Cuifang Hao

Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3

Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women. To identify causative genes, we conducted a genome-wide association study (GWAS) of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved two independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). We identified strong evidence of associations between PCOS and three loci: 2p16.3 (rs13405728; combined P-value by meta-analysis Pmeta = 7.55 × 10−21, odds ratio (OR) 0.71); 2p21 (rs13429458, Pmeta = 1.73 × 10−23, OR 0.67); and 9q33.3 (rs2479106, Pmeta = 8.12 × 10−19, OR 1.34). These findings provide new insight into the pathogenesis of PCOS. Follow-up studies of the candidate genes in these regions are recommended.

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.).

Association of +45G15G(T/G) and +276(G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women.

OBJECTIVE Polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance (IR) and consequently with increased risk of metabolic disorders. Adiponectin is the most abundant adipocytokine and may play a role in the regulation of insulin sensitivity and IR in PCOS. The aim of the present study was to evaluate the genetic influence of the adiponectin (ADIPOQ) gene polymorphisms in the development of PCOS among Han Chinese women. METHODS Two single nucleotide polymorphisms (SNPs),+45G15G(T/G) and +276(G/T), in the ADIPOQ gene were genotyped in 120 patients with PCOS and 120 healthy control subjects. All of them were Han Chinese women. RESULTS Both SNPs were found to be significantly associated with PCOS (P=0.021, odds ratios=1.629, 95% confidence intervals: 1.074-2.469 and P=0.015, 1.576, 1.091-2.279 respectively). In SNP +276(G/T), the allele G was found to be significantly associated with increased fasting insulin levels, homeostasis model assessment to assess IR index, and area under the curve glucose levels, but decreased glucose and insulin ratio in the PCOS patients. Furthermore, the patients carrying genotypes G/G and G/T had significantly decreased levels of serum adiponectin (6.16+/-3.18 plus 5.93+/-3.23 vs 8.96+/-3.21 microg/ml, P=0.030) compared with the patients with genotype T/T. CONCLUSIONS The present study provides evidence that SNPs +45G15G(T/G) and +276(G/T) in the ADIPOQ gene are associated with PCOS in Han Chinese women. SNP +276(G/T) may contribute to an impact of insulin levels and IR, which are implicated in the susceptibility for PCOS.

Birth defects after assisted reproductive technologies in China: analysis of 15,405 offspring in seven centers (2004 to 2008)

This first large-scale report of birth defects in 15,405 offspring conceived by assisted reproductive technologies in China found infants born after IVF alone to have a birth defect frequency comparable to that in the general Chinese population; rates were nonsignificantly higher in infants conceived with use of intracytoplasmic sperm injection compared with those conceived after IVF alone.

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

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.)

Prediction of IVF/ICSI outcome based on the follicular output rate

This study assessed the true accuracy of follicular output rate (FORT) as a prognostic indicator of response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection. A total of 1643 cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of preovulatory follicle count on the day of stimulation×100/small antral follicle count (3-10mm in diameter) at baseline. Low, medium and high FORT groups were defined according to tertile values. Among 1503 non-PCOS cycles, numbers of retrieved oocytes and of all embryos that could be transferred, as well as rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased with FORT. In PCOS patients, FORT were significantly lower in patients who achieved clinical pregnancy compared with those who did not (0.56±0.21 versus 0.66±0.29, P=0.031). Fertilization and good-quality embryo rates were significantly higher with medium FORT than low and high FORT (P=0.001 and P=0.047, respectively). Medium FORT in PCOS patients and high FORT in non-PCOS patients may predict better outcomes for IVF/ICSI.

microRNA‑494 is a potential prognostic marker and inhibits cellular proliferation, migration and invasion by targeting SIRT1 in epithelial ovarian cancer

Ovarian cancer is one of the most common types of gynecological malignancy worldwide, and is the fourth leading cause of cancer-associated mortality among women. Despite improvements in therapeutic treatments, the prognosis for epithelial ovarian cancer (EOC) remains poor, mainly due to the rapid growth and metastasis of ovarian cancer tumors. An increasing number of studies have indicated that microRNAs (miRNAs) are involved in the carcinogenesis and progression of human cancer, suggesting that miRNAs may be used in clinical prognosis and as a therapeutic target in EOC. The aim of the present study was to investigate the expression levels of miRNA-494 in EOC tissues and cell lines. The clinical significance of miRNA-494 in patients with EOC was also evaluated. The results demonstrated that miRNA-494 was significantly downregulated in EOC tissues and cell lines. Low expression levels of miRNA-494 were associated with poor prognostic features, including International Federation of Gynecology and Obstetrics stage, tumor size and lymph node metastasis. In vitro functional studies demonstrated that overexpression of miRNA-494 inhibited proliferation, migration and invasion in EOC cells. By contrast, knockdown of miRNA-494 enhanced cell growth, migration and invasion in EOC cells. Notably, sirtuin 1 (SIRT1) was identified as a direct target of miRNA-494 in EOC. Furthermore, MTT, cell migration and invasion assays verified that EOC cell proliferation, migration and invasion were completely restored with forced miRNA-494 expression and SIRT1 restoration. Together, these findings suggest that miRNA-494 is a potential prognostic marker, and may provide novel therapeutic regimens of targeted therapy for EOC.

ABR-006 Expression of angiopoietin-1/-2 in the process of mouse embryo implantation

This study examined the expression and distribution of angiopoietin-1/-2 (Ang-1/-2) in the endometrium of early pregnant mice. The expression of Ang-1/-2 was detected by immunohisto-chemical staining and in situ hybridization respectively. Computerized image analysis system was used to measure the average optical intensity of Ang-1/-2 in endometria at different time points after gestation. Mice were randomly divided into 5 groups: control group, D2 group (2 days after pregnancy), D4 group (4 days after pregnancy), D6 group (6 days after pregnancy) and D8 group (8 days after pregnancy), each containing 15 mice. The results showed that the expression of Ang-1 and Ang-2 was very different among 4 groups (P<0.01). Immunohistochemical staining revealed that Ang-1 was localized in the cytoplasma of stromal cells 2 days after pregnancy (day 2), and in luminal epithelial cells on day 4. The protein of Ang-2 was mainly expressed in the cytoplasma of glandular epithelia and stromal cells. With gestation time, the positive reactions of Ang-1/-2 were stronger in the endometria of the pregnant mice (P<0.01). In situ hybridization showed Ang-1 mRNA in stromal cells on day 2. Hybridization signal was localized in both stromal cells and vessel epithelial cells on day 4; Ang-2 mRNA was expressed in stromal cells and glandular epithelia on day 2; high mRNA levels appeared in stromal cells, glandular epithelia and vascular endothelia on day 4; an increasing in mRNA expression of Ang-1/-2 was observed on day 6 and day 8 (P<0.01). It is suggested that Ang-1/-2 may play an important role in the cross-talk between blastocyst and maternal endometrium during the process of embryo implantation.