Search

BACKGROUND Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OBJECTIVE AND RATIONALE A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates. SEARCH METHODS The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included. OUTCOMES The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates. WIDER IMPLICATIONS Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

Does late-follicular phase progesterone elevation have a deleterious effect on embryo euploidy, blastocyst formation rate and cumulative live birth rates (CLBR)?A multicentre retrospective cross-sectional study including infertile patients aged 18-40 years who underwent ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol and preimplantation genetic testing for aneuploidies (PGT-A) followed by a freeze-all strategy and euploid embryo transfer between August 2017 and December 2019. The sample was stratified according to the progesterone concentrations on the day of trigger: normal (≤1.50 ng/ml) and high (1.50 ng/ml). Moreover, sensitivity analyses were performed to determine whether different conclusions would have been drawn if different cut-offs had been adopted. The primary outcome was the embryo euploidy rate. Secondary outcomes were the blastocyst formation rate, the number of euploid blastocysts and CLBR.Overall 1495 intracytoplasmic sperm injection PGT-A cycles were analysed. Late-follicular phase progesterone elevation was associated with significantly higher late-follicular oestradiol concentrations (2847.56 ± 1091.10 versus 2240.94 ± 996.37 pg/ml, P 0.001) and significantly more oocytes retrieved (17.67 ± 8.86 versus 12.70 ± 7.00, P 0.001). The number of euploid embryos was significantly higher in the progesterone elevation group (2.32 ± 1.74 versus 1.86 ± 1.42, P = 0.001), whereas the blastocyst formation rate (47.1% [43.7-50.5%] versus 51.0% [49.7-52.4%]), the embryo euploidy rate (48.3% [44.9-51.7%] versus 49.1% [47.7-50.6%], the live birth rate in the first frozen embryo transfer (34.1% versus 31.1%, P = 0.427) and CLBR (38.9% versus 37.0%, P = 0.637) were not significantly different between the two groups.Euploidy rate and CLBR do not significantly differ among PGT-A cycles with and without late-follicular progesterone elevation in a freeze-all approach.

Objective To report a clinical pregnancy resulting from intracytoplasmic sperm injection of prematurely ovulated oocytes retrieved from the posterior cul-de-sac. Design Case report. Setting Academic center. Patient(s) A 40-year-old nulligravid woman underwent ovarian stimulation for in vitro fertilization (IVF). Daily injections of gonadotropin-releasing hormone antagonist were initiated on cycle day 8. A 10,000 IU dose of human chorionic gonadotropin was administered on cycle day 15 to trigger follicular maturation. The estradiol and luteinizing hormone levels on the trigger day were 1528 pg/mL and 2.4 mIU/mL, respectively. The patient underwent oocyte retrieval 35 hours after the trigger. Transvaginal sonography at the time of the retrieval revealed a large pocket of free fluid in the posterior cul-de-sac. Only 3 follicles measuring 10–12 mm were noted in both ovaries. No lead follicles were visualized. Intervention(s) Aspiration of free fluid from the posterior cul-de-sac. Main Outcome Measure(s) Clinical pregnancy. Result(s) The fluid in the posterior cul-de-sac was aspirated, and 3 mature oocytes were retrieved. Aspiration of the smaller ovarian follicles measuring 10–12 mm did not yield oocytes. All mature oocytes retrieved from the posterior cul-de-sac were fertilized with intracytoplasmic sperm injection. Three cleavage-stage embryos were transferred 3 days later. A single intrauterine pregnancy with cardiac activity was confirmed at a gestational age of 7 weeks. Conclusion(s) In the setting of premature ovulation, aspiration of free fluid from the posterior cul-de-sac can result in the retrieval of mature oocytes, which may result in clinical pregnancies.

Postoperative hormone therapy for hormone-sensitive patients with breast cancer is important to prevent a recurrence. As hormone therapy does not induce infertility in patients, fertility-preserving therapy is not provided during treatment. Here, however, we performed controlled ovarian stimulation and embryo freezing for fertility preservation under the influence of a sustained-release gonadotropin-releasing hormone agonist in a patient with breast cancer whose postoperative treatment plan was changed from hormone therapy to chemotherapy. After oocyte retrieval, the patient developed treatment-resistant severe symptomatic ovarian hyperstimulation syndrome. Following treatment with oral gonadotropin-releasing hormone antagonist, her symptoms immediately improved, and she could receive chemotherapy on schedule.

OBJECTIVE To determine the effects of changes in serum luteinizing hormone (LH) levels in the early stages of the gonadotropin-releasing hormone antagonist (GnRH-A) protocol on in vitro fertilization and embryo transfer/intracytoplasmic sperm injection clinical outcomes. METHODS Data from 2116 fresh embryo transfer cycles with the GnRH-A protocol were retrospectively analyzed. Patients were divided into two groups, ΔLH-increased and ΔLH-decreased, according to changes in serum LH levels on the day of GnRH-A addition compared with that on the start day of ovarian stimulation. Patients in whom ΔLH increased were categorized according to early-onset LH increases (serum LH level ≥10 mIU/mL or twice the baseline). RESULTS ΔLH increased and decreased in 14.9% and 85.1% of patients, respectively. The fertilization rate was lower, and fewer oocytes were retrieved in patients with increased ΔLH compared to those with decreased ΔLH (p .05). CONCLUSIONS Early increases in LH levels during GnRH-A protocol might affect the number of oocytes retrieved, but not the clinical outcomes.

Objective The aim of this retrospective case-control study was to analyze the effect of administering indomethacin after triggering final oocyte maturation in patients with poor ovarian response (POR) on the cycle cancellation rate due to premature ovulation (PO), the number of oocytes retrieved and the clinical outcomes of IVF cycles. Study Design A total of 214 patients with POR, diagnosed according to the Bologna criteria, who underwent fresh IVF cycle via flexible gonadotrophin-releasing hormone antagonist (GnRH-ant) protocol were enrolled in the study. The control group consisted of 100 patients, whereas the indomethacin group included 114 patients who received 100 mg rectal indomethacin administered twice within the same day (twelve hours apart) –starting at twelve hours after triggering. Cycle cancelation rates (CCR), number of oocytes retrieved (nOR), implantation rates (IR), biochemical pregnancy (BP) and clinical pregnancy loss rates (CPL), ongoing pregnancy rates (OPR) and live birth rates (LBR) were compared between the indomethacin and control groups. Results The CCR rate was significantly lower in the indomethacin group (1.8%) compared to the control group (1.8% vs %12%, p = 0.01). In the control group, those with cycle cancellation were older than those without cycle cancellation (mean age 42.2 ± 2.3 years vs. 39.36 ± 4.3 years, p = 0.001) and had lower anti-Mullerian hormone levels and lower antral follicle count (0.59 ± 0.2 ng/mL vs 0.79 ± 0.2 ng/mL, p = 0.001 and 4 ± 0.6 vs 5.7 ± 1.7, p = 0.001, respectively). In multivariable analysis, when the dependent variable in the logistic regression model was coded as the absence of cycle cancellation, it was observed that only indomethacin had a statistically significant effect on cycle cancellation (β = −1.931, standard error = 0.832, Exp(B) = 0.145, p = 0.020). nOR was higher in the indomethacin group than control group but the difference did not reach significance (p = 0.07). Moreover, the IR, OPR and LBR, BP and CPL values were similar in the indomethacin and control groups (p > 0.05). Conclusions Based on data from this study, it can be concluded that indomethacin reduces cycle cancelation due to PO in patients with POR –without compromising implantation and pregnancy rates. However, further randomized controlled trials with larger sample sizes are required to clarify the definitive effect of indomethacin in the treatment of patients with POR.

Teverelix trifluoroacetate is a decapeptide, gonadotropin-releasing hormone antagonist that binds competitively and reversibly to gonadotropin-releasing hormone receptors in the pituitary gland, resulting in immediate suppression of luteinizing hormone and follicle-stimulating hormone, which in turn causes a very rapid decrease in testosterone production in the Leydig cells of the testes in men and in estradiol in the ovaries in women. This phase 1 clinical study was an open-label, parallel-design, single-center, single-dose study in older, healthy male subjects. Following injection, teverelix is released into the systemic circulation in a biphasic manner. An initial rapid phase is followed by a slow-release phase thought to be due to the formation of a depot, which limits the diffusion of teverelix into the blood. The release characteristics differ significantly for the subcutaneous (SC) and intramuscular (IM) routes. Teverelix maximum concentration and exposure increased in an approximately dose-proportional manner across the 60 to 120 mg SC doses. All 3 pharmacodynamic end points (luteinizing hormone, follicle-stimulating hormone, and total testosterone) showed reductions that were more prolonged following the 90 mg IM administration compared to 90 mg SC administration.

Serum progesterone levels performed prior to oocyte pick-up is commonly used to guide embryo transfer in in-vitro fertilization (IVF) cycles, as elevated levels can negatively influence pregnancy outcomes. However, levels associated with normal pregnancies should trigger clinicians to consider alternative causes such as a pre-existing pregnancy. We report a case of a 37-year-old patient who underwent controlled ovarian hyperstimulation in a gonadotrophin-releasing hormone antagonist cycle while having an undetected early pregnancy. No oocytes were retrieved at oocyte retrieval despite adequate follicular responses. Her serum progesterone level on the day of her trigger injection was 57.8 nmol/L. She was found to have a pregnancy of unknown location, detected 3 weeks after her oocyte retrieval and was subsequently treated with systemic methotrexate. J Med Cases. 2021;12(9):369-372 doi: https://doi.org/10.14740/jmc3752

This analysis aimed to compare the efficacy of oral contraceptive pill (OCP) pretreatment for gonadotropin-releasing hormone antagonist (GnRH-ant) protocol, especially for different responder women. The PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases were searched for trials on with and without OCP pretreatment before stimulation with gonadotropins. The standardized mean differences (SMDs) or pooled risk ratios (RRs) with 95% confidence intervals (CIs) were used for statistical analysis. Fifteen studies with 5326 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were summarized. The clinical pregnancy rate, moderate or severe ovarian hyper-stimulation syndrome (OHSS) rate, and miscarriage rate was not found to be significantly different between patients with and those without OCP pretreatment, even after sensitivity analyses. In addition, there were still no statistically significant differences for the subgroups analyses of hyper-responders, poor responders, and normal responders. No significant differences were detected in the duration of ovarian stimulation, gonadotropin dose consumed, endometrial thickness on day of oocyte collection, or number of oocytes. This meta-analysis did not find an unequivocally beneficial effect of OCP pretreatment for different responder women with using a GnRH-ant protocol. The clinician should weigh the advantages and disadvantages of OCP pretreatment and guide the treatment scheduling considering the patient���s own situation.

Research question Can luteolysis-targeted drugs, gonadotrophin-releasing hormone antagonist (GnRH-ant), mifepristone and letrozole, administered separately or in combination, prevent the progression of ovarian hyperstimulation syndrome (OHSS) in a rat model? Design Thirty-six female Wistar rats were randomly divided into six groups, including control group (OHSS group, ovarian hyperstimulation-induced OHSS); GnRH-ant group (OHSS with GnRH-ant treatment); mifepristone group (OHSS with mifepristone treatment); letrozole group (OHSS with letrozole treatment); combination group (OHSS with GnRH-ant, mifepristone and letrozole treatment in combination). The main outcomes were the alterations in OHSS-related indices, including ovarian weight, vascular permeability, serum oestradiol and progesterone levels, corpus luteum proportion and diameter, ovarian vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), caspase-3 and cleaved caspase-3 levels. Results No significant difference was found in body weight gain among the six groups. Compared with the control group, the OHSS group showed significant increases in all OHSS-related indices. GnRH-ant treatment showed decreases in vascular permeability, serum oestradiol level, corpus luteum diameter, ovarian VEGF /IL-6 mRNA levels, and increases in ovarian caspase-3 and cleaved caspase-3 levels. Mifepristone treatment demonstrated reduction in serum progesterone level and corpus luteum diameter, and elevation in ovarian caspase-3 and cleaved caspase-3 levels. Letrozole treatment displayed a decline in serum oestradiol level and corpus luteum diameter, and up-regulation in ovarian caspase-3 and cleaved caspase-3 levels. The combination treatment by GnRH-ant, mifepristone and letrozole showed enhanced synergistic effect on reducing OHSS-related indices. Conclusions GnRH-ant, mifepristone and letrozole are beneficial in preventing the progression of OHSS through different luteolytic mechanisms. Cocktail style treatment shows enhanced synergistic effect on preventing the progression of OHSS.

In mice, ovarian stimulation via hormone administration is an effective method for obtaining many ova simultaneously, but its effect is reduced by the influence of aging. In this study, we demonstrate that this problem can be improved by administering the gonadotropin-releasing hormone antagonist Cetrorelix prior to ovarian stimulation. Before 12-month-old female mice were injected with 5 IU pregnant mare serum gonadotropin and 5 IU human chorionic gonadotropin, we administered 5 µg/kg Cetrorelix for 7 consecutive days (7 times) or 3 times once every 3 days. As a result, 8.7 ± 1.9 (mean ± standard error of the mean, n=10) and 9.8 ± 1.3 (n=10) oocytes were obtained, respectively, as opposed to 4.7 ± 1.2 oocytes (n=9) in the case of no administration. Collagen staining of ovarian tissue showed that Cetrorelix administration reduced the degree of fibrosis, which improved ovarian function. In addition, equivalent fertilization and fetal development rates between control and Cetrorelix-treated aged mouse-derived oocytes were confirmed by in vitro fertilization and embryo transfer (Fertilization rate; control: 92.2% vs. 3 times: 96.9%/7 times: 88.5%, Birth rate; control: 56.4% vs. 3 times: 58.3%/7 times: 51.8%), indicating the normality of the obtained oocytes. It is concluded that Cetrorelix improved the effect of superovulation in aged mice without reducing oocyte quality. This procedure will contribute to animal welfare by extending the effective utilization of aged female breeding mice.

Objective Ovarian response from a conventional ovarian stimulation protocol is a crucial step in IVF/ICSI treatments. This ovarian response encompasses a wide range of outcomes at the extremes, leading to either excessive responses with the risk of life-threatening conditions like ovarian hyperstimulation syndrome (OHSS), or poor ovarian response (POR) with poor outcomes. This study aims to integrate biochemical, ultrasonographic and demographic parameters into a mathematical formula able to predict ovarian response to stimulation in IVF/ICSI in gonadotropin-releasing hormone (GnRH) antagonist protocols. Methods This retrospective analysis included 147 patients submitted to an ovarian stimulation protocol combining recombinant FSH and gonadotropin-releasing hormone antagonist. All the parameters were correlated with the Spearman Rho and Pearson´s correlation coefficient. Once the data was normalized, we used the multiple linear regression models, checking the results with the progressive discriminating analysis. Results We classified the database according to the correlation with the number of oocytes retrieved; the progressive discriminating analysis resulted in the following equation: oocytes retrieved = 2.312-0.130 (FSH) + 0.562 (AFC). Conclusions The incorporation of 2 ovarian reserve parameters into a regression equation enables knowing the number of retrieved oocytes in each patient with 80.5% sensitivity and 55.4% specificity.

Aim. To analyze the changes in the indicators of economic availability of anticancer drugs used for the treatment of lymphogranulomatosis in Ukraine.Materials and methods. The individual and group indices of average retail prices, the coefficients of the adequacy of the solvency and the economic availability of anticancer drugs at different levels of the ATC-classification system were studied. Historical, analytical-comparative, systemic, logical, hypothetical-deductive and other methods of scientific analysis and search were used.Results. Based on the results of the analysis of the values and changes in the indicators of individual and group price indices for anticancer drugs an increase in the size of average retail prices in September 2020 was determined compared to the same period in 2019. Top three leading groups by the growth in the group price index in 2020 were drugs from the group of L01B – Antimetabolites, L01D – Cytotoxic antibiotics and related drugs, and L02A-Hormones and related substances. According to data of 2019, the group of leaders indicated included drugs representing L02A-Hormones and related substances, L01X – Other antineoplastic agents, L02B – Hormone antagonists and similar agents. It was proven that in 2020 the prices for drugs belonging to the groups of L02B – hormone antagonists and similar drugs increased to a lesser extent, and in 2019 - for L01C-plant alkaloids and other herbal drugs. The fact was determined that there was a decrease in the economic availability of anticancer drugs in 2020 compared to the indicators observed in 2019. Thus, for example, the average value of indicators for September 2019 was 4.75, and in 2020 – 5.38. The D indicator in 2019 was 1.20, while in 2020 it was only 0.79. It was proven that in 2020 practically for all groups of anticancer drugs in accordance with the level II of the ATC classification system a decrease in economic availability was observed. Thus, the least available drugs in 2020 were trade names from the group of L02B – hormone antagonists and similar drugs. An exception from this list was only drugs from the group of L01D – Cytotoxic antibiotics and related drugs (D = 1.01). According to the comparative analysis of the TOP-3 groups of anticancer drugs with the highest D values in 2019 and 2020, it was found that drugs of such groups as L01C-Alkaloids of plant origin and other drugs of plant origin and L01A – Alkylating compounds were present in both ratings.Conclusions. Taking into account the negative trends towards a decrease in the level of economic availability of anticancer drugs in 2020 it is necessary to systematically consider the issues of strengthening the positions of the domestic drug manufacturer in this segment of the pharmaceutical market at the state level, primarily due to the introduction of state import substitution programs.

Purpose In patients who had advanced endometriosis, we use different protocols including GnRH agonist, GnRH antagonist and progestin-primed ovarian stimulation (PPOS) protocols to assess live-birth congenital malformations delivered after in vitro fertilization (IVF) and vitrified embryo transfer cycles. Methods A retrospective cohort study is conducted by us. It includes 1495 live-born infants in maternal endometriosis. From January 2010 to January 2017, we brought into infants who underwent either gonadotropin-releasing hormone agonist long protocol, gonadotropin-releasing hormone antagonist protocol or PPOS. We chose neonatal outcomes and congenital malformations as our major measures. Results Neonatal outcomes, as well as congenital malformations, were considered as the main measures, and gestational age, birth weight, birth length, multiple births and early neonatal death are included. All groups were comparable. The GnRH antagonist group (1.41%) and the GnRH antagonist protocol group (1.8%) had the same incidence of live-birth defects as the PPOS groups (1.33%) were similar. There were no apparent differences when it came to congenital malformations among the three groups. Multivariate logistic regression showed that infertility-time factors as well as multiple births combined to add the risk of congenital malformations; the adjusted odds were 1.143 (95% confidence interval [CI]: 0.988–1.323) and 3.253 (95% CI: 1.359–7.788). Besides, no association was found among various ovarian stimulations as well as congenital birth defect programs, maternal age, body mass index, parity or infant sex. Conclusion This study suggests that, in contrast to conventional ovarian stimulation, PPOS neither has any effect on neonatal outcomes in IVF adverse effects nor does it elevate the rate of congenital malformations in late endometriosis. However, randomized controlled trials of the long-term outcomes of children born after PPOS protocols for maternal endometriosis are needed and the follow-up studies were conducted to confirm this result.

Background: Premature luteinizing hormone (LH) surge is one of the causes for assisted reproductive technology cycle cancellation, and it is needed to find novel approaches with improved efficacy and safety profile. Objective: To compare the effects of Duphaston and Cetrotide on the prevention of premature LH surge and characteristics of retrieved follicles and embryos in women undergoing intracytoplasmic sperm injection. Materials and Methods: In this retrospective cross-sectional study, 200 patients who were administrated recombinant follicle-stimulating hormone from the third day of menstruation cycle were included. When the follicular diameter reached above 13-14 mm, Cetrotide was prescribed in the control group, while in the case group, Duphaston was taken orally from the third day of cycle. The retrieved oocytes were fertilized in vitro by intracytoplasmic sperm. The level of hormones on the third day of menstruation and the characteristic of follicles, oocytes, and embryos were compared between the two groups. Results: Duphaston successfully inhibits premature LH surge. There was no significant difference in the level of follicle-stimulating hormone, estradiol, and LH between the case and control groups (p > 0.05). However, results also showed that Duphaston causes more oocyte retrieval in comparison with Cetrotide (p = 0.04). Although, the number of follicles above 14 mm, mature oocyte, and the total number of viable embryos in the case group was slightly higher, it did not reach a significant difference compared with the control group (p > 0.05). Conclusion: Duphaston could be used as an appropriate medication instead of gonadotropin-releasing hormone antagonists in women undergoing controlled ovarian hyperstimulation. Duphaston prescription not only prevents premature LH surge but also improves the number of retrieved oocytes. Key words: Duphaston, Cetrorelix, Dydrogesterone, COH, GnRh antagonis.

Objective To determine the cost of achieving a live birth after first transfer using highly purified human menotropin (HP-hMG) or recombinant follicle-stimulating hormone (FSH) for controlled ovarian stimulation in predicted high-responder patients in the Menopur in Gonadotropin-releasing hormone Antagonist Single Embryo Transfer–High Responder (MEGASET-HR) trial. Design Cost minimization analysis of trial results. Setting Thirty-one fertility centers. Patient(s) Six hundred and nineteen women with serum antimullerian hormone ≥5 ng/mL. Intervention(s) Controlled ovarian stimulation with HP-hMG or recombinant FSH in a gonadotropin-releasing hormone (GnRH) antagonist assisted reproduction cycle where fresh transfer of a single blastocyst was performed unless ovarian response was excessive whereupon all embryos were cryopreserved and patients could undergo subsequent frozen blastocyst transfer within 6 months of randomization. Main Outcome Measure(s) Mean cost of achieving live birth after first transfer (fresh or frozen). Result(s) First-transfer efficacy, defined as live birth after first fresh or frozen transfer, was 54.5% for HP-hMG and 48.0% for recombinant FSH (difference 6.5%). Average cost to achieve a live birth after first transfer (fresh or frozen) was lower with HP-hMG compared with recombinant FSH. For fresh transfers, the cost was lower with HP-hMG compared with recombinant FSH. The average cost to achieve a live birth after first frozen transfer was also lower in patients treated with HP-hMG compared with recombinant FSH. Conclusion(s) Treatment of predicted high-responders with HP-hMG was associated with lower cost to achieve a live birth after first transfer compared with recombinant FSH. Clinical Trial Registration Number NCT02554279.

STUDY QUESTION Is one cycle of IVM non-inferior to one cycle of conventional in IVF with respect to live birth rates in women with high antral follicle counts (AFCs)? SUMMARY ANSWER We could not demonstrate non-inferiority of IVM compared with IVF. WHAT IS KNOWN ALREADY IVF with ovarian hyperstimulation has limitations in some subgroups of women at high risk of ovarian stimulation, such as those with polycystic ovary syndrome. IVM is an alternative ART for these women. IVM may be a feasible alternative to IVF in women with a high AFC, but there is a lack of data from randomized clinical trials comparing IVM with IVF in women at high risk of ovarian hyperstimulation syndrome. STUDY DESIGN, SIZE, DURATION This single-center, randomized, controlled non-inferiority trial was conducted at an academic infertility center in Vietnam from January 2018 to April 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 546 women with an indication for ART and a high AFC (≥24 follicles in both ovaries) were randomized to the IVM (n = 273) group or the IVF (n = 273) group; each underwent one cycle of IVM with a prematuration step versus one cycle of IVF using a standard gonadotropin-releasing hormone antagonist protocol with gonadotropin-releasing hormone agonist triggering. The primary endpoint was live birth rate after the first embryo transfer. The non-inferiority margin for IVM versus IVF was −10%. MAIN RESULTS AND THE ROLE OF CHANCE Live birth after the first embryo transfer occurred in 96 women (35.2%) in the IVM group and 118 women (43.2%) in the IVF group (absolute risk difference –8.1%; 95% confidence interval (CI) –16.6%, 0.5%). Cumulative ongoing pregnancy rates at 12 months after randomization were 44.0% in the IVM group and 62.6% in the IVF group (absolute risk difference –18.7%; 95% CI –27.3%, –10.1%). Ovarian hyperstimulation syndrome did not occur in the IVM group, versus two cases in the IVF group. There were no statistically significant differences between the IVM and IVF groups with respect to the occurrence of pregnancy complications, obstetric and perinatal complications, preterm delivery, birth weight and neonatal complications. LIMITATIONS, REASONS FOR CAUTION The main limitation of the study was its open-label design. In addition, the findings are only applicable to IVM conducted using the prematuration step protocol used in this study. Finally, the single ethnicity population limits the external generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS Our randomized clinical trial compares live birth rates after IVM and IVF. Although IVM is a viable and safe alternative to IVF that may be suitable for some women seeking a mild ART approach, the current study findings approach inferiority for IVM compared with IVF when cumulative outcomes are considered. Future research should incorporate multiple cycles of IVM in the study design to estimate cumulative fertility outcomes and better inform clinical decision-making. STUDY FUNDING/COMPETING INTEREST(S) This work was partly supported by Ferring grant number 000323 and funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) and by the Fund for Research Flanders (FWO). LNV has received speaker and conference fees from Merck, grant, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring; TMH has received speaker fees from Merck, Merck Sharp and Dohme, and Ferring; RJN has received conference and scientific board fees from Ferring, is a minor shareholder in an IVF company, and receives grant funding from the National Health and Medical Research Council (NHMRC) of Australia; BWM has acted as a paid consultant to Merck, ObsEva and Guerbet, and is the recipient of grant money from an NHMRC Investigator Grant; RBG reports grants and fellowships from the NHMRC of Australia; JS reports lecture fees from Ferring Pharmaceuticals, Biomérieux, Besins Female Healthcare and Merck, grants from Fund for Research Flanders (FWO), and is co-inventor on granted patents on CAPA-IVM methodology in the US (US10392601B2) and Europe (EP3234112B1); TDP, VQD, VNAH, NHG, AHL, THP and RW have no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER NCT03405701 (www.clinicaltrials.gov). TRIAL REGISTRATION DATE 16 January 2018. DATE OF FIRST PATENT’S ENROLMENT 25 January 2018.

Objective To compare the efficacy of a selective progesterone receptor modulator, ulipristal acetate, and a gonadotropin-releasing hormone antagonist, linzagolix, in a case of severe uterine adenomyosis. Design Case report. Setting Private clinic and infertility research unit. Patient One patient born in 1981 who presented because of heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis confirmed by magnetic resonance imaging (MRI). Intervention The patient received a first treatment of 5 mg UPA daily for one course of 3 months. This therapy was discontinued because MRI revealed a worsened aspect. One year later, a once-daily dose of 200 mg linzagolix administered orally was initiated for 3 months, followed by another 3-month course of 100 mg once daily. Main Outcome Measures Clinical symptoms and MRI aspect. Results During treatment with UPA, the symptoms (pelvic pain, dysmenorrhea, bulk symptoms) worsened and MRI revealed aggravation of the adenomyotic lesions. During the 12-week course of once-daily 200 mg linzagolix, the patient remained in amenorrhea and noted a very significant improvement in symptoms. On MRI, the uterine volume had fallen from 875 cm3 to 290 cm3, and the adenomyotic lesions had significantly regressed. During the 100-mg linzagolix course (weeks 13–24), the patient reported continued alleviation of her symptoms. Conclusion To our knowledge, this is the first reported use of linzagolix, a new oral gonadotropin-releasing hormone antagonist that significantly reduced lesion size and improved quality of life in a patient with severe adenomyosis, who was previously nonresponsive to treatment with a selective progesterone receptor modulator, ulipristal acetate.

Breast cancer is the most common malignancy among women. Therefore, it is of paramount importance to study the adverse effects of oncological treatment of breast cancer, with one of adverse effects being pulmonary fibrosis (PF). PF is an irreversible condition and can significantly reduce the quality of life. Following lumpectomy, radiotherapy is the standard adjuvant treatment for breast cancer. Additionally, hormone receptor-positive breast cancers are treated with adjuvant hormonal therapy. While radiotherapy is one of the known causes of PF, the effect of hormone therapy on its development is not well-defined. Some studies have shown that the concomitant administration of endocrine therapy, primarily tamoxifen, and irradiation may potentiate the development of PF. However, guidelines regarding the timing of hormone therapy administration with respect to adjuvant radiotherapy are not clearly defined. This review aims to provide a comprehensive overview of the available information regarding the effect of hormone therapy and its timing of administration with respect to adjuvant radiotherapy on the incidence of PF.

Purpose Elagolix is an oral gonadotropin-releasing hormone antagonist approved in the United States for the management of moderate to severe pain associated with endometriosis. We performed a real-world evaluation of the demographic and clinical characteristics of women diagnosed with endometriosis who were initiating elagolix therapy in the United States. Patients and methods This retrospective cohort database analysis included women 18-49 years of age with ≥1 pharmacy claim for elagolix between August 2018 and December 2019 from the Copyright © 2020 Truven Health Analytics LLC. All Rights Reserved. Women had continuous medical and pharmacy health plan enrollment during the baseline period (year immediately preceding the index date [date of earliest elagolix claim]) and had ≥1 medical claim with endometriosis (International Classification of Diseases [ICD]-9/10 code [617.x and N80.x]) on or before the index date. Baseline demographics, comorbidities, ICD code-based endometriosis anatomic site, endometriosis-related treatments, and pain symptoms were summarized descriptively. Results The study included 2083 patients with mean age at baseline of 33.2 ± 8.1 years. Comorbidities most commonly recorded were non-cancer, non-endometriosis pain (59.5%), including arthritis/joint pain (43.7%) and back/neck pain (31.7%), and mental disorder (40.7%), including anxiety (32.7%). The majority of endometriosis diagnosis codes recorded referred to unspecified location (52.3%) and pelvic peritoneum (23.0%); 61.0% of patients received a medical endometriosis-related treatment in the baseline period, with the most common treatments being contraceptives (various routes of administration, 40.2%) and progestins (31.7%). Additionally, 35.4% of the patients received an endometriosis-related surgery during baseline, with the most common being laparoscopy (33.2% of all patients). Opioids were used during the baseline period by 57.3% of the patients. For pain symptoms, 71.5%, 30.4%, and 19.3% of the patients had claims for pelvic pain, dysmenorrhea, and dyspareunia, respectively. Conclusion Endometriosis therapies were used by a significant proportion of patients with endometriosis in the year immediately preceding elagolix initiation.

Prostate cancer is the second most common cause of cancer-related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy is the primary treatment for patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical castration. The development of gonadotropin-releasing hormone agonists revolutionized the treatment of advanced prostate cancer, replacing the need for surgical castration. Agonists downregulate gonadotropin-releasing hormone agonist receptors in the pituitary gland, and thus decrease the release of luteinizing hormone and testosterone. Although agonists are a common therapeutic option to date, their use is associated with testosterone surges, metabolic dysfunction and an increase in the risk of cardiovascular disease; they might contribute to tumor flares and potentially an increase in non-cancer mortality. More recently, gonadotropin-releasing hormone antagonists have entered the prostate cancer treatment landscape. Unlike agonists, antagonists directly inhibit the androgen receptor in the pituitary gland, and thus do not cause initial testosterone surges. In this article, we provide a concise review of the mechanism of actions, safety and efficacy of the approved agonists and antagonists for prostate cancer treatment.

Objective To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP). Design A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial. Setting Clinical centers. Patient(s) Women aged 18–45 years with surgically confirmed endometriosis and moderate-to-severe EAP. Intervention(s) The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks. Main Outcome Measure(s) The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD). Result(s) Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was Conclusion(s) Linzagolix significantly reduced EAP and improved QoL at doses of 75–200 mg and decreased BMD dose-dependently. Clinical Trial Registration Number NCT02778399

Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss with an acceptable safety profile in women with uterine leiomyomas., OBJECTIVE: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies. RESULTS: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4–92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: −3.3 (95% CI [−4.1 to −2.5])}. CONCLUSION: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02925494. FUNDING SOURCE: AbbVie Inc funded this study.

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

A 33-year-old with a history of endometriosis presented with pain post-orgasm, accompanied by breakthrough bleeding, nausea, sweatiness, and exhaustion. History and examination suggested a gynaecologic component, likely related to the uterus itself. After several therapeutic trials, a clinical response was obtained with the use of a gonadotropin-releasing hormone antagonist, elagolix. The case is discussed with respect to dysorgasmia and post-orgasm illness syndrome. Post-orgasm pain in women has not been well studied, and it is recommended that such periorgasm phenomena be the topic of future research.

Objective: To compare clinical pregnancy rates following sequential day-3 and day-5 embryo transfer with double or sequential cleavage-stage transfers. Methods: This study enrolled 242 patients undergoing gonadotropin-releasing hormone antagonist protocol and fresh embryo transfer. Basal follicle stimulating hormone, luteinizing hormone, serum estradiol and anti-Müllerian hormone levels and controlled ovarian stimulation outcomes were noted. Of 242 women, 135 underwent double embryo transfer on day 2 or day 3 (the double group), 54 women underwent sequential embryo transfer on day 2 and day 3 (the D2/D3 group), and 53 underwent sequential embryo transfer on day 3 and day 5 (the D3/D5 group). Clinical pregnancy rates were compared among the groups. Results: Female age, body mass index, basal follicle stimulating hormone, luteinizing hormone and estradiol levels were similar among the groups (P>0.05). The D3/D5 group had a significantly higher number of metaphase II oocytes, fertilized oocytes and good quality embryos on day 3 compared with the double group and the D2/D3 group (P < 0.001). Clinical pregnancy rates in the double, D2/D3 and D3/D5 groups were 26.6% (36/135), 16.6% (9/54) and 37.7% (20/53), respectively. There was no significant difference in clinical pregnancy rates between the double group and the D2/D3 group (P =0.204) or the D3/D5 group (P =0.188). The D3/D5 group had significantly higher clinical pregnancy rates compared with the D2/D3 group (P =0.025). Conclusions: Sequential cleavage-stage transfer (D2/D3) or cleavage stage and blastocyst transfer (D3/D5) does not improve clinical pregnancy rates compared with double cleavage-stage embryo transfer. Although sequential transfer seems to be an effective option in certain patient populations, routine application of this technique might not be a suitable approach in an unselected population to improve assisted reproductive technology outcomes.

Background Determining the initiation day of antagonist administration is an important and challenging issue and different results have been reported in the previous studies. The present study was designed to compare the controlled ovarian hyperstimulation (COH) cycles outcomes of early-onset gonadotropin-releasing hormone antagonist (GnRH-ant) protocol with conventional flexible GnRH-ant protocol in patients with poor ovarian response (POR) diagnosis. This randomized clinical trial was performed on infertile women who were diagnosed as poor responders in in vitro fertilization/intra-cytoplasmic sperm injection (IVF/ICSI) cycles at Arash Women’s Hospital affiliated to Tehran University of Medical Sciences. POR was defined according to the Bologna criteria and the eligible women were randomly allocated into an experimental (early-onset GnRH-ant) and control (conventional flexible GnRH-ant) groups. The women in the experimental group received recombinant gonadotropins (150–225 IU) and GnRH-ant (0.25 mg) simultaneously on the second day of the cycle. In the control group, the starting and the dose of gonadotropins were similar but daily administration of GnRH-ant was initiated when the leading follicle diameter was ≥ 13 mm. The COH outcomes were compared between groups (n=58 in each group). Results The analysis showed that the two groups did not have statistically significant differences in terms of the ovarian stimulation duration and the total dose of used gonadotropins. The total number of metaphase II (MII) oocytes in the experimental group was significantly higher than that of in control group (P = 0.04). Moreover, clinical and ongoing pregnancy rates per embryo transfer (ET) in the experimental group were significantly higher than those in the control group (P = 0.02 and P = 0.03, respectively); however, the implantation and miscarriage rates were similar between groups. Conclusions The early-onset GnRH-ant protocol can improve the number of retrieved and MII oocytes and probably the pregnancy outcomes after fresh embryo transfer in POR patients. However, larger randomized clinical trials are required to compare the pregnancy outcomes after this approach with other COH protocols with considering cost-effectiveness issue. Trial registration IRCT20110731007165N9. The name of the registry: Ladan Kashani. The date of trial registration: 8.02.2020.

Background Gonadotropin-releasing hormone antagonist(GnRH-ant) has been shown to have a negative effect on endometrial receptivity. Therefore, the use of lower doses of GnRH-ant during controlled ovarian stimulation (COS) may improve endometrial receptivity and clinical pregnancy rate. However, the GnRH-ant dose is relatively flexible and there is no fixed requirement for guidance. In this retrospective study, we determined the effects of half-dose and full-dose GnRH-ant on IVF-ET outcomes. Methods Of the 316 cycles in the 314 patients analyzed in this study, 149 received GnRH-ant half-dose (Group1), while 167 received GnRH-ant full-dose (Group2). The groups were further classified based on age and BMI. Age subgroups, were divided as age ≤ 35(subgroup A) and age > 35(subgroup B): 180 cycles in subgroup A (107 cycles in subgroup A1,73 cycles in subgroup A2), 136 cycles in subgroup B (42 cycles in subgroup B1,94 cycles in subgroupB2). The subgroups based on BMI were divided as BMI Results The number of fertilized oocytes, superior-quality embryos, clinical pregnancy rate, and live birth rate differed significantly between the two groups. However, the number of retrieved oocytes and available embryos were significantly higher in Group 1 than Group 2 (8.17 ± 4.10 vs. 7.07 ± 4.05, 2.96 ± 2.03 vs. 2.52 ± 1.62, respectively,pp P Conclusions The results showed that half-dose GnRH-ant was as effective as full-dose GnRH-ant for most patients. Moreover, half-dose GnRH-ant may be more suitable in patients with BMI greater than or equal to 25. The findings of this study need to be validated in a large sample RCT. Trial registration Retrospectively registered.

A 35-year-old woman (gravida 1, para 0) underwent termination of pregnancy (ToP) at 12 weeks of gestation. One month after ToP, she experienced significant vaginal bleeding and the mass with blood flow was identified on imaging. The presence of a placental polyp with arteriovenous malformation (AVM) was suspected on transvaginal sonography and MRI. Since the bleeding had ceased when she visited our hospital, we decided to treat the placental polyp with AVM with gonadotropin-releasing hormone (GnRH) antagonist therapy instead of surgery. Two months after GnRH antagonist treatment, the mass and blood flow in the uterus disappeared. Menstruation resumed 1 month after the completion of treatment. In our case, we were able to successfully treat placental polyps with AVM using GnRH antagonist therapy.

This open‐label, phase I dose‐finding study evaluated the gonadotropin‐releasing hormone antagonist, TAK‐385, in Japanese patients with nonmetastatic prostate cancer. In a two‐part design, patients received daily oral TAK‐385 at doses of 320 (loading, day 1)/80 (maintenance, day 2 and thereafter), 320/120, 320/160, or 360/120 mg for 28 days in a dose‐escalation phase (part A, n = 13), and at 320/80 or 320/120 mg for up to 96 weeks in a randomized expansion phase (part B, n = 30). Primary endpoint in both parts was safety, including dose‐limiting toxicity in part A. Secondary endpoints included pharmacokinetics, pharmacodynamics, and prostate‐specific antigen concentration. Ten (77%) patients in part A and all patients in part B experienced an adverse event; hot flush (part A, n = 4; part B, n = 15), viral upper respiratory tract infection (part A, n = 1; part B, n = 10), and diarrhea (part B, n = 8) were most frequent. No dose‐limiting toxicities were observed (part A). In 12 evaluable patients (part A), TAK‐385 was rapidly absorbed after a single loading dose; on day 28 (maintenance dose), median steady‐state T max was ~1‐2 hours and mean t 1/2z was 67‐79 hours. All doses rapidly reduced testosterone concentrations to castration levels within 1 week. Durable reductions in prostate‐specific antigen of >90% from baseline were observed through 96 weeks. TAK‐385 appeared tolerable and resulted in sustained reductions in testosterone to castration levels at all doses. The lowest loading/maintenance dose required for a clinical effect was 320/80 mg. http://ClinicalTrials.gov: NCT02141659., TAK‐385 is an orally active gonadotropin‐releasing hormone (GnRH) antagonist with rapid testosterone‐lowering effects in clinical studies, achieving effective and sustained castration in patients with prostate cancer without the initial testosterone surge observed with GnRH agonists. To date, clinical trials of TAK‐385 for the treatment of prostate cancer have been conducted in a predominantly Western patient population. Building on these data, the current study establishes an appropriate dose range for TAK‐385 in Japanese patients with non‐metastatic prostate cancer, and evaluates safety, pharmacokinetics, pharmacodynamics and preliminary efficacy in this population.

Research question How does the choice of triggering final oocyte maturation affect the cumulus cell transcriptome? Design Sixty patients undergoing gonadotrophin-releasing hormone antagonist (GnRH-ant) IVF cycles were recruited for this nested case–control study. Patients were stratified into three subgroups based on their ovarian reserve (high, normal and low). Triggering final oocyte maturation was accomplished by either single trigger (with human chorionic gonadotrophin [HCG] only or gonadotrophin-releasing hormone agonist [GnRH-ag] only) or dual trigger combining HCG and GnRH-ag. The choice of trigger was at the discretion of the treating physician. Within each group patients receiving a dual trigger were matched by demographic and pre-stimulation parameters with patients receiving a single trigger. The matching was performed to minimize the biological variability within each subgroup. Thirty patients were included in the final analysis. Cumulus cells were stripped away from the retrieved oocytes. Cumulus cells from three sibling oocytes were pooled, the RNA extracted and libraries prepared. Next-generation sequencing was performed on all samples. Results Dual triggering supports key ovarian pathways of oocyte maturation and extracellular matrix remodelling, while attenuating vasculo-endothelial growth and providing antioxidant protection to the growing follicles. Conclusions This is the first study to delineate key transcriptomic changes under dual triggering of final oocyte maturation, across different patient populations. The findings underline the need for larger-scale studies validating transcriptomic effects of methods for triggering final oocyte maturation. Furthermore, there is a need for large-scale clinical randomized controlled studies to relate the findings of this study with clinical outcomes.

Objective: we aimed to compare the first trimester screening profiles of spontaneous (n=972) and in in vitro fertilization (IVF) pregnancies (n=339) in a population of patients who had uncomplicated singleton pregnancies comparable for maternal age, gestation, body mass index, and ethnicity. Material and methods: a non-interventional analysis of retrospective cohort data and review of the literature. Results: all IVF pregnancies were achieved via intracytoplasmic sperm injection using the same ovarian stimulation protocol with recombinant follicle-stimulating hormone and a gonadotropin-releasing hormone antagonist, cetrorelix acetate. The means of the multiple of median (MoM) of pregnancy-associated plasma protein-A (PAPP-A) were slightly lower in the fresh (1.19 +/- 0.6 vs 1.33 +/- 0.7, respectively; p=0.056) and frozen embryo transfer (1.03 +/- 0.5 vs 1.33 +/- 0.7, respectively; p=0.036) IVF pregnancies compared with natural conceptions. However, when the medians of the MoMs of PAPP-A and beta-human chorionic gonadotrophin (beta-hCG), and their distributions were compared across the mode of conception, there were no differences between IVF pregnancies spontaneous pregnancies. Furthermore, the scatterplot diagram and curve fitting regression analyses revealed no difference in the temporal relations of beta-hCG and PAPP-A with each other and gestational age between spontaneous and IVF pregnancies. Conclusion: these results support the notion that uncomplicated singleton IVF pregnancies have similar first trimester screening profiles to spontaneous conceptions., NA

Objective: The study objective was to investigate the effects of luteinizing hormone (LH) supplementation on ovarian response and assisted reproductive technology (ART) outcomes in in vitro fertilization/intracytoplasmic sperm injection cycles with a gonadotropin (Gn)-releasing hormone antagonist protocol. Methods: This is a meta-analysis, and nine published randomized controlled trials (1,685 patients) were included. Continuous data were extracted in the form of mean ± standard deviation and population size, whereas dichotomous data were extracted in the form of odds ratio. Results: The total amount of follicle-stimulating hormone (FSH) used, the duration of stimulation (DOS), the number of eggs in MII stage, the total number of formed embryos, the clinical pregnancy rate, and live birth rates were similar between groups, but the estrogen level on the day of human chorionic Gn (hCG) administration was slightly higher in the LH supplementation group. On subgroup analysis, it was reported that the addition of LH could significantly increase estrogen levels on the day of hCG administration in patients older than 35 years, and LH supplementation starting on the day of FSH administration may slightly extend the DOS. Moreover, regardless of the timing of LH supplementation, an increase in estrogen levels was found on the day of hCG administration. Conclusions: LH supplementation of an antagonist protocol increases estrogen levels on the day of hCG administration, but does not increase the number of mature oocytes retrieved, and also fails to improve ART outcomes.

Endometriosis is a chronic benign estrogen-dependent disease characterized by the presence of endometriotic glands and stroma outside the uterine cavity. Although combined hormonal contraceptives and progestins, currently available first-line treatments for endometriosis, are efficacious and well tolerated for treating disease-related pain, some women experience partial or no improvement of pain or its recurrence is frequent after discontinuation of the therapies. For these reasons, new drugs are under investigation for the treatment of endometriosis.This review aims to give to the reader a complete and updated overview of hormonal and biological therapies for the treatment of endometriosis, underlining the latest developments in this field of research.Among the new drugs investigated, late clinical trials on gonadotropin-releasing hormone (GnRH) antagonists and aromatase inhibitors (AIs) have demonstrated the most promising results. For this reason, elagolix, a new GnRH-antagonist, recently received the approval by the Food and Drug Administration (FDA) for treating pain associated to endometriosis. Other drugs with innovative targets have been identified, but the majority of these compounds have only been evaluated in pre-clinical studies or early clinical trials. Thus, a further extensive clinical research is necessary to better elucidate their pharmacologic characteristics, their efficacy, and safety for the treatment of this benign chronic disease.

Background: Endometriosis commonly presents with dysmenorrhea, non-menstrual pelvic pain, and infertility. Elagolix is an oral, short-acting, gonadotropin-releasing hormone antagonist acting through complete estrogen suppression. Objective: To evaluate the evidence from published randomized controlled trials (RCTs) about the efficacy and safety of Elagolix in the treatment of endometriosis associated pain. Search strategy: Electronic databases containing articles published between January 2000 and February 2020 were searched using the MeSH terms (Elagolix OR gonadotropin-releasing hormone antagonist OR GnRH antagonist OR antigonadotropin) AND (endometriosis) AND (pelvic pain). Selection criteria: All RCTs assessing the efficacy of Elagolix in the treatment of pain associated with endometriosis were considered for this network meta-analysis, where five studies were deemed eligible for this review. Data collection and analysis: The mean difference (MD) and confidence intervals (95% CI) for continuous outcomes including analgesic use, dysmenorrhea, non-menstrual pelvic pain, and quality of life were calculated. Main results: Elagolix 250 mg reduced dysmenorrhea significantly, as compared to placebo, (MD = -0.41, 95% CI [-0.7, -0.13]) at 12 weeks, while Elagolix 200 mg reduced dysmenorrhea significantly (MD= -1.2, 95% CI [-1.9, -0.57]) compared to placebo after 24 weeks of treatment. Conclusions: Elagolix 200 mg seems to be an effective drug with fewer side effects when used to reduce dysmenorrhea and non-menstrual pelvic pain after 24 weeks of treatment in patients with endometriosis.

Lesson Advanced and metastatic prostate cancer is often managed with hormonal blockage. Luteinising hormone-releasing hormone antagonists achieve rapid testosterone suppression and are used for the treatment of advanced or metastatic prostate cancer. Degarelix is a luteinising hormone-releasing hormone antagonist and is given as a loading dose, followed by a monthly maintenance dose. We report a case where a patient was inadvertently given a second loading dose of Degarelix that resulted in acute psychosis in the form of panic attacks, delusions, suicidal thoughts, insomnia and some visual hallucinations, which are not reported as side-effects of Degarelix.

Prostate cancer is the fourth leading cause of cancer in the United States. Treatment of this oncologic disease involves a variety of different modalities including surgery, radiation, and systemic therapy. Systemic therapy is used for locally advanced and metastatic disease, and primarily involves hormonal blockade as a mechanism of disease control. Apalutamide is a nonsteroidal androgen receptor inhibitor that binds directly to the androgen receptor ligand binding-domain to prevent androgen receptor translocation. This agent is used in combination with gonadotropin-releasing hormone antagonists to shut down the production of testosterone through the reproductive system. It is the first drug to receive U.S. Food & Drug Administration approval for the treatment of nonmetastatic, castration-resistant prostate cancer. This article reviews the pharmacology of apalutamide along with its current place in therapy and management of associated adverse events.

Objective To compare the effectiveness of oral progestins and injectable gonadotropin-releasing hormone antagonist medication in cancer fertility preservation in patients with breast cancer. Methods A cross-sectional study with 40 breast cancer patients submitted to cancer fertility preservation, who were divided into two groups according to histochemical analysis of progesterone receptors to define luteinizing hormone block: if positive, use of gonadotropin-releasing hormone antagonist, if negative, use of oral progestins. The mean age, medication days, antral follicle count, number of oocytes in metaphase II and the occurrence of ovarian hyperstimulation syndrome were compared. Results A total of 20 patients both in the group using gonadotropin-releasing hormone antagonist, and in the group with oral progestins, respectively, had a mean age of 33.9 (32-35.8) and 33.8 (32-35.6) years; days of medications of 11 (9.7-12.3) and 12.8 (11.6-13.9), p=0.037; antral follicle count of 9 (7.11-12) and 8.5 (6-11.9), p=0.370; metaphase II oocyte number of 4 (2.1-9.8) and 7.5 (3.1-10), p=0.348; and ovarian hyperstimulation syndrome of 2 (10%) and 5 (25%) cases, p=0.212. Conclusion The use of oral progestins, in spite of requiring longer treatment time, is effective in relation to the protocol with gonadotropin-releasing hormone antagonist, and offers greater comfort at a lower cost in breast cancer patients with negative progesterone receptors, submitted to cancer fertility preservation. RESUMO Objetivo Comparar a efetividade dos progestágenos orais em relação à medicação injetável antagonista de hormônio liberador de gonadotrofina na preservação da fertilidade oncológica de pacientes com câncer de mama. Métodos Estudo transversal com 40 pacientes com câncer de mama submetidas à preservação da fertilidade oncológica, que foram divididas em dois grupos, conforme análise histoquímica dos receptores de progesterona, para definir o bloqueio de hormônio luteinizante: se positivos, uso de antagonista de hormônio liberador de gonadotrofina; se negativos, uso de progestágenos orais. Comparou-se média de idade, dias de medicações, contagem de folículos antrais, número de oócitos em metáfase II e ocorrência de síndrome do hiperestímulo ovariano. Resultados Vinte pacientes, tanto no grupo com uso de antagonista de hormônio liberador de gonadotrofina, quanto no grupo com progestágenos orais, respectivamente, apresentaram média de idade de 33,9 (32-35,8) e 33,8 (32-35,6) anos; 11 (9,7-12,3) e 12,8 (11,6-13,9) de dias de medicações com p=0,037; contagem de folículos antrais de 9 (7,11-12) e 8,5 (6-11,9), com p=0,370; número de oócitos metáfase II de 4 (2,1-9,8) e 7,5 (3,1-10), com p=0,348, e síndrome do hiperestímulo ovariano de 2 casos (10%) e 5 casos (25%), com p=0,212. Conclusão O uso de progestágenos orais, apesar de necessitar de maior tempo de tratamento, é efetivo em relação ao protocolo com antagonista de hormônio liberador de gonadotrofina e oferece maior conforto com menor custo em pacientes com câncer de mama com receptores de progesterona negativos, submetidas à preservação da fertilidade oncológica.

Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis and long-term treatments should balance clinical efficacy (controlling pain symptoms and preventing recurrence of disease after surgery) with an acceptable safety-profile. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives and progestins, available for multiple routes of administration, are commonly administered as first-line hormonal therapies. Several studies demonstrated that they succeed in improving pain symptoms in the majority of patients; moreover, they are well tolerated and not expensive. Gonadotropin-releasing hormone-agonists are prescribed when first line therapies are ineffective, not tolerated or contraindicated. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be reserved only for women with symptoms who are refractory to other treatments only in a research environment. Almost all of the currently available treatment options for endometriosis suppress ovarian function and are not curative. For this reason, research into new drugs is unsurprisingly demanding. Amongst the drugs currently under investigation, gonadotropin-releasing hormone antagonists have shown most promise, currently in late-stage clinical development. There is a number of potential future therapies currently tested only in vitro, in animal models of endometriosis or in early clinical studies with a small sample size. Further studies are necessary to conclude whether these treatments would be of value for the treatment of endometriosis.

A 59-year-old man presented to the urology department with increased urinary urgency, frequency, poor urinary flow and unintentional weight loss. He had a 25-year history of idiopathic urticaria episodes which had increased in frequency over the previous 2 months. On investigation, he was found to have a raised prostate-specific antigen level. He was investigated further with a multiparametric MRI, a local anaesthetic transperineal prostate biopsy, a CT scan of chest/abdomen/pelvis with contrast and a nuclear medicine bone scan. He was diagnosed with metastatic adenocarcinoma of the prostate and commenced on a luteinising hormone-releasing hormone antagonist and referred to oncology for further treatment. Since starting treatment, he has experienced no further episodes of urticaria.

There is no approved medical therapy for adenomyosis and limited evidence to guide treatments in part due to the complexity of nonhistologic diagnosis and the prevalence of concomitant gynecologic conditions. Most available evidence focuses on the treatment of heavy menstrual bleeding, painful menses, and pelvic pain. Data evaluating fertility outcomes, sexual function, and quality of life following treatment are lacking. Additionally, there is no disease-specific measure of quality of life for adenomyosis. The levonorgestrel-releasing intrauterine system appears to be the most effective first-line therapy based on efficacy compared with oral agents, maintenance of steady-state hormonal levels, and contraceptive benefit. In areas where it is marketed, the progestin dienogest appears superior to combined oral contraceptives. Long-acting gonadotropin-releasing hormone agonists are effective and should be considered second-line therapy but are limited by hypogonadal effects. Additional data regarding oral gonadotropin-releasing hormone antagonists are required. While aromatase inhibitors demonstrate improvement in heavy menstrual bleeding and pelvic pain, further research is needed to determine their role in the management of adenomyosis. Progesterone receptor modulators may have a role for this disease if released again to market with appropriate safety parameters. Finally, modulation of prolactin and/or oxytocin may provide novel nonsteroidal treatment options.

Objective To investigate whether the cumulative clinical pregnancy rates (CCPR) and cumulative live birth rates (CLBR) increase as the oocyte retrieval cycle increases in women with poor ovarian response. Design Retrospective cohort study. Setting Not applicable. Patient(s) Women diagnosed of poor ovarian response (POR) according to the Bologna criteria and who completed in vitro fertilization or intracytoplasmic sperm injection cycles between January 2014 and December 2018. Intervention(s) Not applicable. Main Outcome Measure(s) The conservative and optimistic estimations of CCPR and CLBR. Result(s) The conservative and optimistic estimates of CCPR peaked at the 6th complete cycle, reaching 36.44% and 71.61%, respectively. However, the conservative and optimistic estimates of CLBR peaked at the 4th complete cycle, reaching 20.22% and 38.31%, respectively. The live birth rate per complete cycle of mild stimulation protocol was comparable to other protocols after adjusting for the confounding factors. For patients ≤35 years, the live birth rate per complete cycle of progestin-primed ovarian stimulation (adjusted odds ratio = 0.51, 95% confidence interval: 0.30–0.87) and gonadotropin-releasing hormone antagonist protocol (adjusted odds ratio=0.45, 95% confidence interval: 0.24–0.81) were significantly lower than that of the mild stimulation. Conclusion(s) It is not advisable to initiate more than four complete cycles for POR patients since CLBR do not increase after that. For POR patients ≤35 years, the live birth rate per complete cycle increased in women with mild stimulation protocol.

Background Previously, we reported a model for assessing ovarian reserves using 4 predictors: anti-Müllerian hormone (AMH) level, antral follicle count (AFC), follicle-stimulating hormone (FSH) level, and female age. This model is referred as the AAFA (anti-Müllerian hormone level–antral follicle count–follicle-stimulating hormone level–age) model. Objective This study aims to explore the possibility of establishing a model for predicting ovarian reserves using only 3 factors: AMH level, FSH level, and age. The proposed model is referred to as the AFA (anti-Müllerian hormone level–follicle-stimulating hormone level–age) model. Methods Oocytes from ovarian cycles stimulated by gonadotropin-releasing hormone antagonist were collected retrospectively at our reproductive center. Poor ovarian response ( Results The AUCs of the AFA and AAFA models were similar for the same validation set, with values of 0.853 (95% CI 0.841-0.865) and 0.850 (95% CI 0.838-0.862), respectively. We further ranked the ovarian reserves according to their predicted probability of poor ovarian response, which was calculated using our AFA model. The actual incidences of poor ovarian response in groups from A-D in the AFA model were 0.037 (95% CI 0.029-0.046), 0.128 (95% CI 0.099-0.165), 0.294 (95% CI 0.250-0.341), and 0.624 (95% CI 0.577-0.669), respectively. The order of ovarian reserve from adequate to poor followed the order from A to D. The clinical pregnancy rate, live-birth rate, and specific differences in groups A-D were similar when predicted using the AFA and AAFA models. Conclusions This AFA model for assessing the true ovarian reserve was more convenient, cost-effective, and objective than our original AAFA model.

Purpose To systematically evaluate the effect of progestin-primed ovarian stimulation (PPOS) in in vitro fertilization (IVF)/oocyte intracytoplasmic sperm injection–embryo transfer (ICSI-ET) in patients with poor ovarian response and to find an optimal ovulation induction protocol for such patients. Method A literature search of PubMed, Medline, EBSCO, Cochrane Library, Vip.com, CNKI, and the Wanfang database was conducted to find case–control studies of PPOS with medroxyprogesterone acetate and other traditional stimulation regimens for ovulation induction in patients with poor ovarian response. The period of time searched was from the database establishment to August 2020. Patients in the experimental group underwent PPOS and those in the control group underwent another program (e.g., the gonadotropin-releasing hormone antagonist protocol). RevMan 5.3 software was used for meta-analysis. Results A total of sixteen case–control studies (one of them is randomized controlled trial), with 4422 induction cycles, were included. All the included patients met the 2011 Bologna diagnostic criteria for poor ovarian response. The numbers of mature eggs, available embryos, optimal embryos, and the rate of cumulative pregnancies in the PPOS group were all better than those in the control group ( P 0.05 ). There was a lower Serum luteinizing hormone on the day of human chorionic gonadotropin (HCG) injection and a lower rate of cycle cancellation in the PPOS group ( P 0.05 ). No other differences between PPOS and other treatments were statistically significant. Conclusion PPOS can reduce the need for cycle cancellation, improve the follicles and embryos, and improve the pregnancy rate and thus, can present an effective choice for IVF/ICSI-ET in patients with poor ovarian response.

To compare the efficacy of gonadotropin-releasing hormone antagonist versus gonadotropin-releasing hormone agonist long protocol in women belonging to POSEIDON groups 3 and 4.A total of 380 patients with expected low ovarian response [antral follicle count5 and/or anti-Müllerian hormone1.2 ng/mL] were studied retrospectively. The efficiency of the gonadotropin-releasing hormone antagonist protocol and the gonadotropin-releasing hormone agonist long protocol was compared in patients from POSEIDON group 3 (age35 years) and group 4 (age ≥ 35 years), respectively. The primary outcome was the cumulative live birth rate. All patients underwent complete cycles of in vitro fertilization/intracytoplasmic sperm injection for the first time from January 2016 to June 2019.In POSEIDON group 4, age, anti-Müllerian hormone, initial gonadotropin dose and induction protocols were significantly correlated with cumulative live birth by multivariate regression analysis. The optimum cut-off value of anti-Müllerian hormone for prediction of cumulative live birth was 0.785 by receiver operating characteristic analysis. Patients with higher anti-Müllerian hormone levels (anti-Müllerian hormone ≥ 0.785 ng/mL) who received the gonadotropin-releasing hormone agonist long protocol achieved significantly higher cumulative live birth rate than who received the gonadotropin-releasing hormone antagonist protocol, whereas no significant difference in cumulative live birth rate of the two protocols was found in patients with low anti-Müllerian hormone levels (anti-Müllerian hormone0.785 ng/mL). In POSEIDON group 3, only body mass index was significantly correlated with cumulative live birth. There was no correlation between cumulative live birth and induction protocols.Patients with higher anti-Müllerian hormone levels from POSEIDON group 4 are more likely to benefit from the gonadotropin-releasing hormone agonist long protocol than the gonadotropin-releasing hormone antagonist protocol.