Early or late response in poor responders: does it make a difference in cycle outcome?

Ovarian response to stimulation mainly determines the length of stimulation. However, there is no clarity in the literature regarding the optimal duration required to achieve oocyte maturity in patients with the poor ovarian response (POR) defined by Bologna criteria. Therefore, a total of 267 cycles that fulfilled the inclusion criteria were selected retrospectively. Group A constitute of patients with a stimulation period < 9 d (n = 70); and group B included patients with a stimulation period ≥ 9 d (n = 133). The results showed that antral follicle count (5.72 ± 1.82 vs. 5.10 ± 1.78, p = 0.023), serum oestradiol level on hCG day (1286.88 ± 778.18 pg/mL vs. 820.14 ± 479.04 pg/mL, p = 0.001), and total gonadotropin dose used (2949.53 ± 727.92 IU vs 2020.94 ± 415.17 IU, p = 0.0001) were higher in group B when compared to group A. Although the number of total (5.47 ± 3.32 vs 3.86 ± 2.15, p = 0.0001) and mature oocytes retrieved (4.34 ± 2.88 vs 2.84 ± 1.67, p = 0.0001) were higher in group B, no significant difference was observed in the pregnancy rates between groups (25.6 vs 15.7%, p > 0.05). In conclusion, no deleterious effect of a shorter duration of stimulation on cycle outcome was seen in patients with POR.

Researching the Phenomenon of Poor Ovarian Responders and Management Strategies in IVF: A Narrative Review.

This narrative review aims to summarize all the latest studies published between 2015-2021 concerning the management protocols adopted for poor ovarian response (POR) cases. Patients defined as "poor responders" show minimal response to controlled ovarian hyperstimulation, although there is no standard definition for POR. Although infertility specialists are endeavoring to improve cycle outcomes in poor responders by adopting multiple management strategies, still the estimated risk of cycle cancellation is about 20%. All the studies performed during this study period were evaluated and their results were recorded. The latest published protocols to improve oocyte retrieval in poor responders include: anti-Mϋllerian hormone, clomiphene citrate, co-enzyme Q10, corifollitropin, dehydroepiandrosterone, double stimulation, Follicle Stimulation Hormone, Growth Hormone, Gonadotropin-releasing hormone agonists, letrozole, human chorionic gonadotropin, Luteinizing Hormone, progesterone and testosterone. CONCLUSION: Although many strategies have been suggested to manage POR, none has been proven superior to the others. Further large-scale randomized studies are needed to validate experimental techniques leading towards successful individualized treatment regimens.

Predicting IVF outcome in poor ovarian responders.

BACKGROUND: Poor responders to ovarian stimulation are one of the most challenging populations to treat. As a failed cycle can cause a considerable emotional and economical loss, adequate fertility counseling addressing patients' expectations are highly important when facing patients with poor ovarian response. The study aimed to evaluate reproductive outcomes and to identify factors associated with live birth (LB) after fresh autologous IVF/intracytoplasmic sperm injection (ICSI) cycles of patients fulfilling the Bologna criteria for poor ovarian response (POR). METHODS: A retrospective study included 751 IVF/ICSI treatment cycles which yielded up to three retrieved oocytes, at a tertiary referral hospital between January 2016 and February 2020. A logistic regression analysis was used to adjust for confounders. RESULTS: Clinical pregnancy and LB rate per cycle were significantly higher among women younger versus older than 40 years (9.8% and 6.8% vs 4.5% and 2.1%, p < 0.01, respectively). Patients who achieved LB were significantly younger, had higher number of oocytes retrieved, fertilization rate and top-quality embryos (p < 0.05). Multivariable regression analysis identified patient's age (OR 0.90; 95% CI 0.845-0.97; p = 0.005) and mean number retrieved oocytes (OR 1.95; 95% CI 1.20-3.16; p = 0.007) as factors significantly associated with the probability of a LB. CONCLUSIONS: The woman's age and the number of retrieved oocytes are both independent predicting factors of live birth in poor ovarian responders. Considering the risks, the high financial investment and poor reproductive outcomes involved in IVF treatments, raises questions regarding the adequacy of providing treatments in these patients' population. POR younger than 40 years may represent a possible exception due to acceptable probability for a LB.

Pregnancy rate in IVF patients with unexpected poor response to ovarian stimulation.

OBJECTIVE: To evaluate whether an unexpected poor response (cases with ≤3 oocytes) leads to a reduction in the pregnancy rate in IVF cycles compared to a suboptimal response (controls with 4-9 oocytes) in women with adequate ovarian reserve. METHODS: A nested case-control study performed in a retrospective cohort of couples undergoing IVF at the Infertility Unit of the ASST Lariana. Cases and controls had adequate ovarian reserve and were matched 1:1 for female age and number of previous cycles. Cumulative clinical pregnancy rate per oocyte retrieval was the main outcome. RESULTS: Overall, 113 cases and 113 matched controls were included; the median number of available oocytes was 2 and 6, respectively. The cumulative pregnancy rate per cycle was significantly reduced in cases compared to controls with a crude odds ratio = 0.45 [95% Confidence Interval: 0.28-0.82]. A binomial logistic model indicated that an increase in one oocyte increases the odds for cumulative pregnancy rate per cycle by 1.27 in women with 9 oocytes or less. The cumulative pregnancy rates per cycle in cases and controls, according to female age were respectively: 29% versus 54% in patients aged <35 years (p = 0.036); 22% versus 43% in patients aged 36-39 years (p = 0.048) and 11% versus 13% in patients 40-45 years old (p = 0.72). Patients belonging to older age groups showed decreasing probability of cumulative clinical pregnancy rates both among cases and controls group (p < 0.05). CONCLUSIONS: The number of available oocytes significantly affects the probability of success in IVF cycles with unexpected impaired ovarian response.

Effect of rLH Supplementation during Controlled Ovarian Stimulation for IVF: Evidence from a Retrospective Analysis of 1470 Poor/Suboptimal/Normal Responders Receiving Either rFSH plus rLH or rFSH Alone.

We retrospectively studied a real-life population of 1470 women undergoing IVF, with poor/suboptimal/normal ovarian responsiveness to controlled ovarian stimulation (COS), comparing the cumulative live birth rate (cLBR) when COS was performed using rFSH alone or rFSH + rLH in a 2:1 ratio. Overall, we observed significantly higher cLBR in the rFSH alone group than in the rFSH + rLH group (29.3% vs. 22.2%, p < 0.01). However, considering only suboptimal/poor responders (n = 309), we observed comparable cLBR (15.6% vs. 15.2%, p = 0.95) despite the fact that patients receiving rFSH + rLH had significantly higher ages and worse ovarian reserve markers. The equivalent effectiveness of rFSH + rLH and rFSH alone was further confirmed after stratification according to the number of oocytes retrieved: despite basal characteristics were still in favor of rFSH alone group, the cLBR always resulted comparable. Even subdividing patients according to the POSEIDON classification, irrespective of differences in the baseline clinical characteristics in favor of FSH alone group, the cLBR resulted comparable in all subgroups. Despite the retrospective, real-life analysis, our data suggest that rLH supplementation in COS may represent a reasonable option for patients with predictable or unexpected poor/suboptimal ovarian responsiveness to FSH, those matching the Bologna criteria for poor responsiveness, and those included in the POSEIDON classification.

Reliability of AMH and AFC measurements and their correlation: a large multicenter study.

PURPOSE: Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are correlated with the ovarian response, but their reliability and reproducibility are questionable. This large multicenter study describes their distribution, inter-cycle and inter-center variability, and their correlation. METHODS: A total of 25,854 IVF cycles among 15,219 patients were selected in 12 ART centers. Statistical distribution of AMH and AFC was studied by using the Kolmogorov-Smirnov test and Shapiro goodness of fit test. The reproducibility of AFC and AMH was measured using a mixed model regressing the logarithmic transformation of AFC with age. RESULTS: The distribution of AMH and AFC was characterized by a wide dispersion of values, twice more important for AFC, and a logarithmic distribution. The faster decline in AMH than in AFC with age suggests that their correlation changes with age. AMH and AFC showed a very low proportion of concordance in the range of expected poor responders according to Bologna cutoffs. The heterogeneity for AMH and AFC across centers was small, but much larger across patients within each center. Concerning the patients with several successive cycles, the reproducibility for AMH seemed much better than for AFC. Comparing respective performances of AMH and AFC for the prediction of ovarian response depended on the local conditions for measuring these indicators and on the reproducibility of results improved over time. CONCLUSION: Distribution of AMH and AFC was characterized by the wide dispersion of values, and a logarithmic distribution. Establishing cutoffs or a direct relationship AMH/AFC without considering age seems hazardous. Correlation between AMH and AFC was very poor in the range of poor responders.

Effect of dehydroepiandrosterone administration before in vitro fertilization on the live birth rate in poor ovarian responders according to the Bologna criteria: A randomised controlled trial.

OBJECTIVE: To evaluate the effect of dehydroepiandrosterone (DHEA) pre-treatment before in vitro fertilization and embryo transfer (IVF-ET) on the live birth rate in infertile women with poor ovarian response (POR) defined according to the Bologna criteria. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Nine reproductive medical centers in China. POPULATION: A total of 821 participants with POR defined according to the Bologna criteria were enrolled in the study between April 2016 and December 2018. METHODS: Eligible participants were randomly assigned to receive either DHEA (n = 410) or placebo (n = 411) treatments for 4-12 weeks prior to IVF-ET, in a 1:1 ratio. MAIN OUTCOME MEASURES: Live birth rate after the first embryo transfer. RESULTS: Thirty-six (8.8%) of 410 women in the DHEA group and 37 (9.0%) of 411 women in the placebo group had a live birth, with no significant difference observed between groups (relative risk, 0.98, 95% CI, 0.63-1.51; p = 0.911). There were no significant differences in the number of retrieved oocytes, and the rates of clinical pregnancy, pregnancy loss, and cumulative live births between the two groups. CONCLUSIONS: DHEA administration prior to IVF-ET had no beneficial effect on the live birth rate relative to placebo in women with POR defined according to the Bologna criteria. TWEETABLE ABSTRACT: No benefit was found in poor ovarian responders who received DHEA administration prior to IVF.

Four consecutive minimal ovarian stimulation (TetraStim) is a feasible alternative to increase the number of oocytes and improve live birth rates in poor responders who do not accept oocyte donation.

OBJECTIVE: To present our experience using four consecutive minimal COS (TetraStim) followed by oocyte retrieval and vitrification to increase the number of oocytes in patients with POR for whom oocyte donation is not an option. METHODS: We performed an observational study evaluating 128 poor responders submitted to TetraStim instead of oocyte donation cycles. Patients were submitted to four consecutive minimal COS started at luteal phase, oocyte retrieval, oocyte vitrification/warming, ICSI, endometrial priming and embryo transfer. We evaluated the number of vitrified oocytes, survival rate after warming, fertilization rate, cleavage rate, number of embryos transferred, clinical pregnancy rate, miscarriage rate and live birth rate. RESULTS: The mean age was 38.1 ± 3.1 years. A total of 791 oocytes were recovered (6.1 ± 2.7/patient), 682 (86.2%) Metaphase II (5.3 ± 2.4/patient) were vitrified, 95.3% survived warming (5.1 ± 2.3/patient), 82% showed normal fertilization after ICSI (4.2 ± 2/patient), 79.2% reached cleavage stage (3.3 ± 1.6/patient), 313 cleavage stage embryos were transferred to 115 patients (2.7 ± 0.7/patient) and 14.7% of the patients had surplus embryos that were vitrified. Clinical pregnancy rate per patient was 31.3% and live birth rate per patient was 22.6%. CONCLUSION: To our knowledge this is the first study that demonstrates that TetraStim can be an effective alternative for patients with POR with an indication to perform IVF with donated oocytes, but do not agree to use. TetraStim is a feasible alternative to increase the number of oocytes and embryos and improve pregnancy rates with no dropouts and very low cycle cancelation rate. However, randomized controlled studies must be performed to compare TetraStim with other treatments.

Live birth rates in different subgroups of poor ovarian responders according to Bologna and POSEIDON group classification criteria.

PURPOSE: The present study was designed to compare the live birth rates (LBRs) according to Bologna criteria or Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) group classifications to determine the important predictive factors for LBR in patients with POR. BASIC PROCEDURES: In this cross-sectional study, the database of Royan Institute (Tehran, Iran) from December 2015 to December 2017 was evaluated and the fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles outcomes for all the patients with at least one POR after standard controlled ovarian stimulation were collected. The patients divided into five subgroups according to Bologna criteria and four groups on the basis of POSEIDON group classification. MAIN FINDING: 812 patients with POR diagnosis were assessed which 517 (63.6%) of them were underwent embryo transfer (ET) during the last treatment cycle. According to Bologna criteria, 41 patients were not included in any subgroup and the patients in Bologna group II had highest LBR (19.8%). In terms of POSEIDON classification, all of the patients were classified into subgroups and the women in POSEIDON group III had the highest LBR (27%). According to multivariable regression analysis, the significant independent predictive factors for LBR were the number and morphology (good and excellent) of the embryos transferred, and POSEIDON group III classification. PRINCIPAL CONCLUSION: The results indicated that the POSEIDON group classification could be more comprehensive and practical than Bologna criteria for categorizing POR patients and predicting their outcome. Moreover, the number and morphology of transferred embryos were the most important prognostic factors for live births in these patients.

The POSEIDON stratification - moving from poor ovarian response to low prognosis.

Poor ovarian response remains one of the most challenging tasks for an IVF clinician. In this review, we aim to highlight the ongoing research for optimizing the prognosis in poor ovarian response patients. The newly introduced POSEIDON criteria argue that the first step is to move from a poor response to a poor prognosis concept, while improving identification and stratification of the different sub-types of poor prognosis patients prior to ovarian stimulation. The immediate marker of success is the ability of the ovarian stimulation to retrieve the number of oocytes needed to obtain at least one euploid blastocyst for transfer in each patient. This surrogate marker of success should not replace live birth as the most important outcome, but it should be approached as a useful tool for clinicians to evaluate their strategy for achieving live birth in the shortest timespan possible in the individual patient/ couple.

Endometrial scratching for poor responders based on the Bologna criteria in ICSI fresh embryo transfer cycles: a preliminary retrospective cohort study

Objective: This study evaluated the effect of endometrial injury on pregnancy outcomes in patients with a poor ovarian response (POR), based on the Bologna criteria, who underwent intracytoplasmic sperm injection (ICSI) cycles. Material and Methods: Sixty-eight patients were enrolled in this retrospective cohort study. All patients in the endometrial scratching group (group 1, n=32) and control group (group 2, n=36) underwent office hysteroscopy in the early follicular phase of the cycle before controlled ovarian stimulation. Group 1 also underwent endometrial scratching. The main outcome measure was the ongoing pregnancy rate. Results: The study groups had similar baseline demographics, including age, body mass index, duration of infertility, number of ICSI cycles, and hormone levels. However, the antral follicle count was significantly higher in group 1 than in group 2 (4.2±1.9 vs 3.3±1.8; p<0.05). There were no significant group differences in ovarian stimulation characteristics (ovarian stimulation time, trigger day endometrial thickness, number of metaphase II oocytes), number of embryos transferred, or the ratio of embryo transfer on days 3 and 5. Moreover, there were no significant differences between groups 1 and 2 in the rates of chemical pregnancy (25% vs 19.4%), clinical pregnancy (15.6% vs 11.1%) or ongoing pregnancy (9.4% vs 8.3%) (p>0.05 for all). Conclusion: Endometrial scratching did not improve pregnancy outcomes for patients meeting the Bologna criteria for a POR to ICSI cycles using fresh embryo transfer and the GnRH antagonist protocol.

Natural Cycle Results in Lower Implantation Failure than Ovarian Stimulation in Advanced-Age Poor Responders Undergoing IVF: Fertility Outcomes from 585 Patients.

To compare pregnancy rate and implantation rate in poor responder women, aged over 40 years, who underwent natural cycle versus conventional ovarian stimulation. This is a retrospective single-center cohort study conducted at the GENERA IVF program, Rome, Italy, between September 2012 and December 2018, including only poor responder patients, according to Bologna criteria, of advanced age, who underwent IVF treatment through Natural Cycle or conventional ovarian stimulation. Between September 2012 and December 2018, 585 patients were included within the study. Two hundred thirty patients underwent natural cycle and 355 underwent conventional ovarian stimulation. In natural cycle group, both pregnancy rate per cycle (6.25 vs 12.89%, respectively, p = 0.0001) and pregnancy rate per patient101 with at least one embryo-transfer (18.85 vs 28.11% respectively, p = 0.025) resulted significant reduced. Pregnancy rate per patient managed with conventional ovarian stimulation resulted not significantly different compared with natural cycle (19.72 vs 15.65% respectively, p = 0.228), but embryo implantation rate was significantly higher in patients who underwent natural cycle rather than patient subjected to conventional ovarian stimulation (13 vs 8.28% respectively, p = 0.0468). No significant difference could be detected among the two groups in terms of abortion rate (p = 0.2915) or live birth pregnancy (p = 0.2281). Natural cycle seems to be a valid treatment in patients over 40 years and with a low ovarian reserve, as an alternative to conventional ovarian stimulation.

Meta-analysis of GnRH-antagonists versus GnRH-agonists in poor responder protocols.

PURPOSE: Considering the insufficient evidence supporting an ideal protocol for poor responder management in IVF/ICSI cycles, the aim of the current meta-analysis was to compare GnRH-antagonist versus GnRH-agonist protocols in poor responders, evaluating effectiveness and safety. METHODS: Meta-analysis was conducted using Medcalc 16.8 version software. Standardized mean differences (SMD), odds ratios (OR), and the respective 95% confidence intervals (CI) were determined appropriately. The Cochran Q statistic and the I2 test were used to assess studies' heterogeneity. RESULTS: GnRH-agonists were shown to correlate with fewer cancelled IVF/ICSI cycles (p = 0.044, OR = 1.268 > 1, 95% CI 1.007, 1.598), a larger number of embryos transferred (p = 0.008, SMD = - 0.230, 95% CI - 0.400, - 0.0599), and more clinical pregnancies (p = 0.018, OR = 0.748 < 1, 95% CI 0.588, 0.952). However, GnRH-antagonists resulted in a significantly shorter duration of ovarian stimulation (p = 0.007, SMD = - 0.426. 95% CI - 0.736, - 0.115). The number of oocytes and mature oocytes retrieved in both protocols did not differ statistically (p = 0.216, SMD = - 0.130, 95% CI - 0.337, 0.0763 and p = 0.807, SMD = - 0.0203, 95% CI - 0.183, 0.142, respectively). Moreover, a high heterogeneity among studies was observed regarding duration of ovarian stimulation (I2 = 90.6%), number of oocytes (I2 = 82.83%)/mature oocytes retrieved (I2 = 70.39%), and embryos transferred (I2 = 72.83%). CONCLUSIONS: Based on the present meta-analysis, agonist protocols could be suggested as a first choice approach, in terms of effectiveness. Due to the high studies' heterogeneity, results should be considered with caution. Accordingly, larger cohort studies and meta-analyses like the present one will enhance the robustness of the emerging results to identify the ideal protocol for poor responders.

Effect of Antagonist Start Day on Cycle Outcomes in Poor Responders.

BACKGROUND: Despite the great advances in Assisted Reproductive Technologies (ART), management of poor responders has remained a great challenge. Gonadotropin releasing hormone antagonist (GnRH-ant) has been offered as a patient friendly protocol. In the literature, conflicting data exists about the effect of the GnRH-ant starting day on cycle outcomes. AIM: The aim of this study is to evaluate the effect of GnRH-ant starting day on cycle outcomes of patients with poor ovarian response defined by Bologna criteria. SETTING AND DESIGN: This retrospective cohort study was conducted at an ART clinic of a tertiary hospital. MATERIALS AND METHODS: A total of 361 cycles using flexible GnRH-ant, 195 in Group A (GnRH-ant administered before day 6 of stimulation) and 166 cycles in Group B (GnRH-ant started on or after day 6), were selected retrospectively for the study. STATISTICAL ANALYSIS: Statistical analysis of data was carried out using using IBM SPSS Statistics Software (20.0, SPSS Inc., Chicago, IL, USA). Independent samples t-test and Mann-Whitney U test were used to analyze the variables. RESULTS: Total antral follicle count was significantly higher in Group A compared to Group B (P = 0.009). Duration of stimulation was significantly shorter (P < 0.01) and total dose of gonadotropin used was lower in Group A when compared to Group B (P < 0.01). While higher number of oocytes was retrieved from Group A (P = 0.037), no between-group differences were observed in number of mature oocytes, fertilized oocytes, clinical pregnancy rate or ongoing pregnancy rate (OPR) per embryo transfer (P > 0.05). CONCLUSION: Early GnRH-ant start may point out a favourable response to ovarian stimulation in poor responders. However, clinical or OPRs were not different from the late GnRH-ant start group.

Randomised controlled trial on the effect of clomiphene citrate and gonadotropin dose on ovarian response markers and IVF outcomes in poor responders.

STUDY QUESTION: Does the gonadotropin (GN) starting dose and the addition of clomiphene citrate (CC) during the early follicular phase influence oocyte yield in poor responders undergoing ovarian stimulation for IVF treatment? SUMMARY ANSWER: The number of retrieved oocytes was similar regardless of the starting dose of GN (150 versus 450 IU) with or without the addition of CC (100 mg from Day 3 to 7 versus placebo). WHAT IS KNOWN ALREADY: ART in poor responders is a challenge for patients and clinicians. So far, randomised controlled studies addressing interventions have shown that neither the GN dose nor the addition of oral medication has any significant effect on the clinical outcome of ART in poor responders. There is limited knowledge about the effect of GN starting dose in combination with CC during the early follicular phase of ovarian stimulation on ovarian response markers and ART outcome. STUDY DESIGN, SIZE, DURATION: This single-centre randomised double-blinded clinical trial was conducted from August 2013 until November 2017. Using the Bologna criteria, 220 of 2288 patients (9.6%) were identified as poor responders and 114 eligible participants underwent ovarian stimulation in a GnRH-antagonist protocol for ART. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were equally randomised to one of four treatment arms: Group A (n = 28) received 100 mg CC (Day 3-7) and a starting dose of 450 IU HMG, Group B (n = 29) received 100 mg CC and a starting dose of 150 IU HMG, Group C (n = 30) received placebo and a starting dose of 450 IU HMG and Group D (n = 27) received placebo and a starting dose of 150 IU HMG. Serum levels of FSH, LH, estradiol and progesterone were measured on Day 1 and 5 and on the day of ovulation induction. Available embryos were cultured up to the blastocyst stage and were always transferred in the same cycle. The primary outcome was the number of oocytes collected after ovarian stimulation. Other outcome measures were response to ovarian stimulation, embryo development and obstetrical outcome. MAIN RESULTS AND THE ROLE OF CHANCE: All study participants (n = 114) fulfilled at least two of the Bologna criteria for poor responders. Median age of the study population was 38.5 years. There were 109 patients who underwent oocyte retrieval. The number of oocytes retrieved was similar among the groups (±SD; 95% confidence intervals); A: 2.85 (±0.48; 2.04-3.98), B: 4.32 (±0.59; 3.31-5.64); C: 3.33 (±0.52; 2.45-4.54); D: 3.22 (±0.51; 2.36-4.41); P overall = 0.246. However, ovarian stimulation with 150 IU plus CC resulted in a higher number of blastocysts compared to ovarian stimulation with 450 IU plus CC (±SD; 95% confidence intervals); A: 0.83 (±0.15; 0.58-1.2), B: 1.77 (±0.21; 1.42-2.22); P overall = 0.006. Mean FSH serum levels were lower in the groups with a starting dose of 150 IU. Adding CC did not affect mean serum FSH levels. There were no differences in estradiol concentrations among the groups. Endometrial thickness was lower in the groups receiving CC. The overall live birth rate (LBR) was 12.3%, and the cumulative LBR was 14.7%. LIMITATIONS, REASONS FOR CAUTION: The trial was powered to detect differences in neither the number of blastocysts nor the LBR, which would be the preferable primary outcome of interventional trials in ART. WIDER IMPLICATIONS OF THE FINDINGS: We found that ovarian stimulation with 150 IU gonadotrophin in combination with 100 mg CC produced more blastocysts. The effect of adding CC to GN on LBR in poor responders remains to be proven in randomised trials. High GN doses (450 IU) resulted in high FSH serum levels but increased neither the estradiol levels nor the number of retrieved oocytes, implying that granulosa cell function is not improved by high FSH serum levels. Lower starting doses of GN lead to a reduction of costs of medication. The small but significant difference in blastocyst formation and the lower FSH levels in the treatment groups receiving less GN may be an indication of better oocyte quality with higher developmental competence. STUDY FUNDING/COMPETING INTEREST(S): The costs for the HMG used for ovarian stimulation were provided by IBSA Switzerland. The study was also supported by the Repronatal Foundation, Basel, Switzerland. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01577472. TRIAL REGISTRATION DATE: 13 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: August 2013.

Efficacy of the delayed start antagonist protocol for controlled ovarian stimulation in Bologna poor ovarian responders: a systematic review and meta-analysis.

BACKGROUND: Patients with a poor ovarian response (POR) represent the most difficult group of population to deal with in the clinical fertility practice. Bologna criteria are the first uniform definition of POR. Choosing a suitable controlled ovarian stimulation (COS) protocol which could give adequate oocytes to maximize the chance of obtaining at least one euploid blastocyst is crucial in the management for such patients. The delayed start antagonist protocol is a novel COS protocol designed for POR patients, however, its real efficacy is controversial compared to conventional protocols. The present study aims to summarize all available studies on this topic and perform a meta-analysis to explore the real treatment effect of this novel protocol in terms of reproductive outcomes. STUDY DESIGN: PubMed, EMBASE, Google Scholar, and the Cochrane Library from database establishment to June 2019 were searched. Randomized controlled trials (RCTs), which compared delayed start antagonist protocol (Del) to conventional controlled ovarian stimulation (COS) protocols (Con) in terms of reproductive outcomes, were included. The RevMan 5.3 was used to perform statistical analysis. The primary outcomes were the cycle cancellation rate, the clinical pregnancy rate and the miscarriage rate. RESULTS: 5 RCTs yielding 514 patients were eligible, of which 5, 5, 4 studies were included in analyzing the cycle cancellation rate, the clinical pregnancy rate, and the miscarriage rate respectively. Synthesized data of meta-analysis showed: delayed start antagonist protocol introduced a lower risk of cycle cancellation [risk ratio (RR) = 0.63, 95% confidence interval (CI) (0.45, 0.90), P = 0.01; 5 RCTs, 514 women (Del:Con = 256:258); I2 = 0%; with rates of 16.02% (Del) vs. 26.36% (Con)], an increased chance to get clinical pregnancy [RR = 2.30, 95% CI (1.38, 3.82), P = 0.001; 5 RCTs, 514 women (Del:Con = 256:258); I2 = 0%; with rates of 16.80% (Del) vs. 7.36% (Con)], and a comparable miscarriage rate [RR = 0.55, 95% CI (0.24, 1.23), P = 0.15; 4 RCTs, 58 women (Del:Con = 41:17) I2 = 17%; with rates of 19.51% (Del) vs. 35.29% (Con)] compared to conventional COS protocols. CONCLUSIONS: Delayed start antagonist protocol was a potentially valuable alternation for poor ovarian responders. However, future RCTs with large sample size and more scientific design are needed to verify its validity and draw a sound conclusion.

The Conundrum of Poor Ovarian Response: From Diagnosis to Treatment.

Despite recent striking advances in assisted reproductive technology (ART), poor ovarian response (POR) diagnosis and treatment is still considered challenging. Poor responders constitute a heterogeneous cohort with the common denominator of under-responding to controlled ovarian stimulation. Inevitably, respective success rates are significantly compromised. As POR pathophysiology entails the elusive factor of compromised ovarian function, both diagnosis and management fuel an ongoing heated debate depicted in the literature. From the criteria employed for diagnosis to the plethora of strategies and adjuvant therapies proposed, the conundrum of POR still puzzles the practitioner. What is more, novel treatment approaches from stem cell therapy and platelet-rich plasma intra-ovarian infusion to mitochondrial replacement therapy have emerged, albeit not claiming clinical routine status yet. The complex and time sensitive nature of this subgroup of infertile patients indicates the demand for a consensus on a horizontally accepted definition, diagnosis and subsequent effective treating strategy. This critical review analyzes the standing criteria employed in order to diagnose and aptly categorize POR patients, while it proceeds to critically evaluate current and novel strategies regarding their management. Discrepancies in diagnosis and respective implications are discussed, while the existing diversity in management options highlights the need for individualized management.

Update on the management of poor ovarian response in IVF: the shift from Bologna criteria to the Poseidon concept.

Despite the considerate progress to which assisted reproduction technology (ART) has been subject since 1978, some issues remain unresolved. Notably, the clinical management of patients with a poor ovarian response is still a challenge in everyday practice, frustrating to both the patient and the fertility expert. Poor ovarian responders (PORs) embody 9-24% of patients undergoing ovarian stimulation, meaning that up to one in four patients conceals a poor reproductive prognosis. The last decade has witnessed the attempts of the medical community to standardize diagnosis of POR with the developing of the Bologna Criteria and the subsequent evolution of the low prognosis patient elaborated in the POSEIDON classification. The aim of this article is to summarize all evidence concerning etiology and management of poor ovarian response, including the most recent advances and future prospects in this regard.

Stop GnRH-Agonist Combined With Multiple-Dose GnRH-Antagonist Protocol for Patients With "Genuine" Poor Response Undergoing Controlled Ovarian Hyperstimulation for IVF.

Objective: To examine whether the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol may improve conventional IVF/intracytoplasmic sperm injection (ICSI) cycle in poor ovarian response (POR) patients. Design: Cohort historical, proof of concept study. Setting: Tertiary, University affiliated Medical Center. Patient(s): Thirty POR patients, defined according to the Bologna criteria, who underwent a subsequent Stop GnRH-agonist combined with multiple-dose GnRH-antagonist controlled ovarian hyperstimulation (COH) protocol, within 3 months of the previous failed conventional IVF/ICSI cycle, were included. For the purposes of this study, we eliminated a bias in this selection by including only "genuine" poor responder patients, defined as those who yielded up to 3 oocytes following COH with a minimal gonadotropin daily dose of 300 IU. Main Outcome Measure(s): Number of oocytes retrieved, number of top-quality embryos, COH variables. Result(s): The Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol revealed significantly higher numbers of follicles >13 mm on the day of hCG administration, higher numbers of oocytes retrieved, and top-quality embryos (TQE) with an acceptable clinical pregnancy rate (16.6%). Moreover, as expected, patients undergoing the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol required significantly higher doses and a longer duration of gonadotropins stimulation. Conclusion(s): The combined Stop GnRH-ag/GnRH-ant COH protocol is a valuable tool in the armamentarium for treating "genuine" poor ovarian responders. Further, large prospective studies are needed to elucidate its role in POR and to characterize the appropriate patients subgroup (before initiating ovarian stimulation) that may benefit from the combined Stop GnRH-ag/GnRH-ant COH protocol.

Heterogeneity Among Poor Ovarian Responders According to Bologna Criteria Results in Diverging Cumulative Live Birth Rates.

Research Question: Does reproductive outcome differ among the various subgroups of poor ovarian responders according to the Bologna criteria? Design: This was a retrospective, cohort study including poor ovarian responders according to Bologna criteria, undergoing an ICSI cycle from January 2011 until December 2017. Patients were divided into four groups: (1) age ≥ 40 years and abnormal ovarian response test, (2) age ≥ 40 years, abnormal ovarian reserve test and one previous poor response to stimulation, (3) age ≥ 40 years and one previous poor response, (4) abnormal ovarian reserve test and one previous poor response. Result(s): Overall, 846 cycles in 706 Bologna poor ovarian responders were included: 310 cycles in group 1, 169 in group 2, 52 in group 3, and 315 in group 4. There were significant differences in age, antral follicle count, antimüllerian hormone, cycle cancellation rates, and number of retrieved oocytes between the four groups. Live birth and cumulative live birth rate differed significantly between groups and were highest in Group 4 [Live birth rate: 7.4% (1) vs. 4.1% (2) vs. 5.8% (3) vs. 13.4% (4), p = 0.001 and Cumulative live birth rate: 8.3% (1) vs. 4.1 % (2) vs. 9.6% (3) vs. 16.8% (4) p < 0.001]. The multivariate GEE analysis revealed that the number of MIIs and the Bologna criteria pattern were the variables which were significantly associated with cumulative live birth rate. Conclusion(s): Poor ovarian responders represent a heterogeneous population. The young subpopulation has a better clinical prognosis in terms of fresh and cumulative live birth rate.