[Analysis of Risk Factors for Recurrent Pregnancy Loss in Patients Undergoing in vitro Fertilization-Embryo Transfer]. / 体外受精-èƒšèƒŽç§»æ¤æ‚£è€ ä¸­åå¤å¦Šå¨ ä¸¢å¤±çš„å±é™©å› ç´ åˆ†æž.

Objective: Recurrent pregnancy loss (RPL) presents a formidable challenge for individuals undergoing in vitro fertilization-embryo transfer (IVF-ET), forming both a clinical dilemma and a focal point for scientific inquiry. This study endeavors to investigate the intricate interplay between clinical features, such as age, body mass index (BMI), and waist-to-hip ratio (WHR), and routine laboratory parameters, including sex hormones, blood composition, liver and thyroid functions, thyroid antibodies, and coagulation indicators, in RPL patients undergoing IVF-ET. By meticulously analyzing these variables, we aim to uncover the latent risk factors predisposing individuals to RPL. Identifying potential factors such as advanced maternal age, obesity, and insulin resistance will provide clinicians with vital insights and empirical evidence to strengthen preventive strategies aimed at reducing miscarriage recurrence. Methods: This retrospective case-controlled study included RPL patients who underwent IVF-ET treatment at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, between January 2012 and March 2021 as the case cohort, compared with women receiving assisted reproductive treatment due to male infertility as the control cohort. The fasting peripheral blood was collected 5 days before the first menstrual cycle at least 12 weeks after the last abortion. The clinical characteristics and relevant laboratory indexes of the two groups were compared. Employing both univariate and multivariate logistic regression analyses, we sought to unearth potential high-risk factors underlying RPL. Additionally, a linear trend analysis was conducted to assess the linear relationship between total testosterone (TT) levels and the number of miscarriages. Results: In contrast to the control cohort, the RPL cohort exhibited significant increases in age, BMI, and WHR (P<0.05). Notably, TT levels were markedly lower in the RPL cohort (P=0.022), while no significant differences were observed between the two groups concerning basal follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, prolactin levels, and anti-Müllerian hormone levels (P>0.05). Moreover, fasting insulin (FINS) levels and HOMA-IR index were notably elevated in the RPL cohort relative to the control cohort (P<0.001), although no significant differences were observed in fasting blood glucose levels (P>0.05). Furthermore, the neutrophil (NEU) count and NEU-to-lymphocyte ratio were notably higher in the RPL cohort (P<0.01). Univariate logistic regression analysis identified several factors, including age≥35 years old, BMI≥25 kg/m2, WHR>0.8, FINS>10 mU/L, HOMA-IR>2.14, NEU count>6.3×109 L－1, and an elevated NEU/lymphocyte ratio (NLR), as significantly increasing the risk of RPL (P<0.05). Although TT levels were within the normal range for both cohorts, higher TT levels were associated with a diminished RPL risk (odds ratio [OR]=0.67, 95% confidence interval [CI]: 0.510-0.890, P=0.005). After adjustments for confounding factors, age≥35 years old (OR=1.91, 95% CI: 1.06-3.43), WHR>0.8 (OR=2.30, 95% CI: 1.26-4.19), and FINS>10 mU/L (OR=4.50, 95% CI: 1.30-15.56) emerged as potent risk factors for RPL (P<0.05). Conversely, higher TT levels were associated with a reduced RPL risk (OR=0.59, 95% CI: 0.38-0.93, P=0.023). Furthermore, the linear trend analysis unveiled a discernible linear association between TT levels and the number of miscarriages (P trend=0.003), indicating a declining trend in TT levels with escalating miscarriage occurrences. Conclusion: In patients undergoing IVF-ET, advanced maternal age, lower TT levels, increased WHR, and elevated FINS levels emerged as potent risk factors for RPL. These findings provide clinicians with valuable insights and facilitate the identification of patients who are at high risks and the formulation of preventive strategies to reduce the recurrence of miscarriages.

Prevalence of polycystic ovary syndrome under NIH criteria among the tenth-grade Chinese schoolgirls in Guangzhou area: a cross-sectional epidemiological survey.

BACKGROUND: Polycystic ovary syndrome (PCOS) is currently considered to have a peri-adolescence onset and continuously influence the reproductive and metabolic health of the patients, while the diagnostic criteria among adolescent population haven't been universally unified till now. This survey seeks to preliminarily evaluate the prevalence of PCOS in the tenth grade schoolgirls in Guangzhou area under NIH criteria and analyze the clinical features of adolescents with PCOS. METHODS: The cross-sectional epidemiological survey was carried out among the tenth grade schoolgirls in Guangzhou area by the method of cluster sampling. The contents of this survey included the questionnaire, physical exams and serum measurements. Until now, totally 1294 girls underwent this survey and 1095 serum samples were restored. 235 non-hirsute (mFG < 6), postmenarcheally 2-year girls were randomly selected as the control group, among which the cut-off value of biochemical hyperandrogenemia was set accordingly. The prevalence of PCOS among this population was preliminarily evaluated according to the NIH criteria. RESULTS: Along with the increase of gynecological age, the menstruations of girls was becoming more regular and the incidence of oligomenorrhea or amenorrhea was declining. Even among those who were less than 2 years after menarche, those whose menstrual cycle were longer than 90 days accounted for lower than 5%. The 95th percentile of mFG score was 6 among the girls who were < 2 years after menarche, and 5 among the girls who were > 2 years after menarche. Among the 235 healthy girls, the 95th percentile values of Testosterone (T), Free androgen index (FAI) and Androstenedione (A2) were 2.28 nmol/mL, 4.37, and 5.20 nmol/mL respectively. Based on the NIH criteria, the prevalence of PCOS in this survey was 3.86%. The prevalence of adolescent PCOS tend to slightly increase with age and gynecological age, but the difference was not statistically significant. The prevalence of PCOS among obese girls was markedly higher than that in lean girls. CONCLUSION: Based on the NIH criteria, the prevalence of PCOS among the tenth grade schoolgirls in Guangzhou area was 3.86%. The diagnosis of hyperandrogenism among adolescents should also be based on both clinical and biochemical parameters.

Regulating the Inner Helmholtz Plane with a High Donor Additive for Efficient Anode Reversibility in Aqueous Zn-Ion Batteries.

The performance of aqueous Zn ion batteries (AZIBs) is highly dependent on inner Helmholtz plane (IHP) chemistry. Notorious parasitic reactions containing hydrogen evolution reactions (HER) and Zn dendrites both originate from abundant free H2 O and random Zn deposition inside active IHP. Here, we report a universal high donor number (DN) additive pyridine (Py) with only 1 vol. % addition (Py-to-H2 O volume ratio), for regulating molecule distribution inside IHP. Density functional theory (DFT) calculations and molecular dynamics (MD) simulation verify that incorporated Py additive could tailor Zn2+ solvation sheath and exclude H2 O molecules from IHP effectively, which is in favor of preventing H2 O decomposition. Consequently, even at extreme conditions such as high depth of discharge (DOD) of 80 %, the symmetric cell based on Py additive can sustain approximately 500 h long-term stability. This efficient strategy with high DN additives furnishes a promising direction for designing novel electrolytes and promoting the practical application of AZIBs, despite inevitably introducing trace organic additives.

Regulating Interfacial Ion Migration via Wool Keratin Mediated Biogel Electrolyte toward Robust Flexible Zn-Ion Batteries.

Aqueous Zn-ion batteries (ZIBs) have emerged as a promising energy supply for next-generation wearable electronics, yet they are still impeded by the notorious growth of zinc dendrite and uncontrollable side reaction. While the rational design of electrolyte composition or separator decoration can effectively restrain zinc dendrite growth, synchronously regulating the interfacial electrochemical performance by tackling the physical delamination venture between electrode and electrolyte remains a major obstacle for high-performance wearable aqueous ZIB. Herein, a category of hybrid biogel electrolyte containing carrageenan and wool keratin (CWK) is put forward to regulate the interfacial electrochemistry in aqueous ZIB. Systematic electrochemical kinetics analyses and ex situ scanning electrochemical microscopy (SECM) characterizations achieve comprehensive understanding of the keratin enhanced interfacial Zn2+ redox reaction. Thanks to the keratin triggered selective ion permeability, the as-designed CWK hybrid biogel electrolyte manifests a promoted Zn2+ transference number and excellent reversibility of Zn plating/stripping and outstanding Zn utilization (average Coulombic efficiency ≈98%). More impressively, the CWK hybrid biogel electrolyte also demonstrates cathode side-reaction depression and strengthened interfacial adhesion while assembled into a quasi-solid-state flexible ZIB. This work offers a strategy to synchronously solve concurrent challenges for both of Zn anode and cathode toward realistic wearable aqueous ZIB.

Precursor Customized Assembly of Wafer-Scale Polymerized Aniline Thin Films for Ultrasensitive NH3 Detection.

2D conducting polymer thin film recently has garnered numerous interests as a means of combining the molecular aggregate ordering and promoting in-plane charge transport for large-scale/flexible organic electronics. However, it remains far from satisfactory for conducting polymer chains to achieve desirable surface topography and crystallinity due to lack of control over the precursor-involved interfacial assembly. Herein, wafer-size polyaniline (PANI) and tetra-aniline thin films are developed via a controlled interfacial synthesis with customized surface morphology and crystallinity through two typical aniline precursors selective polymerization. Two crucial competing assembly mechanisms, a) direct interfacial polymerization, b) solution polymerization and subsequent interfacial assembly, are investigated to play a vital role in determining elemental chain length and aggregate architecture. The optimal PANI thin film manifests ultraflat surface topography and unambiguous crystalline domains, which also enabling fascinating ammonia sensing capability with 31.4% ppm-1 sensitivity, fast response time (88 s) with astonishing selectivity, repeatability, and recovery capability. The thus-demonstrated strategy with wafer-scale processing potential and flexible microdevice offers a promising route for large-scale manufacturing thin-film organic electronics.

Does elevated luteinizing hormone level before trigger mean premature luteinizing hormone surge in advanced-aged women undergoing mild ovarian stimulation?

OBJECTIVE: To explore whether elevated luteinizing hormone (LH) level before trigger means premature LH surge in advanced aged women undergoing mild ovarian stimulation. METHODS: To retrospectively analyze 235 in vitro fertilization/intracytoplasmic sperm injection cycles in women >35 years old with the poor ovarian response (POR) from January 2012 to March 2016. Cycles are named Group 1, Group 2, and Group 3, being treated with gonadotropin-releasing hormone antagonist protocol (76 cycles), mild stimulation protocol using clomiphene citrate (73 cycles), and tamoxifen (86 cycles), respectively. MAIN OUTCOME MEASURE(S): The dynamic change of LH level during stimulation; the proportion of an elevated LH level defined as >10 IU/L on trigger day; the proportion of premature ovulation in each group. RESULTS: Serum LH level increased early in Group 2 and Group 3 and remained significantly higher than that in Group 1 during stimulation. In a sequence of three groups, the proportion of elevated LH levels before the trigger was 11.84, 43.8, and 37.21% (p＜.001) respectively. And the proportion of premature ovulation in patients with elevated LH levels was 11.11, 18.75, and 25% (p = .11) respectively. CONCLUSION: Elevated LH level before trigger does not mean premature LH surge in women more than 35 years old with POR undergoing mild ovarian stimulation with clomiphene or tamoxifen.

Fucoxanthin Prevents Long-Term Administration l-DOPA-Induced Neurotoxicity through the ERK/JNK-c-Jun System in 6-OHDA-Lesioned Mice and PC12 Cells.

As the most abundant marine carotenoid extracted from seaweeds, fucoxanthin is considered to have neuroprotective activity via its excellent antioxidant properties. Oxidative stress is regarded as an important starting factor for neuronal cell loss and necrosis, is one of the causes of Parkinson's disease (PD), and is considered to be the cause of adverse reactions caused by the current PD commonly used treatment drug levodopa (l-DA). Supplementation with antioxidants early in PD can effectively prevent neurodegeneration and inhibit apoptosis in dopaminergic neurons. At present, the effect of fucoxanthin in improving the adverse effects triggered by long-term l-DA administration in PD patients is unclear. In the present study, we found that fucoxanthin can reduce cytotoxicity and suppress the high concentration of l-DA (200 µM)-mediated cell apoptosis in the 6-OHDA-induced PC12 cells through improving the reduction in mitochondrial membrane potential, suppressing ROS over-expression, and inhibiting active of ERK/JNK-c-Jun system and expression of caspase-3 protein. These results were demonstrated by PD mice with long-term administration of l-DA showing enhanced motor ability after intervention with fucoxanthin. Our data indicate that fucoxanthin may prove useful in the treatment of PD patients with long-term l-DA administration.

Effect of early rescue ICSI and split IVF-ICSI in preventing low fertilization rate during the first ART cycle: A real-world retrospective cohort study.

PURPOSE: To determine the utility of short gamete coincubation in in vitro fertilization (IVF-S) combined with early rescue intracytoplasmic sperm injection (R-ICSI) and split IVF-ICSI in preventing low fertilization based on a retrospective cohort study. METHODS: Couples with a high risk of low IVF fertilization during the first ART cycle underwent IVF-S with R-ICSI or split IVF-ICSI. Fertilization rate, embryo quality, and clinical outcomes were measured. RESULTS: After propensity score matching, we included 188 couples in the IVF-S with R-ICSI group as Group 1 and 720 in the split IVF-ICSI group as Group 2. Normal fertilization rates were similar; however, Group 1 had a higher multiple pronuclei rate (10.42% vs. 4.50%, p < 0.001) but a higher embryo utilization rate (59.84% vs. 53.60%, p < 0.001). The groups were similar in the rates of high-quality embryos, embryo implantation, clinical pregnancy, and live birth. Low IVF fertilization rate was 4.79% and 9.03% in Group 1 and Group 2, respectively, with similar fertilization rate and embryo development. CONCLUSION: IVF-S with early R-ICSI and split IVF-ICSI were effective strategies in preventing low fertilization rate. IVF-S with early R-ICSI could become the preferred approach because of its advantages-higher embryo utilization rate, fewer ICSI procedures, similar clinical pregnancy rate, and live birth rate.

miR-130b regulates gap junctional intercellular communication through connexin 43 in granulosa cells from patients with polycystic ovary syndrome.

MicroRNAs (miRNAs) are small, noncoding RNAs that negatively regulate gene expression post-transcriptionally. We explored whether connexin 43 (Cx43) was differently expressed in luteinized granulosa cells from women with polycystic ovary syndrome (PCOS) compared with luteinized granulosa cells from women with a normal menstrual cycle, and whether certain miRNAs regulate the Cx43 level and gap junctional intercellular communication (GJIC). The miRNA profile was investigated in ovarian cortex tissues from five women with PCOS and five women without PCOS using a miRNA microarray. The levels of miR-130b and Cx43 mRNA were measured using real-time PCR in human luteinized granulosa cells from 20 women with PCOS and 25 women without PCOS. Protein and mRNA expression analysis and luciferase assays were conducted to confirm the substrate of miR-130b. PCOS ovarian cortex showed differential expression of miRNAs compared with non-PCOS ovarian cortex. Furthermore, miR-130b levels were increased in PCOS ovarian cortex and in luteinized granulosa cells compared with those in women with normal menstrual cycles, whereas the level of Cx43 mRNA, the identified target of miR-130b, was decreased in granulosa cells from patients with PCOS. Overexpression of miR-130b in a granulosa cell line resulted in reduced Cx43 protein levels and inhibited GJIC using scrape loading and dye transfer assay. Meanwhile, inhibition of miR-130b increased the Cx43 level. In conclusion, miR-130b was increased in PCOS granulosa cells, where it targets Cx43 to affect GJIC. The results of the present study suggested that miR-130b, via post-transcriptional regulation of Cx43, is involved in the pathophysiology of PCOS, which provides new insight into the pathological mechanism of PCOS.

Does an FSH surge at the time of hCG trigger improve IVF/ICSI outcomes? A randomized, double-blinded, placebo-controlled study.

STUDY QUESTION: Does an artificially induced FSH surge at the time of hCG trigger improve IVF/ICSI outcomes? SUMMARY ANSWER: An additional FSH bolus administered at the time of hCG trigger has no effect on clinical pregnancy rate, embryo quality, fertilization rate, implantation rate and live birth rate in women undergoing the long GnRH agonist (GnRHa) protocol for IVF/ICSI. WHAT IS KNOWN ALREADY: Normal ovulation is preceded by a surge in both LH and FSH. Few randomized clinical trials have specifically investigated the role of the FSH surge. Some studies indicated that FSH given at hCG ovulation trigger boosts fertilization rate and even prevents ovarian hyperstimulation syndrome (OHSS). STUDY DESIGN, SIZE, DURATION: This was a randomized, double-blinded, placebo-controlled trial conducted at a single IVF center, from June 2012 to November 2013. A sample size calculation indicated that 347 women per group would be adequate. A total of 732 women undergoing IVF/ICSI were randomized, using electronically randomized tables, to the intervention or placebo groups. Participants and clinical doctors were blinded to the treatment allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients aged ≤42 years who were treated with IVF/ICSI owing to tubal factor, male factor, unexplained, endometriosis and multiple factors were enrolled in this trial. Subjects all received a standard long GnRHa protocol for IVF/ICSI and hCG 6000-10 000 IU to trigger oocyte maturation. A total of 364 and 368 patients were randomized to receive a urinary FSH (uFSH) bolus (6 ampules, 450 IU) and placebo, respectively, at the time of the hCG trigger. The primary outcome measure was clinical pregnancy rate. The secondary outcome measures were FSH level on the day of oocyte retrieval, number of oocytes retrieved, good-quality embryo rate, live birth rate and rate of OHSS. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in the baseline demographic characteristics between the two study groups. There were also no significant differences between groups in cycle characteristics, such as the mean number of stimulation days, total gonadotrophin dose and peak estradiol. The clinical pregnancy rate was 51.6% in the placebo group and 52.7% in the FSH co-trigger group, with an absolute rate difference of 1.1% (95% CI -6.1% to 8.3%). The number of oocytes retrieved was 10.47 ± 4.52 and 10.74 ± 5.01 (P = 0.44), the rate of good-quality embryos was 37% and 33.9% (P = 0.093) and the implantation rate was 35% and 36% (P = 0.7) in the placebo group and the FSH co-trigger group, respectively. LIMITATIONS, REASONS FOR CAUTION: This was a single-center study, which may limit its effectiveness. The use of uFSH is a limitation, as this is not the same as the natural FSH. We did not collect follicular fluid for further study of molecular changes after the use of uFSH as a co-trigger. WIDER IMPLICATIONS OF THE FINDINGS: Based on previous data and our results, an additional FSH bolus administered at the time of hCG trigger has no benefit on clinical pregnancy rates in women undergoing the long GnRHa protocol in IVF/ICSI: a single hCG trigger is sufficient. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2016YFC1000205); Sun Yat-Sen University Clinical Research 5010 Program (2016004); the Science and Technology Project of Guangdong Province (2016A020216011 and 2017A020213028); and Science Technology Research Project of Guangdong Province (S2011010004662). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: The trial was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-12002246). TRIAL REGISTRATION DATE: 20 May 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 June 2012.

The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome.

RESEARCH QUESTION: Is the sole measurement of total testosterone sufficient to assess the presence of hyperandrogenism in women with polycystic ovary syndrome (PCOS)? DESIGN: Serum samples from 294 patients with PCOS who met the Rotterdam criteria were used for the analysis of total testosterone by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and chemiluminescent immunoassay (CLIA). The free androgen index (FAI) was calculated as total testosterone (TT)/sex hormone-binding globulin (SHBG) × 100%, and the presence/degree of hirsutism were assessed using the modified and simplified Ferriman-Gallwey (mFG and sFG, respectively) scoring systems. RESULTS: The hirsute subjects presented higher LC-MS/MS-based total testosterone and FAI values than the non-hirsute subjects (all P < 0.001), including those defined based on mFG ≥5 or sFG ≥3. Total testosterone and FAI were both positively correlated with the mFG (rank correlation coefficient [RCC] 0.598 and 0.443, P < 0.001) or sFG (RCC 0.747 and 0.568, P < 0.001) score, and a receiver operating characteristic curve analysis indicated that both parameters could significantly predict the presence of hirsutism determined by the mFG (area under the curve [AUC] 0.797 and 0.725, P < 0.001) or sFG (AUC 0.894 and 0.817, P < 0.001) score. However, similar results were not obtained with the CLIA platform. CONCLUSIONS: In this East Asian population, total testosterone was found to be a strong predictor of the presence and degree of hyperandrogenism (i.e. assessed by the presence and degree of hirsutism), but this finding was obtained only if the total testosterone level was measured by LC-MS/MS and not by CLIA. These findings might have important implications for global epidemiologic, phenotypic and clinical studies of PCOS.

A Phase III randomized controlled trial of oral dydrogesterone versus intravaginal progesterone gel for luteal phase support in in vitro fertilization (Lotus II): results from the Chinese mainland subpopulation.

Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population (n = 1034), who were randomized to oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily from the day of oocyte retrieval until 12 weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12 weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12 weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: -3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment.

Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome.

BACKGROUND: The transfer of fresh embryos is generally preferred over the transfer of frozen embryos for in vitro fertilization (IVF), but some evidence suggests that frozen-embryo transfer may improve the live-birth rate and lower the rates of the ovarian hyperstimulation syndrome and pregnancy complications in women with the polycystic ovary syndrome. METHODS: In this multicenter trial, we randomly assigned 1508 infertile women with the polycystic ovary syndrome who were undergoing their first IVF cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. After 3 days of embryo development, women underwent the transfer of up to two fresh or frozen embryos. The primary outcome was a live birth after the first embryo transfer. RESULTS: Frozen-embryo transfer resulted in a higher frequency of live birth after the first transfer than did fresh-embryo transfer (49.3% vs. 42.0%), for a rate ratio of 1.17 (95% confidence interval [CI], 1.05 to 1.31; P=0.004). Women who underwent frozen-embryo transfer also had a lower frequency of pregnancy loss (22.0% vs. 32.7%), for a rate ratio of 0.67 (95% CI, 0.54 to 0.83; P<0.001), and of the ovarian hyperstimulation syndrome (1.3% vs. 7.1%), for a rate ratio of 0.19 (95% CI, 0.10 to 0.37; P<0.001), but a higher frequency of preeclampsia (4.4% vs. 1.4%), for a rate ratio of 3.12 (95% CI, 1.26 to 7.73; P=0.009). There were no significant between-group differences in rates of other pregnancy and neonatal complications. There were five neonatal deaths in the frozen-embryo group and none in the fresh-embryo group (P=0.06). CONCLUSIONS: Among infertile women with the polycystic ovary syndrome, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer. (Funded by the National Basic Research Program of China and others; ClinicalTrials.gov number, NCT01841528.).

Bi-allelic recessive loss-of-function mutations in FIGLA cause premature ovarian insufficiency with short stature.

Premature ovarian insufficiency (POI) is a group of heterogeneous disorders characterized by decreased ovarian reserve and increased follicle stimulating hormone (FSH) levels. It is rarely associated with short stature. FIGLA mutations with POI are identified with regard to heterozygosity; till date, only one affected family has been identified with homozygous mutations in FIGLA but without functional evaluation. Here, we described two POI patients from a consanguineous family from China. An 18-year-old girl and her sister presented with primary amenorrhea and increased FSH and luteinizing hormone levels, but the sister also presented with short stature and bone age delay. Whole-genome sequencing analysis identified a recurrent homozygous mutation in the FIGLA gene, c.2 T > C (p.Met1Thr), in this family member with POI; this variant was segregated within the pedigree. This change was absent in 382 control subjects, and we did not detect any mutations in 39 other idiopathic POI patients. in vitro functional analysis indicates that the p.Met1Thr mutation does not affect the transcription of the FIGLA gene, but blocks the synthesis of the full-length FIGLA protein. Our results support the notion that bi-allelic recessive loss-of-function effects of FIGLA contribute to POI patients with short stature and expand the FIGLA-related phenotypic spectrum.

Close correlation between hyperandrogenism and insulin resistance in women with polycystic ovary syndrome-Based on liquid chromatography with tandem mass spectrometry measurements.

BACKGROUND: To investigate the correlation between hyperandrogenism (HA) and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) by measuring serum total testosterone (TT) using a liquid chromatography and tandem mass spectrometry assay (LC-MS/MS). METHODS: This cohort study included 332 patients with PCOS, 63 patients with IR and 276 with controls. TT levels were measured by LC-MS/MS and chemiluminescent immunoassay (CLIA); glucose and insulin levels were determined by an oral glucose tolerance test (OGTT). RESULTS: Compared with CLIA, LC-MS/MS differentiated more cases with high TT levels among the non-PCOS subjects with IR In patients with PCOS, LC-MS/MS-based TT levels or a combination with the mFG score detected a significantly higher incidence of HA in subjects with IR identified by hyperinsulinemia (HIN), HOMA-IR or impaired fasting glucose (IFG) than in those without IR Conversely, the IR rates demonstrated by HIN, HOMA-IR, or IFG were remarkably higher in the LC-MS/MS-defined high TT subgroup than in the normal TT subgroup. However, the CLIA platform could not discern a difference in HA incidence between IR and non-IR subgroups or in IR rate between high and normal TT populations. ROC curves also proved that HIN, HOMA-IR, and IFG were positive contributors to HA as measured by LC-MS/MS CONCLUSIONS: The correlation between HA and IR has always been underestimated, partly owing to the less accurate methods previously used to measure TT. HIN, HOMA-IR, and IFG are likely to contribute to the development of HA from a clinical perspective.

Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial.

STUDY QUESTION: Is oral dydrogesterone 30 mg daily non-inferior to 8% micronized vaginal progesterone (MVP) gel 90 mg daily for luteal phase support in IVF? SUMMARY ANSWER: Oral dydrogesterone demonstrated non-inferiority to MVP gel for the presence of fetal heartbeats at 12 weeks of gestation (non-inferiority margin 10%). WHAT IS KNOWN ALREADY: The standard of care for luteal phase support in IVF is the use of MVP; however, it is associated with vaginal irritation, discharge and poor patient compliance. Oral dydrogesterone may replace MVP as the standard of care if it is found to be efficacious with an acceptable safety profile. STUDY DESIGN, SIZE, DURATION: Lotus II was a randomized, open-label, multicenter, Phase III, non-inferiority study conducted at 37 IVF centers in 10 countries worldwide, from August 2015 until May 2017. In total, 1034 premenopausal women (>18 to <42 years of age) undergoing IVF were randomized 1:1 (stratified by country and age group), using an Interactive Web Response System, to receive oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects received either oral dydrogesterone (n = 520) or MVP gel (n = 514) on the day of oocyte retrieval, and luteal phase support continued until 12 weeks of gestation. The primary outcome measure was the presence of fetal heartbeats at 12 weeks of gestation, as determined by transvaginal ultrasound. MAIN RESULTS AND THE ROLE OF CHANCE: Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates in the full analysis sample (FAS) at 12 weeks of gestation of 38.7% (191/494) and 35.0% (171/489) in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). Live birth rates in the FAS of 34.4% (170/494) and 32.5% (159/489) were obtained for the oral dydrogesterone and MVP gel groups, respectively (adjusted difference 1.9%; 95% CI: -4.0 to 7.8). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP gel. LIMITATIONS, REASONS FOR CAUTION: The analysis of the results was powered to consider the ongoing pregnancy rate, but a primary objective of greater clinical interest may have been the live birth rate. This study was open-label as it was not technically feasible to make a placebo applicator for MVP gel, which may have increased the risk of bias for the subjective endpoints reported in this study. While the use of oral dydrogesterone in fresh-cycle IVF was investigated in this study, further research is needed to investigate its efficacy in programmed frozen-thawed cycles where corpora lutea do not exist. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates that oral dydrogesterone is a viable alternative to MVP gel, due to its comparable efficacy and tolerability profiles. Owing to its patient-friendly oral administration route, dydrogesterone may replace MVP as the standard of care for luteal phase support in fresh-cycle IVF. STUDY FUNDING/COMPETING INTERESTS(S): This study was sponsored and supported by Abbott. G.G. has received investigator fees from Abbott during the conduct of the study. Outside of this submitted work, G.G. has received non-financial support from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope and Gedeon Richter, as well as personal fees from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope, VitroLife, NMC Healthcare, ReprodWissen, Biosilu, Gedeon Richter and ZIVA. C.B. is the President of the Belgian Society of Reproductive Medicine (unpaid) and Section Editor of Reproductive BioMedicine Online. C.B. has received grants from Ferring Pharmaceuticals, participated in an MSD sponsored trial, and has received payment from Ferring, MSD, Biomérieux, Abbott and Merck for lectures. G.S. has no conflicts of interest to be declared. A.P. is the General Secretary of the Indian Society of Assisted Reproduction (2017-2018). B.D. is President of Pune Obstetric and Gynecological Society (2017-2018). D.-Z.Y. has no conflicts of interest to be declared. Z.-J.C. has no conflicts of interest to be declared. E.K. is an employee of Abbott Laboratories GmbH, Hannover, Germany and owns shares in Abbott. C.P.-F. is an employee of Abbott GmbH & Co. KG, Wiesbaden, Germany and owns shares in Abbott. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Origio, Besins, Ferring and Mithra (now Allergan); and H.T. has received consultancy fees from Finox-Gedeon Richter, Merck, Ferring, Abbott and ObsEva. TRIAL REGISTRATION NUMBER: NCT02491437 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 08 July 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 17 August 2015.

Brief co-incubation of gametes benefits the outcomes of newborns.

PURPOSE: The objective of this study was to determine whether ammonium accumulates in IVF media during fertility process and whether the brief co-incubation of gametes (bIVF) benefited the outcomes of newborns. METHODS: Ammonium levels in IVF media during gamete co-incubation were measured and the effects of bIVF on neonatal outcomes were evaluated retrospectively in this study. RESULTS: A total of 609 live newborns cycles were included in this study. The results showed that ammonium levels in the conventional IVF (cIVF) media was significantly increased than that in bIVF and control media (27.32 ± 5.60 vs 20.71 ± 3.89, P = 0.03; 27.32 ± 5.60 vs 19.46 ± 1.31, P = 0.01, respectively). In the cIVF group, the mean gestational age was significantly lower (37.36 ± 2.29 vs. 37.74 ± 1.94 weeks, P = 0.031) and the incidence of preterm birth (< 37 weeks) was higher than that in the bIVF group (25.80 vs. 17.63%, P = 0.015). Singleton cycles and twin cycles were then analyzed respectively. The gestational age and birth weight of the singleton cycles were similar between the two groups. However, of the twin cycles, the gestational age was significantly decreased and the rate of preterm birth was increased significantly in the cIVF group (35.76 ± 2.31 vs. 36.48 ± 1.73, P = 0.013; 53.33 vs. 31.52%, P = 0.002, respectively). CONCLUSIONS: There is an ammonium accumulation in IVF media during co-incubation of gametes. And bIVF reduces the risk of preterm birth (< 37 weeks), especially with regard to preterm birth of the twin cycles, and seems to be a safe alternative method for improving the neonatal outcomes compared with cIVF.

Genetic evidence of 'genuine' empty follicle syndrome: a novel effective mutation in the LHCGR gene and review of the literature.

Empty follicle syndrome (EFS) is a reproductive disorder in which no oocytes are retrieved during IVF. The existence of genuine EFS (GEFS) is still controversial, and to date, only one missense mutation of Luteinizing Hormone/Choriogonadotropin Receptor (LHCGR) has been reported to be associated with this disease. Here, we describe a GEFS patient in a non-consanguineous family from China. A 27-year-old woman presented with a 5-year history of primary infertility and LH resistance-like ovaries of unequal sizes, but with normal levels of circulating LH. In spite of a satisfactory ovarian reserve and response, no oocytes were retrieved after two cycles of IVF. Her condition did not appear to be failure of the hCG injection. It is more likely to be a genetic cause. A novel homozygous mutation in LHCGR gene, c.1345G>A (p.Ala449Thr), was detected in this patient. Each of her parents is heterozygous for this change, and the change was absent from 407 control subjects. Alanine at this amino acid position was highly conserved and replacement of threonine was predicted to disrupt the third transmembrane helix of the rhodopsin-like G protein-coupled receptor domain. Protein localization studies revealed that a portion of the mutant LHCGR protein molecules was retained intracellularly. Signalling studies demonstrated that this mutation had differing effects on the response of LHCGR to hCG or LH at different concentrations. Specifically, at a concentration <1 IU/ml, the mutant was activated by hCG stimulation but partially resistant to LH stimulation; at a higher concentration (>1 IU/ml), the mutant was activated by both hCG and LH. These data suggest that screening for mutations in the LHCGR gene may assist in the diagnosis of patients with GEFS. The literature describing the relationship between phenotype and genotypes in females is reviewed, and possible aetiologies and treatment options for this disease are proposed based on our and other studies.

Embryo development after mitochondrial supplementation from induced pluripotent stem cells.

PURPOSE: The purpose of this study was to evaluate the effects of mitochondrial supplementation (MS) on early embryonic development and to assess the safety of MS treatments using induced pluripotent stem cells (iPSCs) as the mitochondrial donor. METHODS: In this study, we evaluated the effect of MS on early embryonic development using induced pluripotent stem cells (iPSCs) as the donor. Mouse zygotes were injected with either mitochondria from iPSCs or a vehicle solution. Several parameters were evaluated, including the rates of blastocyst formation and implantation, the weight of E13.5 embryos and placentas, the distribution of the donor mitochondrial DNA (mtDNA), and the pattern of methylation in the differentially methylated regions (DMRs) of the H19 and Snrpn genes. RESULTS: We found that neither the rates of blastocyst formation and implantation nor the weights of E13.5 embryos and placentas were significantly different between the MS and control groups. Additionally, the mtDNA from the iPSC donors could be detected in the muscle tissue of four fetuses and all placentas in the MS group. Finally, the methylation patterns of H19 and Snrpn DMRs remained unchanged by MS. CONCLUSIONS: iPSC-derived mtDNA was directly involved in the process of embryonic development after MS. No adverse effects were seen when using iPSCs as a mitochondrial donor, but it remains to be seen whether this method can improve embryonic development, especially in older mice.

Early fetal reduction of dichorionic triplets to dichorionic twin or singleton pregnancies: a retrospective study.

A retrospective study conducted in an academic reproductive medicine centre evaluated the feasibility and safety of early fetal reduction in dichorionic triplets to dichorionic twin or singleton pregnancies. Thirty-three dichorionic triplets that underwent early transvaginal fetal reduction mechanically between 2002 and 2013 were included, of which 21 patients underwent fetal reduction to dichorionic twins (Group A) and 12 patients underwent fetal reduction to a singleton pregnancy (Group B). A further 84 patients with trichorionic triplets reduced to twins were included as the control group (Group C). The main outcome measures were live birth and preterm labour rates. Both early and late spontaneous abortion rates, were similar in group A compared with groups B and C. Gestational age at delivery was significantly lower in group C versus group A (P = 0.02). The preterm labour rate in group A, which was comparable with that in group C, was greater than in group B, but not significantly. Neonatal birth weight, low birth weight rate and neonatal body height were similar among groups. Small for gestational age rates were comparable. Live birth rates were similar among the groups. Early transvaginal fetal reduction for dichorionic triplets to dichorionic twins may be feasible and safe.