Micronized natural progesterone (Seidigestan®) vs GnRH antagonists for preventing the LH surge during controlled ovarian stimulation (PRO_NAT study): study protocol of a randomized clinical trial.

Introduction: Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in oocyte donors, the use of synthetic progesterone (progestins) has been explored in prospective clinical trials, showing mixed results. This trial was designed to determine whether the use of micronized natural progesterone is as effective as the GnRH-antagonist protocol in terms of the number of mature oocytes (MII) retrieved in oocyte donation cycles as a primary outcome, and it also aims to explore the corresponding results in recipients as a secondary outcome. Methods: We propose a prospective, open-label, non-inferiority clinical trial to compare a novel approach for oocyte donors with a control group, which follows the standard ovarian stimulation protocol used in our institution. A total of 150 donors (75 in each group) will be recruited and randomized using a computer algorithm. After obtaining informed consent, participants will be randomly assigned to one of two ovarian stimulation protocols: either the standard GnRH antagonist or the oral micronized natural progesterone protocol. Both groups will receive recombinant gonadotropins tailored to their antral follicle count and prior donation experiences, if any. The primary outcome is the number of mature metaphase II (MII) oocytes. Secondary measures include treatment duration, pregnancy outcomes in recipients, as well as the economic cost per MII oocyte obtained in each treatment regimen. Analyses for the primary outcome will be conducted in both the intention-to-treat (ITT) and per-protocol (PP) populations. Each donor can participate only once during the recruitment period. The estimated duration of the study is six months for the primary outcome and 15 months for the secondary outcomes. Discussion: The outcomes of this trial have the potential to inform evidence-based adjustments in the management of ovarian stimulation protocols for oocyte donors. Clinical trial registration: ClinicalTrials.gov, identifier, NCT05954962.

Meta-analysis of trigger timing in normal responders undergoing GnRH antagonist ovarian hyperstimulation protocol.

IMPORTANCE: The first meta-analysis focused only on gonadotropin-releasing hormone (GnRH) antagonists, which helped determine the effect of delay trigger on pregnancy outcomes. OBJECTIVE: To evaluate the impact of delay trigger compared with standard trigger in normal responders undergoing GnRH antagonist protocol in improving pregnancy outcomes. METHODS: Studies published before April 2023 in PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, Wanfang, VIP and CBM databases were searched. Randomized controlled trials (RCTs) and cohort studies conducted in normal responders reporting the efficacy of delay trigger using GnRH antagonist protocol were included. Data were combined to calculate mean differences (MD) for continuous variables and odd ratios (OR) for categorical variables with their corresponding 95% confidence intervals (CIs). Heterogeneity was assessed using Cochran's Q test. RESULTS: Endpoints, including clinical pregnancy rate (CPR), live birth rate (LBR), the number of oocyte retrievals and embryos, and fertilization rate, were analyzed. Six (6) clinical studies (4 RCTs and 2 cohort studies) with 1,360 subjects were included. The pooled results showed that the number of oocyte retrievals (MD: 1.20, 95% CI: 1.10, 1.30, p < 0.01), fertilization rate (MD: 0.64, 95% CI: 0.29, 0.99, p < 0.01) and days of stimulation (MD: 0.95; 95% CI: 0.54, 1.37; p < 0.01) in the delay trigger group was significantly higher than that in the standard trigger group. However, there was no significant difference in the number of embryos (MD: 0.19, 95% CI: -0.29, 0.67, p = 0.44), CPR (OR: 1.12; 95% CI: 0.72, 1.75; p = 0.062), and LBR (OR: 1.23; 95% CI: 0.90, 1.66; p = 0.19) between the two trigger groups. CONCLUSION: Delaying trigger time in GnRH antagonist protocol increased the number of oocytes retrieved but not the number of embryos. Furthermore, delay trigger shot was not associated with a clinical benefit towards CPR and LBR in women who underwent fresh embryo transfer cycles. TRIAL REGISTRATION: The International Prospective Register of Systematic Reviews (PROSPERO), registration number: CRD42023413217.

Age and dual trigger were found to be significant predictors of live birth in POSEIDON group 3 and 4 women treated with the GnRH antagonist protocol: a retrospective cohort study.

OBJECTIVE: Despite recent advancements in assisted reproductive technology (ART), the effective management of patients with poor ovarian response (POR) remains a formidable challenge. While various treatment strategies and predictors of live births have been documented to provide guidance to fertility specialists in managing poor responders, research efforts have predominantly encompassed all POSEIDON groups. In this study, our objective was to analyze the factors correlated with live births (LB) within a subset of the POSEIDON groups, with a particular focus on POSEIDON groups 3 and 4. PATIENTS AND METHODS: Charts of 406 patients belonging to POSEIDON groups 3 and 4 who underwent ART treatment at a university-affiliated infertility clinic following a gonadotropin-releasing hormone (GnRH) antagonist cycle between January 2016 and December 2021 were analyzed. Clinically significant factors associated with live births were incorporated into a logistic regression model for multivariate analysis to ascertain independent predictors of LB. Additionally, a receiver operating characteristic (ROC) curve analysis was conducted to establish the optimal cut-off values. RESULTS: Live births were achieved in 48 cycles (8.7%). Female age (OR, 0.930; 95% CI: 0.874-0.991; p < 0.024), baseline serum luteinizing hormone (LH) levels (OR, 0.854; 95% CI: 0.741-0.984; p < 0.029), and dual triggers (OR, 4.004; 95% CI: 1.290-12.426; p < 0.016) were identified as independent factors associated with LB following multivariate logistic regression analysis. The optimal age cut-off was determined to be 33 years, with a sensitivity of 70.8% and specificity of 75%. CONCLUSIONS: Younger age, lower baseline serum LH levels, and dual-trigger administration appear to enhance the likelihood of live birth in POSEIDON groups 3 and 4 following treatments with the GnRH antagonist protocol.

Evaluation of the Impact of Letrozole in Combination with the GnRH Antagonist Ovarian Stimulation Protocol in Patients Expected to Have a Poor Ovarian Response (POSEIDON Groups 3 and 4).

Background and Objectives: The objective of this study was to evaluate the impact of adjuvant letrozole administration during ovarian stimulation using the gonadotropin-releasing hormone (GnRH) antagonist protocol on treatment outcomes in women categorized into POSEIDON groups 3 and 4. Materials and Methods: This retrospective cohort study analyzed data from patients classified into POSEIDON groups 3 and 4 who underwent fresh embryo transfer subsequent to intracytoplasmic sperm injection following a GnRH antagonist stimulation protocol between January 2017 and December 2021. Patients were divided into two groups: the GnRH-LZ group, who received letrozole at a dosage of 5 mg/day for five consecutive days, and the GnRH-ant group, who did not receive adjuvant letrozole. The primary outcome measure of the study was a comparative analysis of live birth rates between the two groups. Results: A total of 449 patients were deemed suitable for final analysis and were allocated into two groups: 281 patients in the GnRH-ant group and 168 patients in the GnRH-LZ group. Live birth rates were found to be comparable in both groups (11% vs. 9%, p = 0.497). Letrozole administration significantly reduced the total amount of gonadotropins required (2606.2 ± 1284.5 vs. 3097.8 ± 1073.3, p < 0.001), the duration of ovarian stimulation (11.2 ± 3.9 vs. 10.2 ± 3, p = 0.005), and the serum peak estradiol concentration (901.4 ± 599.6 vs. 463.8 ± 312.3, p < 0.001). Conclusions: Adjuvant letrozole administration did not demonstrate a significant impact on live birth rates among women categorized into POSEIDON groups 3 and 4. However, this approach may offer potential cost reductions by diminishing the necessity for exogenous gonadotropins and shortening the duration of ovarian stimulation.

Comparing blastocyst euploid rates between the progestin-primed and gonadotrophin-releasing hormone antagonist protocols in aneuploidy genetic testing: a randomised trial protocol.

INTRODUCTION: Progestin can inhibit the pituitary luteinising hormone (LH) surge during ovarian stimulation for in vitro fertilisation (IVF) and studies show progestin-primed ovarian stimulation (PPOS) is effective in blocking the LH surge in IVF. More and more centres are using PPOS because this regimen appears simpler and cheaper. This study aims to compare the euploidy rate of blastocysts following the PPOS protocol and the gonadotropin-releasing hormone antagonist protocol in women undergoing preimplantation genetic testing for aneuploidy (PGT-A). METHODS/ANALYSIS: This is a randomised trial. A total of 400 women undergoing PGT-A will be enrolled and randomised according to a computer-generated randomisation list to either (1) the antagonist group: an antagonist given once daily from day 6 of ovarian stimulation till the day of the ovulation trigger; or (2) the PPOS group: dydrogesterone from the first day of ovarian stimulation till the day of ovulation trigger. The primary outcome is the euploidy rate of blastocysts. ETHICS/DISSEMINATION: An ethical approval was granted from the ethics committee of assisted reproductive medicine in Shanghai JiAi Genetics and IVF institute (JIAIE2020-03). A written informed consent will be obtained from each woman before any study procedure is performed, according to good clinical practice. The results of this randomised trial will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04414748.

Cumulative live birth rate of in vitro fertilization cycle via progestin-primed ovarian stimulation versus gonadotropin-releasing hormone antagonist protocol in infertile women with normal ovarian reserve: an open-label, randomized controlled trial.

This study aimed to evaluate the cumulative live birth rate (cLBR) of progestin-primed ovarian stimulation (PPOS) protocol versus gonadotropin-releasing hormone antagonist (GnRH-ant) protocol for in vitro fertilization (IVF) cycle in infertile women with normal ovarian reserve (NOR). Infertile women with NOR who underwent their first IVF cycle were enrolled in an open-label randomized controlled trial. Patients were randomly assigned 1:1 to receive a freeze-all strategy with delayed embryo transfer (PPOS group, n = 174) and fresh embryo transfer first (GnRH-ant group, n = 174). The primary outcome was the cLBR per aspiration. The cLBR between the PPOS group and GnRH-ant group were comparable (55.75% vs. 52.87%, p = 0.591). A premature luteinizing hormone surge was not observed in the PPOS group, while there were six cases (3.45%) in the GnRH-ant group, but no premature ovulation in either of the groups. The pregnancy outcomes, including implantation rate, clinical pregnancy rate and miscarriage rate, were all comparable. In addition, the number of retrieved oocytes, mature oocytes and viable embryos were similar (all p > 0.05) between the two groups.

Comparison of progesterone protocol versus gonadotropin-releasing hormone antagonist protocol in terms of preventing premature LH surge and assisted reproductive technology outcome in infertile women: a randomized controlled trial.

INTRODUCTION: Progesterone can be used instead of GnRH agonists and antagonists in order to avert a premature LH surge during controlled ovarian stimulation (COS) protocol. Nonetheless, there is limited knowledge regarding its utilization. Thus, this study compared the effects of progesterone and GnRH antagonists (GnRH-ant) on premature LH surges and assisted reproductive technology (ART) results in infertile women undergoing ART. MATERIALS AND METHODS: In this clinical trial, the progesterone protocol (study group) and GnRH-ant protocol (control group) were tested in 300 infertile individuals undergoing IVF/ICSI. The main outcome was the number of oocytes retrieved. The secondary outcomes included premature LH rise/surge, the quantity of follicles measuring ≥ 10 and 14 mm, oocyte maturity and fertilization rate, the number of viable embryos, high-quality embryo rate and pregnancy outcomes. RESULTS: The study group exhibited a statistically significant increase in the number of retrieved oocytes, follicles measuring 14 mm or greater, and viable embryos compared to the control group (P < 0.05). The study group also increased oocyte maturity, chemical pregnancy rate, and clinical pregnancy rate (P < 0.05). Both groups had similar mean serum LH, progesterone, and E2 levels on trigger day. The control group had more premature LH rise than the study group, although this difference was not statistically significant. CONCLUSION: In conclusion, it can be stated that the progesterone protocol and the GnRH-ant protocol exhibit similar rates of sudden premature LH surge in infertile patients. However, it is important to note that the two regiments differ in their outcomes in ART. TRIAL REGISTRATION: This study was retrospectively registered in the Iranian website ( www.irct.ir ) for clinical trials registration ( http://www.irct.ir : IRCT-ID: IRCT20201029049183N, 2020-11-27).

Sex-dependent regulation of social avoidance by oxytocin signaling in the ventral tegmental area.

It has been hypothesized that oxytocin increases the salience of social stimuli, whether the valence is positive or negative, through its interactions with the ventral tegmental area (VTA). Indeed, oxytocin neurons project to the VTA and activate dopamine neurons that are necessary for social experiences with positive valence. Surprisingly, though, there has not been an investigation of the role of oxytocin in the VTA in mediating social experiences with negative valence (e.g., social stress). Given that there are sex differences in how oxytocin regulates the salience of positively-valenced social interactions, we hypothesized that oxytocin acting in the VTA also alters the salience of social stress in a sex-dependent manner. To test this, female and male Syrian hamsters were site-specifically infused with either saline, oxytocin (9 µM), or oxytocin receptor antagonist (90 µM) into the VTA. Subjects were then exposed to either no defeat or a single, 15 min defeat by one RA. The day following social defeat, subjects underwent a 5 min social avoidance test. There was an interaction between sex and drug treatment, such that the oxytocin antagonist increased social avoidance compared to saline treatment in socially stressed females, while oxytocin decreased social avoidance compared to saline treatment in socially stressed males. Contrary to expectations, these results suggest that oxytocin signaling generally acts to decrease social avoidance, regardless of sex. These sex differences in the efficacy of oxytocin and oxytocin receptor antagonists to alter negatively-valenced social stimuli, however, should be considered when guiding pharmacotherapies for disorders involving social deficits.

LH supplementation in IVF: human nature, politics, and elephants in the room.

Luteinizing hormone (LH) is present throughout the natural follicular phase. However, the debate is still not settled on whether LH is needed during ovarian stimulation in IVF. This commentary looks at the evolution of this debate, mentioning three elephants in the room that were ignored by the Pharma industry, professional organizations, and clinicians alike: 1. The different endocrinology between the long agonist and the antagonist protocols. 2. The fixed dose of the two most widely commercially available antagonist preparations, namely cetrorelix and ganirelix. 3. The fact that most research in this area uses population-based criteria, ignoring endocrine parameters. Individual genetics of the LH receptor gene may also serve to individualize LH needs during stimulation; however, the jury is still out regarding this approach. CONCLUSIONS: Individual endocrine and genetics parameters may shed meaningful light on the question of LH supplemental during ovarian stimulation.

Evolution of protein domain repertoires of CALHM6.

Calcium (Ca2 +) homeostasis is essential in conducting various cellular processes including nerve transmission, muscular movement, and immune response. Changes in Ca2 + concentration in the cytoplasm are significant in bringing about various immune responses such as pathogen clearance and apoptosis. Various key players are involved in calcium homeostasis such as calcium binders, pumps, and channels. Sequence-based evolutionary information has recently been exploited to predict the biophysical behaviors of proteins, giving critical clues about their functionality. Ion channels are reportedly the first channels developed during evolution. Calcium homeostasis modulator protein 6 (CALHM6) is one such channel. Comprised of a single domain called Ca_hom_mod, CALHM6 is a stable protein interacting with various other proteins in calcium regulation. No previous attempt has been made to trace the exact evolutionary events in the domain of CALHM6, leaving plenty of room for exploring its evolution across a wide range of organisms. The current study aims to answer the questions by employing a computational-based strategy that used profile Hidden Markov Models (HMMs) to scan for the CALHM6 domain, integrated the data with a time-calibrated phylogenetic tree using BEAST and Mesquite, and visualized through iTOL. Around 4,000 domains were identified, and 14,000 domain gain, loss, and duplication events were observed at the end which also included various protein domains other than CALHM6. The data were analyzed concerning CALHM6 evolution as well as the domain gain, loss, and duplication of its interacting partners: Calpain, Vinculin, protein S100-A7, Thioredoxin, Peroxiredoxin, and Calmodulin-like protein 5. Duplication events of CALHM6 near higher eukaryotes showed its increasing complexity in structure and function. This in-silico phylogenetic approach applied to trace the evolution of CALHM6 was an effective approach to get a better understanding of the protein CALHM6.

The clinical trial of alternative relugolix administration for uterine leiomyoma prior to surgically treatment: a study protocol for Non-Adverse Relugolix Administration (NARA) trial.

BACKGROUND: Uterine leiomyomas are common for reproductive-aged women and affect women's quality of life due to heavy menstrual bleeding or dysmenorrhea. Leiomyomas grow according to estradiol exposure and decrease after post-menopause. In case serious symptoms are caused by leiomyomas, pharmacotherapy or surgical treatment is proposed. Prior to surgical treatment, pharmacotherapies aimed at the reduction of leiomyoma and uterine volume or improvement of anemia are introduced to conduct minimum invasive surgery (i.e., to reduce blood loss or surgical duration). Recently, relugolix (40 mg orally once daily) as a gonadotropin-releasing hormone (GnRH) receptor antagonist has proved its sufficient efficacy in suppressing estradiol levels without the transient estradiol flare-up compared with GnRH agonist. However, long-term administration should not be permitted liable to for climacteric disorder or osteoporosis, and evidence is lacking on the actual efficacy and extent of adverse effects of the every-other-day dosing regimen. This trial aimed to prove non-inferiority in volume reduction effect on leiomyoma and safety (i.e., reduction of adverse effects) by every-other-day administration after 2 months of everyday administration compared to daily administration throughout the duration. METHODS: A minimization adaptive randomized control trial (RCT) will be conducted. Patients (over 20 years old) harboring leiomyoma who will be undergoing surgical treatment will be invited to participate. Patients who are enrolled in the intervention group will receive every-other-day administration for 16 weeks after 8 weeks of daily administration. Patients who are enrolled in the control group will receive daily throughout the 24 weeks. The primary outcome is the leiomyoma volume reduction, and the secondary endpoints are the reduction of uterine volume, the occurrence of the climacteric disorder, genital bleeding days, change rate of serum hormone or bone turnover markers, and bone mineral density after 24 weeks compared to before administration. DISCUSSION: This study aims to prove both the non-inferiority in leiomyoma volume reduction and superiority in adverse effects occurrence reduction, which will provide a novel method to escape adverse effects while maintaining the effect of leiomyoma reduction. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051230078. Registered on 26 July 2023.

Oocyte competence is comparable between progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) and GnRH-antagonist protocols: A matched case-control study in PGT-A cycles.

OBJECTIVE: To outline oocyte competence after progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) compared to conventional GnRH-antagonist protocol. STUDY DESIGN: Retrospective matched case-control study involving advanced-maternal-age women undergoing ICSI with PGT-A. 89 NETA-PPOS were matched with 178 control patients based on maternal age and ovarian reserve biomarkers. Both groups underwent recombinant-FSH OS with GnRH-agonist ovulation trigger and collected ≥1 MII. In the study group, NETA (10 mg/day) was administered orally starting from day2 of the menstrual cycle. Euploid blastocyst rate per cohort of metaphase-II oocytes (EBR per MII) was the primary outcome. All other embryological and clinical outcomes were reported. Gestational age, birthweight and length were also assessed. RESULTS: The EBR per MII was comparable among PPOS and control (13.9 % ± 19.3 % versus 13.3 % ± 17.9 %; the sample size allowed to exclude up to a 10 % difference). Blastocysts morphology and developmental rate were similar. No difference was reported for all clinical outcomes among the 61 and 107 vitrified-warmed euploid single blastocyst transfers respectively conducted. The cumulative live birth delivery rate per concluded cycles was also comparable (24.7 % versus 21.9 %). Neonatal outcomes were analogous. CONCLUSIONS: Oocyte competence after NETA-PPOS and standard OS is comparable. This evidence is reassuring and, because of its lower cost and possibly higher patients' compliance, supports PPOS administration whenever the patients are indicated to freeze-all (e.g., fertility preservation, PGT-A, oocyte donation). More data are required about follicle recruitment, oocyte yield, gestational and perinatal outcomes. Randomized-controlled-trials are advisable to confirm our evidence.

The effects of flexible short protocol with gonadotropin-releasing hormone antagonist on preventing premature ovulation in poor responders.

PURPOSE: The proportion of patients with poor ovarian response (POR) is increasing, but effective treatment remains a challenge. To control the hidden peaks of luteinizing hormone (LH) and premature ovulation for poor responders, this study investigated the efficacy of flexible short protocol (FSP) with gonadotropin-releasing hormone antagonist (GnRH-ant) on trigger day. METHODS: The 662 cycles of POR patients were retrospectively analyzed. The cohort was divided into control and intervention groups. The intervention group (group A) with 169 cycles received a GnRH-ant given on trigger day. The control (group B) with 493 cycles received only FSP. The clinical outcomes of the two groups were compared. RESULTS: Compared with group B, with gonadotropin-releasing hormone antagonist (GnRH-ant) on trigger day in group A the incidences of spontaneous premature ovulation decreased significantly (2.37% vs. 8.72%, P < 0.05). The number of fresh embryo-transfer cycles was 45 in group A and 117 in group B. There were no significant differences in clinical outcomes, including implantation rate, clinical pregnancy rate, live birth rate and the cumulative live birth rate (12.0% vs. 9.34%; 22.22% vs. 21.93%; 17.78% vs. 14.91%; 20.51% vs. 20%, respectively; P > 0.05) between the two group. CONCLUSION: FSP with GnRH-ant addition on trigger day had no effect on clinical outcomes, but could effectively inhibit the hidden peaks of luteinizing hormone (LH) and spontaneous premature ovulation in POR. Therefore, it is an advantageous option for POR women.

GnRH antagonist protocol versus progestin-primed ovarian stimulation in patients with polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: The aim of this meta-analysis was comparing the efficacy of GnRH antagonist (GnRH-ant) protocol and progestin-primed ovarian stimulation (PPOS) in polycystic ovarian syndrome (PCOS) women. METHODS: A search was conducted from PubMed, Embase, The Cochrane library, Web of Science, and Scopus databases to collect clinical papers regarding GnRH-ant protocol and PPOS protocol from inception to September 2023. Subsequently, the retrieved documents were screened, and the content of the documents that conformed to the requirements was extracted. Moreover, statistical meta-analyses were conducted using the RevMan 5.4 software. Furthermore, with the use of a star-based system and the Cochrane handbook, the methodological quality of the covered papers was evaluated on the Ottawa-Newcastle scale. RESULTS: A total of eight papers were covered in the meta-analysis, with 2156 PCOS women enrolled (i.e., 1085 patients in the GnRH-ant protocol group and 1071 patients in the PPOS group). As indicated by the meta-analysis results, the PPOS group was correlated with a lower risk of ovarian hyperstimulation syndrome (OHSS) (SMD = 9.24, [95% CI: (2.50, 34.21)], P = 0.0009), more gonadotropin (Gn) dose (SMD = - 0.34, [95% CI: (- 0.56, - 0.13)], P = 0.002) compared with GnRH-ant group. No statistical difference was identified on the oocytes condition and pregnancy outcomes. CONCLUSIONS: As revealed by the data of this study, the progesterone protocol is comparable with the GnRH-ant protocol in oocytes condition and clinical outcomes. The progestin-primed ovarian stimulation could serve as an alternative for polycystic ovarian syndrome women who have failed in GnRH antagonist protocol. The above-described conclusions should be verified by more high-quality papers due to the limitation of the number and quality of included papers. TRIAL REGISTRATION: PROSPERO registration: CRD42023411284.

Efficacy of the long-acting gonadotropin-releasing hormone agonist long protocol on IVF/ICSI outcomes of patients with repeated implantation failure.

OBJECTIVE: The present study aimed to investigate the effect of long-acting gonadotropin-releasing hormone agonist (GnRHa) long protocol on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes of patients with repeated implantation failure (RIF). METHODS: The present study was carried out from June 1, 2016 to June 30, 2021. A total of 665 patients with RIF were enrolled into the study and classified by the ovarian stimulation protocols. The outcome parameters were compared in each group. In addition, we evaluated the expression of homeobox A10 (HOXA10), integrin ß3 and leukemia inhibitory factor (LIF) in endometrial tissues between groups by quantitative RT-PCR. RESULTS: Patients who received the long-acting GnRHa long protocol had significantly higher clinical pregnancy rates (58.0%, 41.7% and 39.9%, respectively; P = 0.008 and 0.003), implantation rates (38.1%, 30.3%, and 30.1%, respectively; P = 0.001 and <0.001) and live birth rates (50.3%, 36.3%, and 31.3%, respectively; P = 0.020 and 0.002) compared with the short-acting GnRHa long protocol and GnRH antagonist protocol. In addition, we found that long-acting GnRHa could improve the expression of HOXA10 (P < 0.05). CONCLUSION: The long-acting GnRHa long protocol could improve endometrial receptivity and IVF/ICSI clinical outcomes of RIF patients compared with the short-acting GnRHa long protocol and GnRH antagonist protocol.

Steroid profile in patients with breast cancer and in mice treated with mifepristone.

Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

Live birth rate of gonadotropin-releasing hormone antagonist versus luteal phase gonadotropin-releasing hormone agonist protocol in IVF/ICSI: a systematic review and meta-analysis.

In vitro fertilization (IVF) and embryo transfer and intracytoplasmic sperm injection (ICSI) have allowed millions of infertile couples to achieve pregnancy. As an essential part of IVF/ICSI enabling the retrieval of a high number of oocytes in one cycle, controlled ovarian stimulation (COS) treatment mainly composes of the standard long gonadotrophin-releasing hormone agonist (GnRH-a) protocol and the gonadotrophin-releasing hormone antagonist (GnRH-ant) protocol. However, the effectiveness of GnRH-ant protocol is still debated because of inconsistent conclusions and insufficient subgroup analyses. This systematic review and meta-analysis included a total of 52 studies, encompassing 5193 participants in the GnRH-ant group and 4757 in the GnRH-a group. The findings of this study revealed that the GnRH-ant protocol is comparable with the long GnRH-a protocol when considering live birth as the primary outcome, and it is a favourable protocol with evidence reducing the incidence of ovarian hyperstimulation syndrome in women undergoing IVF/ICSI, especially in women with polycystic ovary syndrome. Further research is needed to compare the subsequent cumulative live birth rate between the two protocols among the general and poor ovarian response patients since those patients have a lower clinical pregnancy rate, fewer oocytes retrieved or fewer high-grade embryos in the GnRH-ant protocol.

Efficacies of different ovarian hyperstimulation protocols in elderly patients with poor ovarian response.

OBJECTIVE: The aim of the study was to explore which controlled ovarian hyperstimulation (COH) protocol is most suitable for elderly patients with poor ovarian response (POR) undergoing assisted reproductive technology (ART). PATIENTS AND METHODS: This retrospective cohort study evaluated clinical data from 2,660 patients from January 2017 and October 2020. The patients were divided into three groups: modified Gonadotropin-releasing hormone (GnRH) agonist protocol (1,225 patients), GnRH antagonist protocol (1,038 patients), and Mild stimulation protocol (397 patients). Clinical variables and pregnancy outcomes were compared among the three groups. RESULTS: The GnRH agonist protocol was associated with a higher number of oocyte number (3.99±2.82 vs. 3.02±1.34 vs. 2.51±1.14, p<0.001), a higher number of transferable embryos (1.39±1.32 vs. 1.24±1.24 vs. 1.18±1.11, p = 0.035), higher cumulative live birth rate [26.53% (323/1,225) vs. 22.44% (233/1,038) vs. 21.66% (86/397), p = 0.043], lower OHSS rate [5.14% (63/1,225) vs. 3.08% (32/1,038) vs. 2.02% (8/397), p = 0.005] than GnRH antagonist protocol and Mild stimulation protocol, the Mild stimulation protocol was associated with higher miscarriage rates [30.4% (24/71) vs. 25.0% (33/192) vs. 29.6% (35/168), p = 0.014] than the other two groups. CONCLUSIONS: The three protocols can be used in elderly patients with POR; however, if patients require more frozen-thawed embryo transfers to achieve better cumulative live birth rates, the modified GnRH agonist protocol may be the better choice. It should be emphasized that the mild stimulation had a slightly higher miscarriage rate than the other two groups.

A review of phase II and III drugs for the treatment and management of endometriosis.

INTRODUCTION: Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy. AREAS COVERED: The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis. EXPERT OPINION: Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.

Analysis of controlled ovarian hyperstimulation protocols in women over 35 years old with poor ovarian response: a real-world study.

The objective of this study was to investigate the optimal controlled ovarian hyperstimulation (COH) protocol for patients aged 35 and above with poor ovarian response (POR), utilizing real-world data. This retrospective cohort study examined clinical information from a total of 4256 patients between January 2017 and November 2022. The patients were categorized into three groups: modified GnRH agonist protocol (2116 patients), GnRH antagonist protocol (1628 patients), and Mild stimulation protocol (512 patients). Comparative analysis was conducted on clinical variables and pregnancy outcomes across the three groups. The GnRH agonist protocol was associated with a higher number of oocyte number (4.02 ± 2.25 vs. 3.15 ± 1.52 vs. 2.40 ± 1.26, p < 0.001), higher number of transferable embryos (1.73 ± 1.02 vs. 1.35 ± 1.22 vs. 1.10 ± 0.86, p = 0.016), higher cumulative live birth rate 28.50(603/2116) vs. 24.94(406/1628) vs. 20.51(105/512), p < 0.001) than GnRH antagonist protocol and Mild stimulation protocol, the Mild stimulation protocol was associated with a higher miscarriage rates 16.27(62/381) vs. 16.61(48/289) vs. 32.22(29/90), p = 0.001) than the other two groups. Therefore, it can be concluded that all three protocols can be used in patients over 35 years old with poor ovarian response. However, if patients require more frozen-thawed embryo transfers to achieve better cumulative live birth rates, the modified GnRH agonist protocol may be the preferable option.