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Qi X.,Peking University | Qi X.,Key Laboratory of Assisted Reproduction | Qi X.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | Pang Y.,Peking University | And 5 more authors.
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2016

Polycystic ovarian syndrome (PCOS) is one of the major causes of anovulatory infertility. High levels of anti-Müllerian hormone (AMH) in the serum of PCOS patients participate in the major steps of the anovulation, and are related to pathogenesis and pathophysiological characteristic of PCOS, including the interactions of AMH with intra/extra ovarian factors like FSH, LH, androgen, and estrogen, as well as the role of AMH in folliculogenesis of PCOS. AMH promotes follicular atresia which may participate in the follicle pattern in PCOS patients. Recent years, the abnormally increased AMH in serum and follicle fluid of PCOS patients have attracted many scholars' attention. In this review, we summarized the role of AMH played in PCOS patients. It is of great significance for clarifying the role of AMH in the diagnosis and treatment of PCOS patients because AMH has the potential to increase our understanding of ovarian pathophysiology and to guide the clinical management of a broader range of conditions. © 2016 Elsevier Ireland Ltd.


Li M.,Peking University | Li M.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | Zhao Y.,Peking University | Zhao Y.,Key Laboratory of Assisted Reproduction | And 17 more authors.
Human Reproduction | Year: 2013

Study Questio: NDo different concentrations of FSH in the assisted reproductive technology (ART) procedure in vitro or in vivo affect the developmental competence of oocytes, the embryos and the offspring conceived from these embryos? Summary Answer: Improper FSH treatment (200 IU/l in vitro, 10 IU/ml in vivo and 200 IU/ml in vivo) impairs the development competence of oocyte and embryo, but does not influence offspring physiology and behavior. What Is Known Already: Exogenous FSH has been widely used in the field of ART. However, the effects of different concentrations of FSH on the developmental competence of oocytes, embryos and the offspring conceived from these embryos, are still unknown.STUDY Design: , SIZE, DURATIONIn a prospective study, a total of 45 mice at 8-10 weeks of age were primed in vivo with different dosages of FSH (9 mice in the 10 IU/ml, 10 mice in the 50 IU/ml, 10 mice in the 100 IU/ml and 16 mice in the 200 IU/ml groups). Fresh MII oocytes were retrieved from ovaries: this was Design: ated as in vivo group. Thirty six mice at 8-10 weeks of age were sacrificed by cervical dislocation to obtain ovaries without FSH treatment (9 mice in the 0 IU/l, 9 mice in the 50 IU/l, 8 mice in the 100 IU/l and 10 mice in the 200 IU/l groups), and then the immature oocytes were collected from these ovaries and cultured in vitro matured medium supplemented with 0, 50, 100 and 200 IU/l FSH: this was Design: ated as in vitro group.MATERIALS, SETTING, METHODSSpindle assembly of matured MII oocytes was stained via an immunofluorescence method and the oocytes ratio of normal spindle was analyzed. The developmental competence of the resulting fertilized embryos in the pre-and post-implantation stages was examined in in vitro and in vivo groups. Furthermore, physiological index, including reproductive potential and body weight, of the offspring was investigated by mating experiments and behavior index, including learning, memory, probing and intelligence, was tested by Morris water maze in in vitro and in vivo groups. Main Results and the Role of Chance: In the in vitro groups, the oocyte maturation competence, normal spindle assembly, blastocyst formation and implantation, as well as viable pup production were all impaired in the group treated with 200 IU/l FSH (P < 0.05). No differences were observed among the other three groups (P > 0.05). In the in vivo groups, 10 IU/ml FSH but not 200 IU/ml treatment influenced blastocyst formation and viable pup production (P < 0.05), although the high proportion of spindle assembly abnormality was only observed in the 200 IU/ml FSH treatment group (P < 0.05). Furthermore, there were no significant differences in terms of physiological index (reproductive potential and body weight) and behavior index (learning, memory, probing and intelligence) in offspring from in vitro and in vivo groups (P > 0.05).LIMITATIONS, REASONS FOR CAUTIONThe mouse model was used in this study. The results of the mouse follicle growth and oocyte development in responding to different concentrations of FSH are not 100% transferable to human, because of the physiological differences between mouse and human. Wider Implications of the Findings: The findings indicated that FSH application in the field of ART is safe to the resulted offspring, but it should be more carefully used for each women in ART cycles because the inappropriate FSH concentration would decrease the oocyte developmental competence. Study Funding/Competing Interest: (S)This work was partially supported by the Ministry of Science and Technology of China Grants (973 program; 2011CB944504), the Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China (30825038), the National Natural Science Funds for Young Scholar (31000661) and by the Joint Research Fund for Overseas, Hong Kong and Marco Scholars (31128013/C120205). None of the authors has any conflicts of interest. © 2013 The Author.


Gao J.-M.,Peking University | Gao J.-M.,Key Laboratory of Assisted Reproduction | Yan J.,Peking University | Yan J.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | And 17 more authors.
Human Reproduction | Year: 2013

STUDY QUESTIONDoes basic fibroblast growth factor (bFGF) in combination with fibrin hydrogel improve follicle development and revascularization of heterotopically transplanted mouse ovarian tissues?SUMMARY ANSWERTreatment of transplanted ovarian tissues with higher concentrations (75, 100 and 150 μg/ml), but not lower concentrations (25 and 50 μg/ml), of bFGF significantly improved primordial follicle survival and angiogenesis, while apoptosis of follicles and stromal cells was significantly decreased.WHAT IS KNOWN ALREADYUse of transplanted ovarian tissues in female fertility preservation is limited by the massive loss of follicles and ischemia-reperfusion injury due to the expected delay in revascularization.STUDY DESIGN, SIZE AND DURATIONOvarian tissues from 18-day-old ICR mice were encapsulated in brin hydrogel mixed with different concentrations of bFGF, then transplanted under the skin of adult female mice for 1 week. The ovarian tissues treated without fibrin hydrogels and bFGF were designated as Control group I, and the ovarian tissues treated with fibrin hydrogels but without bFGF were designated as Control group II. The ovarian tissues treated with 25 and 50 μg/ml bFGF were designated as the lower concentration group, and the ovarian tissues treated with 75, 100 and 150 μg/ml bFGF were designated as the higher concentration group.MATERIALS, SETTING AND METHODSAssessment of follicular quantity and follicle classification was carried out by histologic analysis. Follicle proliferation was evidenced by immunostaining with proliferating cell nuclear antigen and apoptosis was verified by anti-active caspase-3 staining. Epithelial cells of new blood vessels were stained using CD31 antibody to evaluate neoangiogenesis, and the blood vessel density was analyzed by immunohistochemistry.MAIN RESULTS AND THE ROLE OF CHANCEThe ovarian tissues were recovered 1 week post-transplantation. Compared with the control group, the survival and proliferation of the follicles was significantly increased, the apoptosis of follicles and stromal cells was significantly decreased, and angiogenesis was significantly enhanced when the transplanted ovarian tissues were treated with a higher concentration of bFGF. Treatment with a lower concentration of bFGF did not improve follicle survival and blood revascularization.LIMITATIONS, REASONS FOR CAUTIONThe results obtained may not be fully extrapolated to humans because of the physiologic differences between mice and humans.WIDER IMPLICATIONS OF THE FINDINGSFor the first time, the present study investigated the role of bFGF in transplanted ovarian tissues and demonstrated that bFGF might significantly improve the quality of transplanted ovarian tissues by increasing follicle quantity and promoting neoangiogenesis. This study sets the stage for further study and application of ovarian tissue transplantation in clinics, and may eventually benefit females for fertility preservation. © The Author 2013.


Yu Y.,Peking University | Yu Y.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | Yu Y.,Key Laboratory of Assisted Reproduction | Zhao Y.,Peking University | And 11 more authors.
Journal of Proteome Research | Year: 2013

Preimplantation genetic diagnosis (PGD) is important for screening genetic and chromosome mutations in embryos so that the efficiency of assisted reproductive treatment can be increased and birth defects can be decreased; however, some studies have reported a risk from this technology as well as other assisted reproductive technologies. We have developed a blastomere biopsy mouse model to assess the potential effects of blastomere biopsy that was one key procedure in PGD on the fertility of female mice at different ages. We showed that female fertility was decreased in the biopsied mouse model with an increase in age. Moreover, the ovarian weight, serum hormone levels, and the number of primordial, primary, preantral, and antral stage follicles were also decreased in the middle-aged biopsied mouse model. To elucidate the underlying molecular mechanism, we did proteomics analysis on ovarian tissues from puberty biopsied and nonbiopsied mice of the 23 differentially expressed proteins that were screened for in both groups, 3 proteins (PSMB8, ALDH1A1, and HSPA4) were selected and identified by Western blotting and quantitative RT-PCR methods, which showed the 3 proteins to regulate 12 cellular pathways. Furthermore, these three proteins were shown to be located in ovarian tissues, and the dynamic changes of expression profiling in middle-aged biopsied and nonbiopsied mice were demonstrated. The present study showed that blastomere biopsy technology impairs fertility when mice are middle-aged, which possibly resulted in abnormal expression profiling of PSMB8, ALDH1A1, and HSPA4 proteins. Thus, additional studies should be performed to assess the overall risk of blastomere biopsies during PGD procedures. © 2013 American Chemical Society.


Zhao H.-C.,Peking University | Zhao H.-C.,Key Laboratory of Assisted Reproduction | Zhao Y.,Peking University | Zhao Y.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | And 14 more authors.
Biology of Reproduction | Year: 2013

Preimplantation genetic diagnosis (PGD) has been prevalent in the field of assisted reproductive technology, yet the longterm risks of PGD to offspring remain unknown. In the present study, the early development of PGD embryos, postimplantation characteristics, and birth rate following PGD were determined. Moreover, the behavior of the offspring conceived from the biopsied embryos was evaluated with the Morris water maze and pole climbing tests. Finally, the epigenetic modification of the global genome and methylation patterns for the H19, Igf2, and Snrpn imprinted genes were identified. The results indicated a significant delay in the blastocoel formation of PGD embryos and a decrease in the implantation ability of these embryos, which was related to the decreased number of cells in the PGD blastocysts. The PGD mice spent more time on both the nontrained quadrant of the water maze and climbing down the pole. Furthermore, the 5-hydroxymethylcytosine content in the brain tissues of PGD mice was significantly increased, but no difference was found in 5-methylcytosine content. The differentially methylated regions of H19/Igf2 exhibited decreased methylation patterns, but that of Snrpn was normal, compared to the control group. Quantitative RT-PCR indicated that Igf2 mRNA expression was significantly decreased but that H19 and Snrpn mRNAs were expressed normally. In conclusion, blastomere biopsies in PGD procedures carry potential risks to embryo development and the behavior of resulting offspring; these risks may arise from aberrant epigenetic modification and methylation patterns in brain tissues. Further studies are needed to better understand the risks associated with PGD. © 2013 by the Society for the Study of Reproduction, Inc.


Fan Y.,Guangzhou University | Li R.,Peking University | Huang J.,Peking University | Yu Y.,Peking University | And 4 more authors.
Cell Cycle | Year: 2013

Human embryonic stem cells have shown tremendous potential in regenerative medicine, and the recent progress in haploid embryonic stem cells provides new insights for future applications of embryonic stem cells. Disruption of normal fertilized embryos remains controversial; thus, the development of a new source for human embryonic stem cells is important for their usefulness. Here, we investigated the feasibility of haploid and diploid embryo reconstruction and embryonic stem cell derivation using microsurgically repaired tripronuclear human zygotes. Diploid and haploid zygotes were successfully reconstructed, but a large proportion of them still had a tripolar spindle assembly. The reconstructed embryos developed to the blastocyst stage, although the loss of chromosomes was observed in these zygotes. Finally, triploid and diploid human embryonic stem cells were derived from tripronuclear and reconstructed zygotes (from which only one pronucleus was removed), but haploid human embryonic stem cells were not successfully derived from the reconstructed zygotes when two pronuclei were removed. Both triploid and diploid human embryonic stem cells showed the general characteristics of human embryonic stem cells. These results indicate that the lower embryo quality resulting from abnormal spindle assembly contributed to the failure of the haploid embryonic stem cell derivation. However, the successful derivation of diploid embryonic stem cells demonstrated that microsurgical tripronuclear zygotes are an alternative source of human embryonic stem cells. In the future, improving spindle assembly will facilitate the application of triploid zygotes to the field of haploid embryonic stem cells. © 2013 Landes Bioscience.


Zhao Y.,Peking University | Zhao Y.,Key Laboratory of Assisted Reproduction | Zhao Y.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | Qiao J.,Peking University | And 2 more authors.
Steroids | Year: 2013

Polycystic ovary syndrome (PCOS) is the most common endocrine problem affecting women of reproductive age and is investigated from many regions of the world. Some reports have indicated ethnic difference in its manifestation. This review addressed the evidences for ethnic variation in the expression of PCOS phenotypes and explored the potential ethnic-specific diagnosis of this syndrome. To determine ethnic variation, community prevalence and clinical and metabolic problems, including hyperandrogenism, oligomenorrhoea/amenorrhoea, polycystic ovaries, obesity, insulin resistance and the metabolic syndrome, had been compared from differing backgrounds and populations. Moreover, a link between ethnicity and variation in the metabolic phenotype of PCOS had also been identified. East Asian women with PCOS have a lower BMI and a milder hyperandrogenic phenotype, but with the highest prevalence of metabolic syndrome. South Asians in particular have a high prevalence of insulin resistance and metabolic syndrome, and are at risk for type 2 diabetes, with central obesity more than BMI reflecting their metabolic risk. African American and Hispanic women are more obese and more prone to metabolic problems. Besides, there is a higher prevalence of hirsutism among women of Middle Eastern and Mediterranean origin. Ethnically appropriate guidelines are needed for identifying anthropometric thresholds for better screening and diagnosis in high-risk ethnic groups.


Fan Y.,Guangzhou University | Li R.,Peking University | Li R.,Key Laboratory of Assisted Reproduction | Huang J.,Peking University | And 11 more authors.
Stem Cells and Development | Year: 2014

Human embryonic stem cells (hESCs) hold great promise for future clinical cell therapies because of their unique potential to differentiate into all human cell types. However, the destruction of normal fertilized embryos and the derivation of hESCs for research has resulted in polarized ethical debates, with most of the controversy centered on embryo destruction. Therefore, due to less ethical controversy surrounding them, abnormal fertilized zygotes that are usually discarded are a potential feasible resource for the derivation of hESCs. Microsurgery on human polyspermic zygotes can contribute to the derivation of hESCs, but the efficiency is much lower. Here, we reported a culture system to enhance the developmental competence of such microsurgical human polyspermic zygotes by EGF-BDNF-IGF-1 combination, which eventually resulted in the increased derivation efficiency of hESCs from them. We found that the developmental efficiency of microsurgical enucleated tripronuclear (3PN) embryos cultured with the EGF-BDNF-IGF-1 combination was significantly increased compared with the control group. More importantly, when the microsurgical enucleated 3PN embryos were cultured in medium supplemented with EGF-BDNF-IGF-1, the frequency ratio of chromosome abnormality was reduced. Our present study will facilitate the development of hESC line derivation in subsequent studies and also provide an additional choice for infertile couples. © Mary Ann Liebert, Inc. 2014.


Zhao Y.,Peking University | Zhao Y.,Key Laboratory of Assisted Reproduction | Zhao Y.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | Fu L.,Peking University | And 24 more authors.
BMC Medicine | Year: 2012

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications.Methods: A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS).Results: Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity.Conclusions: Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin sensitivity and could be considered as the potential biomarkers for long-term risk assessment of diabetes mellitus. © 2012 Zhao et al; licensee BioMed Central Ltd.


Li M.,Peking University | Li M.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | Yu Y.,Peking University | Yu Y.,Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology | And 15 more authors.
PLoS ONE | Year: 2012

It is important to identify effective contraceptive drugs that cause minimal disruption to physiological processes. Phosphodiesterase 3 (PDE3) inhibitors suppress meiosis in oocytes by decreasing the level of cAMP and blocking the extrusion of the first polar body. In this study, we tested the PDE3 inhibitor, cilostazol, as a potential contraceptive agent. The effects of cilostazol treatment in vitro and in vivo on the suppression of oocyte maturation in a mouse model were investigated. The results indicated that treatment with increasing concentrations of cilostazol led to a dose-dependent arrest in meiosis progression. The effective in vitro concentration was 1 μM and was 300 mg/kg in vivo. The effect of cilostazol was reversible. After removal of the drug, meiosis resumed and mouse oocytes matured in vitro, and showed normal chromosome alignment and spindle organization. After fertilization using an ICSI method, the oocytes showed normal morphology, fertilization rate, embryo cleavage, blastocyst formation, and number of viable pups when compared with controls. The offspring showed similar body weight and fertility. In vivo, the mice became infertile if the drug was injected sequentially, and became pregnant following discontinuation of cilostazol. More importantly, no side effects of cilostazol were observed in treated female mice as demonstrated by blood pressure and heart rate monitoring. It is concluded that cilostazol, a drug routinely used for intermittent claudication, can effectively inhibit oocyte maturation in vitro and in vivo, does not affect the developmental potential of oocytes following drug removal and has few side effects in female mice treated with this drug. These findings suggest that cilostazol may be a potential new contraceptive agent that may facilitate an efficacy and safety study of this drug. © 2012 Li et al.

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