Extending letrozole treatment duration is effective in inducing ovulation in women with polycystic ovary syndrome and letrozole resistance.

OBJECTIVE: To evaluate whether extending letrozole (LE) treatment duration could induce ovulation in women with polycystic ovary syndrome (PCOS) who previously failed to ovulate after a 5-day regimen of 5 mg LE daily for at least 1 ovulation induction cycle, defined as "LE resistance". DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENT(S): A total of 69 women with PCOS and LE resistance were included. INTERVENTION(S): The duration of LE treatment was increased in a stepwise manner (named as "2-step extended LE regimen"): a 7-day regimen of 5 mg LE daily was prescribed in the first ovulation induction cycle, and if ovulation did not occur, a 10-day regimen was prescribed in the subsequent cycle. MAIN OUTCOME MEASURE(S): Ovulation rate was the primary outcome. Clinical pregnancy rate, live birth rate, spontaneous ovulation rate, and ovarian hyperstimulation syndrome rate were the secondary outcomes. RESULT(S): Of the 69 patients, 48 ovulated after the 7-day and 16 after the 10-day regimen. Overall, the cumulative ovulation rate reached 92.75% (64/69) after the 2-step extended LE regimen, with a cumulative clinical pregnancy rate of 31.88% (22/69) and a cumulative live birth rate of 24.63% (17/69). All patients ovulated spontaneously without exogenous trigger agents and none experienced ovarian hyperstimulation syndrome. CONCLUSION(S): Extending LE treatment duration is a feasible method for inducing ovulation in women with PCOS and LE resistance.

The Key Role of Peroxisomes in Follicular Growth, Oocyte Maturation, Ovulation, and Steroid Biosynthesis.

The absence of peroxisomes can cause disease in the human reproductive system, including the ovaries. The available peroxisomal gene-knockout female mouse models, which exhibit pathological changes in the ovary and reduced fertility, are listed in this review. Our review article provides the first systematic presentation of peroxisomal regulation and its possible functions in the ovary. Our immunofluorescence results reveal that peroxisomes are present in all cell types in the ovary; however, peroxisomes exhibit different numerical abundances and strong heterogeneity in their protein composition among distinct ovarian cell types. The peroxisomal compartment is strongly altered during follicular development and during oocyte maturation, which suggests that peroxisomes play protective roles in oocytes against oxidative stress and lipotoxicity during ovulation and in the survival of oocytes before conception. In addition, the peroxisomal compartment is involved in steroid synthesis, and peroxisomal dysfunction leads to disorder in the sexual hormone production process. However, an understanding of the cellular and molecular mechanisms underlying these physiological and pathological processes is lacking. To date, no effective treatment for peroxisome-related disease has been developed, and only supportive methods are available. Thus, further investigation is needed to resolve peroxisome deficiency in the ovary and eventually promote female fertility.

UHPLC-MS-MS analysis of oxylipins metabolomics components of follicular fluid in infertile individuals with diminished ovarian reserve.

BACKGROUND: Diminished ovarian reserve (DOR) refers to a decrease in the number and quality of oocytes in the ovary, which results in a lack of sex hormones and a decline of fertility in women. DOR can potentially progress to premature ovarian failure (POF), which has a negative impact on women's quality of life and is a major cause of female infertility. Oxidative stress is a major contributor to fertility decrease in DOR patients, affecting the follicular microenvironment, oocyte maturation, fertilization, and embryo development. Understanding intracellular signal transduction can be achieved by defining specific oxidized lipid components in follicular fluid (FF) of DOR infertile patients. METHODS: The oxylipins metabolic signatures in the FF of DOR patients and females with normal ovarian reserve (NOR) enrolled for the in vitro fertilization (IVF) cycle were analyzed using UHPLC-MS-MS technology. Principal component analysis (PCA) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) were used to analyze the derived metabolomic profiles. Pathway enrichment analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaboAnalyst databases. Furthermore, the Spearman rank correlation coefficient was used to determine the correlation between age, FSH, AMH, AFC, oocytes retrieved, MII oocytes, fertilization, high-quality embryos, and the concentration of differential oxidized lipid metabolites in FF. RESULTS: Fifteen oxylipins metabolites were found to be lower in the FF of DOR patients than those in the NOR group, including ±20-HDoHE, ±5-iso PGF2α-VI, 12S-HHTrE, 15-deoxy-Δ12,14-PGJ2, 1a,1b-dihomo PGE2, 1a,1b-dihomo PGF2α, 20-COOH-AA, 20-HETE, 8S,15S-DiHETE, PGA2, PGD2, PGE1, PGF1α, PGF2α, and PGJ2. The pathway enrichment analysis revealed that the 15 differentially oxidized lipid metabolites were closely related to the arachidonic acid metabolic pathway. Correlation analysis revealed that the concentration of 8 different oxidized lipid metabolites in FF was negatively correlated to FSH and positively correlated with AFC. AMH, the number of oocytes retrieved, MII oocytes and fertilization, were all positively correlated with 9 different oxidized lipid metabolites, but only one metabolite was positively correlated with the number of high-quality embryos. CONCLUSIONS: Metabolomic analysis of FF revealed that oxylipins metabolism disorders were closely related to ovarian reserve function. Among these oxylipins metabolites, arachidonic acid metabolism undergoes significant changes that may be related to oocyte development, resulting in decreased fertility in DOR patients. TRIAL REGISTRATION: ChiCTR, ChiCTR2000038182 , Registered 12 September 2020-Retrospectively registered.

Premature ovarian insufficiency patients with viable embryos derived from autologous oocytes through repeated oocyte retrievals could obtain reasonable cumulative pregnancy outcomes following frozen-embryo transfer.

BACKGROUND: Women with premature ovarian insufficiency (POI) are often discouraged from using autologous oocytes; however, some patients have a strong desire to be genetically linked to their offspring. In the present study, we aimed to estimate cumulative pregnancy outcomes following frozen-embryo transfer (FET) in POI patients who could obtain viable embryos with their eggs during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments. METHODS: In this matched-retrospective cohort study, only patients undergoing IVF/ICSI treatments with a freeze-all strategy were screened, and 103 POI patients were matched with 515 normal controls in terms of the same number of viable embryos obtained at the same age. The primary outcome was the cumulative clinical pregnancy rate (CCPR) following FET per patient. RESULTS: Patients with POI and normal ovarian reserve had comparable CCPRs of 62.14% (64/103) and 65.24% (336/515), respectively (P=0.547), and no statistical difference was found in the cumulative live-birth rate (CLBR) between the study group (43.69%) and the control group (53.01%). Based on binary logistic regression, the CCPR and CLBR showed no association with the type of ovarian function (POI or normal ovarian reserve). The number of embryos per transfer and the sum of all viable embryos per patient were positively associated with the CCPR and CLBR. The clinical pregnancy rate (CPR) per FET cycle was 38.17% for the study group and 52.1% for the control group, while the CPRs per oocyte retrieval cycle in the 2 groups were 11.25% and 69.9%, respectively, and both were statistically different (P<0.05). Moreover, POI patients had a lower implantation rate (27.8% vs. 37.94%) and a higher early miscarriage rate per transfer (26.76% vs. 15%) than patients in the control group (P<0.05). CONCLUSIONS: Cumulative pregnancy outcomes following FET were reasonable for POI patients using viable embryos derived from autologous oocytes through repeated oocyte retrievals.

Progesterone protocol versus gonadotropin-releasing hormone antagonist protocol in women with polycystic ovarian syndrome undergoing in vitro fertilization treatments with frozen-thawed embryo transfer: a prospective randomized controlled trial.

BACKGROUND: Exogenous progestational agents have recently been introduced as an alternative pituitary modulator for the prevention of premature luteinizing hormone (LH) surges during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments. There is increasing evidence that frozen-embryo transfer (FET) is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS) in women with polycystic ovary syndrome (PCOS). Herein, we compared the clinical outcomes of the progesterone protocol with the gonadotropin releasing hormone antagonist (GnRH-ant) protocol in PCOS patients with a ''freeze-all'' strategy. METHODS: In this prospective single-central randomized controlled trial, a total of 120 PCOS patients undergoing their first IVF/ICSI treatment were randomly assigned to receive the progesterone protocol (study group) or GnRH-ant protocol (control group). The main outcome was the number of oocytes retrieved. Secondary outcomes included the incidence of premature LH rise/surge, the number of viable embryos, and pregnancy outcomes. RESULTS: The number of retrieved oocytes (14.65±7.64 versus 12.8±8.57) and viable embryos (5.38±3.54 versus 5.03±3.92) in the study group were comparable to those in the control group (P>0.05). Similarly, no between-group differences were found in the number of mature oocytes, fertilized oocytes, cleaved embryos, and the viable embryo rate per oocyte retrieved (P>0.05). However, the oocyte retrieval rate (66.02%±19.63% versus 54.38%±26.39%) and fertilization rate (78.12%±18.41% versus 62.76%±23.32%) in the study group were significantly more than that in the control group (P<0.05). The mean serum LH value on day 6-7 was lower in the study group than that in the control group (7.47±0.97 versus 3.98±0.52 IU/L, P<0.05), and the incidence of premature LH rise was higher in the study group than in the control group, although no patients experienced premature LH surge. The clinical pregnancy rate [58.82% vs. 57.32%, RR 0.94 (95% CI: 0.508, 1.738), P>0.05] and implantation rate [43.21% vs. 41.4%, RR 0.929 (95% CI: 0.595, 1.448), P>0.05] were also similar between the two groups. CONCLUSIONS: The progesterone protocol is comparable with the GnRH-ant protocol regarding oocyte/embryo yields and the probability of clinical pregnancy in PCOS patients, but the two regimens were distinct in the regulation of pituitary LH secretion. TRIAL REGISTRATION NUMBER: Chictr.org.cn: ChiCTR-IOR-15006633.

Embryo incubation by time-lapse systems versus conventional incubators in Chinese women with diminished ovarian reserve undergoing IVF/ICSI: a study protocol for a randomised controlled trial.

INTRODUCTION: The time-lapse imaging system (TLS) is a newly developed non-invasive embryo assessment system. Compared with conventional incubators, a TLS provides stable culture conditions and consistent observations of embryo development, thereby potentially improving embryo quality and selection of the best quality embryo. Although TLSs have been routinely used in many in vitro fertilisation (IVF) centres globally, there is insufficient evidence to indicate that TLSs result in higher cumulative live birth rates over conventional incubators. The purpose of this study is to compare the cumulative live birth rates and safety including miscarriage in infertile patients with diminished ovarian reserve (DOR) from both TLSs and conventional incubators. METHODS AND ANALYSIS: This study is a double-blind randomised controlled clinical trial (1:1 treatment ratio of TLSs vs conventional incubator). A total of 730 patients with DOR undergoing the first or second cycle of IVF or intracytoplasmic sperm injection (ICSI) will be enrolled and randomised into two parallel groups. Participants will undergo embryo culture in the TLSs (group A) or the conventional incubators (group B), respectively. Embryos are selected for transfer in both groups by the morphological characteristics. The embryo selection algorithm software is not used in the TLSs. The primary outcome is the cumulative live birth rate of the trial IVF/ICSI cycle within 12 months after randomisation. This study is powered to detect an absolute difference of 10% (35% vs 25%) at the significance level of 0.05% and 80% statistical power based on a two-sided test. ETHICS AND DISSEMINATION: This trial has been approved by the Institutional Ethical Committee of Shanghai First Maternity and Infant Hospital (KS1958). All participants in the trial will provide written informed consent. The study will be conducted according to the principles outlined in the Declaration of Helsinki and its amendments. Results of this study will be disseminated in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR1900027746).

Late Follicular Phase Ovarian Stimulation Without Exogenous Pituitary Modulators.

Introduction: A gonadotropin-releasing hormone antagonist is the most common modulator used to prevent the premature luteinizing hormone (LH) surge when ovarian stimulation was initiated in the late follicular phase. We aimed in this study to evaluate the feasibility of performing ovarian stimulation in the late follicular phase without the use of exogenous pituitary modulators. Methods: Data were retrospectively collected from 404 normo-ovulatory patients who underwent their first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment in our department. One hundred sixteen subjects in the study group received ovarian stimulation when a dominant follicular diameter of ≥ 10 mm was confirmed by transvaginal ultrasonography after menstrual cycle day 6, which entailed a daily injection of gonadotropin until the trigger day, while 288 subjects in the control group received ovarian stimulation in the early follicular phase under a progesterone protocol. The primary outcome was the number of mature oocytes. Results: There was no statistical difference in the number of mature oocytes between the two groups (9.67 ± 5.33 in the study group vs. 9.38 ± 5.15 in the control group, P = 0.693). No secondary LH surges in the study group and no premature LH surges in the control group were found during ovarian stimulation. The good-quality embryo rate per oocyte retrieved showed no significant difference between the two groups (35.22 vs. 35.91%, P = 0.665). The clinical pregnancy rate per transfer was 54.55% in the study group and 56.48% in the control group (P = 0.718), and the implantation rate was similar between the two groups (36.94 vs. 37.77%, P = 0.829). Conclusions: Our study revealed that late follicular phase ovarian stimulation could be performed without an exogenous pituitary modulator.

Efficacy of Different Progestins in Women With Advanced Endometriosis Undergoing Controlled Ovarian Hyperstimulation for in vitro Fertilization-A Single-Center Non-inferiority Randomized Controlled Trial.

Object: Is it possible to use different progestins cotreatment with human menopausal gonadotrophin (hMG) in women with advanced endometriosis but normal ovulation during controlled ovarian hyperstimulation (COH) in vitro fertilization (IVF)? Whether different progestins treatments can be an alternative choice for women with severe endometriosis in considering IVF/ICSI treatment remains unknown? Design: Non-inferiority randomized clinical trial. Setting: Tertiary-care academic medical center. Population: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI between May 2016 and March 2017. Methods: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI were randomized to: medroxyprogesterone acetate +hMG; dydrogesterone +hMG; and progesterone +hMG. Ovulation was induced with a gonadotropin-releasing hormone agonist (GnRH-a) and chorionic gonadotropin (hCG). Viable embryos were cryopreserved for later transfer. Main Outcome Measures: The primary endpoint outcome was the number of oocytes retrieved. Secondary indicators included the incidence of a premature surge in luteinizing hormone (LH), the number of viable embryos, and clinical pregnancy outcomes. Results: The number of oocytes retrieved was higher in the medroxyprogesterone acetate +hMG group than the two other groups (9.3 ± 5.7 vs. 8.0 ± 4.5 vs. 7.8 ± 5.2, P = 0.021). LH levels were suppressed after a 6-day progestin treatment in the medroxyprogesterone acetate +hMG and dydrogesterone +hMG groups, but there was a rebound of LH values in the progesterone +hMG group. No premature LH surge and ovarian hyperstimulation syndrome (OHSS) occurred. No significant differences among the three groups were observed in fertilization and pregnancy outcomes. Conclusion: It is mandatory to point out that our conclusions are valid for patients with ovarian advanced endometriosis but normal ovarian functions. These results suggest three different progestins protocols are equivalent in terms of pregnancy outcomes for women with advanced endometriosis. PPOS protocol can be an alternative choice for women with severe endometriosis and normal ovarian reserve in IVF/ICSI treatment. These methods could be tested with other populations of women with endometriosis. Clinical Trial Registration: www.ClinicalTrials.gov, identifier:ChiCTR-OIN-16008529. Trial registration date: 2014-05-25. Date of first patient enrollment: May 2016.

Pregnancy and neonatal outcomes of artificial oocyte activation in patients undergoing frozen-thawed embryo transfer: a 6-year population-based retrospective study.

PURPOSE: To evaluate the impact of artificial oocyte activation (AOA) in pregnancy and neonatal outcomes in infertile patients undergoing cryopreserved embryo transfer. METHOD: This retrospective study included 5686 patients' transferred embryos from routine intracytoplasmic sperm injection (ICSI) and 194 patients' transferred embryos from ICSI combined with AOA (ICSI-AOA) from January 2011 to December 2016. Pregnancy and neonatal outcomes of couples undergoing routine ICSI or ICSI-AOA were analyzed before and after propensity score matching. Artificial oocyte activation was performed with ionomycin. RESULTS: The pregnancy outcomes showed no significant difference in the rates of biochemical pregnancy, clinical pregnancy, implantation, miscarriage, ectopic pregnancy, multiple pregnancy, and live births between the routine ICSI and ICSI-AOA groups before and after propensity score matching, respectively. The assessment of neonatal outcomes showed no statistically significant differences in the birth defect rate, birth weight, gestational age, preterm birth rate, early-neonatal death rate, and fetal sex ratio between the two groups, and similar results were also observed in the two matched cohorts. CONCLUSION: Artificial oocyte activation with ionomycin does not adversely affect pregnancy and neonatal outcomes in patients undergoing frozen-thawed embryo transfer, which is beneficial to clinicians counseling patients on the risks of artificial oocyte activation.

Evaluation of Ovarian Stimulation Initiated From the Late Follicular Phase Using Human Menopausal Gonadotropin Alone in Normal-Ovulatory Women for Treatment of Infertility: A Retrospective Cohort Study.

Objective: To investigate the feasibility of ovarian stimulation initiated in the late follicular phase using human menopausal gonadotropin (hMG) alone in ovulatory patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments by comparison with that of the short gonadotropin-releasing hormone agonist (GnRH-a) protocol in terms of ovarian response, embryological characteristics, and pregnancy outcomes following frozen-thawed embryo transfer (FET) cycles. Design: Retrospective cohort study. Setting: A university-affiliated tertiary hospital. Patients: 135 infertile women undergoing their first IVF/ICSI treatment with the freeze-all strategy. Interventions: In the study group, ovarian stimulation was initiated in the late follicular phase using hMG alone, with the confirmation of dominant follicular diameter ≥ 14 mm, while a short GnRH-a protocol was adopted in the control group. Oocyte maturation was induced by human chorionic gonadotropin in both groups. All good quality embryos were cryopreserved for later transfer. Main Outcome Measures: The primary outcome was the incidence of premature luteinizing hormone (LH) surge. Secondary outcomes were the number of mature oocytes retrieved, good-quality embryo rate per oocyte retrieved, and clinical pregnancy rate following FET cycles. Results: No premature LH surge was detected during ovarian stimulation in the study group. There was no statistically significant difference in the number of mature oocytes between the two groups (10 ± 5.6 in the study group vs. 8.51 ± 5.03 in the control group, P = 0.11). Good-quality embryo rate per oocyte retrieved did not differ between the two groups: 40.18% (313/779) vs. 36.67% (253/690), P = 0.167. Clinical pregnancy rate per transfer following FET was comparable between the two groups (61.33 vs. 52.5%, P = 0.267). Conclusions: Our study shows that ovarian stimulation initiated in the late follicular phase using hMG alone may be a feasible alternative for normal-ovulatory women undergoing IVF/ICSI treatment with the freeze-all strategy.

Randomized, Controlled Pilot Study of Low-Dose Human Chorionic Gonadotropin Administration Beginning From the Early Follicular Phase for Women With Polycystic Ovarian Syndrome Undergoing Ovarian Stimulation Using the Progesterone Protocol.

Purpose: To illustrate whether low-dose human chorionic gonadotropin (hCG) administration during the early follicular phase could reduce the number of large preovulatory follicles in women with polycystic ovarian syndrome (PCOS) undergoing ovarian stimulation using the progesterone protocol. Methods: We performed a randomized, controlled pilot trial at a university-affiliated tertiary hospital. A total of 40 infertile women undergoing their first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment with the freeze-all strategy were included. Human menopausal gonadotropin (hMG) and progesterone soft capsule 100 mg/d were added simultaneously beginning from menstrual cycle day 3 for all participants. Low-dose hCG (200 IU) was injected every 3 days in the study group from the first day of ovarian stimulation until trigger. The primary outcome was the number of large preovulatory follicles. Secondary outcomes included the incidence of ovarian hyperstimulation syndrome (OHSS); the number of oocytes retrieved, mature oocytes, and good-quality embryos; and clinical results after frozen-thawed embryo transfer (FET) cycles. Results: The study group had slightly more large preovulatory follicles than the control group (17.75 ± 10 vs. 13.2 ± 5.34; P > 0.05). None of the participants experienced severe OHSS. There were no statistically significant differences in the number of oocytes retrieved (15.9 ± 8.46 vs. 15.75 ± 6.96), mature oocytes (13.55 ± 6.56 vs. 13.4 ± 6.34), and good-quality embryos (5.5 ± 3.41 vs. 4.9 ± 2.99) between the two groups (P > 0.05). Clinical pregnancy rates (65.52 vs. 41.94%; P = 0.067) and live birth rates (48.28 vs. 35.48%; P = 0.315) per transfer following FET of the study group were higher than those of the control group, but without statistical significance. Conclusions: Administration of low-dose hCG from the early follicular phase for PCOS patients undergoing ovarian stimulation with progesterone protocol may lead to slightly more early preovulatory follicles and marginally, but not significantly, higher clinical pregnancy rates. A continuous trial should be performed to explore the effects of supplementation with different doses of hCG from the start of ovarian stimulation in PCOS patients using the progesterone protocol. Clinical Trial Registration: Chictr.org.cn, identifier: ChiCTR-IOR-15007165.

Decrease in preovulatory serum estradiol is a valuable marker for predicting premature ovulation in natural/unstimulated in vitro fertilization cycle.

BACKGROUND: Premature ovulation occurs at a high rate in natural-cycle in vitro fertilization (IVF), and cycle cancellation further hampers the overall efficiency of the procedure. While lower levels of estradiol (E2) are observed in preovulatory follicles, it is unclear whether declines in E2 can be used as an effective marker of premature ovulation. METHODS: This retrospective analysis includes 801 natural/unstimulated IVF/ICSI cycles undergoing scheduled ovum pick-up (OPU) and 153 natural/unstimulated IVF/ICSI cycles undergoing emergency OPU at a university IVF center from May 2014 to February 2017. RESULTS: Among the 801 IVF/ICSI cycles undergoing scheduled OPU, preovulatory E2 levels increased by more than 10% in 403 (50.31%) cycles of the sample (Group A), while 192 (23.97%) cycles experienced a plateau (increased or decreased by 10%; Group B), and 206 (25.72%) cycles decreased by more than 10% (Group C). Group C had more patients who experienced premature LH surges, premature ovulation, as well as the fewest oocytes retrieved, frozen embryos, and top-quality embryos. A multivariate logistic regression analysis indicated that premature ovulation was associated with preovulatory E2/-1E2 ratio and premature LH surge. Moreover, preovulatory E2/-1E2 ratio served as a valuable marker for differentiating premature ovulation, with an AUC (area under the receiver operating curve) of 0.708 and 0.772 in cycles with premature LH surges and cycles without premature LH surges, respectively. Emergency OPU resulted in a significantly decreased rate of premature ovulation and increased number of frozen embryos. CONCLUSION: Decreases in preovulatory serum E2 was a valuable marker for premature ovulation in natural/unstimulated IVF cycle. Emergency OPU based on the preovulatory E2/-1E2 ratio decreased the rate of premature ovulation in cycles that experienced E2 decreases.

Elevated basal luteinizing hormone does not impair the outcome of human menopausal gonadotropin and medroxyprogesterone acetate treatment cycles.

The potential effects of high basal luteinizing hormone (LH) levels on human reproduction were controversial. To demonstrate the effects of elevated basal LH levels on the outcome of patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles, we performed a retrospective data analysis of 1011 polycystic ovarian syndrome (PCOS) patients treated with human menopausal gonadotropin and medroxyprogesterone acetate (hMG + MPA) protocol at our center between Nov. 2013 and Jun. 2017. PCOS patients with elevated basal LH levels had significantly higher LH exposure during the stimulation period. The group with LH ≥ 10 mIU/mL showed a lower mean total hMG dose used but higher numbers of oocytes retrieved, metaphase II oocytes, embryos and top-quality embryos developed than the groups with lower basal LH levels. Moreover, partial correlation analysis showed that the basal LH level was negatively correlated with the total hMG dose but positively correlated with the numbers of oocytes retrieved, metaphase II oocytes, embryos, and top-quality embryos. There were no significant differences in the rates of oocyte retrieval, fertilization, implantation, clinical pregnancy and miscarriage between the groups based on frozen embryo transfer (FET). We concluded that elevated basal LH level does not impair the final outcome of hMG + MPA-treated IVF/ICSI cycles in PCOS women.

Comparison of neonatal outcomes and live-birth defects after progestin-primed ovarian stimulation versus conventional ovarian stimulation for in vitro fertilization: A large retrospective cohort study.

Progestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation regimen for in vitro fertilization (IVF), with the advantages of an oral administration route and more control over preovulatory luteinizing hormone (LH) levels. Assessing the safety of this novel regimen is an important premise for its routine practice.We conducted a large retrospective cohort study for infants born between August 2014 and April 2017 from IVF and embryo transfer cycles after either PPOS and the conventional gonadotropin-releasing hormone-agonist (GnRH-a) short protocol at our center. Around 1589 live-born infants were finally enrolled, corresponding to 1258 frozen-thawed (FET) cycles, which led to 855 live-born infants from PPOS (659 FET cycles) and 734 live-born infants from the short protocol (599 FET cycles).Birth characteristics regarding gestational age, birth weight and length, infant sex, and early neonatal death were comparable between the 2 groups. The incidence of live-birth defects in the PPOS group (1.52%) was similar to that in the short protocol group (1.63%) and was not statistically significant. For birth defects, the risk significantly increased for multiple births, and the adjusted odds ratio was 3.14 (95% confidence interval [CI]: 1.25-7.88). No associations were found between congenital birth defects and maternal age, body mass index (BMI), the duration of infertility, method of insemination, infant sex, embryo stage at transfer, the number of embryos transferred or ovarian stimulation regimen.Our study shows that the neonatal outcomes and risk of congenital malformations were similar between the PPOS and conventional GnRH-a short protocol. However, multiple pregnancy led to a higher likelihood of birth defects.

Lipidomic Components Alterations of Human Follicular Fluid Reveal the Relevance of Improving Clinical Outcomes in Women Using Progestin-Primed Ovarian Stimulation Compared to Short-Term Protocol.

BACKGROUND Increasing the success rate of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) is a duty of clinicians that has made many seek a variety of protocols. This study was undertaken to use a liquid chromatography-mass spectrometry (LC-MS) to define the alterations of follicular fluid (FF) lipid metabolites in patients undergoing progestin-primed ovarian stimulation (PPOS) compared with short-term protocol, revealing potential correlations between the differentially expressed lipids and ameliorative clinical outcomes. MATERIAL AND METHODS Ninety-three infertile women undergoing IVF/ICSI treatment with PPOS (n=62) or a short-term protocol (n=31) were prospectively enrolled in a randomized controlled trial. FF samples were obtained from dominant follicles at the time of oocyte retrieval. Lipid metabolism profiles were analyzed using LC-MS. RESULTS Twelve lipids were found to be higher in patients treated with the PPOS protocol than in those receiving the short-term protocol, including triacylglycerols (TAG-34: 1+NH4, TAG-58: 0+NH4, TAG-64: 3+NH4, and TAG-64: 8+NH4), diacylglycerol DAG-38: 6+NH4, phosphatidylglycerols (PG-26: 0, PG-30: 2, and PG-40: 5), phosphatidylethanolamine PE-32: 2, lysophosphatidylethanolamine LPE-14: 1, lysophosphatidylinositol LPI-12: 0, and lysophosphatidylcholine LPC-16: 0. CONCLUSIONS Our data demonstrate that the PPOS protocol increases the levels of 12 lipids in FF, which reveals a strong association between the differentially elevated lipids and better IVF/ICSI outcomes.

Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility.

Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when deleted in vivo. In clinical practice, some infertility case subjects suffer from recurrent failure of in vitro fertilization and intracytoplasmic sperm injection attempts due to fertilization failure, but the genetic basis of fertilization failure in humans remains largely unknown. Wee2 is a key oocyte-specific kinase involved in the control of meiotic arrest in mice, but WEE2 has not been associated with any diseases in humans. In this study, we identified homozygous mutations in WEE2 that are responsible for fertilization failure in humans. All four independent affected individuals had homozygous loss-of-function missense mutations or homozygous frameshift protein-truncating mutations, and the phenotype of fertilization failure was shown to follow a Mendelian recessive inheritance pattern. All four mutations significantly decreased the amount of WEE2 protein in vitro and in affected individuals' oocytes in vivo, and they all led to abnormal serine phosphorylation of WEE2 and reduced tyrosine 15 phosphorylation of Cdc2 in vitro. In addition, injection of WEE2 cRNA into affected individuals' oocytes rescued the fertilization failure phenotype and led to the formation of blastocysts in vitro. This work presents a novel gene responsible for human fertilization failure and has implications for future therapeutic treatments for infertility cases.

The role of combining medroxyprogesterone 17-acetate with human menopausal gonadotropin in mouse ovarian follicular development.

Medroxyprogesterone 17-acetate (MPA) combined with human menopausal gonadotropin (hMG) has been effectively used for ovarian stimulation in clinical practice. However, the molecular mechanism of MPA + hMG treatment in follicular development is poorly described. Here we performed a study to investigate the impact of MPA + hMG on ovarian stimulation utilizing a mouse model in vivo. Forty female BALB/C mice were randomly divided into four groups of 10 each and treated during ciestrus stage and continued for 5 days: control group, MPA group, hMG group, and MPA + hMG group. Morphological and molecular biology methods were used for detecting serum hormones and ovarian function. MPA + hMG group exhibited increasing follicle stimulating hormone (FSH), antral follicle, FSH receptor (FSHR) and phosphorylated mammal target of rapamycin (p-mTOR), and decreasing luteinizing hormone (LH), estradiol (E2), progesterone (P), corpus luteum, phosphoinositide 3-kinase (PI3K), Akt and mTOR compared with control group. In contrast, MPA + hMG group showed reduced FSH, LH, E2, P, corpus luteum, LH receptor (LHR), and activated PI3K,/Akt/mTOR pathway compared with hMG group (P < 0.05). Collectively, these data definitively established that MPA plus hMG may modulate the hormone, hormone receptor and PI3K/Akt/mTOR signaling pathway to influence follicular development in the mouse ovary. Our study provides overwhelming support for MPA + hMG as an effective treatment for infertility in women.

The effect of human chorionic gonadotrophin contained in human menopausal gonadotropin on the clinical outcomes during progestin-primed ovarian stimulation.

Progestin-primed ovarian stimulation (PPOS) protocol has recently been demonstrated to be an novel regimen for preventing premature LH surges during controlled ovarian hyperstimulation (COH) in combination with frozen-thawed embryo transfer (FET). Our prospective controlled study was to explore the effect of human chorionic gonadotropin (hCG) contained in human menopausal gonadotropin (hMG) on the clinical outcomes in normalovulatory women undergoing COH with PPOS. A total of 180 patients were allocated into three groups according to the gonadotropin (Gn) used: group A (human menopausal gonadotropin, hMG-A), group B (hMG-B) or group C (follicle stimulating hormone, FSH). The primary outcome measured was the number of oocytes retrieved. The number of oocytes retrieved in group A B C was 10.72±5.78 11.33±5.19and13.38±8.97, respectively, with no statistic significance (p>0.05). Other embryological indicators were also similar (p>0.05). The concentration of serum and urinary ß-hCG on the trigger day in group A and B were not associated with embryo results (p>0.05). There was no significant differences in the clinical pregnancy rate (41.67% vs. 51.56% vs. 39.51%, p>0.05) and implantation rate (31.58%vs. 34.75%vs.25.33%) after FET among the three groups. Thus the clinical characteristics were not affected by the hCG contained in hMG in normalovulatory women treated with PPOS.

Use of medroxyprogesterone acetate in women with ovarian endometriosis undergoing controlled ovarian hyperstimulation for in vitro fertilization.

This study investigated the use of medroxyprogesterone acetate (MPA) or a short protocol for controlled ovarian hyperstimulation (COH) in patients with advanced endometriosis who have normal ovarian function, and to compare cycle characteristics and pregnancy outcomes after frozen-thawed embryo transfer (FET). This was a retrospective case-control study of 244 patients with advanced endometriosis undering COH. The patients were allocated to three groups: the surgery group with MPA COH (62 patients, 71 IVF/ICSI cycles, 78 FET cycles); the aspiration group with MPA COH (85 patients had ovarian "chocolate" cysts (>3 cm) aspirated, 90 IVF/ICSI cycles, 76 FET cycles); and the short protocol group (97 patients, 101 IVF/ICSI cycles, 51 FET cycles). The results showed that higher rates of mature oocyte, D3 high quality embryo, hMG dose were observed in the two study groups using MPA compared with the short protocol. The number of >10-14 mm follicles on the trigger day, D3 top-quality embryos, viable embryos, rates of cancellation, fertilization, implantation, pregnancy outcomes were similar among the three groups. The oocytes, embryos, and pregnancy outcomes were not influenced by endometrioma surgery or presence of endometrioma. MPA COH could be effective for women with ovarian advanced endometriosis who had normal ovarian function.