The BISTIM study: a randomized controlled trial comparing dual ovarian stimulation (duostim) with two conventional ovarian stimulations in poor ovarian responders undergoing IVF.

STUDY QUESTION: Is the total number of oocytes retrieved with dual ovarian stimulation in the same cycle (duostim) higher than with two consecutive antagonist cycles in poor responders? SUMMARY ANSWER: Based on the number of total and mature oocytes retrieved in women with poor ovarian response (POR), there is no benefit of duostim versus two consecutive antagonist cycles. WHAT IS KNOWN ALREADY: Recent studies have shown the ability to obtain oocytes with equivalent quality from the follicular and the luteal phase, and a higher number of oocytes within one cycle when using duostim. If during follicular stimulation smaller follicles are sensitized and recruited, this may increase the number of follicles selected in the consecutive luteal phase stimulation, as shown in non-randomized controlled trials (RCT). This could be particularly relevant for women with POR. STUDY DESIGN, SIZE, DURATION: This is a multicentre, open-labelled RCT, performed in four IVF centres from September 2018 to March 2021. The primary outcome was the number of oocytes retrieved over the two cycles. The primary objective was to demonstrate in women with POR that two ovarian stimulations within the same cycle (first in the follicular phase, followed by a second in the luteal phase) led to the retrieval of 1.5 (2) more oocytes than the cumulative number of oocytes from two consecutive conventional stimulations with an antagonist protocol. In a superiority hypothesis, with power 0.8 alpha-risk 0.05 and a 35% cancellation rate, 44 patients were needed in each group. Patients were randomized by computer allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-eight women with POR, defined using adjusted Bologna criteria (antral follicle count ≤5 and/or anti-Müllerian hormone ≤1.2 ng/ml) were randomized, 44 in the duostim group and 44 in the conventional (control) group. HMG 300 IU/day with flexible antagonist protocol was used for ovarian stimulation, except in luteal phase stimulation of the duostim group. In the duostim group, oocytes were pooled and inseminated after the second retrieval, with a freeze-all protocol. Fresh transfers were performed in the control group, frozen embryo transfers were performed in both control and duostim groups in natural cycles. Data underwent intention-to-treat and per-protocol analyses. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference between the groups regarding demographics, ovarian reserve markers, and stimulation parameters. The mean (SD) cumulative number of oocytes retrieved from two ovarian stimulations was not statistically different between the control and duostim groups, respectively, 4.6 (3.4) and 5.0 (3.4) [mean difference (MD) [95% CI] +0.4 [-1.1; 1.9], P = 0.56]. The mean cumulative numbersof mature oocytes and total embryos obtained were not significantly different between groups. The total number of embryos transferred by patient was significantly higher in the control group 1.5 (1.1) versus the duostim group 0.9 (1.1) (P = 0.03). After two cumulative cycles, 78% of women in the control group and 53.8% in the duostim group had at least one embryo transfer (P = 0.02). There was no statistical difference in the mean number of total and mature oocytes retrieved per cycle comparing Cycle 1 versus Cycle 2, both in control and duostim groups. The time to the second oocyte retrieval was significantly longer in controls, at 2.8 (1.3) months compared to 0.3 (0.5) months in the duostim group (P < 0.001). The implantation rate was similar between groups. The cumulative live birth rate was not statistically different, comparing controls versus the duostim group, 34.1% versus 17.9%, respectively (P = 0.08). The time to transfer resulting in an ongoing pregnancy did not differ in controls 1.7 (1.5) months versus the duostim group, 3.0 (1.6) (P = 0.08). No serious adverse events were reported. LIMITATIONS, REASONS FOR CAUTION: The RCT was impacted by the coronavirus disease 2019 pandemic and the halt in IVF activities for 10 weeks. Delays were recalculated to exclude this period; however, one woman in the duostim group could not have the luteal stimulation. We also faced unexpected good ovarian responses and pregnancies after the first oocyte retrieval in both groups, with a higher incidence in the control group. However, our hypothesis was based on 1.5 more oocytes in the luteal than the follicular phase in the duostim group, and the number of patients to treat was reached in this group (N = 28). This study was only powered for cumulative number of oocytes retrieved. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT comparing the outcome of two consecutive cycles, either in the same menstrual cycle or in two consecutive menstrual cycles. In routine practice, the benefit of duostim in patients with POR regarding fresh embryo transfer is not confirmed in this RCT: first, because this study demonstrates no improvement in the number of oocytes retrieved in the luteal phase after follicular phase stimulation, in contrast to previous non-randomized studies, and second, because the freeze-all strategy avoids a pregnancy with fresh embryo transfer after the first cycle. However, duostim appears to be safe for women. In duostim, the two consecutive processes of freezing/thawing are mandatory and increase the risk of wastage of oocytes/embryos. The only benefit of duostim is to shorten the time to a second retrieval by 2 weeks if accumulation of oocytes/embryos is needed. STUDY FUNDING/COMPETING INTERESTS: This is an investigator-initiated study supported by a research Grant from IBSA Pharma. N.M. declares grants paid to their institution from MSD (Organon France); consulting fees from MSD (Organon France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. I.A. declares honoraria from GISKIT and support for travel and meetings from GISKIT. G.P.-B. declares Consulting fees from Ferring and Merck KGaA; honoraria from Theramex, Gedeon Richter, and Ferring; payment for expert testimony from Ferring, Merck KGaA, and Gedeon Richter; and support for travel and meetings from Ferring, Theramex, and Gedeon Richter. N.C. declares grants from IBSA pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. E.D. declares support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Ferring, Gedeon Richter, Theramex, and General Electrics. C.P.-V. declares support for travel and meetings from IBSA Pharma, Merck KGaA, Ferring, Gedeon Richter, and Theramex. M.Pi. declares support for travel and meetings from Ferring, Gedeon Richetr, and Merck KGaA. M.Pa. declares honoraria from Merck KGaA, Theramex, and Gedeon Richter; support for travel and meetings from Merck KGaA, IBSA Pharma, Theramex, Ferring, Gedeon Richter, and MSD (Organon France). H.B.-G. declares honoraria from Merck KGaA, and Gedeon Richter and support for travel and meetings from Ferring, Merck KGaA, IBSA Pharma, MSD (Organon France), Theramex, and Gedeon Richter. S.G. and M.B. have nothing to declare. TRIAL REGISTRATION NUMBER: Registration number EudraCT: 2017-003223-30. ClinicalTrials.gov identifier: NCT03803228. TRIAL REGISTRATION DATE: EudraCT: 28 July 2017. ClinicalTrials.gov: 14 January 2019. DATE OF FIRST PATIENT'S ENROLMENT: 3 September 2018.

The Clinical Application of Growth Hormone and Its Biological and Molecular Mechanisms in Assisted Reproduction.

Growth hormone (GH) has been used as a co-gonadotrophin in assisted reproduction, particularly in poor ovarian responders. The application of GH has been alleged to activate primordial follicles and improve oocyte quality, embryo quality, and steroidogenesis. However, the effects of GH on the live birth rate among women is controversial. Additionally, although the basic biological mechanisms that lead to the above clinical differences have been investigated, they are not yet well understood. The actions of GH are mediated by GH receptors (GHRs) or insulin-like growth factors (IGFs). GH regulates the vital signal transduction pathways that are involved in primordial follicular activation, steroidogenesis, and oocyte maturation. However, the therapeutic windows and duration of GH administration during assisted reproductive technology require further investigation. The review aimed to clarify the role of GH in human fertility from a molecular and biological point of view to provide evidence for proper GH administration.

Dual trigger with the combination of gonadotropin-releasing hormone agonist and standard dose of human chorionic gonadotropin improves in vitro fertilisation outcomes in poor ovarian responders.

The study aimed to evaluate the impact of the dual trigger with the combination of GnRH agonist and standard dose of recombinant hCG on IVF outcomes in poor ovarian responders with GnRH antagonist protocol. 1283 cycles of 1010 poor responder patients according to Bologna criteria were retrospectively analysed in terms of final oocyte maturation: dual trigger group (250 µg hCG + 0.2 mg triptorelin) or standard group (250 µg hCG). Primary outcome measures were the number of retrieved and mature oocytes. The secondary outcome measures were clinical pregnancy rates and live birth rates.The number of retrieved oocytes, mature oocytes, and the top-quality embryos transferred were significantly higher in the dual trigger group (p < .001). Fertilisation rates (73.6% vs 69.6%, p = .009), implantation rates (18.7% vs 14.6, p = .039), clinical pregnancy rate per embryo transfer (27.5% vs. 19.9%, p = .010) and live birth rate per embryo transfer (21.6% vs. 14.9%, p = .011) were also significantly higher in the dual trigger group as compared to the hCG trigger group. The usage of dual trigger with a GnRH agonist and a standard dosage of hCG could improve clinical pregnancy rates and live birth rates in poor ovarian responders undergoing GnRH antagonist IVF/ICSI cycles.IMPACT STATEMENTWhat is already known on this subject? Dual trigger with standard dose of hCG has been the subject of trials in normal responders to optimise IVF outcomes. The results of these studies showed significant improvements in implantation and pregnancy rates with an increase in the number of mature oocytes retrieved. As a result, dual trigger has become a popular ovulation trigger option in GnRH antagonist cycles.What do the results of this study add? There is limited data about the use of dual trigger in poor ovarian responders (PORs). According to our study, increasing the number of retrieved oocytes, mature oocytes, the number of fertilised oocytes, the number of transferred embryos and top quality embryos transferred by using dual trigger in patients with PORs have a positive impact on pregnancy outcomes.What are the implications of these findings for clinical practice and/or further research? These findings implies potential advantages of dual trigger usage for improving IVF outcomes in PORs. With large sample sized prospective randomised trials, dual trigger with combination of GnRHa and a standard dose of hCG might replace the traditional ovulation trigger with hCG in PORs.

Preimplantation genetic testing for aneuploidy in poor ovarian responders with four or fewer oocytes retrieved.

PURPOSE: To assess whether preimplantation genetic testing for aneuploidies (PGT-A) at the blastocyst stage improves clinical outcomes compared with transfer of embryos without PGT-A in poor ovarian response (POR) patients. METHODS: Retrospective cohort study of IVF cycles from 2016 to 2019 at a single academic fertility center. IVF cycles with POR and four or fewer oocytes retrieved were stratified into PGT-A (n = 241) and non-PGT (n = 112) groups. In PGT-A cycles, trophectoderm biopsy, next-generation sequencing with 24-chromosome screening, and single euploid frozen embryo transfer were performed. In non-PGT cycles, fresh or frozen transfer of untested embryos on day 3 or 5 was performed. Main outcomes included live birth rate and miscarriage rate per retrieval. RESULT(S): Patients who underwent PGT-A cycles were significantly less likely to reach embryo transfer compared with those who underwent non-PGT cycles (13.7% vs 70.6%). The live birth rate per retrieval did not differ between the PGT-A and non-PGT groups (6.6% vs 5.4%). Overall, the miscarriage rate was low. The PGT-A group demonstrated a significantly lower miscarriage rate per retrieval (0.4% vs 3.6%) as well as per pregnancy (5.9% vs 40.0%) compared with the non-PGT group. The number needed to treat to avoid one clinical miscarriage was 31 PGT-A cycles. CONCLUSION(S): PGT-A did not improve live birth rate per retrieval in POR patients with four or fewer oocytes retrieved. PGT-A was associated with a lower miscarriage rate; however, a fairly large number of PGT-A cycles were needed to prevent one miscarriage.

Six-week pretreatment with growth hormone improves clinical outcomes of poor ovarian responders undergoing in vitro fertilization treatment: A self-controlled clinical study.

AIM: The purpose was to explore whether the 6 weeks of growth hormone (GH) pretreatment could increase the live birth rate of poor ovarian responders (POR). METHODS: This self-controlled, retrospective study was performed among 380 POR who had GH adjuvant (GH+) at a university-affiliated hospital in Guangzhou, China, from October 2010 to April 2016. Growth hormone was injected daily beginning with the previous menstruation and maintained until ovum pickup, for approximately 6 weeks. Clinical variables between the GH+ cycle and the other GH-free (GH-) cycle of each patient were compared. Both cycles were conducted with a similar conventional control ovarian hyperstimulation protocol for in vitro fertilization treatment. One to one case-control matching was performed to adjust essential confounding factors between GH+ cycles and GH- cycles. RESULTS: GH pretreatment improved embryo quality (1.14 ± 1.50 vs 0.11 ± 0.48, P < 0.05) and decreased miscarriage (18.8% vs 80.0%, P < 0.05) significantly, resulting in an increase in the live birth rate (23.5% vs 3.9%, P < 0.05). The oocyte utilization rate in GH+ cycles was remarkably improved, even with older patients and more failed previous attempts. Significant improvement in embryo quality was shown by an increased number of good-quality embryos and improved oocyte utilization rate after matching. CONCLUSIONS: The longer term use of low-dose GH administration for 6 weeks could be beneficial for the utilization of oocytes and for finally increasing the live birth rates of POR.

Outcomes of poor responders following growth hormone co-treatment with IVF/ICSI mild stimulation protocol: a retrospective cohort study.

PURPOSE: No research has studied the effect of GH co-treatment in mild stimulation protocol for poor responders. We therefore conducted this retrospective analysis to assess the outcome of IVF/ICSI cycles after the adjunct GH use to the mild stimulation protocol in poor responders. METHODS: 132 poor responders who received mild stimulation protocol at Reproductive Medicine Center of Changzheng Hospital from January 2014 to December 2016 were included in this study. Good-quality embryo rate, clinical pregnancy rate, and live birth rate were compared between the GH group (n = 61) and control group (n = 71). RESULTS: IVF good-quality embryo rate (68.1 versus 51.5%; P = 0.008*) and ICSI good-quality embryo rate (53.9 versus 36.7%; P = 0.045*) was significantly higher in the GH group. Though the clinical outcomes did not reach a statistically significant difference between the two groups due to the limited sample size, there was a trend of higher rate in GH group in the aspect of clinical pregnancy rate (52.4 versus 47.1%; P = 0.609) and live birth rate (35.7 versus 27.5%; P = 0.392). CONCLUSION: The results suggested that the adjuvant GH treatment in mild stimulation protocol for poor responders could significantly improve good-quality embryo rate, and might therefore improve the clinical outcomes.

Effect of mid-follicular phase recombinant LH versus urinary HCG supplementation in poor ovarian responders undergoing IVF - a prospective double-blinded randomized study.

Luteinizing hormone (LH) is crucial for the development of follicular growth and oocyte maturation, especially in the management of poor ovarian responders (PORs). This study presents the results of a prospective double-blinded randomized study to compare the effect of mid-follicular phase recombinant LH (rLH) supplementation with urinary human chorionic gonadotrophin (uHCG) supplementation when using a fixed gonadotrophin-releasing hormone (GnRH) antagonist protocol in IVF cycles. A total of 49 women with poor ovarian response (POR) according to the Bologna criteria were recruited. This study showed no statistically significant difference in cycle cancellation rates, numbers of oocytes retrieved per cycle initiated, fertilization rates, the numbers of embryos obtained per cycle initiated, implantation, clinical pregnancy and live birth rates, although the live birth rate per cycle initiated in the uHCG group (29.2%) was 3.6 times that of the rLH group (8.0%). Further studies are required to verify if uHCG supplementation produces better clinical outcomes compared with rLH in women with POR.

Protection of cumulus cells following dehydroepiandrosterone supplementation.

BACKGROUND: Growing studies have demonstrated that dehydroepiandrosterone (DHEA) may improve fertility outcomes in poor ovarian responders (PORs). The aim of this study was to compare clinical outcomes and cumulus cell (CC) expression before and after DHEA treatment in PORs undergoing in vitro fertilization (IVF) cycles. METHODS: Six patients with poor ovarian response were enrolled in the study according to Bologna criteria. DHEA was supplied at least 2 months before patients entered into the next IVF cycle. Expression of apoptosis-related genes in CCs was determined by quantitative real-time PCR. Mitochondrial dehydrogenase activity of CCs was assessed by cell counting kit-8 assay. RESULTS: Metaphase II oocytes, maturation rate, embryos at Day 3, and fertilization rate significantly increased following DHEA treatment. Expression of cytochrome c, caspase 9, and caspase 3 genes in CCs were significantly reduced after DHEA therapy. Additionally, increased mitochondrial activity of CCs was observed following DHEA supplementation. CONCLUSIONS: DHEA supplementation may protect CCs via improved mitochondrial activity and decreased apoptosis, leading to better clinical outcomes in PORs.

Younger poor ovarian response women achieved better pregnancy results in the first three IVF cycles.

This retrospective cohort study observed the live birth rates as well as cumulative live birth rates in women with poor ovarian response (POR) undergoing IVF-embryo transfer treatment, stratified for age and cycle number. Four hundred and one patients with POR diagnosed according to the Bologna criteria were enrolled and 700 IVF-ET cycles were analysed. The overall live-birth rate per cycle was 18.3%. From cycle 1 up to cycle 3, the live-birth rates decreased significantly from 22.2% to 11.1%. The live-birth rate fell to 2.4% in cycles 4 and over. When age advanced, the live birth rates decreased obviously (P < 0.01): 30.0% for women < 35 years old, 17.0% for those 35-40 years old, and 9.0% for women older than 40 years. Similarly, the cumulative live birth rates dropped from 48.0% (< 35 years) to 16.9% (≥ 40 years) accordingly. Younger patients (< 35 years old) with POR achieved better pregnancy results compared with patients of advanced age. Extremely low live-birth rates could be anticipated after three unsuccessful cycles; therefore it may not be appropriate to suggest more IVF cycles in POR women.

Endometriosis has no negative impact on outcomes of in vitro fertilisation in women with poor ovarian response.

OBJECTIVE: To compare the in vitro fertilisation (IVF) outcomes of poor ovarian responders among women with laparoscopically diagnosed minimal-mild endometriosis (Group A), moderate-severe endometriosis (Group B) and those without endometriosis (Group C). The comparisons were made separately for age groups younger than 35 years and 35 years or older. DESIGN: Retrospective study. SETTING: A university-affiliated hospital in Guangzhou, China. POPULATION: 495 women younger than 35 years old and 543 women aged 35 or older who had poor ovarian response with or without laparoscopically diagnosed endometriosis. METHODS: Poor ovarian response (POR) was diagnosed using the Bologna criteria. First cycle parameters were analysed over the same period of time from January 2011 to October 2014. MAIN OUTCOME MEASURES: The primary endpoint was the live birth rate per embryo transfer cycle. Secondary outcome measures were clinical pregnancy rate, cycle cancellation rate and miscarriage rate. RESULTS: In women aged 35 or older no differences were found among the three subgroups in terms of live birth rate, clinical pregnancy rate, cycle cancellation rate or miscarriage rate; in women aged younger than 35 years, the clinical pregnancy rates were 62.96, 45.45 and 43.27% for Groups A, B and C, respectively (P = 0.028). The live birth rate, cycle cancellation rate and miscarriage rate were not significantly different. Compared with the older group of women, the younger women had a significantly higher live birth rate (P < 0.001). CONCLUSIONS: A woman's age is the most important factor governing the live birth rate with IVF. Endometriosis has no consistent impact on IVF outcomes in women with POR. TWEETABLE ABSTRACT: Endometriosis has no negative impact on IVF outcomes in women with poor ovarian response.

An upper limit of gonadotropin dose in patients undergoing ART should be advocated.

AIM: As no upper limit of the daily dose of gonadotropins (DD GN) used for controlled ovarian hyperstimulation (COH) in patients undergoing assisted reproductive technology (ART) has been established, we aimed to evaluate the efficacy of using different DD GN in terms of live-birth achievement. METHODS: Data of patients treated at a single university medical center during the same period was analyzed retrospectively. Four groups were analyzed according to the DD GN administered: group I ("high dose"): >225- ≤ 375 IU; Group II ("Very high dose"): 376-450 IU; group III ("extremely high dose"): 451-600 IU. Normo-responders treated with DD GN ≤250 IU served as control (C). Variables included were DD GN, total GN dose/cycle, age, FSH, BMI, gravidity, parity, cycle number, IVF/ICSI, infertility diagnosis treatment protocol and outcome parameters. RESULTS: The analysis of 1394 treatment cycles of 943 patients indicated that DD and total dose of GN correlated negatively with the number of oocytes, implantation, clinical pregnancy and live-birth rate (25.9%, 14.6%, 11.4% and 4.7% in groups C, I, II and III, respectively) The logistic regression analysis indicated that the adjusted odds ratios for LBR correlated inversely with the DD administered - independently from age, baseline FSH, BMI and previous failed cycles. CONCLUSIONS: Increasing the daily dose of GN to doses higher than 450 IU or a total dose of 3000 IU/cycle is at least questionable if not harmful.

A comparison among different methods of letrozole combined with gonadotropin in an antagonist protocol and high-dose gonadotropin ovarian stimulation antagonist protocol in poor ovarian responders undergoing in vitro fertilization.

PURPOSE: This study aimed at comparing the effects of different methods of letrozole combined with gonadotropin (Gn) and high-dose Gn ovarian stimulation in antagonist protocol. METHODS: Retrospectively reviewed 220 poor responders from August 2012 to July 2014 at Peking University Third Hospital Reproductive Medical Center. Patients were divided into Group 1 (LZ 5 mg for 5 days sequentially overlapping with Gn cycles; n = 60), group 2 (LZ 7.5 mg for 3 days sequentially with Gn cycles; n = 60), and group 3 (high-dose Gn cycles; n = 100). We compared the basic status of patients and clinical outcomes of the three groups. RESULTS: Basic characteristics of patients were comparable among groups. Group 1 had significantly higher LH levels on day 7 and hCG than Group 2 and 3 (P < 0.05). Group 1 had significantly higher early LH elevation rate (>20 IU/L) on the hCG day than Groups 2 and 3 (11.7 vs. 6.7 and 2.0 %; P < 0.05). The amount of Gn used in LZ groups was significantly lower than Group 3 (P < 0.01). However, the clinical pregnancy rate and live birth rate were comparable among groups. CONCLUSION: In conclusion, the LZ/antagonist protocol is a cost-effective and patient friendly protocol, LZ 5 mg for 5 days sequentially overlapping with Gn protocol has comparable pregnancy outcomes, and LZ 7.5 mg for 3 days sequentially with the Gn protocol even has better clinical outcomes when compared with the standard GnRH antagonist protocol in poor responders. LZ 7.5 mg for 3 days sequentially with the Gn protocol appeared to have resulted in fewer improper LH surges and better outcomes than LZ 5 mg for 5 days sequentially overlapping with Gn in antagonist protocol.

Dehydroepiandrosterone supplementation and the impact of follicular fluid metabolome and cytokinome profiles in poor ovarian responders.

BACKGROUND: Poor ovarian responders (POR) are women undergoing in-vitro fertilization who respond poorly to ovarian stimulation, resulting in the retrieval of lower number of oocytes, and subsequently lower pregnancy rates. The follicular fluid (FF) provides a crucial microenvironment for the proper development of follicles and oocytes through tightly controlled metabolism and cell signaling. Androgens such as dehydroepiandrosterone (DHEA) have been proposed to alter the POR follicular microenvironment, but the impact DHEA imposes on the FF metabolome and cytokine profiles is unknown. Therefore, the objective of this study is to profile and identify metabolomic changes in the FF with DHEA supplementation in POR patients. METHODS: FF samples collected from 52 POR patients who underwent IVF with DHEA supplementation (DHEA +) and without (DHEA-; controls) were analyzed using untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics and a large-scale multiplex suspension immunoassay covering 65 cytokines, chemokines and growth factors. Multivariate statistical modelling by partial least squares-discriminant regression (PLSR) analysis was performed for revealing metabolome-scale differences. Further, differential metabolite analysis between the two groups was performed by PLSR ß-coefficient regression analysis and Student's t-test. RESULTS: Untargeted metabolomics identified 118 FF metabolites of diverse chemistries and concentrations which spanned three orders of magnitude. They include metabolic products highly associated with ovarian function - amino acids for regulating pH and osmolarity, lipids such fatty acids and cholesterols for oocyte maturation, and glucocorticoids for ovarian steroidogenesis. Four metabolites, namely, glycerophosphocholine, linoleic acid, progesterone, and valine were significantly lower in DHEA + relative to DHEA- (p < 0.05-0.005). The area under the curves of progesterone glycerophosphocholine, linoleic acid and valine are 0.711, 0.730, 0.785 and 0.818 (p < 0.05-0.01). In DHEA + patients, progesterone positively correlated with IGF-1 (Pearson r: 0.6757, p < 0.01); glycerophosphocholine negatively correlated with AMH (Pearson r: -0.5815; p < 0.05); linoleic acid correlated with estradiol and IGF-1 (Pearson r: 0.7016 and 0.8203, respectively; p < 0.01 for both). In DHEA- patients, valine negatively correlated with serum-free testosterone (Pearson r: -0.8774; p < 0.0001). Using the large-scale immunoassay of 45 cytokines, we observed significantly lower MCP1, IFNγ, LIF and VEGF-D levels in DHEA + relative to DHEA. CONCLUSIONS: In POR patients, DHEA supplementation altered the FF metabolome and cytokine profile. The identified four FF metabolites that significantly changed with DHEA may provide information for titrating and monitoring individual DHEA supplementation.

The effects of intraovarian injection of autologous menstrual blood-derived mesenchymal stromal cells on pregnancy outcomes in women with poor ovarian response.

BACKGROUND: Assisted reproduction faces a significant obstacle in the form of poor ovarian response (POR) to controlled ovarian stimulation. To address this challenge, mesenchymal stem cell therapy has been proposed as a potential treatment for female infertility and/or restoration of ovarian function in POR women. Our previous research has demonstrated that menstrual blood-derived-mesenchymal stromal cells (MenSCs) injected into the ovaries of women with POR can increase pregnancy rates. The objective of this study was to examine whether MenSC therapy could enhance ovarian reserve parameters and pregnancy outcomes in a larger population of individuals with POR. METHOD: This study consisted of 180 infertile individuals with POR who declined oocyte donation. Participants were divided into two groups: those who received bilateral MenSCs intraovarian injection and those who received no intervention. Our primary aim was to compare the rates of spontaneous pregnancy between the two groups, followed by an investigation of any alterations in the ovarian reserve parameters, such as serum FSH, AMH, and AFC levels, as well as the ICSI/IVF outcomes, in both groups of participants. RESULTS: The MenSC therapy exhibited a favourable tolerability profile and did not raise any safety concerns. Following the 2-month follow-up period, women who received MenSC treatment demonstrated a significantly higher rate of spontaneous pregnancy (P < 0.005) and an improvement in anti-Müllerian hormone (AMH) levels (P = 0.0007) and antral follicle count (AFC) (P < 0.001), whereas the control group demonstrated a considerable decline in these parameters (Both P < 0.001). The MenSC therapy led to a greater number of mature oocytes and embryos among women who underwent ICSI/IVF. Our age subgroup analysis demonstrated a significant difference in the number of spontaneous pregnancies and ICSI/IVF outcomes between the treatment and control groups only among individuals below 40 years of age. CONCLUSION: The results of our study indicate that MenSCs treatment may be a viable option for treating women experiencing POR. However, in order to be widely implemented in clinical practice, the clinical effectiveness of MenSCs therapy will need to be established through rigorous prospective randomized clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05703308. Registered 01/26/2023, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05703308 . IRCT, IRCT20180619040147N4. Registered 08/01/2020.

The effect of ovarian injection of autologous platelet rich plasma in patients with poor ovarian responder: a systematic review and meta-analysis.

Objective: To evaluate the effects of ovarian injection of autologous platelet rich plasma (aPRP) on patients with poor ovarian responder (POR) based on the existing clinical evidence. Methods: According to systematic review and meta-analysis, we comprehensively searched nine databases established as of September 6, 2023, and evaluated the impact of ovarian PRP infusion on poor ovarian responder. The research results include serum follicle-stimulating hormone(FSH) and anti-Mullerian hormone(AMH) levels, antral Follicle Count(AFC), oocyte number, and embryo number. The Newcastle Ottawa Scale (NOS) was used to evaluate the quality of inclusion in trials. Results: Add up to 10 studies consisting of 793 participants were included in the meta-analysis. A review of existing evidence showed that intraovarian injection of PRP has significant therapeutic effects in increasing levels of anti-Müllerian hormone (AMH) (SMD=0.44,95% CI [0.07,0.81], p=0.02), antral follicle count (AFC) (MD=1.15,95% CI [0.4,1.90], p=0.003), oocyte count (MD=0.91, 95% CI [0.40, 1.41], p=0.0004), and embryo number (MD=0.78, 95% CI [0.5,1.07], p<0.0001). We compared the relevant data of patients before and after treatment after 2 months of intervention. It can be seen that ovarian injection of PRP treatment for 2 months has better effects in reducing FSH levels, increasing AMH levels, increasing antral follicle count, and increasing the number of oocytes and embryos (p<0.05). When the dose of PRP injected into each ovary was ≥ 4ml, there was also a significant correlation (p<0.05) with improving the number of AFC, oocytes and embryos. Significant heterogeneity existed among the studies. Conclusion: The pooled results suggest that intra-ovarian injection of PRP can promote ovarian regeneration and improve the reproductive outcomes of patients with ovarian dysfunction. This therapy may have significant clinical potential in improving sex hormone levels, increasing AFC, oocyte count, and embryo count. However, this findings still requires more rigorous and extensive trials worldwide to determine the value of intra-ovarian injection of PRP in POR patients. Systematic review registration: https://www.crd.york.ac.uk, Identifier CRD42023451232.

Comparison of cumulative live birth rates between progestin-primed ovarian stimulation protocol and gonadotropin-releasing hormone antagonist protocol in different populations.

Objective: To compare cumulative live birth rate (LBR) between progestin-primed ovarian stimulation (PPOS) and GnRH antagonist protocols of preimplantation genetic testing (PGT) cycles in different populations. Methods: This was a retrospective cohort study. A total of 865 patients were enrolled and separate analyses were performed for three populations: 498 patients with predicted normal ovarian response (NOR), 285 patients with PCOS, and 82 patients with predicted poor ovarian response (POR). The primary outcome was cumulative LBR for one oocyte retrieval cycle. The results of response to ovarian stimulation were also investigated, including numbers of oocytes retrieved, MII oocytes, 2PN, blastocysts, good-quality blastocysts, and usable blastocysts after biopsy, as well as rates of oocyte yield, blastocyst formation, good-quality blastocysts, and moderate or severe OHSS. Univariable and multivariable logistic regression analyses were used to identify potential confounders that may be independently associated with cumulative live birth. Results: In NOR, the cumulative LBR of PPOS protocol was significantly lower than that of GnRH antagonists (28.4% vs. 40.7%; P=0.004). In multivariable analysis, the PPOS protocol was negatively associated with cumulative LBR (adjusted OR=0.556; 95% CI, 0.377-0.822) compared to GnRH antagonists after adjusting for potential confounders. The number and ratio of good-quality blastocysts were significantly reduced in PPOS protocol compared to GnRH antagonists (2.82 ± 2.83 vs. 3.20 ± 2.79; P=0.032 and 63.9% vs. 68.5%; P=0.021), while numbers of oocytes, MII oocytes and 2PN did not show any significant difference between GnRH antagonist and PPOS protocols. PCOS patients had similar outcomes as NOR. The cumulative LBR of PPOS group appeared to be lower than that of GnRH antagonists (37.4% vs. 46.1%; P=0.151), but not significantly. Meanwhile, the proportion of good-quality blastocysts in PPOS protocol was also lower compared to GnRH antagonists (63.5% vs. 68.9%; P=0.014). In patients with POR, the cumulative LBR of PPOS protocol was comparable to that of GnRH antagonists (19.2% vs. 16.7%; P=0.772). There was no statistical difference in the number and rate of good-quality blastocysts between the two protocols in POR, while the proportion of good-quality blastocysts appeared to be higher in PPOS group compared to GnRH antagonists (66.7% vs. 56.3%; P=0.182). In addition, the number of usable blastocysts after biopsy was comparable between the two protocols in three populations. Conclusion: The cumulative LBR of PPOS protocol in PGT cycles is lower than that of GnRH antagonists in NOR. In patients with PCOS, the cumulative LBR of PPOS protocol appears to be lower than that of GnRH antagonists, albeit lacking statistical difference, whereas in patients with diminished ovarian reserve, the two protocols were comparable. Our findings suggest the need for caution when choosing PPOS protocol to achieve live births, especially for normal and high ovarian responders.

The Impact of Growth Hormone Co-Treatment Duration on Outcomes in IVF/ICSI Cycles Among Poor Ovarian Responders.

Background: The efficiency of in vitro fertilization is improved by growth hormone (GH) during ovarian stimulation. Additionally, patients with diabetes experience impaired insulin resistance and compromised glucose tolerance, which further exacerbate their condition. Due to these side effects, in this study, the duration of GH treatment was compared in IVF/ICSI cycles among poor ovarian responders. Methods: In this study, POSEIDON criteria were used to choose patients. Subcutaneous administration of gonadotropin-releasing hormone (GnRH) antagonist was done beginning on the sixth day of the cycle and continuing through the day of human chorionic gonadotropin (hCG) injection. In one group, GH was administered 4 units/day from the 2nd day of the cycle until hCG injection, and in another group, the first dose was administered on the 6th day of the cycle. Following the administration of hCG, which lasted from 24 to 36 hr, oocytes were retrieved with the support of B-mode sonography. Results: In our analysis, no significant differences were observed between the two groups in terms of the number of retrieved oocytes, metaphase II oocytes, and quality of grade A and B embryos. The results show that the treatment or conditions did not have a significant impact on the outcomes among the studied groups. Conclusion: Our findings indicate that a shorter duration of GH administration can yield similar outcomes compared to a longer duration in IVF/ICSI cycles involving poor ovarian responders. This result holds the potential for a more cost-effective and patient-friendly approach in managing assisted reproductive technology procedures. It may lead to reduced side effects and improved adherence to medication regimens in patients.

Type and dose of gonadotropins in poor ovarian responders: does it matter?

Infertile patients with a diminished ovarian reserve, also referred to as poor ovarian responders, constitute a substantial and increasing population of patients undergoing in vitro fertilization. The management of patients with poor ovarian response is still a controversial issue. Almost a century has passed since the introduction of the first gonadotropin. A broad collection of urinary and recombinant gonadotropins, including biosimilars, is commercially available now. Despite great advances in assisted reproductive technology, there remains uncertainty about the optimal treatment regimen for ovarian stimulation in poor ovarian responders. Although oocyte donation is the most successful and ultimate remedy for poor ovarian responders, most patients persist on using their own oocytes in several attempts, to achieve the desired pregnancy. The aim of this review is twofold: first, to provide an overview of the commercially available gonadotropins and summarize the available evidence supporting the use of one or another for ovarian stimulation in poor ovarian responders, and second, to address the controversies on the dosage of gonadotropins for this specific in vitro fertilization population.

Comparison of Dydrogesterone and Medroxyprogesterone in the Progestin-Primed Ovarian Stimulation Protocol for Patients With Poor Ovarian Response.

Objective: To compare the clinical outcomes of dydrogesterone (DYG) and medroxyprogesterone (MPA) in the progestin-primed ovarian stimulation (PPOS) protocol for patients with poor ovarian response (POR). Patients and Methods: This was a retrospective cohort study. Women with POR who underwent IVF/ICSI at the Reproductive Center of Third Affiliated Hospital of Zhengzhou University between January 2020 and January 2021 were included. The primary outcome measure of our study was the number of oocytes retrieved. The secondary outcome measures in the present study were the number of 2PN, number of available embryos, oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved, cancellation rate and pregnancy outcomes of the first embryo transfer cycle, including the biochemical pregnancy, clinical pregnancy and miscarriage rates. Results: In total, 118 women underwent hMG +DYG protocols, and 692 women who underwent hMG +MPA met the Bologna criteria for POR. After baseline characteristics were balanced using the PSM model, 118 hMG +DYG protocols were matched to 118 hMG +MPA protocols, and the baseline characteristics were comparable between the two groups. The numbers of oocytes retrieved, 2PN, and available embryos and the oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved and cancellation rate of the hMG+DYG and hMG+MPA protocols were comparable. Altogether, 66 women in the hMG+DYG group and 87 women in the hMG+MPA group underwent first embryo transfers. In the hMG+DYG group, 81.8% (54/66) of the patients underwent cleavage embryo transfers; similarly, 79.3% (69/87) of patients in the hMG+MPA group had cleavage embryo transfers (P=0.70).The biochemical pregnancy rate of the hMG+DYG group was 42.4%, and this was comparable to the rate in the hMG+DYG group, at 34.5% (P=0.32). The clinical pregnancy rates were similar between the two groups (36.4% vs. 31.0%, P=0.49), and there was no significant difference in the rate of miscarriage between the two groups (12.5% vs. 29.6%, P=0.14). Conclusion: For women with POR, the clinical outcome of the hMG + DYG group was similar to that of the hMG + MPA group, indicating that both combinations can be useful options for PPOS protocols.

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.