Vitrified–warmed blastocyst transfer timing related to LH surge in true natural cycle and its impact on ongoing pregnancy rates

Objective: To examine the correlation between serum luteinizing hormone (LH) levels on the day of GnRH agonist (GnRH-a) trigger and reproductive outcomes following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment and fresh embryo transfer, and to identify a pre-trigger serum LH threshold which would be compatible with the most optimal cycle outcome.Design: This study is based on data from a previously published randomized controlled trial conducted from 2014 to 2016.Patients: A total of 322 participants were enrolled.Setting: Private IVF center. Intervention(s): GnRH-antagonist-based IVF cycles triggered with GnRH-a. For the purpose of the study, patients were stratified according to preovulatory LH quartiles (Q1-Q4). Main Outcome Measure(s): Ongoing pregnancy rates (OP), live birth rates (LB) and early pregnancy loss (EPL) rates.Results: The results of the present study showed increasing OP as well as LB rates and decreasing EPL rates with increasing pre-trigger serum LH levels (P for trend < 0.06, 0.07, and 0.02), respectively. The absolute difference between the highest LH(Q4) and the lowest LH (Q1) group was 13.4%, 12.1%, and 12% in OP, LB, and EPL rates, respectively. In multivariate regression analysis, a pre-trigger serum LH level of 1.60 mIU/ml was identified as a threshold below which reproductive outcomes decreased. The ROC curve values were statistically significant for OP, LB, and EPL; the AUC (95% CI) = [0.57 (0.50–0.63) P < 0.04; 0.57 (0.50–0.63) P < 0.05, and 0.60 (0.51–0.70) P < 0.04], respectively. A significant positive correlation was found on the day of GnRH-a trigger between serum LH, the number of follicles, serum P4, and serum E2, p < 0.03; P < 0.03; and P < 0.001, respectively.Conclusion: Low serum LH levels on the day of GnRH-a trigger is associated with reduced ongoing pregnancy and live birth rates and increased early miscarriage rates. Our findings suggest a lower threshold of serum LH values on the day of GnRH-a trigger necessary to optimize reproductive outcomes in fresh embryo transfer cycles.Clinical Trial Registration: www.ClinicalTrials.gov, Number: 02053779

Does premature luteinizing hormone (LH) elevation in the absence of elevated progesterone influence outcome in antagonist in vitro fertilization (IVF) cycles?

Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting

BackgroundSince progesterone alone does not seem to be enough for luteal phase support (LPS), especially in frozen embryo transfer (FET) cycles, so gonadotropin-releasing hormone agonist (GnRH-a) is suggested as an adjuvant therapy in combination with progesterone for LPS.ObjectiveTo evaluate the effects of the administration of GnRH-a with vaginal progesterone compared to vaginal progesterone alone in luteal phase support of the frozen-thawed embryo transfer cycles.Materials and Methods In this randomized controlled clinical trial, 240 infertile women who were candidates for FET were evaluated into two groups (n = 120/each). Group I received 400 mg vaginal progesterone twice a day from the time of transfer. The second group received vaginal progesterone and also 0.1 mg diphereline on days 0, 3, and 6 of FET for LPS. Finally, the clinical and ongoing pregnancy rates, and the implantation, and spontaneous abortion rates were compared in two groups.ResultsResults showed that there was no significant difference between the mean age of women and the duration of infertility (p = 0.78, p = 0.58, respectively). There were no significant differences between groups in the terms of implantation and spontaneous abortion rates (p = 0.19, p = 0.31, respectively). However, in terms of clinical and ongoing pregnancy rates, the significant differences were seen between groups (p = 0.008 and p = 0.005, respectively).ConclusionCo-administration of GnRH-a and vaginal progesterone in LPS may be superior to vaginal progesterone alone in women who underwent a frozen-selected embryo transfer cycle.

GnRH agonist administration in the luteal phase was reported to beneficially affect the clinical outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This double blind, randomized, placebo controlled trial evaluates whether a single dose GnRH agonist administered 6 days after ICSI increases ongoing pregnancy rates following ET in cycles stimulated with the long GnRH agonist protocol. Five hundred and seventy women undergoing ET following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal phase support with progesterone, women were randomized to receive a single 0.1 mg dose of triptorelin or placebo 6 days after ICSI. Randomization was done on the day of ET according to a computer generated randomization table. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 12% absolute increase from an assumed 38% ongoing pregnancy rate in the placebo group, with an alpha error level of 0.05 and a beta error level of 0.2. There were 89 (31.2%) ongoing pregnancies in the GnRH agonist group, and 84 (29.5%) in the control group (absolute difference +1.7%, 95% confidence interval -5.8% to +9.2%). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRH agonist and placebo groups. Single 0.1 mg triptorelin administration 6 days after ICSI following ovarian stimulation with the long GnRH agonist protocol does not seem to result in an increase >or=12% in ongoing pregnancy rates.

Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders

Study question Does reducing estradiol levels with letrozole co-treatment during ovarian stimulation with gonadotropins for IVF impact endocrinological and reproductive outcome markers in expected normal responders? Summary answer Letrozole co-treatment maintained follicular phase physiological serum estradiol levels, increased gonadotropin and androgen levels, and increased progesterone in the luteal phase. What is known already Ovarian stimulation for IVF causes supraphysiologic estradiol levels, which exert pituitary suppression reducing gonadotropin stimulation of the corpus luteum. Furthermore, stimulation may increase progesterone in the late follicular phase, reported to impair clinical outcomes, through a putative effect on endometrial maturation and embryo-endometrial asynchrony. Co-treatment with the highly selective aromatase inhibitor letrozole during ovarian stimulation has been shown to reduce estradiol levels and FSH consumption in poor responders, but conflicting data in relation to oocyte yield and implantation rates. The impact of letrozole co-treatment on hormonal changes and reproductive outcome after co-treatment in normal responders remains to be clarified. Study design, size, duration A multicentre double-blinded randomised placebo-controlled trial conducted in 4 fertility clinics at university hospitals in Denmark from August 2016 to November 2018. 159 women were randomised and 129 completed the study; 67 women in the letrozole group and 62 women in the placebo group. The study was conducted in accordance with the Helsinki Declaration and the ICH-Good-Clinical-Practice. Data collection and reporting followed the guidelines of CONSORT to achieve transparent reporting of trials. Participants/materials, setting, methods Women with expected normal ovarian reserve received an antagonist IVF protocol with fixed-dose FSH and fresh single embryo transfer. Co-treatment consisted of once-daily 5 mg letrozole or placebo from the start of stimulation until the day of triggering final oocyte maturation with human chorionic gonadotropin. Serum was collected on 7 visits from stimulation start to 8 days after oocyte retrieval. Clinical pregnancy was determined with a viable foetus by vaginal ultrasound at gestational week 7. Main results and the role of chance The proportion of patients with progesterone &amp;gt;1.5 ng/ml in the late follicular phase was similar in the letrozole versus placebo group with 6% versus 0%, respectively (OR 0, 95 % CI [0;1.6], P =.12). Mid-luteal progesterone levels &amp;gt;30 ng/ml were observed in 59% versus 31%, respectively, of subjects in the letrozole and placebo group (OR 3.3, 95% CI [1.4;7.1], P =.005). Letrozole treatment decreased estradiol levels by 69% (95 % CI [60%;75%], P &amp;lt;.0001) and increased luteinizing hormone (LH), testosterone, and androstenedione levels significantly in both the follicular and luteal phase. Follicle-stimulating hormone (FSH) concentration was elevated in the letrozole group at stimulation day 5 and at trigger day, and overall FSH consumption was diminished. The ongoing pregnancy rate did not differ between the letrozole and placebo group (31% versus 39% (risk-difference of 8%, 95% CI [-25%;11%], P =.55). Letrozole had no significant additional side effects apart from those frequently seen during ovarian stimulation, though a trend towards less nausea and vomiting was observed in the letrozole co-treated group versus the placebo group (28% versus 44% (risk-difference of 16%, 95% CI [-2%;33%], P =.11). Limitations, reasons for caution The diurnal variation of progesterone has been confirmed since this study was completed, hence the timing of the blood samples was not standardized . However, bias is unlikely due to the randomized design. The study was not powered to show an effect on ongoing pregnancy rates. Wider implications of the findings Letrozole co-treatment during ovarian stimulation with gonadotropins maintained serum estradiol at physiological levels, increased follicular phase levels of gonadotropins and androgens, and luteal progesterone levels. These data indicate that letrozole co-treatment may ameliorate the detrimental impacts of gonadotropin stimulation during IVF in normal responders. Trial registration number NCT02939898 and NCT02946684

Day 2 embryo transfer (ET) and day 3 ET afford similar reproductive outcomes in the poor responder

To evaluate the impact of autologous platelet-rich plasma (PRP) intrauterine perfusion on endometrial receptivity and pregnancy outcomes in patients with implantation failure. This retrospective cohort study included patients who visited our hospital between January 2019 and January 2024, all suffering from recurrent implantation failures and diagnosed with thin endometrium. Participants were divided into two groups: conventional-treatment (n=116) and PRP-treatment (n=104). Serum levels of estradiol 2 (E2), follicle stimulating hormone (FSH), and luteinizing hormone (LH) were measured before and 14 days after treatment. Transvaginal Doppler ultrasound assessed uterine artery, arcuate artery, and spiral artery pulsatility index (PI) and resistance index (RI) at both timepoints. Endometrial thickness was measured before and 14 days post-treatment. Pregnancy outcomes, including implantation rate, clinical pregnancy rate, ongoing pregnancy rate, and live birth rate, were recorded. The PRP-treatment group showed a significant increase in endometrial thickness (P=0.037). Uterine artery PI (P=0.004) and RI (P=0.015), arcuate artery PI (P=0.037) and RI (P=0.003), and spiral artery PI (P=0.002) significantly decreased in the PRP-treatment group compared to the conventional-treatment group. Hormonal measurements indicated higher E2 (P=0.001) and lower FSH (P=0.002) and LH (P=0.002) levels post-treatment in the PRP-treatment group. Pregnancy outcomes significantly favored the PRP-treatment group, with higher implantation rates (P=0.004), clinical pregnancy rates (P=0.044), ongoing pregnancy rates (P=0.031), and live birth rates (P=0.032). PRP intrauterine perfusion significantly improves endometrial parameters, uterine hemodynamics, and pregnancy outcomes in patients with recurrent implantation failure and thin endometrium.

Background and Objective: The endometrium and embryos have been reported to be directly affected by GnRH agonists (GnRHa). Additionally, as demonstrated by numerous meta-analyses, the utilization of GnRHa during the luteal phase of fresh IVF cycles has been correlated with an increase in the rates of live birth and pregnancy. This study aimed to ascertain whether GnRHa administration during the luteal phase could enhance the results of in vitro fertilization (IVF) in patients who are undergoing frozen embryo transfer (FET) cycles.Materials and Methods: In order to prepare the endometrium, hormone replacement therapy (HRT) was implemented in a total of 166 frozen embryo transfer cycles during this randomized controlled trial. The cycles were divided into two equal groups, each consisting of 83 cycles. Two hours after the embryo transfer, a single subcutaneous dose of 0.2 mg triptorelin (Decapeptyl) was administered to the GnRHa group. Devoid of the administration of luteal GnRHa, the control group underwent embryo transfer. In this study, the clinical pregnancy rate was the primary outcome, while the ongoing pregnancy rate was the secondary outcome.Results: Both groups exhibited remarkable similarities in their baseline and cycle characteristics. The luteal GnRHa group has a clinical pregnancy rate that was significantly higher than those of the control group (57.8% vs. 41.0%, P = 0.030). Rates of ongoing pregnancy were comparable in both groups (41.0% vs. 25.3%; P = 0.476). Furthermore, the use of a luteal GnRH agonist was identified as a significant independent predictor of clinical pregnancy in FET-HRT cycles, as indicated by the multivariate analysis (OR 1.512, 95% CI 1.020-2.241, P = 0.039).Conclusions: The clinical pregnancy rates of patients who are undergoing the HRT-FET protocol may be enhanced by addition of a single luteal dose of GnRHa.

Background:Different progesterone doses and routes are used for luteal phase support in stimulated intrauterine insemination (IUI) cycles, but the optimal supplementation scheme has not yet been determined. Therefore, our aim was to compare the administration of two different doses of vaginal progesterone with two doses of intramuscular (IM) progesterone for luteal phase support in patients undergoing IUI cycles.Methods:In this randomized clinical trial, 312 women with unexplained or malefactor infertility intending to start IUI cycles between April 2015 and January 2018 were included. They were randomized into four groups (n=78/each) including group 1 who received IM progesterone in oil (25 mg daily), group 2 who received IM progesterone in oil (50 mg daily), group 3 who received progesterone suppository (400 mg daily), and group 4 who received progesterone suppository (800 mg daily; 400 mg twice daily). The primary outcome was the clinical pregnancy rate. The ongoing pregnancy rate, abortion rate, and patients’ satisfaction, and convenience the secondary outcomes.Results:In our study, the overall clinical and ongoing pregnancy rates per cycle with COS and IUI were 16.02% and 12.8%, respectively. There were no significant differences in clinical pregnancy, ongoing pregnancy, and abortion rates among groups (p=0.84). The overall patients’ satisfaction and convenience was significantly higher in the vaginal progesterone suppository groups than the IM progesterone groups (p=0.001).Conclusion:The results of this study showed that vaginal progesterone administration provides a more easy-to-use and convenient method than IM progesterone administration for luteal phase support in IUI cycles with comparable pregnancy rates.

Study question Is SHR7280, an oral GnRH antagonist, non-inferior to ganirelix injection in premature luteinizing hormone (LH) surge inhibition and oocyte number retrieved during COH for ART? Summary answer Oral SHR7280 desmontrated non-inferiority to ganirelix injection in suppressing premature LH surges and in number of oocytes retrieved per cycle. SHR7280 was well-tolerated and safe. What is known already All GnRH antagonists currently approved for preventing premature LH surges are injectable, peptide-based formulations, which can cause inconvenience and injection site reactions. This highlights a significant unmet need for an orally available GnRH antagonist. In a previous phase 2 trial, SHR7280 at a dose of 200 mg Q12h showed effective LH suppression and a favorable safety profile in women undergoing COH for ART. Study design, size, duration This multi-center, randomized, double-blind, double-dummy, active-controlled, non-inferiority phase 3 trial was conducted in 22 hospitals in China. Between Sep. 25, 2023 and Jun. 28, 2024, 315 infertile women aged 20-39 years, for whom in vitro fertilization or intracytoplasmic sperm injection with embryo transfer was indicated, were enrolled and treated (SHR7280, n = 154; ganirelix, n = 161). Participants/materials, setting, methods Patients were randomized 1:1 to receive oral SHR7280 at 200 mg Q12h or ganirelix acetate injection at 0.25 mg Q24h. GnRH antagonists were started on day 5 of Gonal-F stimulation until human chorionic gonadotropin administration. The dual primary endpoints were rate of premature LH surge (LH ≥ 10 IU/L and progesterone ≥1.0 ng/mL) suppression during treatment period of study drugs (noninferiority margin, -10%) and number of oocytes retrieved after 1 stimulation cycle (noninferiority margin, -3). Main results and the role of chance The mean (±SD) treatment duration was 5.5±1.1 days for SHR7280 and 5.4±1.1 days for ganirelix. The rate of premature LH surge suppression was 99.4% (153/154; 95% CI 96.4–100.0) with SHR7280 and 99.4% (160/161; 95% CI 96.6–100.0) with ganirelix (difference, 0.0% [95% CI -1.8 to 1.8]; p &amp;lt; 0.0001 for non-inferiority). The LS mean number of oocytes retrieved was 9.9 (95% CI 8.9–10.9) with SHR7280 and 9.9 (95% CI 9.0–10.9) with ganirelix (LS mean difference, -0.0 [95% CI -1.0 to 1.0]; p &amp;lt; 0.0001 for non-inferiority). The mean (±SD) number of two-pronuclei zygotes was 6.6±3.6 in the SHR7280 group and 6.9±3.7 in the ganirelix group; the mean (±SD) number of high-quality embryos was 4.1±3.1 and 4.3±3.2, respectively. Per transfer, the blood pregnancy test positive rate was 63.1% (77/122; 95% CI 53.9–71.7) in the SHR7280 group vs 53.0% (61/115; 95% CI 43.5–62.4) in the ganirelix group; clinical pregnancy rates was 54.9% (67/122; 95% CI 45.7–63.9) vs 52.2% (60/115; 95% CI 42.7–61.6), and ongoing pregnancy rate was 49.2% (60/122; 95% CI 40.0–58.4) vs 47.8% (55/115; 95% CI 38.4–57.3). Treatment-related adverse events (TRAEs) occurred in 2 (1.3%) patients with SHR7280 and 10 (6.2%) with ganirelix. No serious TRAEs occurred. Limitations, reasons for caution This study involved a general ART population, excluding specific groups like those with diminished ovarian reserve or polycystic ovary syndrome. Additionally, the utility of SHR7280 in COH for diverse racial/ethnic populations remains underexplored, requiring further investigation to establish broader efficacy and safety. Wider implications of the findings This is the first head-to-head phase 3 trial comparing an oral GnRH antagonist to a standard, peptide-based formulation. The findings suggest that oral GnRH antagonists could be a convenient, non-invasive alternative to injectable formulations, improving overall treatment experience in women undergoing COH for ART. Trial registration number Yes

<h3>Introduction</h3> Progesterone is an essential hormone involved in the process of implantation and pregnancy maintenance. Evidence from recent studies has supported the importance of serum progesterone level around the time...

Increased expansion and decreased contraction of embryos corresponds to increased clinical pregnancy rates in single FET cycles

Study question What is the optimal ovulation trigger size for ongoing pregnancies in Letrozole-induced modified natural Frozen Embryo Transfer (FET) cycles? Summary answer Triggering ovulation at &amp;gt; 19 mm follicle size increased ongoing pregnancy rates and serum progesterone levels What is known already Frozen Embryo Transfer (FET) cycles are widely used in assisted reproduction, and letrozole-stimulated modified natural cycles are gaining traction due to their alignment with natural physiology. Serum progesterone (P) levels on the day of embryo transfer (ET) are crucial for pregnancy success. However, the optimal follicle size at which ovulation should be triggered in letrozole-modified FET cycles remains unclear. Our study aimed to investigate the ideal follicle size for triggering to maximize ongoing pregnancy rates, focusing on how follicle size affects luteal phase preparation and implantation outcomes. Study design, size, duration An observational study conducted between 2022 and 2024 across two IVF centers, Participants/materials, setting, methods Infertile women with at least one frozen blastocyst from their previous ovarian stimulation cycles. Letrozole (2.5 mg twice daily) was administered on cycle days 3-7, followed by follicular monitoring. Ovulation was triggered when the endometrial thickness was &amp;gt;7.0 mm and the leading follicle size exceeded 15 mm. Serum P levels were measured on ET day. Blastocyst transfer was performed on the 7th day post-trigger. No additional luteal support was given. Main results and the role of chance A total of 165 women undergoing modified natural FET cycles were included in this study. The mean age of participants was 31.2 ± 4.8 years, and the mean body mass index (BMI) was 24.8 ± 2.2 kg/m. The average endometrial thickness on the day of hCG administration was 9.1 ± 1.1 mm. The mean serum P level on the day of ET was 23.5 ± 6.4 ng/mL, with a mean leading follicle size of 19.4 ± 2.2 mm on the hCG trigger day. Positive hCG results were observed in 54% of cases, with ongoing pregnancy rates recorded in 40% of participants. The optimal ovulation triggering size for ongoing pregnancy, identified through ROC analysis, was 19.0 mm, while the optimal serum P level on the day of ET was 23.21 ng/mL. Ongoing pregnancy rates were significantly higher in the &amp;gt;19 mm group (62.7%, 47/75) compared to the 15–19 mm group (40%, 30/75), (p = 0.00). A significantpositive correlation was observed between leading follicle size and serum P levels on the day of ET(r = 0.29, p = 0.0002). Limitations, reasons for caution The sample size is relatively small and specific to letrozole-induced modified FET cycles, limiting generalizability. Variability in clinical practices may affect outcomes, emphasizing the need for larger multi-center studies. Wider implications of the findings This study suggests integrating individualized follicle size monitoring and serum P measurements to optimize clinical protocols in letrozole-induced modified natural FET cycles. Findings support broader adoption of patient-friendly letrozole-induced protocols. Trial registration number No