Live Birth with or without Preimplantation Genetic Testing for Aneuploidy.

BACKGROUND: Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the cumulative live-birth rate as compared with conventional in vitro fertilization (IVF). METHODS: In this multicenter, randomized, controlled trial, we randomly assigned subfertile women with three or more good-quality blastocysts to undergo either PGT-A or conventional IVF; all the women were between 20 and 37 years of age. Three blastocysts were screened by next-generation sequencing in the PGT-A group or were chosen by morphologic criteria in the conventional-IVF group and then were successively transferred one by one. The primary outcome was the cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. We hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7 percentage points higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A. RESULTS: A total of 1212 patients underwent randomization, and 606 were assigned to each trial group. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional-IVF group (absolute difference, -4.6 percentage points; 95% confidence interval [CI], -9.2 to -0.0; P<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups. CONCLUSIONS: Among women with three or more good-quality blastocysts, conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A. (Funded by the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03118141.).

Association between hysteroscopic features of chronic endometritis and pregnancy outcomes of patients after in vitro fertilization: a retrospective cohort study.

This retrospective cohort study explored the morphological features of chronic endometritis (CE) and pregnancy outcomes during in vitro fertilization (IVF) in women with CE (429) at Yantai Yuhuangding Hospital between January 2017 and September 2018. The primary outcome was the clinical pregnancy rate (CPR). The women displayed haemorrhagic spots (175), hyperaemia (122), micropolyps (75), hyperaemia combined with micropolyps (49) and others (8). The CPR and live birth rate (LBR) were different among the hysteroscopic features of CE in fresh embryo transfer cycles (p = .002, p = .011). The miscarriage and premature birth rates were not significantly different among groups (p > .05). Hyperaemia (0.47 [95% CI, 0.29; 0.77]), micropolyps (0.40 [95% CI, 0.23; 0.72]), hyperaemia combined with micropolyps (0.35 [95% CI, 0.18; 0.69]) and others (0.36 [95% CI, 0.19; 0.69]) were associated with the CPR. In conclusion, the hysteroscopic features of CE are associated with IVF pregnancy outcomes, and there were differences in pregnancy outcomes with different CE hysteroscopic features.IMPACT STATEMENTWhat is already known on this subject? Chronic endometritis (CE) is associated with adverse pregnancy outcomes such as infertility, premature delivery and miscarriage. CE can reduce the success rate of pregnancy and even lead to obstetric and neonatal complications, and is an adverse factor for the success of in vitro fertilization (IVF). There are different types of CE, but their impact on IVF outcomes is unknown.What the results of this study add? The CPR and LBR were different among the hysteroscopic features of CE in fresh embryo transfer cycles (p = .002, p = .011). The miscarriage and premature birth rates were not significantly different among groups (p > .05). After adjustment, the multivariable analysis showed that hyperaemia (OR = 0.47, p = .002), micropolyps (OR = 0.40, p = .002), hyperaemia combined with micropolyps (OR = 0.35, p = .002) and others (OR = 0.36, p = .002) were associated with the CPR among patients with CE.What the implications are of these findings for clinical practice and/or further research? The hysteroscopic features of CE are associated with IVF pregnancy outcomes, and there were differences in pregnancy outcomes with different CE hysteroscopic features. Hence, women with repeated IVF failure should undergo hysteroscopy to examine for the presence of CE and its nature.

Transfer of Fresh versus Frozen Embryos in Ovulatory Women.

BACKGROUND: Elective frozen-embryo transfer has been shown to result in a higher live-birth rate than fresh-embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen-embryo transfer increases live-birth rates among ovulatory women with infertility. METHODS: In this multicenter, randomized trial, we randomly assigned 2157 women who were undergoing their first in vitro fertilization cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. Up to two cleavage-stage embryos were transferred in each participant. The primary outcome was a live birth after the first embryo transfer. RESULTS: The live-birth rate did not differ significantly between the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.89 to 1.06; P=0.50). There were also no significant between-group differences in the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy. Frozen-embryo transfer resulted in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh-embryo transfer (0.6% vs. 2.0%; relative risk, 0.32; 95% CI, 0.14 to 0.74; P=0.005). The risks of obstetrical and neonatal complications and other adverse outcomes did not differ significantly between the two groups. CONCLUSIONS: The live-birth rate did not differ significantly between fresh-embryo transfer and frozen-embryo transfer among ovulatory women with infertility, but frozen-embryo transfer resulted in a lower risk of the ovarian hyperstimulation syndrome. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China; Chinese Clinical Trial Registry number, ChiCTR-IOR-14005406 .).

The effect of thyroid autoantibody on assisted reproduction technology outcome in euthyroid women: One center experience.

Thyroid dysfunction is an important factor to cause failure in assisted reproduction technology (ART) procedures. In this study, we recorded the serum level of thyroid autoantibody to fig. out its relationship with the ART outcome. The results showed that the serum concentrations of TSH had a statistically significant increase between the basal level and the levels at time of serum pregnancy test both in women with and without thyroid autoantibody (p= 0.002 and p=0.019, respectively). Additionally, the TSH level increased significantly in thyroid autoantibody-positive group than those in thyroid autoantibody-negative group during controlled ovarian hyper stimulation (COH) process(p = 0.006). The risk of preterm delivery was lower in thyroid autoantibody-negative group. In sum, the present study provided evidence of an association between thyroid autoantibody and preterm delivery in euthyroid women.

Regenerative Potential of Menstrual Blood-Derived Stem Cells and Platelet-Derived Growth Factor in Endometrial Injury.

BACKGROUND Endometrial regeneration is essential for normal endometrial function; however, it is unclear whether and how menstrual blood-derived stem cells (MenSCs) and platelet-derived growth factor (PGDF) are associated with this phenomenon. The present study explored this topic. MATERIAL AND METHODS EM-E6/E7/hTERT cells were divided into 5 groups: control group, NC group, PDGF group, MenSCs group, and PDGF+MenSCs group. The effects of MenSCs and PDGF on cell proliferation, invasion, and microvascular formation of endometrial epithelium were investigated by CCK-8, Transwell, and tube formation assays, respectively. Mouse endometrial injury models were established and mice were randomly divided into control, model, PDGF, MenSCs, and PDGF+MenSCs groups. Pathological change was examined with hematoxylin and eosin (H&E) staining. Microvessel formation of endometrial epithelium was estimated by detecting the expression of CD34 protein with immunohistochemical (IHC) staining. Western blot analysis was used to detect the activation of Akt and Bad proteins in endometrial tissue. RESULTS MenSCs, PDGF, and the combination treatments significantly promoted the proliferation, migration, and tube formation of endometrial epithelium compared to the control and NC group. The combination of MenSCs and PDGF remarkably promoted re-epithelialization and endometrial repair. IHC staining analysis showed significant increases in CD34 expression of the endometrial tissue following treatment with PDGF and MenSCs. The combination treatments also markedly enhanced the phosphorylation of Akt and Bad in endometrial tissue. CONCLUSIONS These results suggest that MenSCs and PDGF may be candidate substances for endometrial injury repair.

Investigation of platelet-rich plasma in increasing proliferation and migration of endometrial mesenchymal stem cells and improving pregnancy outcome of patients with thin endometrium.

BACKGROUND: Platelet-rich plasma (PRP) contains abundant growth factors and is gradually used in the field of reproduction. A thin endometrium is recognized as a critical factor in embryo implantation failure. Endometrial mesenchymal stem cells (EnMSCs), which were isolated from human menstrual blood, are highly proliferative and show multiple differentiation capacity. The current study was to investigate the effect of PRP on the proliferation and migration of EnMSCs, and the effectiveness of PRP in the treatment of patients with thin endometrium. MATERIALS AND METHODS: EnMSCs were treated with PRP in vitro, followed by measuring cell proliferation, migration, and adhesion by using CCK8, scratch, and adhesion test, respectively. Twenty patients undergoing in vitro fertilization (IVF) with refractory thin endometrium history were given PRP by infusion into the uterine cavity after the treatment of hormone replacement therapy (HRT). RESULTS: All components of PRP significantly stimulated the growth, migration, and adhesion of EnMSCs when compared with the negative control. Cell proliferation and migration were induced by PRP in a dose-dependent manner with maximum proliferation at a 2% PRP dose. The clinical data showed that successful endometrial expansion and pregnancy were discovered in 12 patients after PRP infusion, and the pregnancy rate increased to 60%. CONCLUSION: Intrauterine PRP infusion represents a new way for female patients with thin endometrium with poor response. This study lays the foundations for the potential treatment of thin endometrium with PRP in vivo.

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.).

Novel circular RNA expression in the cumulus cells of patients with polycystic ovary syndrome.

PURPOSE: Circular RNAs (circRNAs) mediate the posttranscriptional regulation of multiple genes by functioning as microRNA (miRNA) sponges. This study aimed to detect the novel expression of circRNAs in the cumulus cells (CCs) of polycystic ovary syndrome (PCOS) patients and their potential significance in the pathogenesis of PCOS. METHODS: circRNAs in the CCs from 6 PCOS patients and 6 normal control individuals were collected for microarray analysis, and an independent cohort study including 25 PCOS patients and 25 normal control individuals was conducted to validate the circRNA microarray results using quantitative real-time polymerase chain reaction (qRT-PCR). Spearman's rank correlation and receiver operating characteristic (ROC) were performed to delineate the potential correlation between novel circRNAs and patients' clinical characteristics and their potential efficacy for the diagnosis of PCOS. Bioinformatics analysis was applied to investigate the potential roles of circRNAs in the pathogenesis of PCOS. RESULTS: A total of 286 circRNAs (167 upregulated and 119 downregulated) were identified by microarray that was differentially expressed between the PCOS and non-PCOS groups. After qRT-PCR validation, the expression levels of hsa_circ_0043533 (p < 0.05) and hsa_circ_0043532 (p < 0.01) were significantly higher in the PCOS group, while the expression level of hsa_circ_0097636 (p < 0.01) was prominently lower versus the non-PCOS group. Spearman's rank correlation indicated that the serum testosterone (T) level positively correlated with the expression of hsa_circ_0043533 and hsa_circ_0097636 in the PCOS group. The ROC curve analysis found that the combination of hsa_circ_0097636 and T resulted in a larger area under the curve (AUC) (0.893) compared with each circRNA alone (0.709, 0.738, and 0.718 for hsa_circ_0043533, hsa_circ_0097636 and hsa_circ_0043532, respectively). Bioinformatics analysis revealed that the dysregulated circRNAs were potentially involved in cell cycle, oocyte meiosis, progesterone-mediated oocyte maturation, the FOXO signaling pathway, phosphatidylinositol signaling and glycerophospholipid metabolism. CONCLUSIONS: The expression of circRNAs in CCs was significantly different between PCOS and normal control individuals. We validated three circRNAs, which could lead to a better understanding of disease pathogenesis and the development of effective therapeutic interventions for PCOS patients.

Intrauterine administration of human chorionic gonadotropin improves the live birth rates of patients with repeated implantation failure in frozen-thawed blastocyst transfer cycles by increasing the percentage of peripheral regulatory T cells.

INTRODUCTION: Repeated implantation failure (RIF) frustrates both patients and their clinicians. Our aim was to observe the effects of intrauterine administration of human chorionic gonadotropin (hCG) on pregnancy outcomes of patients who received frozen-thawed embryo transfer (FET). METHODS: A prospective cohort study was conducted to evaluate the impact of intrauterine administration of hCG on pregnancy outcomes in FET cycles of patients with RIF from January 1st 2016 to December 31st 2016. The treatment group (n = 153, 152 cycles) received an infusion of 500 IU of hCG diluted in normal saline 3 days before embryo transfer. The control group (n = 152, 151 cycles) received embryo transfer with a previous intrauterine injection of normal saline without hCG. Early morning fasting blood samples were obtained from each patient for the measurement of peripheral regulatory T cells (Tregs) on the day of embryo transfer. The outcome parameters including Tregs in each group were compared. RESULTS: The patients in the hCG-treated group had significantly higher clinical pregnancy rates, implantation rates and live birth rates than the controls (37.5% versus 25.17%, 29.19% versus 19.4%, 26.97% versus 17.22%, respectively). They also had significantly higher percentages of peripheral Tregs than the controls (6.1 ± 0.6% versus 5.4 ± 1.0%). In addition, the clinical pregnancy rate, implantation rate and live birth rate in patients who received blastocyst transfer were significantly higher in the hCG-treated group when compared to the control group (41.38% versus 26.44%, 42.22% versus 26.14%, 33.33% versus 17.24%, respectively). We also showed that the clinical pregnancy rate, implantation rate and live birth rate were significantly higher in hCG-treated group when compared to the control group (49.12% versus 28.07%, 49.15% versus 28.07%, 40.35% versus 17.54%, respectively) of RIF patients with blastocyst transfer under 35 years, while there was on difference in patients above 35 years. CONCLUSIONS: Intrauterine administration of hCG significantly improves the clinical pregnancy rate, implantation rate and live birth rate in FET cycles of patients with RIF by increasing Tregs. The treatment improves the pregnancy outcomes much more for younger RIF patients transferred blastocysts.

A Retrospective Study of Letrozole Treatment Prior to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome Undergoing In Vitro Fertilization at Risk of Ovarian Hyperstimulation Syndrome.

BACKGROUND Women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF) are given letrozole before a trigger injection of human chorionic gonadotropin (hCG) to lower estrogen (E2) levels, but can experience ovarian hyperstimulation syndrome (OHSS). The aim of this study was to evaluate the effect of oral letrozole, prior to administration of hCG, on the outcome of IVF and development of OHSS. MATERIAL AND METHODS Retrospective clinical review included 181 cases of women with PCOS who underwent IVF cycles with intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) (IVF/ICSI-ET). The day before the use of hCG, cases were divided into a letrozole-treated group (N=78) and a non-letrozole group (N=103). An oral dose of 2.5 mg qd of letrozole was given when the peak level of E2 was ≥4000 pg/ml during ovarian stimulation and ceased before the day of egg retrieval. RESULTS The letrozole-treated group had a significant increase in the number of retrieved oocytes, viable embryos, and fresh ET rate (P>0.05); peak levels of E2, and E2 levels on the day of the egg retrieval, were significantly higher, and the fertilization rate was significantly lower (P<0.001). No significant differences were found in the rates of pregnancy, abortion, or ectopic pregnancy between the two groups (P>0.05). The incidence OHSS was lower in the letrozole-treated group, but this difference did not reach statistical significance (P>0.05). CONCLUSIONS Women with PCOS who underwent IVF, oral treatment with letrozole a day prior to treatment with hCG lowered E2 levels, but did not significantly reduce the incidence of OHSS.

The expression of cytokines IFN-γ, IL-4, IL-17A, and TGF-ß1 in peripheral blood and follicular fluid of patients testing positive for anti-thyroid autoantibodies and its influence on in vitro fertilization and embryo transfer pregnancy outcomes.

The aim of this work was to study the expression of the cytokines IFN-γ, IL-4, IL-17 A, and TGF-ß1 in peripheral blood and follicular fluid (FF) of patients positive for antithyroid autoantibodies (ATA+) with normal thyroid gland function and the influence of these autoantibodies on in vitro fertilization and embryo transfer (IVF-ET) pregnancy outcomes. Nineteen patients were in the ATA+ group, and 27 patients tested negative for anti-thyroid autoantibody (ATA-). Blood samples were drawn from the two groups of patients on the oocyte retrieval day and the 5th and 14th days of transplantation; in addition, FF was extracted on the oocyte retrieval day from both groups of patients and tested through enzyme-linked immunosorbent assay (ELISA) for IFN-γ, IL-4, IL-17 A, and TGF-ß1. For the ATA+ group, the concentration of IFN-γ increased whereas the concentration of TGF-ß1 decreased in peripheral blood on the oocyte retrieval day (p < .05); the concentration of IL-4 decreased in peripheral blood on the 5th and 14th days of transplantation for the ATA+ group (p < .05); further, the concentration of IL-17 A increased whereas that of TGF-ß1 decreased in FF (p < .05). The ratio of IL-17 A/TGF-ß1 in the ATA+ group significantly increased in FF and peripheral blood on the oocyte retrieval day and the 14th day of transplantation (p < .05). The ratio of IL-17 A/TGF-ß1 in FF of the pregnant patients was significantly lower than in the non-pregnant patients (p < .05). The findings suggested that the ratio between pro-inflammatory and anti-inflammatory cytokines was adversely affected; therefore, adverse pregnancy outcomes of patients with ATA+ undergoing IVF-ET treatment may be attributed to immunological mechanisms.

Effect of GnRHa on Th17/Treg cells in peripheral blood of patients with unexplained repeated implantation failure.

OBJECTIVE: To investigate the effect and possible mechanism of downregulation of gonadotropin-releasing hormone agonist (GnRHa) on Th17/Treg (regulatory T cell) cells in peripheral blood of patients with unexplained repeated implantation failure (RIF). METHODS: Fifty-two patients who had RIF (≥ 3 consecutive transfers of ≥ 4 high-grade embryos in women under the age of 40 (excluding 40)) of frozen-thawed embryos were studied. Twenty-nine cases receiving simple hormone replacement therapy (HRT) were defined as transfer group, and the remaining 23 cases with HRT combined with GnRHa downregulation were defined as GnRHa downregulation group. In addition, 30 cases of the normal early pregnancy group were selected as control group. RESULTS: Before HRT, the number of Th17 and Treg cells in CD4+ lymphocytes was increased and decreased, respectively, with the ratio of Th17/Treg cells increased in HRT group compared with the control group (p < 0.05). On the day of progesterone conversion, compared with the HRT group, the percentage of Th17 and Treg cells was decreased and increased, respectively, with the ratio of Th17/Treg cells decreased significantly in GnRHa downregulation group (p < 0.05). The estrogen E2 levels of the GnRHa downregulation group were slightly higher than those of the HRT group, with no significant difference between the two groups (p > 0.05). Further, there was no significant difference in the levels of chorionic gonadotropin at the 14th day and the 21st day after transplantation between HRT group and GnRHa downregulation group (p > 0.05). CONCLUSION: There were an increase and a decrease in the number of Th17 and Treg cells, respectively, with Th17/Treg cells imbalanced in unexplained RIF. GnRHa downregulation may play a direct immunomodulatory role in disrupting the imbalance and then improve the endometrial receptivity. These effects did not depend on the E2 levels in peripheral blood, nor affect early embryonic development.

A potential determinant role of adiponectin and receptors for the early embryo development in PCOS patients with obesity hinted by quantitative profiling.

OBJECTIVE: To identify the quantitative profiling of adiponectin and its receptors (AdipoR1, AdipoR2, and T-cadherin) in cumulus cells (CCs) and to evaluate their roles in the early embryo development of polycystic ovary syndrome (PCOS) patients, in part, with obesity. METHODS: Fifty-five subjects were divided into two groups according to the body mass index. Oocytes were further inseminated and only mature and normal fertilized oocytes (2PN) were included in this research. Real-time PCR and western blot were performed to identify adiponectin and its receptors in CCs. RESULTS: Adiponectin and receptors were ubiquitously expressed in CCs of PCOS and non-PCOS patients. The level of AdipoR2 in CCs from the oocytes yielding blastocyst after 5/6 days in vitro culture was markedly higher than in those from oocytes could not develop to blastocyst stage after Day 6, for non-obese or obese PCOS patients (0.1647 ± 0.0161 versus 0.0783 ± 0.0385, 0.1948 ± 0.0307 versus 0.1057 ± 0.0236, respectively, p < 0.05). In addition, only in patients with PCOS and concurrent obesity the AdipoR1 in CCs was considerably increased in CC-B+ compared with CC-B- subgroup (0.5162 ± 0.0371 versus 0.2448 ± 0.0333, p < 0.01). CONCLUSION: The development of early embryo was associated with the up-regulation of AdipoR1 and AdipoR2 in PCOS patients. Our results suggested that adiponectin could positively modulate embryo development in humans. Further investigations should be carried out to unlock the crucial role that adiponectin plays in embryo development.

Effect of elevated estradiol levels on the hCG administration day on IVF pregnancy and birth outcomes in the long GnRH-agonist protocol: analysis of 3393 cycles.

INTRODUCTION: This retrospective study aimed to evaluate the association between elevated serum estradiol (E 2) levels on the human chorionic gonadotrophin (hCG) administration day and in vitro fertilization (IVF) pregnancy and birth outcomes in the long GnRH-agonist protocol. METHODS: This study analyzed the data of 3393 infertile women who underwent initial fresh IVF. The patients were categorized into high and low E 2 groups based on their serum E 2 levels on the hCG day. Pregnancy and birth outcomes were compared. RESULTS: The implantation rate, clinical pregnancy rate, and live birth rate were all significantly higher in the high E 2 group than in the low E 2 group (p < 0.05). The good-quality embryo rate and abortion rate did not significantly differ between the two groups. There were no significant differences in the mode of delivery, gestational age, birth weight, and fetal gender between the two groups. Furthermore, there were no differences in the risk of preterm birth, low birth weight, and fetal malformation between the two groups in 860 single live births. Subgroup analysis of singleton pregnancies in the high E 2 (E 2 ≥ 3757 pg/mL) group revealed a significant increase in abortion rate in the age group of ≥37 years. CONCLUSIONS: Elevated serum E 2 levels associated with controlled ovarian stimulation did not increase the risks of preterm birth, low birth weight, and fetal malformation. High E 2 on the hCG day had no detrimental effect on the implantation rate, clinical pregnancy rate, and live birth rate.

Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial.

Importance: Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. Objective: To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. Design, Setting, and Participants: A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Interventions: Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. Main Outcomes and Measures: The primary outcome was live birth. Secondary outcomes included adverse events. Results: Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, -0.6%; 95% CI, -5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Conclusions and Relevance: Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. Trial Registration: clinicaltrials.gov Identifier: NCT01573858.

Identification of altered microRNAs and mRNAs in the cumulus cells of PCOS patients: miRNA-509-3p promotes oestradiol secretion by targeting MAP3K8.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women and is characterised by polycystic ovaries, hyperandrogenism and chronic anovulation. Although the clinical and biochemical signs of PCOS are typically heterogeneous, abnormal folliculogenesis is considered a common characteristic of PCOS. Our aim is to identify the altered miRNA and mRNA expression profiles in the cumulus cells of PCOS patients to investigate their molecular function in the aetiology and pathophysiology of PCOS. In this study, the miRNA expression profiles of the cumulus cell samples isolated from five PCOS and five control patients were determined by an miRNA microarray. At the same time, the altered mRNA profiles of the same cumulus cell samples were also identified by a cDNA microarray. From the microarray data, 17 miRNAs and 1263 mRNAs showed significantly different expression in the PCOS cumulus cells. The differentially expressed miRNA-509-3p and its potential target gene (MAP3K8) were identified from the miRNA and mRNA microarrays respectively. The expression of miRNA-509-3p was up-regulated and MAP3K8 was down-regulated in the PCOS cumulus cells. The direct interaction between miRNA-509-3p and MAP3K8 was confirmed by a luciferase activity assay in KGN cells. In addition, miRNA-509-3p mimics or inhibitor transfection tests in KGN cells further confirmed that miRNA-509-3p improved oestradiol (E2) secretion by inhibiting the expression of MAP3K8 These results help to characterise the pathogenesis of anovulation in PCOS, especially the regulation of E2 production.

Different transcriptional levels of GABAA receptor subunits in mouse cumulus cells around oocytes at different mature stage.

γ-Aminobutyric acid (GABA) is a principal inhibitory neurotransmitter in the central nervous system (CNS) of vertebrates. However, GABA and its receptor are found not only in peripheral neuronal tissue but also in many peripheral nonneuronal tissues, and thought to have multiple physiological functions. The bidirectional communication between oocytes and cumulus cells (CCs) plays a significant role in oocyte maturation and metabolism. In our previously study, the expression level of α5 subunit in CCs isolated from oocytes of patients with polycystic ovary syndrome had been found to be associated with oocyte nuclear maturity. In this study, we investigated the transcriptional levels of GABAA receptor subunits in germinal vesicle (GV) and metaphase II (MII) mouse CCs, and explored the role of GABA-A receptor subunits during ovarian follicular development and oocyte maturation. We found that GABAA receptor subunits exhibited differential transcriptional levels in CCs at different oocyte nuclear maturity stages. It suggested an involvement of GABA-A receptor subunits related to oocyte maturation and certain functions.

Aberrant expression of angiopoietin-like proteins 1 and 2 in cumulus cells is potentially associated with impaired oocyte developmental competence in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with obesity, insulin resistance, hyperandrogenism, alterations in ovarian angiogenesis and impaired oocyte competence. Emerging evidence demonstrates that angiopoietin-like protein 1 (ANGPTL1) and angiopoietin-like protein 2 (ANGPTL2) have an important influence on angiogenesis, androgen biosynthesis, insulin resistance and adipocytes function. In this study, we set out to determine the potential relationship between ANGPTL1, ANGPTL2 and oocyte competence in PCOS through analyzing the expression levels and dynamic pattern of the two genes in cumulus cells (CCs) during different phases of nuclear maturation of PCOS patients and control groups undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer. We found that the relative abundance of ANGPTL1 and ANGPTL2 transcripts in CCs from patients with PCOS showed dynamic changes during oocyte maturation. Specifically, their expressions were increased significantly at the Metaphase II stage. In summary, the present novel evidence indicates that the expression patterns of ANGPTL1 and ANGPTL2 mRNAs are disordered during oocyte maturation in PCOS, which were potentially related to aberrant oocyte quality and developmental potency, at least in part, via pathological angiogenesis and metabolism.

Aberrant expression of long noncoding RNAs in cumulus cells isolated from PCOS patients.

PURPOSE: To describe the long noncoding RNA (lncRNA) profiles in cumulus cells isolated from polycystic ovary syndrome (PCOS) patients by employing a microarray and in-depth bioinformatics analysis. This information will help us understand the occurrence and development of PCOS. METHODS: In this study, we used a microarray to describe lncRNA profiles in cumulus cells isolated from ten patients (five PCOS and five normal women). Several differentially expressed lncRNAs were chosen to validate the microarray results by quantitative RT-PCR (qRT-PCR). Then, the differentially expressed lncRNAs were classified into three subgroups (HOX loci lncRNA, enhancer-like lncRNA, and lincRNA) to deduce their potential features. Furthermore, a lncRNA/mRNA co-expression network was constructed by using the Cytoscape software (V2.8.3, http://www.cytoscape.org/ ). RESULTS: We observed that 623 lncRNAs and 260 messenger RNAs (mRNAs) were significantly up- or down-regulated (≥2-fold change), and these differences could be used to discriminate cumulus cells of PCOS from those of normal patients. Five differentially expressed lncRNAs (XLOC_011402, ENST00000454271, ENST00000433673, ENST00000450294, and ENST00000432431) were selected to validate the microarray results using quantitative RT-PCR (qRT-PCR). The qRT-PCR results were consistent with the microarray data. Further analysis indicated that many differentially expressed lncRNAs were transcribed from chromosome 2 and may act as enhancers to regulate their neighboring protein-coding genes. Forty-three lncRNAs and 29 mRNAs were used to construct the coding-non-coding gene co-expression network. Most pairs positively correlated, and one mRNA correlated with one or more lncRNAs. CONCLUSIONS: Our study is the first to determine genome-wide lncRNA expression patterns in cumulus cells isolated from PCOS patients by microarray. The results show that clusters of lncRNAs were aberrantly expressed in cumulus cells of PCOS patients compared with those of normal women, which revealed that lncRNAs differentially expressed in PCOS and normal women may contribute to the occurrence of PCOS and affect oocyte development.

A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia.

A genome-wide association study of Han Chinese subjects was conducted to identify genetic susceptibility loci for nonobstructive azoospermia (NOA). In the discovery stage, 802 azoospermia cases and 1,863 controls were screened for genetic variants in the genome. Promising SNPs were subsequently confirmed in two independent sets of subjects: 818 azoospermia cases and 1,755 controls from northern China, and 606 azoospermia cases and 958 controls from central and southern China. We detected variants at human leukocyte antigen (HLA) regions that were independently associated with NOA (HLA-DRA, rs3129878, p(combine) = 3.70 × 10(-16), odds ratio [OR] = 1.37; C6orf10 and BTNL2, rs498422, p(combine) = 2.43 × 10(-12), OR = 1.42). These findings provide additional insight into the pathogenesis of NOA.