Effect of GnRH agonist alone or combined with different low-dose hCG on cumulative live birth rate for high responders in GnRH antagonist cycles: a retrospective study.

BACKGROUND: There is insufficient evidence regarding the impact of dual trigger on oocyte maturity and reproductive outcomes in high responders. Thus, we aimed to explore the effect of gonadotropin-releasing hormone agonist (GnRHa) trigger alone or combined with different low-dose human chorionic gonadotropin (hCG) regimens on rates of oocyte maturation and cumulative live birth in high responders who underwent a freeze-all strategy in GnRH antagonist cycles. METHODS: A total of 1343 cycles were divided into three groups according to different trigger protocols: group A received GnRHa 0.2 mg (n = 577), group B received GnRHa 0.2 mg and hCG 1000 IU (n = 403), and group C received GnRHa 0.2 mg and hCG 2000 IU (n = 363). RESULTS: There were no significant differences in age, body mass index, and rates of oocyte maturation, fertilization, available embryo, and top-quality embryo among the groups. However, the incidence of moderate to severe ovarian hyperstimulation syndrome (OHSS) was significantly different among the three groups (0% in group A, 1.49% in group B, and 1.38% in group C). For the first frozen embryo transfer (FET) cycle, there were no significant differences in the number of transferred embryos and rates of implantation, clinical pregnancy, live birth, and early miscarriage among the three groups. Additionally, the cumulative ongoing pregnancy rate and cumulative live birth rate were not significantly different among the three groups. Similarly, there were no significant differences in gestational age, birth weight, birth height, and the proportion of low birth weight among subgroups stratified by singleton or twin. CONCLUSIONS: GnRHa trigger combined with low-dose hCG (1000 IU or 2000 IU) did not improve oocyte maturity and embryo quality and was still associated with an increased risk of moderate to severe OHSS. Therefore, for high responders treated with the freeze-all strategy, the single GnRHa trigger is recommended for final oocyte maturation, which can prevent the occurrence of moderate to severe OHSS and obtain satisfactory pregnancy and neonatal outcomes in subsequent FET cycles.

Is it necessary to monitor the serum luteinizing hormone (LH) concentration on the human chorionic gonadotropin (HCG) day among young women during the follicular-phase long protocol? A retrospective cohort study.

BACKGROUND: The normal physiological function of LH requires a certain concentration range, but because of pituitary desensitization, even on the day of HCG, endogenous levels of LH are low in the follicular-phase long protocol. Therefore, our study aimed to determine whether it is necessary to monitor serum LH concentrations on the day of HCG (LHHCG) and to determine whether there is an optimal LHHCG range to achieve the desired clinical outcome. METHODS: A retrospective cohort study included 4502 cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) from January 1, 2016, to June 30, 2019, in a single department. The main outcome measures included retrieved eggs, available embryos, and live birth rate. RESULTS: The LHHCG was divided into five groups: Group A (LH ≤ 0.5), Group B (0.5 IU/L < LH ≤ 1.2 IU/L), Group C (1.2 IU/L < LH ≤ 2.0 IU/L), Group D (2.0 IU/L < LH ≤ 5.0 IU/L), Group E (LH > 5 IU/L). In terms of the numbers of retrieved eggs (15.22 ± 5.66 vs. 13.54 ± 5.23 vs. 12.90 ± 5.05 vs. 12.30 ± 4.88 vs. 9.6 ± 4.09), diploid fertilized oocytes (9.85 ± 4.70 vs. 8.69 ± 4.41 vs. 8.39 ± 4.33 vs. 7.78 ± 3.96 vs. 5.92 ± 2.78), embryos (7.90 ± 4.48 vs. 6.83 ± 4.03 vs. 6.44 ± 3.88 vs. 6.22 ± 3.62 vs. 4.40 ± 2.55), and high-quality embryos (4.32 ± 3.71 vs. 3.97 ± 3.42 vs. 3.76 ± 3.19 vs. 3.71 ± 3.04 vs. 2.52 ± 2.27), an increase in the LHHCG level showed a trend of a gradual decrease. However, there was no significant difference in clinical outcomes among the groups (66.67% vs. 64.33% vs. 63.21% vs. 64.48% vs. 63.33%). By adjusting for confounding factors, with an increase in LHHCG, the number of retrieved eggs decreased (OR: -0.351 95%CI - 0.453-[- 0.249]). CONCLUSION: In the follicular-phase long protocol among young women, monitoring LHHCG is recommended in the clinical guidelines to obtain the ideal number of eggs.

Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study.

OBJECTIVE: To evaluate the efficacy and safety of 40-mg relugolix (REL) compared with those of leuprorelin (LEU) in women with endometriosis-associated pain. DESIGN: Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study in Japanese patients. SETTING: Hospitals and clinics. PATIENT(S): Women aged ≥20 years with regular menstrual cycles (25-38 days) experiencing endometriosis or ovarian endometrioma and reporting pelvic pain. INTERVENTION(S): In the REL group, 40 mg of REL was orally administered once a day for 24 weeks. In the LEU group, 3.75 or 1.88 mg of LEU was subcutaneously injected every 4 weeks for 24 weeks. MAIN OUTCOME MEASURE(S): The primary endpoint was the change in the maximum visual analog scale score for pelvic pain from baseline until 28 days before the end of treatment. RESULT(S): Changes in the maximum visual analog scale score were -52.6 ± 1.3 for REL and -57.5 ± 1.4 for LEU. Ovarian endometrioma decreased by 12.26 ± 17.52 cm3 for REL and 14.10 ± 18.81 cm3 for LEU. Drug-related treatment emergent adverse events with an incidence of >10% for both groups were hot flush, metrorrhagia, headache, and genital hemorrhage. Discontinuations from treatment emergent adverse events were 2.9% for REL and 4.3% for LEU. CONCLUSION(S): Relugolix was noninferior to LEU for treating endometriosis-associated pelvic pain. Safety profiles of both medications were comparable, although menses returned earlier in patients taking REL, a huge benefit for women who plan to conceive after treatment. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03931915.

Exploration of the value of progesterone and progesterone/estradiol ratio on the hCG trigger day in predicting pregnancy outcomes of PCOS patients undergoing IVF/ICSI: a retrospective cohort study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder with the disorders of estrogen(E2) and progesterone(P) secretion. The purpose of this study was to evaluate the association between the progesterone level or progesterone/estradiol(P/E2) ratio on human chorionic gonadotropin (hCG) trigger day and the outcome of in vitro fertilization in PCOS patients and explore the value of progesterone and P/E2 ratio for predicting the clinical pregnancy. METHODS: The clinical data of 1254 PCOS patients who satisfied the inclusion criteria were retrospectively analyzed, including baseline characteristics such as age, body mass index, basal sex hormone levels, et al., as well as ovarian stimulation data and clinic outcome. RESULTS: The number of follicles larger than 14 mm in diameter (P < 0.001) and retrieved oocytes (P < 0.001) was greater in the high progesterone group (progesterone ≥ 0.92 ng/mL). In the high P/E2 group(P/E2 ratio ≥ 0.3), the number of follicles larger than 14 mm in diameter (P < 0.001) and retrieved oocytes (P < 0.001), as well as the rate of high-quality embryos (P = 0.040) were significantly decreased. In ultralong GnRH agonist protocol, the implantation rate(P < 0.001), hCG positive rate (P < 0.001), clinical pregnancy rate (P < 0.001) and live birth rate (P < 0.001) were all significantly higher than long GnRH agonist protocol and GnRH antagonist protocol. The clinical pregnancy rate of high progesterone group was significantly lower than that of low progesterone group in ultralong GnRH agonist (P = 0.008). The progesterone level could be used as an indicator to predict the positive clinical pregnancy (long GnRH agonist: P = 0.001; ultralong GnRH agonist: P < 0.001) except in cycles using GnRH antagonist (P = 0.169). In the ultralong GnRH agonist, the value of progesterone level in the prediction of clinical pregnancy was significantly higher than that of the P/E2 ratio (P = 0.021). CONCLUSIONS: In PCOS patients, the progesterone level is associated with clinical pregnancy rate while P/E2 ratio is not. In subgroup analysis using three different COS protocols, a significant association between progesterone level and clinical pregnancy rate can be observed in the long GnRH agonist protocol and ultralong GnRH agonist protocol. The progesterone level is significantly better than the P/E2 ratio in predicting the pregnancy outcome of PCOS patients, especially in ultralong GnRH agonist cycles.

Endometrial Preparation for Frozen-Thawed Embryo Transfer With or Without Pretreatment With GnRH Agonist: A Randomized Controlled Trial at Two Centers.

Objective: This prospective randomized controlled trial compared the reproductive outcomes of frozen embryo transfer (FET) with hormone replacement treatment (HRT) with or without gonadotropin-releasing hormone agonist (GnRHa) pretreatment. Methods: A total of 133 patients scheduled for HRT-FET mainly because of tubal and/or male factors who received two high-quality cleavage-stage embryos were enrolled at two participating centers. The GnRHa group (n = 65) received GnRHa pretreatment, while the control group (n = 68) did not. Analysis was based on the intention-to-treat (ITT) principle. Results: Among the 133 participants, 130 (97.7%) underwent embryo transfer and 127 (95.5%) completed the protocol. The clinical pregnancy rate according to ITT did not differ between the GnRHa and control groups [39/65 (60.0%) vs. 41/68 (60.3%), p = 0.887]. The implantation rate (47.6% vs. 45.3%, p = 0.713), early pregnancy loss rate (5.1% vs. 19.5%, p = 0.09), and live birth rate (49.2% vs. 50.0%, p = 0.920) were also comparable between groups. Conclusion: Pretreatment with GnRHa does not improve the reproductive outcomes for women receiving HRT-FET. Clinical Trial Registration: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-17014170; http://www.chictr.org.cn).

Predictive factors for fertility preservation in pediatric and adolescent girls with planned gonadotoxic treatment.

PURPOSE: To characterize female pediatric and adolescent patients seen for fertility preservation consultation at an academic medical center and to describe the association between demographic or clinical factors and the use of fertility preservation treatment (FPT). METHODS: This is a retrospective chart analysis of female pediatric and adolescent patients seen for fertility preservation consultation at an academic fertility center over a 14-year period from 2005 to 2019. RESULTS: One hundred six females aged 3-21 years were seen for fertility preservation consultation with a mean age of 16.6 years. Diagnoses included hematologic malignancies (41.5%), gynecologic malignancies (9.4%), other malignancies (31.1%), non-malignant hematologic disease (14.2%), and non-malignant conditions (3.8%). Overall, 64.2% of subjects pursued fertility preservation, including oocyte cryopreservation (35.8%) and ovarian tissue cryopreservation (23.6%). Overall, age, minority race, diagnosis, time since diagnosis, and median household income were not significantly associated with odds of completing an FPT procedure. Among all patients, those who underwent gonadotoxic therapy prior to consultation had a lower odds of receiving FPT (OR= 0.24, 95% CI 0.10-0.55). Among patients without chemotherapy exposure, no factors were associated with FPT. CONCLUSIONS: Among pediatric and adolescent patients at an academic center undergoing a fertility preservation consultation, there were no socioeconomic or clinical barriers to FPT use in those who had not yet undergone gonadotoxic therapy. The only factor that was negatively associated with odds of pursuing FPT was prior chemotherapy exposure.

A machine learning algorithm can optimize the day of trigger to improve in vitro fertilization outcomes.

OBJECTIVE: To determine whether a machine learning causal inference model can optimize trigger injection timing to maximize the yield of fertilized oocytes (2PNs) and total usable blastocysts for a given cohort of stimulated follicles. DESIGN: Descriptive and comparative study of new technology. SETTING: Tertiary academic medical center. PATIENT(S): Patients undergoing IVF with intracytoplasmic sperm injection from 2008 to 2019 (n = 7,866). INTERVENTION(S): Causal inference was performed with the use of a T-learner. Bagged decision trees were used to perform inference. The decision was framed as either triggering on that day or waiting another day. All patient characteristics and stimulation parameters on a given day were used to determine the recommendation. MAIN OUTCOME MEASURE(S): Average outcome improvement in total 2PNs and usable blastocysts compared with the physician's decision. RESULT(S): For evaluation of average outcome improvement on 2PNs, the benefit of following the model's recommendation was 3.015 (95% CI 2.626, 3.371) more 2PNs. For total usable blastocysts, the benefit was 1.515 (95% CI 1.134, 1.871) more usable blastocysts. Given that the physicians-model agreement was 52.57% and 61.89%, respectively, algorithm-assisted trigger decisions yield, on average, 1.430 more 2PNs and 0.577 more total usable blastocysts per stimulation. The most important features weighted in the model's decision were the number of follicles 16-20 mm in diameter, the number of follicles 11-15 mm in diameter, and estradiol level, in that order. CONCLUSION(S): The use of this machine learning algorithm to optimize trigger injection timing may lead to a significant increase in the number of 2PNs and total usable blastocysts obtained from an IVF stimulation cycle when compared with physician decisions. Future research is required to confirm these findings prospectively.

How far is too far? Does time interval between GnRH antagonist and GnRH agonist trigger in GnRH antagonist cycles matter?

RESEARCH QUESTION: What is a suitable time interval between the last GnRH antagonist exposure and GnRH agonist (GnRHa) triggering for final follicular maturation? DESIGN: A retrospective cohort study including 413 patients undergoing GnRH antagonist cycles in which GnRHa trigger was used, either solely or as a dual trigger. The primary outcome measure was the follicle/mature oocyte ratio. Cycles were analysed according to the time interval between the last GnRH antagonist exposure and the GnRHa triggering: Group 1 included patients with a 12-14 h interval; Group 2: 7-10 h interval; Group 3: 5-6 h interval and Group 4: 2-4 h interval. LH concentration was measured 11-13 h post-GnRHa injection. RESULTS: Median LH value was 65 IU/l. There was a weak but significant correlation between basal LH and the LH surge (R2 = 0.137, P < 0.001). Although square root LH values differed significantly between study groups (P < 0.001; higher in Groups 2 and 3), the follicle/mature oocyte ratio was not different across the four antagonist-agonist interval groups and no correlation was detected between the post-trigger LH concentration and the follicle/oocyte ratio (R2 = 0.011). In a model integrating age, day 3 FSH concentration, maximal oestradiol and body mass index along with the study groups, none of these factors was significantly related to the follicle/mature oocyte outcome ratio. Insufficient surge (LH < 15 IU/l) occurred in 14 (3.4%) cases. Rates of insufficient LH surge did not differ significantly between the groups (2.4%, 3.2%, 3.4% and 7.1% in Groups 1 to 4, respectively; P = 0.5). CONCLUSIONS: LH concentrations post-GnRHa trigger differ in regard to antagonist-agonist intervals, but the follicle/mature oocyte ratio achieved was not affected.

Comparison of Stimulated Cycles with Low Dose r-FSH versus Hormone Replacement Cycles for Endometrial Preparation Prior to Frozen-Thawed Embryo Transfer in Young Women with Polycystic Ovarian Syndrome: A Single-Center Retrospective Cohort Study from China.

OBJECTIVE: The principal purpose of this study was to compare reproductive outcomes for stimulated cycles (STC) and hormone replacement cycles (HRC) for endometrial preparation before frozen-thawed embryo transfer (FET) in young women with polycystic ovary syndrome (PCOS). METHODS: We conducted a retrospective study of 1434 FET cycles from January, 2017 to March, 2020 in our reproductive center, in which stimulated and hormone replacement cycles were used for endometrial preparation. Pregnancy outcomes of couples undergoing routine STC-FET or HRC-FET were analyzed by propensity score matching (PSM) and multivariable logistic regression analyses. RESULTS: Data on 1234 HRC protocols (86% of the total) and 200 STC protocols (14%) were collected. After PSM, 199 patients were included in both groups, respectively. There was no significant difference in positive pregnancy rate (52.7% vs 54.8%, p=0.763), clinical pregnancy rate (51.8% vs 52.8%, p=0.841), live birth rate (45.2% vs 43.7%, p=0.762), pregnancy loss rate (9.7% vs 16.2%, p=0.164) and ectopic pregnancy rate (1.5% vs 0.5%, p=0.615) between STC and HRC protocols. Subsequent multivariate logistic regression analysis also yielded similar results. CONCLUSION: STC for endometrial preparation had similar pregnancy outcomes compared with HRC protocols. Evidence is available which shows that for young women with PCOS in preparation for FET, HRC could be a reasonable choice for patients who are unwilling to accept injections. However, STC may reduce unnecessary anxiety and operational costs and offer more flexibility for patients. Eventually, we must embrace the concepts of individualization, securitization, and optimization in the clinic.

Application of Pulsed Rhythmic Drug Administration to Ovulation Induction Therapy in PCOS Patients with Clomiphene-Resistance: a Retrospective Research.

There is currently a dispute over the choice of ovulation induction treatment for infertile women with polycystic ovary syndrome (PCOS). The objective of this study is to compare the therapeutic effect of pulsed rhythmic administration protocol (PRAP) with conventional letrozole + human menopausal gonadotropin (HMG) in patients with clomiphene-resistance polycystic ovary syndrome (PCOS). A retrospective analysis of 821 intrauterine insemination (IUI) cycles between January 2015 and January 2020 was performed. Of these, 483 cycles were treated with a pulsed rhythmic administration protocol (PRAP), and 338 cycles were treated with conventional letrozole + HMG protocol (LHP). The therapeutic effect of the two protocols has been compared. The pregnancy rate was 18.07% in the LHP and 27.07% in the PRAP. The ongoing pregnancy rate in LHP was 14.46% and in PRAP was 22.73%. The research suggests that PRAP is more effective than LHP and could be an adequate ovulation induction strategy for the IUI cycle of patients with clomiphene-resistance PCOS.

Oocyte stimulation parameters influence the number and proportion of mature oocytes retrieved in assisted reproductive technology cycles.

PURPOSE: Whether differences in stimulation parameters alter the number and proportion of MII oocytes retrieved. METHODS: Records of 2546 patients were examined, looking at age, day 2/3 follicle-stimulating hormone (FSH) and estradiol (E2) levels, total dose of gonadotropins administered (including FSH and human menopausal gonadotropin [hMG]), fraction of hMG administered, number of days of treatment with gonadotropins, and the dose of gonadotropins administered per day. We segregated the patients into 3 different classes depending on the trigger method used and 2 groups based on egg freeze vs. ICSI. Multiple regression methods were used to examine associations between stimulation parameters and the total number of eggs, number of immature oocytes (Poisson regression), and the fraction of retrieved oocytes that were immature (Logistic regression). RESULTS: After adjustments for different triggers and egg freeze versus ICSI, both the #immature oocytes and the immature fraction of oocytes were associated with the total gonadotropin dose (inversely) and the gonadotropin dose/day (positively). Other parameters were associated with the number of immature oocytes but were also associated with the number of oocytes retrieved. CONCLUSIONS: Stimulations using less total gonadotropin and more gonadotropin per day were associated with more immaturity. The type of trigger method used for final maturation was associated with immaturity but was believed to be predominantly due to trigger assignment to patients based on response. The association between use of ICSI and less immaturity was believed to be due to additional time for maturation in the ICSI group.

Intramuscular progesterone optimizes live birth from programmed frozen embryo transfer: a randomized clinical trial.

OBJECTIVE: To determine whether vaginal progesterone for programmed endometrial preparation is noninferior to intramuscular progesterone in terms of live birth rates from frozen embryo transfer (FET). DESIGN: Three-armed, randomized, controlled noninferiority trial. SETTING: Multicenter fertility clinic. PATIENT(S): A total of 1,346 volunteer subjects planning vitrified-warmed transfer of high-quality nonbiopsied blastocysts were screened, of whom 1,125 subjects were ultimately enrolled and randomly assigned to treatment. INTERVENTION(S): The subjects were randomly assigned to receive, in preparation for FET, 50 mg daily of intramuscular progesterone (control group), 200 mg twice daily of vaginal micronized progesterone plus 50 mg of intramuscular progesterone every third day (combination treatment), or 200 mg twice daily of vaginal micronized progesterone. MAIN OUTCOME MEASURE(S): The primary outcome was live birth rate per vitrified-warmed embryo transfer. The secondary outcomes were a positive serum human chorionic gonadotropin test 2 weeks after FET, biochemical pregnancy loss, clinical pregnancy, clinical pregnancy loss, total pregnancy loss, serum luteal progesterone concentration 2 weeks after FET, and patient's experience and attitudes regarding the route of progesterone administration, on the basis of a survey administered to the subjects between FET and pregnancy test. RESULT(S): A total of 1,060 FETs were completed. The live birth rate was significantly lower in women receiving only vaginal progesterone (27%) than in women receiving intramuscular progesterone (44%) or combination treatment (46%). Fifty percent of pregnancies in women receiving only vaginal progesterone ended in miscarriage. CONCLUSION(S): The live birth rate after vaginal-only progesterone replacement was significantly reduced, due primarily to an increased rate of miscarriage. Vaginal progesterone supplemented with intramuscular progesterone every third day was noninferior to daily intramuscular progesterone, offering an effective alternative regimen with fewer injections. CLINICAL TRIAL REGISTRATION NUMBER: NCT02254577.

Changing stimulation protocol on repeat conventional ovarian stimulation cycles does not lead to improved laboratory outcomes.

OBJECTIVE: To evaluate whether physicians' choice of ovarian stimulation protocol is associated with laboratory outcomes. DESIGN: Retrospective cohort study. SETTING: Single academic center. PATIENT(S): The subjects were 4,458 patients who completed more than one in vitro fertilization ovarian stimulation cycle within 1 year. On second stimulation, 49% repeated the same protocol and 51% underwent a different one. INTERVENTION(S): Estradiol priming antagonist, antagonist +/- oral contraceptive pill priming, long luteal protocol, Lupron (Lupron [AbbVie Inc, North Chicago, IL]) stop protocol, and flare were compared. Logistic or linear regression with cluster robust standard errors to account for covariates and paired data was used. MAIN OUTCOME MEASURE(S): Oocytes collected (OC), fertilization rate, blastocyst progression (BP), usable embryos (UE), and euploid rate (ER). RESULT(S): First stimulation outcomes were comparable across all protocols for FR, BP, UE, and ER but were different for OC, after adjustment for covariates. For OC, the effect of switching protocols differed according to the type of the second stimulation. There was improvement in OC if the same stimulation was repeated, except for flare. In addition, there were slight, significant improvements in fertilization rate (difference in values or coefficient of 0.02; 95% confidence interval [CI], 0.004, 0.4) and UE (coefficient 1.25; 95% CI, 0.79, 1.72) when the same stimulation was repeated. There were no changes in BP (coefficient 0.03; 95% CI, -0.01, 0.08) or ER (coefficient 0.01; 95% CI, -0.04, 0.06) when protocols were changed. In a low-BP subgroup, greater improvement was seen when the same protocol was repeated (coefficient 0.03; 95% CI 0.01, 0.04). CONCLUSION(S): There was a slight but significant improvement in laboratory outcomes when the same stimulation protocol was repeated, so careful consideration should be made before switching stimulation protocols for the purpose of improving laboratory outcomes.

Mathematical Modeling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation.

New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts ("waves") of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modeling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test ovarian stimulation protocols in silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.

Human Menopausal Gonadotropin Commenced on Early Follicular Period Increases Live Birth Rates in POSEIDON Group 3 and 4 Poor Responders.

Human menopausal gonadotropin (hMG) has LH activity, and it may have beneficial effects in terms of oocyte quality and endometrial receptivity similar to recombinant LH supplementation. The aim of this study was to assess the effects of hMG, and its commencement time on the outcome of assisted reproductive technology (ART) cycles of POSEIDON group 3 and 4 poor responders. Data of 558 POSEIDON group 3 and 4 poor responders who underwent ART treatment following a GnRH antagonist cycle at a university-based infertility clinic between January 2014 and December 2019 were reviewed. hMG was commenced at the early follicular phase or mid-follicular phase in the study groups. The control group did not receive hMG stimulation. Live birth rate (LBR) was the main outcome measure. The mean duration of stimulation was significantly shorter in early follicular hMG group than in mid-follicular hMG group (11.9 ± 3.6 days vs. 12.8 ± 4 days, respectively; P = 0.027). The mean numbers of oocytes retrieved and MII oocytes were comparable between the groups. The LBRs per embryo transfer in early follicular hMG, mid-follicular hMG, and control groups were 21.9%, 11.7%, and 11.6%, respectively (P = 0.035). In conclusion, there is a significant association between the commencement time of hMG and live birth chance in ART cycles of POSEIDON group 3 and 4 poor responders. Early initiation of hMG together with rFSH seems to be beneficial in this specific population.

Progestin-Primed Ovarian Stimulation with Clomiphene Citrate Supplementation May Be More Feasible for Young Women with Diminished Ovarian Reserve Compared with Standard Progestin-Primed Ovarian Stimulation: A Retrospective Study.

PURPOSE: The present study was designed to compare the efficiency of the progestin-primed ovarian stimulation (PPOS) protocol with clomiphene citrate (CC) supplementation (PPOS+CC) and the standard PPOS protocol for women of different ages with diminished ovarian reserve (DOR). PATIENTS AND METHODS: This retrospective cohort study included 364 DOR women who underwent controlled ovarian stimulation with PPOS+CC (n = 223) or standard PPOS (n = 141). They were divided into subgroups based on age: ≤35 years and >35 years. Differences in baseline characteristics, ovarian stimulation characteristics, endocrinological characteristics, and clinical outcome between the two groups were assessed. Statistical analyses were stratified by age. RESULTS: In all women with DOR, PPOS+CC was associated with a lower percentage of women with profound pituitary suppression than standard PPOS (0.0% vs 18.6%, P < 0.001 and 1.3% vs 11.0%, P = 0.002). In young women with DOR, more high-quality cleavage-stage embryos were harvested (1.96 vs 1.38, P = 0.018) and a lower dosage of gonadotropin per oocyte retrieved was required (558.37 vs 909.82, P = 0.036) in PPOS+CC. In older women with DOR, PPOS+CC led to an increase in the incidence of luteinizing hormone (LH) surge levels above 10 IU/L on trigger day (12.7% vs 4.9%, P = 0.028) and a decrease in the rate of oocyte maturation (84.7% vs 89.9%, P = 0.034) compared to standard PPOS. CONCLUSION: Clomiphene citrate is an effective adjuvant to alleviate pituitary suppression in PPOS protocols; for young women with DOR, CC supplementation had a positive impact on the number of high-quality embryos. However, older women with DOR would be at risk of developing a premature LH surge and having poor oocyte maturation rate under the PPOS+CC protocol.

Ovulation induction with high progesterone levels may be more suitable for elderly patients with low ovarian response.

BACKGROUND: The objective of this study was to explore the outcomes of using the progestin-primed ovarian stimulation (PPOS) protocol in aged infertile women. The patients recruited in the study had displayed a poor ovarian response (POR) in the first IVF/ICSI-ET cycles with the ultra-short gonadotropin-releasing hormone agonist (GnRH-a) protocols. MATERIALS AND METHODS: A self-controlled retrospective study was conducted to investigate the clinical outcomes of 117 aged infertile women who met the inclusion criteria. The patients were grouped into two; group B included patients who had displayed a poor ovarian response (POR) in the first IVF/ICSI-ET cycle with the ultra-short GnRH-a protocol. Group A was made up of patients who underwent the PPOS protocol in the second cycle. The study was done between January 2015 to May 2018 in the reproductive and genetic centre of integrated traditional and western medicine, Affiliated hospital of Shandong University of traditional Chinese medicine. Reproduction-related clinical outcomes in the two groups were compared. RESULTS: There were no statistically significant differences in the serum levels of LH, E2, and P on the trigger day between group A and group B (P＞0.05). The number of follicles with a diameter > 14 mm was significantly higher in the PPOS protocol patients than in the ultra-short GnRH-a protocol group (4.83 ± 2.82 vs. 3.25 ± 2.53, P < 0.01). The duration and total dosage of gonadotropin of the PPOS protocol group were less than in the previous ultra-short GnRH-a protocol, although the statistical differences were not significant (P > 0.05). The number of eggs obtained in the PPOS group was significantly higher than that of the previous one (4.29 ± 3.11 vs. 2.76 ± 2.33, P < 0.05). The numbers of MII eggs, cleavage, 2 P N, transplantable embryos, and high quality embryos were higher in the PPOS protocol group than that in the ultra-short protocol group. However, the differences between the two groups in all the above parameters were not statistically significant (P > 0.05). The rate of high-quality embryos was significantly higher in the PPOS protocol group than in the ultra-short protocol group (38.61(100/259) vs. 32.02(65/203), P < 0.05). Although not statistically significant (P > 0.05), the abortion rate of the PPOS protocol group was higher than that of the ultra-short protocol group. The clinical pregnancy and live birth rates were significantly higher in the PPOS protocol group than in the ultra-short protocol group (p < 0.05). The clinical pregnancy rates in the PPOS protocol group and the ultra-short protocol group were 32.35 % and 25.53 % respectively while the live birth rates were 27.45 % and 21.28 % respectively. CONCLUSION: Compared with the ultra-short protocol, the PPOS protocol improves the number of follicles, the number of eggs, clinical pregnancy, and live birth rates in POR patients. The PPOS protocol could, therefore, provide a novel treatment strategy for inducing ovulation in POR patients.

Does the Time of Starting Progesterone Luteal Support Affect Embryo Transfer in Long Agonist Protocol Downregulated ICSI Cycles? A Randomized Controlled Trial.

The aim of this study was to compare the effects of starting progesterone (P4) luteal support (LS) on day of egg retrieval (ER) or day of embryo transfer (ET) on the ratio of difficult ET and cycle outcome. This was a RCT ( ClinicalTrials.gov Identifier: NCT03040830) carried out at Mansoura Integrated Fertility Center (MIFC), Mansoura, Egypt, from November 2015 to January 2017. A total of 171 eligible long agonist ICSI cases were randomly allocated on day of ER into group A (86) starting LS as daily IM 100 mg P4 on day of ER and group B (85) starting P4-LS on day of ET. Difficult ET was defined as blood on ET catheter and/or sounding or dilating the cervix. Primary outcome was the overall ratio of difficult ET and ratios on day 3 and 5 ET. Secondary outcome was the ongoing pregnancy rate (OPR) and implantation rate (IR). The results are presented as % for groups A and B respectively: overall difficult ET (44.1, 24.7) (p = 0.009); day 3 difficult ET (23.2, 24.4) (p = 0.45); day 5 difficult ET (62.7, 25.6) (p = 0.001); overall OPR (38.3, 44.7) (p = 0.43); day 3 ET OPR (41.8, 33.3) (p = 0.51); day 5 ET OPR (34.8, 57.5) (p = 0.048); overall IR (20.0, 22.5) (p = 0.62); day 3 ET IR (17.8, 13.4) (p = 0.44); day 5 ET IR (22, 34.1) (p = 0.09). In conclusion, starting P4 luteal support on egg retrieval day is associated with significantly higher ratio of difficult embryo transfer and lower ongoing pregnancy rate and tendency to lower IR in day 5 ET, so starting P4-LS on day of ET is recommended.

Letrozole versus clomiphene citrate for ovulation induction in anovulatory women with polycystic ovarian syndrome: A randomized controlled trial.

OBJECTIVE: To compare the efficacy of letrozole and clomiphene citrate (CC) for ovulation induction in infertile women with polycystic ovarian syndrome (PCOS). METHODS: In this assessor blind, randomized controlled trial, 90 infertile women with PCOS were randomized to receive either letrozole or CC for ovulation induction in incremental doses for a maximum of three cycles. Main outcome measures studied were endometrial thickness, ovulation rate, pregnancy rate, rate of monofollicular development, and time to conception. RESULTS: Mean endometrial thicknesses were 9.86 ± 2.32 mm and 9.39 ± 2.06 mm with letrozole and CC, respectively (P=0.751). Cumulative ovulation rates were 86.7% and 85.2% with letrozole and CC, respectively (P=0.751). Pregnancy was achieved in 42.2% of women in the letrozole group and 20.0% of women in the CC group (P=0.04). Monofollicular development was seen in 68.4% of ovulatory cycles in the letrozole group compared with 44.8% in the CC group (P=0.000). Mean time to achieve pregnancy was significantly shorter (log rank P=0.042) with letrozole (9.65 weeks) than with CC (11.07 weeks). CONCLUSION: Letrozole is a better alternative for ovulation induction in anovulatory women with PCOS as pregnancy rates are higher, time to pregnancy is shorter, and chances of multiple pregnancy are less because of high monofollicular growth.

Endometrial thickness after ovarian stimulation with gonadotropin, clomiphene, or letrozole for unexplained infertility, and association with treatment outcomes.

OBJECTIVE: To study the association of endometrial thickness (EMT) with live birth rates (LBR) in ovarian stimulation with intrauterine insemination (OS-IUI) treatments for unexplained infertility. DESIGN: Prospective cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial. SETTING: Multicenter randomized controlled trial. PATIENTS: A total of 868 couples with unexplained infertility (n=2,459 cycles). INTERVENTIONS: OS-IUI treatment cycles (n = 2,459) as part of the AMIGOS clinical trial. MAIN OUTCOME MEASURES: Live birth rates; unadjusted and adjusted risk ratios (RR) for live birth by EMT category, calculated using generalized estimating equations. RESULTS: The overall mean EMT on day of human chorionic gonadotropin administration in cycles with a live birth was significantly greater than in those without. Compared to the referent EMT group of 9 to 12 mm, the unadjusted RR for live birth for the EMT groups of ≤5 and 6-8 were 0.48 and 0.92, respectively. The test for trend indicated evidence of decreasing LBR with decreasing EMT. After adjustment for ovarian stimulation medication, a linear trend was no longer supported. Stratified analyses revealed no differences in associations by treatment group. CONCLUSIONS: In OS-IUI for unexplained infertility, higher LBR are observed with increasing EMT; however, EMT is not significantly associated with LBR when adjusted for OS treatment type. Appreciable LBR are seen at all EMT, even those of ≤5 mm, suggesting that OS-IUI cycles should not be canceled for thin endometrium. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862.