Stimulation For Assisted Reproductive Technology Research Articles

Safety profiles of offspring born from early-follicular long-acting GnRH agonist protocol and daily mid-luteal GnRH agonist protocol: a retrospective study

BackgroundThe gonadotropin hormone-releasing hormone agonists (GnRH-a) have been widely used for controlled ovarian stimulation in assisted reproductive technology (ART). The early-follicular long-acting GnRH-a long protocol (EFL) and the luteal phase short-acting GnRH-a long protocol (LPS) are commonly used GnRH agonist protocols. We conducted a retrospective analysis to assess and compare the rates of congenital abnormalities and safety profiles in offspring born from the EFL and LPS protocols.MethodsWe conducted a retrospective cohort study to analyze and compare neonatal data from patients who using EFL or LPS protocols at our center between January 1, 2014, and June 30, 2017. The study ultimately included 1810 neonates from 1401 cycles using the EFL protocol and 2700 neonates from 2129 cycles using the LPS protocol.The main outcome measures are gestational age at delivery, birth weight, and congenital anomaly rate.To assess the influence of various factors on congenital abnormalities, a random-effects logistic regression model was employed.ResultsThe EFL and LPS protocols led to similar congenital anomaly rates (1.64% vs. 2.35%, P = 0.149). No significant differences were found between the two groups regarding birth weight and its categories, newborn gender and congenital anomaly rate. The results of the multivariate logistic regression model indicated no association between congenital anomaly and BMI, duration of infertility, treatment protocol, fertilization method, or embryo transfer stage. Compared with singleton pregnancies, the probability of congenital defects in multiple pregnancies was 2.64 times higher (OR: 2.64, 95% CI: 1.72–4.05, P < 0.0001). Newborns with congenital defects were born with a lower gestational age compared with full-term pregnancies.ConclusionIn conclusion, the EFL protocol is considered a safe option for ensuring offspring safety, comparable with the LPS protocol; however, multiple pregnancies represent an independent risk factor for congenital abnormalities. This approach can be widely adopted; however, prioritizing single embryo transfers is strongly recommended to minimize the potential risks associated with multiple pregnancies in offspring.

A Dose-Response Study on Functional and Transcriptomic Effects of FSH on Ex Vivo Mouse Folliculogenesis.

Follicle-stimulating hormone (FSH) binds to its membrane receptor (FSHR) in granulosa cells to activate various signal transduction pathways and drive the gonadotropin-dependent phase of folliculogenesis. Both FSH insufficiency (due to genetic or nongenetic factors) and FSH excess (as encountered with ovarian stimulation in assisted reproductive technology [ART]) can cause poor female reproductive outcomes, but the underlying molecular mechanisms remain elusive. Herein, we conducted single-follicle and single-oocyte RNA sequencing analysis along with other approaches in an ex vivo mouse folliculogenesis and oogenesis system to investigate the effects of different concentrations of FSH on key follicular events. Our study revealed that a minimum FSH threshold is required for follicle maturation into the high estradiol-secreting preovulatory stage, and such threshold is moderately variable among individual follicles between 5 and 10 mIU/mL. FSH at 5, 10, 20, and 30 mIU/mL induced distinct expression patterns of follicle maturation-related genes, follicular transcriptomics, and follicular cAMP levels. RNA sequencing analysis identified FSH-stimulated activation of G proteins and downstream canonical and novel signaling pathways that may critically regulate follicle maturation, including the cAMP/PKA/CREB, PI3K/AKT/FOXO1, and glycolysis pathways. High FSH at 20 and 30 mIU/mL resulted in noncanonical FSH responses, including premature luteinization, high production of androgen and proinflammatory factors, and reduced expression of energy metabolism-related genes in oocytes. Together, this study improves our understanding of gonadotropin-dependent folliculogenesis and provides crucial insights into how high doses of FSH used in ART may impact follicular health, oocyte quality, pregnancy outcome, and systemic health.

Real-world practices of hormone monitoring during ovarian stimulation in assisted reproductive technology: a global online survey.

The aim of this study is to understand the global practice of routine hormonal monitoring (HM) during ovarian stimulation (OS) in the context of assisted reproductive technique (ART) treatment. An open-access questionnaire was available to 3,845 members of IVF-Worldwide.com from September 8 to October 13, 2021. The survey comprised 25 multiple-choice questions on when and how ultrasound (US) and hormone tests were conducted during ovarian stimulation OS. For most questions, respondents were required to select a single option. Some questions allowed the selection of multiple options. In all, 528 (13.7%) members from 88 countries responded to the questionnaire. Most respondents (98.9%) reported using US to monitor OS cycles. HM was used by 79.5% of respondents during any of the cycle monitoring visits and was most commonly performed on the day of, or a day prior to final oocyte maturation. Overall, 87% of respondents claimed adjusting the dose of gonadotropin during OS, with 61.7% adjusting the dose based on hormonal levels. Oestradiol (E2) was the most frequently monitored hormone during all visits and was used by 74% of respondents for the prediction of ovarian hyperstimulation syndrome (OHSS). On or a day prior to ovulation triggering (OT), the number of respondents who measured progesterone increased from 34.3% in the second/third visit to 67.7%. Approximately one-third of respondents measured luteinizing hormone during all visits. Globally, most ART specialists (~80%) use HM, along with US, for monitoring OS, especially for the prevention of OHSS.

Debate: Mild Versus Conventional Stimulation in Assisted Reproductive Technology

An exciting session, delivered at the 39th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), saw a debate regarding mild and conventional stimulation in assisted reproductive technology (ART). Chaired by Barış Ata, Koç University, Istanbul, Türkiye, and Mette Tanvig, Odense University Hospital, Denmark, the accessibility, efficiency, cost, and complications associated with mild and conventional stimulation were discussed, with thought-provoking, and often conflicting, opinions considered.

Free your patients and yourself from day 2–3: start ovarian stimulation any time in freeze-all cycles

Ovarian stimulation for assisted reproductive technology is traditionally started in the early follicular phase. The essential rationale is to allow timely follicle growth and oocyte retrieval to ensure synchronization of the in-vitro cultured embryos with the receptive period of the endometrium in a fresh transfer cycle. In addition, conventional thought suggested that follicle recruitment happened only once, around menstruation. A deeper understanding of folliculogenesis, advances in cryobiology and an increasing proportion of freeze-all cycles provide a unique opportunity here. Experience from oncofertility patients as well as infertile women and oocyte donors who underwent ovarian stimulation in different phases of the menstrual cycle, dubbed ‘random start’ cycles, suggests that the number of oocytes collected and their reproductive potential do not depend on the time of starting ovarian stimulation, although the duration of stimulation and gonadotrophin consumption can vary slightly. It may be time to free both patients and clinics from the obsession with starting ovarian stimulation in the early follicular phase in planned freeze-all cycles. The flexibility provided by random start cycles is one aspect of individualizing treatment to patients’ needs.

P-133 A study of the relationship between in vitro embryo development and maternal hypothyroidism

Abstract Study question Are there an association between the maternal thyroid condition and in vitro fertilization (IVF) outcomes? Summary answer Maternal hypothyroidism was found to be related to oocyte maturation and blastocyst development. What is known already Previous studies have shown that thyroid-stimulating hormone (TSH) levels affect ovarian stimulation in assisted reproductive technology (ART). In addition, changes in serum TSH levels have been linked to a sub-optimal environment for the implantation and development of the embryo. Thyroid-related receptors are present in granulosa cells, ovaries, and the endometrium. In addition, those receptors play a role in ovulation and folliculogenesis. This study aims to determine the association between maternal hypothyroidism and adverse implications for IVF outcomes in IVF/ICSI treated women. Study design, size, duration This retrospective study performed 333 cycles of 208 patients with TSH levels ranging from 0.043-16.627 µIU/mL, treated at the RMC National IVF Center between 2019 and 2022. The study population consisted of 1171 oocytes, which were divided into two groups based on their maternal basal TSH levels: normal TSH ≤ 2.5 µIU/mL (control group, n = 865, euthyroid) and higher TSH &amp;gt; 2.5 µIU/mL (case group, n = 306, hypothyroid). Participants/materials, setting, methods Maternal basal serum TSH levels were measured using Fluorescence Enzyme Immunoassay on the third day of the menstrual cycle. IVF outcome expressed oocyte maturation, fertilization, cleavage, and blastocyst formation rate. Oocytes were divided into mature (metaphase II) and immature (metaphase I and prophase I) groups. Blastocysts are graded by the Kato Ladies Clinic classification system and divided into high potential (A and B grades) and low potential (C, D, and E grades) groups. Main results and the role of chance In our study, there was no statistically significant difference in age and partner’s semen criteria between the two groups (p &amp;gt; 0.05). As regards oocyte maturation, MII oocytes retrieved significantly higher in the control group (82.2% vs. 75.8%). Logistic regression analysis found that TSH levels &amp;gt; 2.5 µIU/mL were related to statistically significantly increased risks of oocyte maturation stages like MI or GV (Age affect adjusted model: B = 0.456, p = 0.005; OR = 1.578, 95% CI = 1.146-2.175). The fertilization, cleavage, and blast formation rates have no differences between the groups. However, 91% (n = 324/356) of higher potential blastocysts in the control group were significantly higher than the case group (79.7%, n = 106/133). While, by the logistic regression analysis found that higher TSH levels ( &amp;gt; 2.5 µIU/mL) were related to statistically significantly increased risks of lower potential for implantation grades (B = 0.947, p = 0.001; OR = 2.579, 95%CI = 1.477-4.502). Limitations, reasons for caution The study relied on TSH as the primary indicator of thyroid function and excluded participants with abnormal prolactin levels. Other markers, such as FT4 and TSHR, should also be considered for a thorough evaluation of thyroid function. Wider implications of the findings Thyroid dysfunction can negatively impact IVF success, and screening and managing thyroid function in women undergoing IVF are essential. More research is needed to understand the mechanisms and develop strategies to improve oocyte and blastocyst quality. Trial registration number not applicable

The HERA (Hyper-response Risk Assessment) Delphi consensus definition of hyper-responders for in-vitro fertilization.

To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)? A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus. 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2ng/ml (14.3pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10mm that would define a hyper-response. The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.

Prothrombotic biomarkers during controlled ovarian stimulation for assisted reproductive technology

To assess the impact of 3 different ovarian stimulation protocols on surrogate biomarkers of coagulation. Observational multicenter cohort study. The study was conducted in assisted reproductive technology (ART) units. Infertile women undergoing ART in 2017-2019 were included. None. Our primary outcome was the endogenous thrombin potential (ETP) assessed by the calibrated automated thrombogram. The ETP was measured at baseline (T1), on the day of ovulation triggering (T2), and 7 days after triggering (T3). Three protocols were prescribed according to the standards used and without hormonal before treatment: agonist protocol with human chorionic gonadotropin (hCG) trigger (ag-hCG), antagonist protocol with hCG trigger (atg-hCG), or GnRH agonist trigger. The evolution of ETP was compared among groups using a mixed-effects linear regression model. Sixty-four women with a mean age of 37.8 years participated in the study: of which 24, 16, 24 received ag-hCG, atg-hCG, and GnRH agonist triggers, respectively. As expected, the mean serum estradiol levels in GnRH agonist trigger were statistically higher at T2 and lower at T3 than that for both ag-hCG and atg-hCG. Overall, the ETP evolution over time was statistically different between the groups. Values were similar between groups at T1 and increased at T2 in each group. The greatest difference occurred between T2 and T3 in each group. The ETP continued to increase at T3 in ag-hCG (+110 nM/L × min) and atg-hCG (+171 nM/L × min), but it remained stable in GnRH agonist trigger (-2 nM/L × min). Sex hormone-binding globulin showed persistent increase at T3 despite the fall in estradiol levels, particularly in the GnRH agonist trigger group. The ag-hCG and atg-hCG groups were associated with a higher hypercoagulable state at T3 than the GnRH agonist trigger group. However, our results show the persistence of a hypercoagulable state after the GnRH agonist triggering despite a sharp drop in estradiol levels. These findings may support the use of GnRH agonist trigger protocol in patients with high thrombotic risk and gives new insight into the fact that coagulation parameters could be disturbed for long time periods. NCT04188444.

Effect of Coenzyme Q10 and transcutaneous electrical acupoint stimulation in assisted reproductive technology: a retrospective controlled study

PurposeTo investigate the effects of coenzyme Q10 (CoQ10) and transcutaneous electrical acupoint stimulation (TEAS) pretreatment on pregnancy in patients with poor ovarian response (POR).MethodsA total of 330 POR patients who were pretreated with CoQ10 or CoQ10 combined with TEAS before their in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) cycles and who were not pretreated were selected and divided into CoQ10 group (group A, n = 110), CoQ10 + TEAS group (group B, n = 110) and control group (group C, n = 110). For patients with 2 or more transfer cycles, only the information of the first cycle was included. Ovarian function, response to gonadotropin (Gn) stimulation, and pregnancy outcomes of the three groups were compared in the IVF/ICSI-ET cycles.ResultsAfter pretreatment, basal FSH, total Gn dosage and duration were comparable among the three groups (all p-value > 0.05), basal E2 in group B decreased significantly compared with the control group (p = 0.022). Endometrial thickness on the human chorionic gonadotropin (hCG) day, antral follicle counts (AFC), the numbers of oocytes, metaphase II (MII) eggs and excellent embryos in the two pretreatment groups were significantly increased compared with group C (all p-value < 0.001), but the rates of MII oocytes, fertilization and excellent embryos had no apparent change. The endometrial thickness on the day of hCG, the numbers of MII eggs and excellent embryos in group B were higher than those in group A (p < 0.001; p = 0.020; p = 0.027; respectively). The embryo implantation rate (IR), clinical pregnancy rate (CPR) and live birth rate (LBR) in group B were significantly higher than those in group C (p = 0.022; p = 0.010; p = 0.019; respectively), but not significantly different from group A.ConclusionCoQ10 alone or in combination with TEAS are effective methods for IVF/ICSI-ET adjuvant therapy, which can significantly improve ovarian reactivity, increase the numbers of retrieved eggs and superior embryos, and improve endometrial receptivity. Adjuvant TEAS on the basis of CoQ10 can significantly enhance pregnancy rates, but CoQ10 alone failed to present such an obvious effect.

Comparison of recombinant human FSH biosimilar QL1012 with Gonal-f® for ovarian stimulation: a phase-three trial

Research questionAre QL1012 and Gonal-f® equivalent in women undergoing ovarian stimulation for assisted reproductive technology (ART)? DesignThis multicentre, randomized, assessor-blinded, phase-three trial was conducted at 13 centres in China. Eligible patients were infertile women; age 20–39 years; body mass index 18–30 kg/m2; regular menstrual cycles; and indication for ART. After successful pituitary downregulation, patients were randomly assigned (1:1) to receive QL1012 or Gonal-f®, stratified by age (initial dose of 75–150 IU for women younger than 30 years, 150–225 IU for women aged 30–34 years and 225–300 IU for women aged ≥35 years, subcutaneously, once daily). The primary end point was the number of oocytes retrieved. ResultsBetween October 2018, and June 2019, 341 patients were included in the per-protocol set. The mean numbers of oocytes retrieved were 14.7 ± 7.0 in the QL1012 group (n = 169) and 13.4 ± 6.1 in the Gonal-f® group (n = 172). Adjusted by analysis of covariance model, the least-squares mean difference was 1.3 oocytes (95% CI –0.1 to 2.7; P = 0.0650), within the pre-defined equivalence margins of ±3.0. Similar results were observed in the full analysis set. Additionally, no statistical differences were found in secondary end points except oestradiol concentration (median 3948.0 pg/ml versus 3545.3 pg/ml; P = 0.0015). Ovarian hyperstimulation syndrome (12.4% versus 13.1 %) and other adverse events were similar between the two groups. ConclusionsTherapeutic equivalence and similar safety profiles were demonstrated between QL1012 and Gonal-f® in women undergoing ovarian stimulation for ART.

Predictive performance of peritoneal fluid in the pouch of Douglas measured five days after oocyte pick-up in predicting severe late-onset OHSS: A secondary analysis of a randomized trial

ObjectivesTo investigate if the amount of peritoneal fluid (PF) in the Pouch of Douglas at oocyte pick-up (OPU) or OPU + 5 days predict severe late-onset ovarian hyperstimulation syndrome (OHSS) in women undergoing ovarian stimulation for assisted reproductive technology (ART). Study designA secondary analysis of a dual-centre RCT on 1050 women referred for their first ART treatment in two public fertility clinics in Denmark and randomized 1:1 to GnRH-antagonist or GnRH-agonist protocol. All women from the two arms who were examined on day of OPU and OPU + 5 days were included in this study (n = 940). The ability of PF in the pouch of Douglas to predict severe late-onset OHSS was assessed by multivariate logistic regression analyses and receiver operator characteristics (ROC) curve analyses and compared with other known predictors of OHSS. The final models were cross-validated by the leave-one-out method to assess the models’ generalizability. ResultsA total of 28 (3%) women developed severe late-onset OHSS. PF in the pouch of Douglas measured on OPU + 5 days predicted severe late-onset OHSS. The optimal cut-off value was 17.5 mm at OPU + 5 days with a 61% sensitivity and 71% specificity (Area under the curve = 0.70 95% CI 0.61–0.80). PF on the day of OPU was not predictive of late on-set OHSS as the adjusted multivariate logistic regression analyses showed insignificant results. ConclusionAlthough PF in the pouch of Douglas could predict late-onset severe OHSS, the low sensitivity underlines that it is not useful as a sole marker to decide whether to perform blastocyst transfer or to use a freeze-all strategy.

A novel orally active gonadotropin‐releasing hormone antagonist, relugolix, is a potential substitute for injectable GnRH antagonists in controlled ovarian stimulation in assisted reproductive technology

PurposeTo evaluate the efficacy of an oral gonadotropin‐releasing hormone antagonist (GnRH Ant), relugolix (R), for assisted reproductive technology (ART).MethodsWe enrolled women undergoing ART using a GnRH Ant for controlled ovarian stimulation. We compared R; 20 mg/day with cetrorelix acetate (C); 0.125 mg. C was administered to 88 women in 2019, and R to 93 women in 2020. Clinical outcomes associated with ART were assessed in both groups.ResultsThe luteinizing hormone levels on the day of human chorionic gonadotropin injection in the R group (1.26 ± 0.93 IU/L) were significantly lower than those in the C group (2.85 ± 3.02 IU/L). There were no cases in which egg retrieval was canceled in both groups. The total doses of gonadotropins administered were greater in the R group compared with the C group. The number of days of GnRH Ant administration in the R group (1.71 ± 0.57 days) was significantly longer compared with the C group (1.48 ± 0.58 days). The number of oocytes collected, fertilization rates, and pregnancy rates (R; 47.1% vs C; 45.8%) did not differ between the two groups.ConclusionAn orally active GnRH Ant, relugolix, when used in controlled ovarian stimulation for ART, showed comparable clinical outcomes with cetrorelix.

AMH IS STRONGLY ASSOCIATED WITH CUMULATIVE LIVE BIRTH RATE INDEPENDENT OF AGE: AN ANALYSIS OF 132,466 CYCLES FROM THE SART-CORS DATABASE FOR 2014-2016

Serum antimullerian hormone (AMH) is frequently used to predict a woman’s response to ovarian stimulation in assisted reproductive technology (ART). However, it has historically shown weak predictability for outcomes per embryo transfer (i.e. pregnancy and live birth rate) as traditionally reported by The Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SARTCORS) prior to 2014. We hypothesized that the association of AMH with ART cumulative live birth rate (CLBR) per cycle start as reported from 2014 onward by SARTCORS may be more informative as CLBR accounts for the entire embryo cohort (fresh and frozen) that are created and linked to a single identified index retrieval.

Corifollitropin alfa in different variants of ovarian response in assisted reproductive technology programmes: literature review

This literature review focuses on the use of corifollitropin alfa for ovarian stimulation in assisted reproductive technology (ART) programmes in different groups of patients. Corifollitropin alfa is a gonadotropin drug with prolonged FSH activity. The main difference between corifollitropin alfa and other gonadotropins is the higher level of peak FSH, which leads to the recruitment of more follicles. Another feature is the inability to adjust the gonadotropin dose during the first days of ovarian stimulation. In contrast to traditional indications/contraindications for gonadotropins, the use of cortifollitropin is not recommended in combination with GnRH agonists or in patients with polycystic ovary syndrome.Evidence for the feasibility and efficacy of using corifollitropin alfa in patients with various ovarian response variants in ART programmes has been analysed. Most researchers agree that the use of corifollitropin alfa can be recommended for patients with a presumed poor or normal ovarian response. The use of corifollitropin alfa in patients with a presumed excessive response to ovarian timulation is possible when embryo transfer is not expected: in oocyte donation/oocyte vitrification cycles or in "freeze-all" cycles.A significant advantage of using corifollitropin alfa for oocyte donor patients is the single administration of the drug, which can be done in a medical facility, which reduces the risk of prescription non-compliance.The use of corifollitropin alfa in protocols with GnRH agonists requires further research: firstly, corifollitropin alfa has no LH component and secondly, there is no possibility of ovulation trigger replacement in this protocol if there is a high risk of early ovarian hyperstimulation syndrome.

Dopamine agonists for preventing ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of ovarian stimulation in assisted reproduction technology (ART). It is characterised by enlarged ovaries and an acute fluid shift from the intravascular space to the third space, resulting in bloating, increased risk of venous thromboembolism, and decreased organ perfusion. Most cases are mild, but forms of moderate or severe OHSS appear in 3% to 8% of in vitro fertilisation (IVF) cycles. Dopamine agonists were introduced as a secondary prevention intervention for OHSS in women at high risk of OHSS undergoing ART treatment. OBJECTIVES: To assess the effectiveness and safety of dopamine agonists in preventing OHSS in women at high risk of developing OHSS when undergoing ART treatment. We searched the following databases from inception to 4 May 2020: Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and PsycINFO for randomised controlled trials (RCTs) assessing the effect of dopamine agonists on OHSS rates. We also handsearched reference lists and grey literature. We considered RCTs for inclusion that compared dopamine agonists with placebo/no intervention or another intervention for preventing OHSS in ART. Primary outcome measures were incidence of moderate or severe OHSS and live birth rate. Secondary outcomes were rates of clinical pregnancy, multiple pregnancy, miscarriage, and adverse events. Two review authors independently screened titles, abstracts, and full texts of publications; selected studies; extracted data; and assessed risk of bias. We resolved disagreements by consensus. We reported pooled results as odds ratios (OR) and 95% confidence interval (CI) by the Mantel-Haenszel method. We applied GRADE criteria to judge overall quality of the evidence. The search identified six new RCTs, resulting in 22 included RCTs involving 3171 women at high risk of OHSS for this updated review. Thedopamine agonists were cabergoline, quinagolide, and bromocriptine. Dopamine agonists versus placebo or no intervention Dopamine agonists probably lowered the risk of moderate or severe OHSS compared to placebo/no intervention(OR 0.32, 95% CI 0.23 to 0.44; 10 studies, 1202 participants; moderate-quality evidence). This suggests that ifthe risk of moderate or severe OHSS following placebo/no intervention is assumed to be 27%, the risk following dopamine agonists would be between 8% and 14%.We are uncertain of the effect of dopamine agonists on rates of live birth(OR 0.96, 95% CI 0.60 to 1.55; 3 studies, 362 participants; low-quality evidence). We are also uncertain of the effect of dopamine agonists onclinical pregnancy, multiple pregnancy,miscarriageor adverse events(very low to low-quality evidence). Dopamine agonists plus co-intervention versus co-intervention Dopamine agonist plus co-intervention (hydroxyethyl starch, human albumin, or withholding ovarian stimulation 'coasting') may decrease the risk of moderate or severe OHSS compared to co-intervention(OR 0.48, 95% CI 0.28 to 0.84; 4 studies, 748 participants; low-quality evidence). Dopamine agonists may improve rates of live birth(OR 1.21, 95% CI 0.81 to 1.80; 2 studies, 400 participants; low-quality evidence). Dopamine agonists may improve rates of clinical pregnancyandmiscarriage, but we are uncertain if they improve rates ofmultiple pregnancy or adverse events (very low to low-quality evidence). Dopamine agonists versus other active interventions We are uncertain if cabergoline improves the risk of moderate or severe OHSScompared to human albumin (OR 0.21, 95% CI 0.12 to 0.38; 3 studies, 296 participants; very low-quality evidence), prednisolone (OR 0.27, 95% CI 0.05 to 1.33; 1 study; 150 participants; very low-quality evidence), hydroxyethyl starch (OR 2.69, 95% CI 0.48 to 15.10; 1 study, 61 participants; very low-quality evidence), coasting (OR 0.42, 95% CI 0.18 to 0.95; 3 studies, 320 participants; very low-quality evidence), calcium infusion (OR 1.83, 95% CI 0.88 to 3.81; I² = 81%; 2 studies, 400 participants; very low-quality evidence), or diosmin (OR 2.85, 95% CI 1.35 to 6.00; 1 study, 200 participants; very low-quality evidence). We are uncertain of the effect of dopamine agonists on rates oflive birth(OR 1.08, 95% CI 0.73 to 1.59; 2 studies, 430 participants; low-quality evidence). We are uncertain of the effect of dopamine agonists on clinical pregnancy, multiple pregnancy or miscarriage (low to moderate-quality evidence). There were no adverse events reported. Dopamine agonists probably reduce the incidence of moderate or severe OHSScompared to placebo/no intervention, while we are uncertain of the effect onadverse events andpregnancy outcomes (live birth, clinical pregnancy,miscarriage). Dopamine agonists plus co-intervention may decrease moderate or severe OHSS rates compared to co-intervention only, but we are uncertain whether dopamine agonists affect pregnancy outcomes. When compared to other active interventions, we are uncertain of the effects of dopamine agonists on moderate or severe OHSS and pregnancy outcomes.

The Review of Compared Progestins Type and Dose Utility against the Pituitary Suppression during Ovarian Stimulation for Assisted Reproductive Technology

Abstract We performed a literature review of studies comparing the effectiveness of progestins in preventing premature ovulation during ovarian stimulation for assisted reproductive technology (ART). Five randomized trials and cohort studies involving a total of 2404 women, which compared; i) two different progestins or ii) two different doses of the same progestin were included. The primary outcome was live birth rate (LBR) per woman. Secondary outcomes were live birth or ongoing pregnancy (LB/OP) per woman and per embryo transfer (ET), ongoing pregnancy, clinical pregnancy, positive pregnancy test, numbers of oocytes and metaphase-two oocytes, duration of stimulation and gonadotropin consumption. The primary outcome was not reported in most studies however there were no differences between progestins for secondary outcomes. All progestins seem to effectively prevent premature ovulation in ART cycles. Low-quality evidence suggests that progestins can effectively prevent premature ovulation in ART cycles.

Progestins versus GnRH analogues for pituitary suppression during ovarian stimulation for assisted reproductive technology: a systematic review and meta-analysis.

This systematic review and meta-analysis of comparative studies investigated whether progestins are as effective as gonadotrophin releasing hormone (GnRH) analogues for pituitary suppression in assisted reproduction. The primary outcome was live birth rate per woman. Secondary outcomes were live birth or ongoing pregnancy per woman and per embryo transfer, ongoing pregnancy, clinical pregnancy, numbers of oocytes and metaphase-two oocytes, duration of stimulation and gonadotrophin consumption. Adverse events included miscarriage, ectopic pregnancy and multiple pregnancy rates. The GRADE system was used to assess the quality of evidence. Seven studies involving a total of 2047 women were included. Three studies compared a progestin with a GnRH antagonist and four studies compared a progestin with a GnRH agonist. Most studies are non-randomized and report outcomes per embryo transfer, rather than per woman. Although progestins were similar to GnRH antagonists in effectiveness and safety parameters, they were associated with significantly higher live birth or ongoing pregnancy per embryo transfer compared with the short GnRH agonist protocol (RR 1.49, 95% CI 1.16 to 1.91). Progestin primed stimulation lasted significantly longer (mean difference 0.61 days, 95% CI 0.33 to 0.89) and required significantly more gonadotrophins (mean difference 433.2 IU, 95% CI 311.11 to 555.19) than the short GnRH agonist protocol, but the differences were clinically negligible. Safety parameters were similar between progestins and GnRH agonists. In conclusion, progestins can effectively prevent premature ovulation in assisted reproductive technology cycles. If larger and well-designed studies confirm these findings, progestins may be an effective and low-cost alternative to GnRH analogues when a fresh embryo transfer is not planned owing to a medical indication.

Comparative study between agonist and antagonist protocols in PCOS patients undergoing ICSI: a cross-sectional study

BackgroundPolycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5–10% of women of reproductive age. The syndrome is surrounded by controversies regarding both its diagnosis and treatment. The introduction of long-acting GnRH agonists in the late 1980s revolutionized the approach to ovarian stimulation in assisted reproductive technologies by providing the means to downregulate endogenous pituitary gonadotropin secretion and thereby prevent a premature luteinizing hormone surge during exogenous gonadotropin stimulation. The relatively recent introduction of GnRH antagonists in clinical practice has provided another option for ovarian stimulation in IVF. The purpose of this study was to compare the efficacy of the fixed GnRH antagonist vs. GnRH agonist long protocol in patients with polycystic ovary syndrome treated by ICSI.ResultsThere is a statistically significant difference between both groups in view of the received dose of gonadotrophin (1901.7 ± 400.6 vs. 1789 ± 368 with p = .004) and duration of stimulation (11.3 ± 0.8 vs. 10.3 ± 1.1 with p = .017). There is no significant difference between both groups in view of pregnancy outcome (37% vs. 32% with p = .125). There is a significant difference between both groups in view of ovarian hyperstimulation syndrome (OHSS) incidence where the rates were 15%, 6%, and 1.5% vs. 4.5%, 2.5%, and .05% with p = 0.04 for mild, moderate, and severe, respectively, form of OHSS in group 1 and group 2.ConclusionThe antagonist protocol may be the preferred stimulation protocol for PCOS patients treated by ICSI in view of the reduction of OHSS incidence rates without compromising the pregnancy outcome.

The role of the growth hormone in assisted reproductive technologies cycles

The paper analyzes the literature data on the use of the growth hormone (GH) in ovarian stimulation in assisted reproductive technologies (ART). Routine use of GH in ovarian stimulation in patients with a normal GH level does not increase pregnancy and childbirth rates in ART. Also, no benefits of using GH have been identified for patients with polycystic ovary syndrome, despite the increase in insulin and IGF-1 blood levels. The main research focus is to study the use of GH in patients with poor ovarian response. According to the meta-analysis conducted by X.-L. Li et al. (2017), GH in ovarian stimulation of poor ovarian responders increases the number of received oocytes, mature oocytes number, reduces the embryo transfer cancellation rate and does not affect the fertilization rate. The pregnancy and live birth rates are significantly higher in the group of GH use - by 1.65 (95% CI 1.23-2.22) and 1.73 (95% CI 1.25-2.40) times, respectively. Thus, it is advisable to use GH in ovarian stimulation in poor ovarian responders, since it allows to increases live birth rate in ART. However, further studies should determine the optimal GH dose and assesse it`s safety in ART programs.

Successful reversal of ovarian hyperstimulation syndrome in a mouse model by rapamycin, an mTOR pathway inhibitor

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening, iatrogenic complication of ovarian stimulation in assisted reproduction technology. This complex syndrome is characterised by enlarged ovaries with multiple corpora luteum, elevated sex steroid hormones in serum and increased capillary permeability. Until now, the pathogenesis of OHSS remains obscure, and no absolute strategy can fully prevent OHSS without any side effect on ovulation and clinical pregnancy. Using cultured human or mouse granulosa cells, our study revealed the time-dependent activation of the mTOR signaling pathway after human chorionic gonadotropin (hCG) treatment. The involvement of the mTOR signaling pathway was also observed in the development of OHSS in a mouse model. Selectively inhibiting mTOR signals by only two injections of rapamycin (2mg/kg body weight), before or just after hCG treatment, significantly reduced vascular leakage and the severity of OHSS symptoms. Although ovarian angiogenesis was significantly inhibited, rapamycin could not decrease the elevated levels of vascular endothelial growth factor, IL-6 and IL-11 in OHSS ovaries. Further study showed the functional roles of the mTOR signaling pathway in the hyperstimulation-induced ovarian extracellular matrix remodeling as the expression of α2M, a broad proteolytic inhibitor in both ovary and serum, was dramatically decreased after rapamycin treatment. Since a single injection of rapamycin during superovulation had no side effects on ovulation and early embryonic development, we propose rapamycin may be a good candidate to lower and prevent the risk of OHSS in the future.