Do women with severely diminished ovarian reserve undergoing modified natural-cycle in-vitro fertilization benefit from earlier trigger at smaller follicle size?

OBJECTIVE: To evaluate whether trigger and oocyte collection at a smaller follicle size decreases the risk of premature ovulation while maintaining the reproductive potential of oocytes in women with a severely diminished ovarian reserve undergoing modified natural-cycle in-vitro fertilization. METHODS: This was a retrospective cohort study including women who had at least one unsuccessful cycle (due to no response) of conventional ovarian stimulation with a high dosage of gonadotropins and subsequently underwent a modified natural cycle with a solitary growing follicle (i.e. only one follicle > 10 mm at the time of trigger). The association between follicle size at trigger and various cycle outcomes was tested using regression analyses. RESULTS: A total of 160 ovarian stimulation cycles from 110 patients were included in the analysis. Oocyte pick-up (OPU) was performed in 153 cycles and 7 cycles were canceled due to premature ovulation. Patients who received their trigger at smaller follicle sizes (≤ 15 mm) had significantly lower rates of premature ovulation and thus higher rates of OPU (98.9% vs 90.8%; odds ratio, 9.56 (95% CI, 1.58-182.9); P = 0.039) compared with those who received their trigger at larger follicle sizes (> 15 mm). On multivariable analysis, smaller follicle sizes at trigger (> 10 to 13 mm, > 13 to 15 mm, > 15 mm to 17 mm) were not associated significantly with a lower rate of cumulus-oocyte complex (COC) retrieval, metaphase-II (MII) oocytes or blastulation when compared to the > 17-mm group. On sensitivity analysis including only the first cycle of each couple, the maturity rate among those with COC retrieval was highest in follicle sizes > 15 to 17 mm (92.3%) and > 13 to 15 mm (91.7%), followed by > 10 to 13 mm (85.7%) and lowest in the > 17-mm group (58.8%). During the study period, five euploid blastocysts developed from 48 fertilized MII oocytes with follicle sizes of 12 mm (n = 3), 14 mm (n = 1) and 16 mm (n = 1) at trigger. Of those, four were transferred and resulted in two live births, both of which developed from follicles with a size at trigger of 12 mm. CONCLUSIONS: The ideal follicle size for triggering oocyte maturation may be smaller in women with a severely diminished ovarian reserve managed on a modified natural cycle when compared to conventional cut-offs. The risk of OPU cancellation was significantly higher in women triggered at follicle size > 15 mm and the yield of mature oocytes was not adversely affected in women triggered at follicle size > 13 to 15 mm compared with > 15 to 17 mm. Waiting for follicles to reach sizes > 17mm may be detrimental to achieving optimal outcome. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

The Kisspeptin and Kisspeptin receptor in follicular microenvironment: is that really necessary for oocyte maturation and fertilisation?

The aim of this study was to determine whether Kisspeptin and Kisspeptin receptor in the follicular microenvironment is necessary for human oocyte maturation and fertilisation. The cumulus cell (CC) and follicle fluids (FF) obtained from the first aspirated follicles (n = 52) from 32 patients were divided into three groups considering nuclear maturation and fertilisation results of oocytes: (1) Metaphase I or germinal vesicle stage oocytes (incomplete nuclear maturation, n = 10), (2) unfertilised metaphase II oocytes (incomplete cytoplasmic maturation, n = 16), and (3) fertilised metaphase II oocytes (completed nuclear-cytoplasmic maturation, n = 26). The gene expression levels were assessed by RT-PCR. The levels of Kisspeptin (KISS1) and Kisspeptin receptor (KISS1R) were measured by ELISA. There were no significant efficacy KISS1 and KISS1R gene expressions in cumulus cells in terms of oocyte nuclear maturation stage (Group 1, vs Group 2 + Group 3) (respectively p = .49; p = .45). In terms of the cytoplasmic maturation stage (Group 2, vs Group 3); KISS1 and KISS1R expressions in CCs were comparable (respectively p = .07; p = .08). In FFs, KISS1 and KISS1R concentrations were similar between all groups (respectively p = .86; p = .26). In conclusion, the relative KISS1 and KISS1R expressions in CC and also KISS1 and KISS1R level of FF were independent of oocytes nuclear and/or cytoplasmic maturation. Impact statementWhat is already known on this subject? It has been demonstrated that Kisspeptin is an essential regulator of reproductive function and plays a key role in the modulation of GnRH secretion and gonadotropin release. Still, no information is available about the link between gene expression or concentration in the follicular microenvironment and oocyte development.What do the results of this study add? The study has shown that the relative Kisspeptin (KISS1) and Kisspeptin receptor (KISS1R) and expressions in cumulus cell (CC) and also KISS1 and KISS1R levels of follicle fluids (FF) were independent of oocytes nuclear and/or cytoplasmic maturation.What are the implications of these findings for clinical practice and/or further research? Based on the findings, it is difficult to establish a concept that kisspeptin can directly induce oocyte maturation. Nevertheless, to confirm these findings, further studies with a larger sample size are needed.

GnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study.

STUDY QUESTION: Does co-administration of GnRH agonist and Human chorionic gonadotropin (hCG; dual trigger) in IVF cycles improve the number of mature oocytes and pregnancy outcome compared to hCG alone? SUMMARY ANSWER: Using the dual trigger for final follicular maturation increases the number of oocytes, mature oocytes and number of blastocysts (total and top-quality) compared to triggering with hCG alone. WHAT IS KNOWN ALREADY: hCG is used at the end of controlled ovarian hyperstimulation as a surrogate LH surge to induce final oocyte maturation. Recently, based on retrospective studies, the co-administration of GnRH agonist and hCG for final oocyte maturation (dual trigger) has been suggested to improve IVF outcome and pregnancy rates. STUDY DESIGN, SIZE, DURATION: A single center, randomized controlled, double-blinded clinical trial between May 2016 and June 2018 analyzed by intention to treat (ITT). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: One hundred and fifty-five normal responder patients were randomized either to receive hCG or dual trigger for final oocyte maturation. Data on patients age, BMI, AMH, number of oocytes retrieved, number of metaphase 2 (MII) oocytes, zygotes and blastocysts, clinical pregnancy rate and live birth rate were assessed and compared between the dual trigger group and the hCG group. We performed a planned interim analysis after the recruitment of 50% of the patients. Based on the totality of outcomes at the interim analysis we decided to discontinue further recruitment. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred and fifty-five patients were included in the study. The age (36 years versus 35.3 years P = NS), BMI (24 kg/m2 versus 23.7 kg/m2) and the AMH (20.1 pmol/l versus 22.4 pmol/l) were comparable between the two groups. Based on ITT analysis, the number of eggs retrieved (11.1 versus 13.4, P = 0.002), the MII oocytes (8.6 versus 10.3, P = 0.009), total number of blastocysts (2.9 versus 3.9, P = 0.01) and top-quality blastocysts transferred (44.7% versus 64.9%; P = 0.003) were significantly higher in the dual trigger group compared to the hCG group. The clinical pregnancy rate (24.3% versus 46.1%, OR 2.65 (1.43-1.93), P = 0.009) and the live birth rate per transfer (22% versus 36.2%, OR= 1.98 (1.05-3.75), P = 0.03) were significantly higher in the dual trigger group compared to the hCG group. LIMITATIONS, REASONS FOR CAUTION: None. WIDER IMPLICATIONS OF THE FINDINGS: The enhanced response observed with the dual trigger might lead to better IVF outcomes were it used more widely. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by TRIO Fertility. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02703584. DATE OF TRIAL REGISTRATION: March 2016. DATE OF FIRST PATIENT'S ENROLLMENT: May 2016.

Elevated estradiol-17ß levels inhibit final oocyte maturation via G protein-coupled estrogen receptor (Gper) in yellowfin porgy, Acanthopagrus latus.

Yellowfin porgy a protandrous teleost, exhibits asynchronous oocyte development and multiple spawning. Seasonal profiles of plasma estradiol-17ß (E2) levels showed a peak in three-year-old females during the spawning season, when batches of fully-grown oocytes undergo final oocyte maturation (FOM). Because E2 has been shown to inhibit FOM via the G protein-coupled estrogen receptor (Gper) in several teleost species, we investigated the role of this "paradoxical" increase in E2 during FOM in yellowfin porgy. In vivo treatment with a GnRH-agonist stimulated germinal vesicle breakdown (GVBD) and increased E2 plasma levels, and ovarian cyp19a1a transcripts, confirming the increase in E2 production at the time of FOM. Ovarian transcripts of gper peaked at the time of FOM, indicating an increase in ovarian responsiveness to Gper-mediated E2 effects. In vitro, E2 and the Gper agonist, G-1, inhibited the stimulatory effect of maturation-inducing steroids (MIS) on GVBD, while an aromatase inhibitor enhanced the MIS effect, in agreement with a physiological inhibitory role of E2 on FOM via Gper. Immunohistological studies showed that the Gper protein was specifically located on the oocyte plasma membrane. Ovarian membranes displayed high-affinity and limited-capacity specific [3H]-E2 receptor binding which was displaced by G-1, characteristic of Gper. Expression of gper increased at the time of FOM in mid-vitellogenic oocytes, but not in larger oocytes undergoing GVBD. These results suggest increases in both E2 production and E2 responsiveness via Gper upregulation in mid-vitellogenic oocytes, may maintain meiotic arrest in this oocyte stage class during the period when full-grown oocytes are undergoing FOM. This study indicates a critical involvement of E2 in the control of asynchronous oocyte maturation and the multiple spawning pattern in Sparidae.

Is there a pre-retrieval serum human chorionic gonadotrophin (hCG) threshold level for prediction of subsequent retrieval outcomes and pregnancy in fresh ICSI cycles?

Modern ICSI (intracytoplasmic sperm injection) cycles' outcomes are difficult to predict. Whether human chorionic gonadotrophin (hCG) or luteinizing hormone (LH) serum levels 24 h prior to oocyte retrieval are correlated with retrieval and subsequent cycle results is unclear. An observational historic cohort study of 645 fresh ICSI cycles was conducted. After controlled oocyte stimulation, and 10-12 h after a self-administered trigger, serum levels of hCG (hCG trigger n = 563) and LH (GnRHa trigger n = 82) were measured. Correlations between pre-retrieval hormone levels and cycle results were assessed. No correlation (p > .12) was found between serum pre-retrieval hCG levels or LH levels (in GnRHa-triggered cycles) and total oocytes, M2, M1 + M2 or oocyte maturity rates (OMR) for any of the stimulation protocols. ROC (receiver operator curve) analysis for fertilization rates showed a possible cutoff for LH levels. Pregnancy rates (PR) were higher in rising hCG groups; a cutoff of 117 IU/L was associated with an increase in PR (30.9% to 45.6%) and a moderate sensitivity and specificity (60.6% and 55.0%). However, HCG was not predictive of pregnancy in a logistic regression model. We conclude that preretrieval hCG serum levels are not useful for pre-retrieval estimation of aspiration results but might have a role in prediction of pregnancy.

GnRH triggering may improve euploidy and live birth rate in hyper-responders: a retrospective cohort study.

PURPOSE: Despite the increasing use of GnRHa to trigger final oocyte maturation in segmented IVF cycles, the effects of trigger modality on chromosomal competence and embryo quality remain controversial. Hence, the purpose of this study was to compare euploidy rates and pregnancy outcomes among hyper-responding women using hCG versus GnRHa trigger. METHODS: This retrospective study included 333 hyper-responders, defined as >15 oocytes retrieved, who underwent preimplantation genetic testing (PGT-A) in segmented IVF cycles using either GnRHa or urinary hCG trigger. Live birth rate (LBR) was the primary outcome of interest. Implantation rate (IR), clinical pregnancy rate (CPR), and euploidy rate were secondary outcomes. RESULTS: GnRH triggering was associated with improved IR (70.5 vs. 53.2%, p = 0.0475), LBR (51.3 vs. 33.8%, p = 0.0170) compared to hCG. A greater number of oocytes were retrieved (21.9 vs 18.4%, p < 0.001) and euploid embryos produced (2.8 vs. 2.1, p = 0.0109) after GnRHa triggering, while higher euploidy rates were only observed among women <35-years-old (62.0 vs. 51.7%, p = 0.0307) using GnRHa trigger. Higher OHSS rates were observed after hCG triggering (10.6 vs. 2.1%, p = 0.0009). CONCLUSION: Hyper-responders who received GnRHa trigger experienced improved pregnancy outcomes and lower rates of OHSS compared to hCG triggering. The higher number of oocytes retrieved and euploid embryos produced may reflect an improved developmental competence using GnRHa triggering due to physiologic induction of both LH and FSH surge or other undefined mechanisms that improve embryo development. However, higher overall euploid rates were only observed among women <35-years-old using the GnRHa trigger. Further prospective studies are required to validate this observation and evaluate the specific influence of different ovulation triggers on gamete developmental competence among hyper-responder women.

In vivo induction of human chorionic gonadotropin by osmotic pump advances sexual maturation during pre-spawning phase in adult catfish.

Gonadal maturation is a critical event wherein gonads, under the influence of several hormones and factors, undergo cyclic morphological and physiological changes to produce functional gametes during the spawning phase. However, artificial induction can be effectively used to advance the maturation of gonad vis-à-vis spawning like behavior in seasonal breeders during the off-breeding season. In the present study, osmotic pumps loaded with 5000IU of human chorionic gonadotropin (hCG) or saline as control were implanted intraperitoneally for 21days during the pre-spawning phase (May-June) in catfish Clarias batrachus and C. gariepinus. Significant increase in gonado-somatic index and sperm motility, and in the levels of certain sex steroids were observed in the hCG treated catfish when compared to control while estradiol-17ß (E2) was low. Histological analysis in hCG treated testis revealed densely packed sperm and/or spermatids inside the lumen wherein the control testis displayed normal characteristics of the pre-spawning phase. In females, histological analysis showed a significant increase in post-vitellogenic full-grown immature follicles as seen in the spawning phase. In accordance with this, the steroid hormone profile correlated well with steroidogenic shift from E2 to 17α,20ß-DP indicating oocyte maturation. However, in the control ovaries of C. batrachus, perinucleolar and pre-vitellogenic oocytes were seen to be predominant. In addition, when compared with the control, the hCG treated group displayed a significant increase in the transcripts of several genes associated with gonadal growth. Taken together, artificial induction by slow release of hCG is an effective strategy to advance sexual maturation in catfish in a programmed manner.

The type of spawning agent affects the egg composition during out-of-season spawning but not during in-season spawning in Eurasian perch, Perca fluviatilis.

The aim of the study was to verify the effect of various hormonal agents [human chorionic gonadotropin (hCG) and salmon gonadoliberine analogue (sGnRHa)] applied at different stages of maturity of the females [out-of-season (maturation stage I) and in-season spawning (maturation stages II and IV)] on the proximate composition (PC) and fatty acid (FA) profile of eggs of Eurasian perch, Perca fluviatilis. The egg samples (7 samples from each group) were also collected from spontaneous spawning (without hormonal treatment) fish representing each maturation stage (I, II and IV for groups C-I, C-II and C-IV, respectively). The results were also compared with the eggs collected in nature (seven randomly chosen egg samples from natural spawning; group NS). Embryonic survival rate was recorded and analysis of PC and FA profile were performed, for all the groups. Embryonic survival rate varied among the groups, and only differences (P<0.05) between group C-I and NS were recorded. In-season spawning operation did not affect PC and FA profiles. Application of hCG or spontaneous spawning (group C-I) were found to have the highest effect on the FA profile. It concerned mostly total n-3 polyunsaturated fatty acids, but also stearic (C18:0), oleic [C18:1(cis9)], linoleic [C18:2(n-6)], arachidonic [C20:4(n-6)] and docosahexaenoic[C22:6(n-3)] acids. The application of sGnRHa during out-of-season spawning had the lowest effect on the FA profile. The results presented indicate that controlled reproduction can affect the FA profile only during out-of-season spawning. This negative effect can be presumably compensated by the application of sGnRHa as a spawning agent.

Reference gene validation for quantification of gene expression during final oocyte maturation induced by diethylstilbestrol and di-(2-ethylhexyl)-phthalate in common carp.

Final oocyte maturation is the key step to successful spawning and fertilization. Quantitative real-time PCR (qPCR) is the technique of election to quantify the abundance of functional genes in such study. Reference gene is essential for correct interpretation of qPCR data. However, an ideal universal reference gene that is stable under all experimental circumstances has not been described. Researchers should validate their reference genes while performing qPCR analysis. The expression of 6 candidate reference genes: 18s rRNA, 28s rRNA, Cathepsin Z, Elongation factor 1-α, Glyceraldehyde-3-phosphate dehydrogenase and ß-actin were investigated during final oocyte maturation induced by different compounds (DES and DEHP) in common carp (Cyprinus carpio). Four softwares (Bestkeeper, geNorm, NormFinder and RefFinder) were used to screen the most stable gene in order to evaluate their expression stability. The results revealed that EF1α was highly stable expressed when final oocyte maturation was induced by DES, while gapdh was the most stable gene when final oocyte maturation was induced by DEHP. Stable expressed reference gene selection is critical for all qPCR analysis to get accurate target gene mRNA expression information.

Co-administration of GnRH-agonist and hCG, for final oocyte maturation (double trigger), in patients with low proportion of mature oocytes.

OBJECTIVE: Human chorionic gonadotropin (hCG) is usually used at the end of controlled ovarian hyperstimulation (COH), as a surrogate LH surge, to induce final oocyte maturation and resumption of meiosis. Recently, the co-administration of GnRH agonist and hCG for final oocyte maturation - 40 and 34 h prior to OPU, respectively (double trigger) was suggested to improve IVF outcome in patient with genuine empty follicle syndrome. In the present study, we aim to evaluate whether the double trigger might improve the proportions of metaphase-II (MII) oocytes in patients with low proportion of mature oocytes (<66%) per number oocytes retrieved. PATIENTS AND METHODS: We compared the stimulation characteristics of 12 IVF cycles, which include the cycle with the double trigger to the same patients' previous IVF attempt, triggered with hCG-only. RESULTS: Patients who received the double trigger (study group) had a significantly higher number of mature oocytes - MII (6.5 versus 3.6 p < 0.008), number of embryos transferred (2.4 versus 1.1 p < 0.03), a significantly higher proportions of MII oocytes per number of oocytes retrieved (69.7% versus 47.1% p < 0.03) and a higher number of top quality embryos (3.1 versus 1 p < 0.02), as compared to their previous control cycles (hCG-only trigger). Six pregnancies were recorded in the study group and none in the control group. CONCLUSIONS: Co-administration of GnRH-agonist and hCG for final oocyte maturation, 40 and 34 h prior to OPU, respectively (double trigger) improves IVF outcome in patients with high proportion of immature oocytes.

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.

Endocrine Regulation of Maturation and Sex Change in Groupers.

Groupers are widely distributed in tropical and subtropical areas worldwide, are key species to coastal ecosystems, and valuable fishery targets. To facilitate artificial seed production technology for grouper aquaculture, the mechanisms of reproduction and gonad development are being elucidated for these important species. In addition, since groupers are sexually dimorphic fish with female-first maturity (protogynous hermaphrodite fish), research is being conducted to clarify the ecological mechanism of sex change and their reproductive physiology, focusing on the endocrine system. In recent years, research on groupers has also been conducted to understand changes in the coastal environment caused by ocean warming and man-made chemicals. However, due to difficulties associated with conducting research using wild populations for breeding experiments, knowledge of the physiology and ecology of these fish is lacking, especially their reproductive physiology. In this review, we present information on the reproductive physiology and endocrinology of groupers obtained to date, together with the characteristics of their life history.

Male Pheromones Induce Ovulation in Female Honeycomb Groupers (Epinephelus merra): A Comprehensive Study of Spawning Aggregation Behavior and Ovarian Development.

This study characterizes the spawning phenomena of the honeycomb grouper (Epinephelus merra), which is a lunar-synchronized spawner that spawns a few days after full moon. To elucidate the aggregation characteristics of wild honeycomb groupers, the numbers of males and females at the spawning grounds were counted before and after the full moon. Approximately 20 males were consistently observed at the spawning grounds throughout the study period. Females appeared several days after full moon and rapidly increased in number, peaking four days after full moon (41 individuals). The maturation status of the females aggregating at the spawning grounds was investigated. The gonadosomatic index increased rapidly three days after full moon, and ovulation was confirmed. Individuals with ovulatory eggs were present for three days, after which the number of females at the spawning grounds decreased. Additionally, the role of males in final oocyte maturation (FOM) and ovulation in females during the spawning phase was investigated in captivity. FOM was induced in females reared in water with mature males, suggesting that male pheromones in the water induced FOM via activation of the hypothalamic-pituitary-gonadal axis. This suggests that spawning at the natural spawning grounds was the result of male-female interactions via pheromones.

Ovarian stimulation for oocyte donation: a systematic review and meta-analysis.

BACKGROUND: Since its introduction in the 1980s, oocyte donation (OD) has been largely integrated into ART. Lately, both demand and the indications for OD have increased greatly. Oocyte donors are healthy and potentially fertile women undergoing voluntarily ovarian stimulation (OS). Selection of the optimal type of stimulation is of paramount importance in order to achieve the most favourable outcomes for the oocyte recipients, but most importantly for the safety of the oocyte donors. OBJECTIVE AND RATIONALE: This is the first systematic review (SR) with the objective to summarize the current evidence on OS in oocyte donors. The scope of this SR was to evaluate the OD programme by assessing four different aspects: how to assess the ovarian response prior to stimulation; how to plan the OS (gonadotrophins; LH suppression; ovulation trigger; when to start OS); how to control for the risk of ovarian hyperstimulation syndrome (OHSS) and other complications; and the differences between the use of fresh versus vitrified donated oocytes. SEARCH METHODS: A systematic literature search was conducted in May 2020, according to PRISMA guidelines in the databases PubMed and Embase, using a string that combined synonyms for oocytes, donation, banking, freezing, complications and reproductive outcomes. Studies reporting on the safety and/or efficacy of OS in oocyte donors were identified. The quality of the included studies was assessed using ROBINS-I and ROB2. Meta-analysis was performed where appropriate. Data were combined to calculate mean differences (MD) for continuous variables and odd ratios (OR) for binary data with their corresponding 95% CIs. Heterogeneity between the included studies was assessed using I2 and tau statistics. OUTCOMES: In total, 57 manuscripts were selected for the review, out of 191 citations identified. Antral follicle count and anti-Müllerian hormone levels correlate with ovarian response to OS in OD but have limited value to discriminate donors who are likely to show either impaired or excessive response. Five randomized controlled trials compared different type of gonadotrophins as part of OS in oocyte donors; owing to high heterogeneity, meta-analysis was precluded. When comparing different types of LH control, namely GnRH antagonist versus agonist, the studies showed no differences in ovarian response. Use of progesterone primed ovarian stimulation protocols has been evaluated in seven studies: the evidence has shown little or no difference, compared to GnRH antagonist protocols, in mean number of retrieved oocytes (MD 0.23, [95% CI 0.58-1.05], n = 2147; 6 studies; I2 = 13%, P = 0.33) and in clinical pregnancy rates among recipients (OR 0.87 [95% CI 0.60-1.26], n = 2260, I2 = 72%, P < 0.01). There is insufficient evidence on long-term safety for babies born. GnRH agonist triggering is the gold standard and should be used in all oocyte donors, given the excellent oocyte retrieval rates, the practical elimination of OHSS and no differences in pregnancy rates in recipients (four studies, OR 0.86, 95%CI 0.58-1.26; I2 = 0%). OS in OD is a safe procedure with a low rate of hospitalization after oocyte retrieval. The use of a levonorgestrel intrauterine device or a progestin contraceptive pill during OS does not impact the number of oocytes retrieved or the clinical pregnancy rate in recipients. Ultrasound monitoring seems enough for an adequate follow up of the stimulation cycle in OD. Use of fresh versus vitrified donated oocytes yielded similar pregnancy outcomes. WIDER IMPLICATIONS: This update will be helpful in the clinical management of OS in OD based on the most recent knowledge and recommendations, and possibly in the management of women under 35 years undergoing oocyte vitrification for social freezing, owing to the population similarities. More clinical research is needed on OS protocols that are specifically designed for OD, especially in term of the long-term safety for newborns, effective contraception during OS, and treatment satisfaction.

Dual trigger in normally-responding assisted reproductive technology patients increases the number of top-quality embryos.

OBJECTIVE: The feasibility of a gonadotropin-releasing hormone agonist (GnRHa) trigger in normal responders is still a matter of debate. The aim of this study was to compare the number of mature oocytes, the number of good-quality embryos, and the live birth rate in normal responders triggered by GnRHa alone, GnRHa and human chorionic gonadotropin (hCG; a dual trigger), and hCG alone. METHODS: A retrospective cohort study was conducted at the infertility clinic of a university hospital. Data from 200 normal responders who underwent controlled ovarian hyperstimulation and intracytoplasmic sperm injection with a GnRH antagonist protocol between January 2016 and January 2017 were reviewed. The first study group consisted of patients with cycles triggered by GnRHa alone. The second study group consisted of patients with cycles triggered by both GnRHa and low-dose hCG (a dual trigger). The control group consisted of patients with cycles triggered by hCG alone. RESULTS: The groups were comparable in terms of demographics and cycle characteristics. The numbers of total oocytes retrieved and metaphase II oocytes were similar between the groups. The total numbers of top-quality embryos were 3.2±2.9 in the GnRHa group, 4.4±3.2 in the dual-trigger group, and 2.9±2.1 in the hCG group (p=0.014). The live birth rates were 21.4%, 30.5%, and 28.2% in those groups, respectively (p=0.126). CONCLUSION: In normal responders, a dual-trigger approach appears superior to an hCG trigger alone with regard to the number of top-quality embryos produced. However, no clinical benefit was apparent in terms of live birth rates.

Significant Serum Progesterone Variations on the Day of Final Oocyte Maturation in Stimulated IVF Cycles.

Objective: To evaluate intraday serum progesterone levels on the day of final oocyte maturation in women undergoing ovarian stimulation in a GnRH-antagonist protocol. Study design, size, and duration: The study was done as a prospective observational study at a Private IVF centre in Muscat, Oman. 30 patients were recruited from May 2018 to March 2019. Patients: Thirty patients with primary/secondary infertility and an indication for ovarian stimulation for IVF/ICSI treatment. The study was registered at the clinicaltrials.gov under the number: NCT03519776. Main outcome measures: Progesterone levels at 4 time points (8 a.m., 11 a.m., 2 p.m. and 5 p.m.) on the day of final oocyte maturation. Results: A total of 120 samples from 30 patients were included in this prospective study. Progesterone levels on the day of final oocyte maturation showed a significant decline over the day with the mean values at 8 a.m.:1.0 ng/ml, at 11 a.m.:0.8 ng/ml, at 2 a.m.: 0.7 ng/ml and at 5 p.m.:0.6 ng/ml. The difference between the first and the last progesterone level was 0.4 ng/ml, reflecting a 37.8% decline of the progesterone level within 9 h and there was a highly significant decrease in the progesterone levels recorded between 8 a.m. and 11 a.m., between 8 a.m. and 2 p.m., between 8 a.m. and 5 p.m. and 11 a.m. and 5 p.m. (p < 0.001). Conclusion: The study findings have two clinically important conclusions: Firstly, progesterone levels on the day of final oocyte maturation decline significantly from the morning to the afternoon in patients, questioning the reliability of one arbitrarily taken progesterone level regarding the decision to perform a fresh embryo transfer or to cryopreserve the embryos. Secondly, declining progesterone levels 12 h after the last administration of gonadotropins support the theory that enhanced ovarian stimulation at the end of the follicular phase leads to an overload of the capacity of the enzymes metabolizing progesterone further on, therefore resulting in elevated progesterone levels in circulation.

Reproductive outcomes after a single dose of gonadotropin-releasing hormone agonist compared with human chorionic gonadotropin for the induction of final oocyte maturation in hyper-responder women aged 35-40 years.

OBJECTIVE: To investigate the reproductive outcomes after the use of GnRH agonist (GnRHa) compared with hCG for the induction of final oocyte maturation in GnRH antagonist cycles performed in hyper-responder women aged 35-40 years. DESIGN: Retrospective study. SETTING: Academic fertility center. PATIENT(S): Two hundred seventy-two hyper-responder women aged 35-40 years who underwent controlled ovarian stimulation under GnRH antagonist suppression were included. Final oocyte maturation was performed with GnRHa (n = 168) or hCG (n = 104). Embryos were cryopreserved at the blastocyst stage and transferred in subsequent warming cycles (n = 542). Subjects were included in the analysis until live birth was achieved, after which they were excluded from further analysis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative live birth rate. RESULT(S): Subjects in the GnRHa group achieved a higher number of oocytes (22 vs. 21) and a higher number of mature oocytes (16 vs. 14). The number of cryopreserved blastocysts (median of five blastocysts in both groups) was similar. Women in the hCG group needed a lower number of warming cycles to achieve live birth (1.32 vs. 2.12), had higher embryo implantation rates (48% vs. 39%), and the proportion of embryos transferred until live birth was lower (33% vs. 57%). The cumulative live birth rate was similar between the groups (48.15% vs. 48%). CONCLUSION(S): Although the cumulative live birth rate is similar, a single dose of GnRHa possibly results in suboptimal oocyte and embryo competence, as manifested by decreased embryo implantation rates and increased time needed to achieve live birth.

Avoiding ovarian hyperstimulation syndrome with the use of gonadotropin-releasing hormone agonist trigger.

Ovarian hyperstimulation syndrome (OHSS) is one of the most serious, and potentially lethal, complications of controlled ovarian stimulation (COS). Induction of final oocyte maturation with a bolus of gonadotropin-releasing hormone (GnRH) agonist (GnRHa), instead of the criterion standard hCG, in patients undergoing ovarian stimulation significantly reduces the risk of OHSS and could be considered to be more physiologic. A bolus of GnRHa used in this context also acts as a luteolytic agent. From a clinical point of view, the most significant benefit of GnRHa trigger is its ability to induce quick and reversible luteolysis and thus reducing the risk of OHSS development. This paper describes the pathophysiology of OHSS, focusing specifically on the luteolytic benefits of using GnRHa to decrease OHSS and the possible corpus luteum rescue modalities available.

Nuclear progestin receptor (pgr) knockouts in zebrafish demonstrate role for pgr in ovulation but not in rapid non-genomic steroid mediated meiosis resumption.

Progestins, progesterone derivatives, are the most critical signaling steroid for initiating final oocyte maturation (FOM) and ovulation, in order to advance fully-grown immature oocytes to become fertilizable eggs in basal vertebrates. It is well-established that progestin induces FOM at least partly through a membrane receptor and a non-genomic steroid signaling process, which precedes progestin triggered ovulation that is mediated through a nuclear progestin receptor (Pgr) and genomic signaling pathway. To determine whether Pgr plays a role in a non-genomic signaling mechanism during FOM, we knocked out Pgr in zebrafish using transcription activator-like effector nucleases (TALENs) and studied the oocyte maturation phenotypes of Pgr knockouts (Pgr-KOs). Three TALENs-induced mutant lines with different frame shift mutations were generated. Homozygous Pgr-KO female fish were all infertile while no fertility effects were evident in homozygous Pgr-KO males. Oocytes developed and underwent FOM normally in vivo in homozygous Pgr-KO female compared to the wild-type controls, but these mature oocytes were trapped within the follicular cells and failed to ovulate from the ovaries. These oocytes also underwent normal germinal vesicle breakdown (GVBD) and FOM in vitro, but failed to ovulate even after treatment with human chronic gonadotropin (HCG) or progestin (17α,20ß-dihydroxyprogesterone or DHP), which typically induce FOM and ovulation in wild-type oocytes. The results indicate that anovulation and infertility in homozygous Pgr-KO female fish was, at least in part, due to a lack of functional Pgr-mediated genomic progestin signaling in the follicular cells adjacent to the oocytes. Our study of Pgr-KO supports previous results that demonstrate a role for Pgr in steroid-dependent genomic signaling pathways leading to ovulation, and the first convincing evidence that Pgr is not essential for initiating non-genomic progestin signaling and triggering of meiosis resumption.