous gonadotropin is a cornerstone for success and safety in all controlled ovarian stimulation (COS) protocols. Providing the best FSH starting dose according to each woman’s own characteristics is the key to the success of individualized treatment. The objective of this investigation was to evaluate the potential application of a novel nomogram based on antral follicle counting (AFC), anti-Müllerian hormone (AMH) and body mass index (BMI) as a tool to optimize the follicle-stimulating hormone (FSH) starting dose in women with poor ovarian response in in-vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) cycles in progestin-primed ovarian stimulation (PPOS). We performed a retrospective analysis involving 130 poor ovarian responders undergoing IVF/ICSI cycles in a PPOS protocol from June 2017 to February 2019 in our reproductive center. The individual FSH starting dose was selected according to patients’ clinical history and characteristics. The influence of variables including age, BMI, AMH and AFC on the FSH starting dose was assessed through multiple regression analysis. We used the variables reaching the statistical significance for calculation for the final predictive model. In the univariate analysis, BMI, AMH and AFC were significant (P < 0.05) predictors of FSH starting dose, age was canceled. In the multivariate analysis, BMI, AMH and AFC remained significant (P < 0.05). According to the nomogram, 118 patients (90.77% of 130) would have received a higher FSH starting dose and 12 patients (9.23% of 130) a lower FSH starting dose than practice dose. The application of the nomogram based on three variables easily determined in clinical practice: BMI, AMH and AFC would lead to a more tailored FSH starting dose in women with poor ovarian response.

Comparison of cumulative live birth rates between progestin-primed ovarian stimulation protocol and gonadotropin-releasing hormone antagonist protocol in different populations.

To compare cumulative live birth rate (LBR) between progestin-primed ovarian stimulation (PPOS) and GnRH antagonist protocols of preimplantation genetic testing (PGT) cycles in different populations. This was a retrospective cohort study. A total of 865 patients were enrolled and separate analyses were performed for three populations: 498 patients with predicted normal ovarian response (NOR), 285 patients with PCOS, and 82 patients with predicted poor ovarian response (POR). The primary outcome was cumulative LBR for one oocyte retrieval cycle. The results of response to ovarian stimulation were also investigated, including numbers of oocytes retrieved, MII oocytes, 2PN, blastocysts, good-quality blastocysts, and usable blastocysts after biopsy, as well as rates of oocyte yield, blastocyst formation, good-quality blastocysts, and moderate or severe OHSS. Univariable and multivariable logistic regression analyses were used to identify potential confounders that may be independently associated with cumulative live birth. In NOR, the cumulative LBR of PPOS protocol was significantly lower than that of GnRH antagonists (28.4% vs. 40.7%; P=0.004). In multivariable analysis, the PPOS protocol was negatively associated with cumulative LBR (adjusted OR=0.556; 95% CI, 0.377-0.822) compared to GnRH antagonists after adjusting for potential confounders. The number and ratio of good-quality blastocysts were significantly reduced in PPOS protocol compared to GnRH antagonists (2.82 ± 2.83 vs. 3.20 ± 2.79; P=0.032 and 63.9% vs. 68.5%; P=0.021), while numbers of oocytes, MII oocytes and 2PN did not show any significant difference between GnRH antagonist and PPOS protocols. PCOS patients had similar outcomes as NOR. The cumulative LBR of PPOS group appeared to be lower than that of GnRH antagonists (37.4% vs. 46.1%; P=0.151), but not significantly. Meanwhile, the proportion of good-quality blastocysts in PPOS protocol was also lower compared to GnRH antagonists (63.5% vs. 68.9%; P=0.014). In patients with POR, the cumulative LBR of PPOS protocol was comparable to that of GnRH antagonists (19.2% vs. 16.7%; P=0.772). There was no statistical difference in the number and rate of good-quality blastocysts between the two protocols in POR, while the proportion of good-quality blastocysts appeared to be higher in PPOS group compared to GnRH antagonists (66.7% vs. 56.3%; P=0.182). In addition, the number of usable blastocysts after biopsy was comparable between the two protocols in three populations. The cumulative LBR of PPOS protocol in PGT cycles is lower than that of GnRH antagonists in NOR. In patients with PCOS, the cumulative LBR of PPOS protocol appears to be lower than that of GnRH antagonists, albeit lacking statistical difference, whereas in patients with diminished ovarian reserve, the two protocols were comparable. Our findings suggest the need for caution when choosing PPOS protocol to achieve live births, especially for normal and high ovarian responders.

Progestin-primed ovarian stimulation for fertility preservation in women with cancer: A comparative study.

In women scheduled for cancer treatment, oocytes cryopreservation is a well-established procedure. Random start protocols have been a substantial improvement in this setting, allowing to prevent delay in the initiation of cancer treatments. However, there is still the need to optimize the regimen of ovarian stimulation, to make treatments more patient-friendly and to reduce costs. This retrospective study compares two periods (2019 and 2020), corresponding to two different ovarian stimulation regimens. In 2019, women were treated with corifollitropin, recombinant FSH and GnRH antagonists. Ovulation was triggered with GnRH agonists. In 2020, the policy changed, and women were treated with a progestin-primed ovarian stimulation (PPOS) protocol with human menopausal gonadotropin (hMG) and dual trigger (GnRH agonist and low dose hCG) Continuous data are reported as median [Interquartile Range]. To overcome expected changes in baseline characteristics of the women, the primary outcome was the ratio between the number of mature oocytes retrieved and serum anti-mullerian hormone (AMH) in ng/ml. Overall, 124 women were selected, 46 in 2019 and 78 in 2020. The ratio between the number of mature oocytes retrieved and serum AMH in the first and second period was 4.0 [2.3-7.1] and 4.0 [2.7-6.8], respectively (p = 0.80). The number of scans was 3 [3-4] and 3 [2-3], respectively (p<0.001). The total costs of the drugs used for ovarian stimulation were 940 € [774-1,096 €] and 520 € [434-564 €], respectively (p<0.001). Random start PPOS with hMG and dual trigger represents an easy and affordable ovarian stimulation protocol for fertility preservation in women with cancer, showing similar efficacy and being more friendly and economical.

Application value of Early-Follicular Phase Long-Acting Gonadotropin-Releasing Hormone Agonist Long Protocol in patients with resistant ovary syndrome

BackgroundResistant ovarian syndrome(ROS) is a rare disease. It is difficult to diagnose and treat. Most of the literature reports on assisted pregnancy treatment for ROS patients are individual case reports. In this paper, the ovulation stimulation protocol and assisted pregnancy process of ROS infertile patients in our reproductive center were summarized and analyzed to provide information and support for the clinical treatment of ROS patients.MethodsFrom January 2017 to March 2022, assisted reproductive technology treatments and clinical characteristics parameters of six patients with ROS were retrospectively reviewed. Based on controlled ovarian stimulation protocols, these stimulation cycles were separated into four groups: Early-Follicular Phase Long-Acting Gonadotropin-Releasing Hormone Agonist Long Protocol (EFLL) group (n = 6), Progestin Primed Ovarian Stimulation(PPOS) protocol group (n = 5), mild-stimulation protocol group (n = 2), and Natural cycle protocol group (n = 3).ResultsA total of 16 cycles of ovulation stimulation were carried out in 6 patients with ROS. A total of 19 oocytes were retrieved, as well as 13 MII oocytes, 11 two pronuclear(2PN) fertilized embryos, and 8 excellent embryos. The oocytes acquisition rate was 50% and the fertilization rate of 2PN was 57.9%, and the excellent embryo rate was 72.7%. The EFLL protocol obtained 17 oocytes, 12 MII oocytes, 11 2PN fertilized embryos, and 8 excellent embryos; the mild-stimulation protocol obtained 1 oocyte; the Natural cycle protocol obtained 1 oocyte, and oocytes were not matured after in vitro maturation (IVM); the PPOS protocol obtained no oocytes. Compared with three other protocols, The fertilization rate of 2PN (64.7%) and excellent embryo rate (72.7%) in the EFLL protocol were higher than those of other protocols(0%). Two fresh cycle embryo transfers resulted in live births, while two frozen-thawed embryo transfer cycles resulted in one live birth and one clinical pregnancy using the EFLL protocol.ConclusionAlthough the current study is based on a small sample of participants, the findings suggest that the EFLL protocol can be employed for ovarian stimulation and may result in a live birth in ROS patients.

Letrozole cotreatment improves the follicular output rate in high-body-mass-index women with polycystic ovary syndrome undergoing IVF treatment.

Women who have polycystic ovary syndrome (PCOS) with high body mass index (BMI) typically have an attenuated ovarian response and decreased follicular size, which are linked to unfavourable clinical outcomes following in vitro fertilization (IVF) therapy. The follicular output rate (FORT), a qualitative indicator of follicular response, seems to be positively linked to the clinical outcomes of IVF. Progestin-primed ovarian stimulation (PPOS) has become an alternative to gonadotropin-releasing hormone (GnRH) analogues to inhibit the premature luteinizing hormone (LH) surge. As letrozole (LE) shows promise in enhancing ovarian response, we compared PPOS with and without LE for PCOS in high BMI women with a focus on the FORT and associated clinical and pregnancy outcomes. For the recruited 1508 women, ten variables including AFC; age; basal sex hormone level; BMI; infertility type; period of infertility and number of previous IVF attempts were chosen in the propensity score matching (PSM) model to match 1374 women who taken the MPA+ hMG protocol with 134 women who received the MPA+ hMG+ LE treatment at a 1:1 ratio. FORT was selected as the primary outcome measure. The number of oocytes retrieved, viable embryos, hMG dosage, duration, oocyte maturity rate, fertilization rate, and implantation rate were established as secondary outcomes. FORT was substantially elevated in the MPA+hMG+LE group compared with the MPA+hMG group (61% [35%, 86%] vs. 40% [25%, 60%], P <.001). Interestingly, the LE cotreatment group had a considerably lower mature oocyte rate despite having a similar number of mature oocytes and embryos recovered. The average hMG dosages and durations in the study group were similar to those in the control group. The implantation rate in the study group was numerically higher but without statistic significant than that in the control groups (43.15% (107/248) vs. 38.59% (115/298), OR 1.008, 95% CI 0.901-1.127; P >.05). The effect of LE combined with PPOS on FORT is better than the effect of the standard PPOS treatment in women with PCOS and a high BMI, but there is no substantially beneficial impact on pregnancy outcomes or the cycle features of COS, including consumption of hMG.

Analysis of euploidy rates in preimplantation genetic testing for aneuploidy cycles with progestin-primed versus GnRH agonist/antagonist protocol

BackgroundProgestins can suppress endogenous luteinising hormone (LH) secretion from the pituitary gland and have shown similar efficacy in terms of collecting competent oocytes and embryos; however, some inconsistencies have been proposed regarding the quality of embryos collected with the use of progestins. This study aimed to evaluate euploidy rates and pregnancy outcomes in preimplantation genetic testing for aneuploidy (PGT-A) cycles using the progestin-primed ovarian stimulation (PPOS) protocol versus the gonadotropin-releasing hormone (GnRH) agonist/antagonist protocol.MethodsThis retrospective cohort study included 608 PGT-A cycles: 146 women in the PPOS group, 160 women in the GnRH agonist group, and 302 women in the GnRH antagonist group. This study was performed at the in vitro fertilisation (IVF) centre of Shanghai First Maternity and Infant Hospital between January 2019 and December 2021. Additionally, 267 corresponding first frozen embryo transfer (FET) cycles were analysed to assess pregnancy outcomes.ResultsThe euploid blastocyst rate per injected metaphase II(MII) oocytes (14.60% vs. 14.09% vs. 13.94%) was comparable among the three groups (p > 0.05). No significant differences were observed among the three groups regarding pregnancy outcomes, including biochemical pregnancy, clinical pregnancy, ongoing pregnancy, implantation, miscarriage, ectopic pregnancy, and live birth rates per transfer in the first FET cycles (p > 0.05).ConclusionsThe PPOS protocol had no negative effect on euploid blastocyst formation, and the pregnancy outcomes in FET cycles using the PPOS protocol were similar to those of the GnRH agonist and antagonist protocols.Trial registration This trial was retrospectively registered