Due to the comprehensive examination of 50 patients with ovarian polycystosis the authors suggested that ultrasound, laparoscopic, hormonal and endometrial parameters should be employed as diagnostic criteria.

Diagnostic criteria for polycystic ovary syndrome

Human cancers commonly have mutations in epigenetic regulatory genes, and several small molecules that target epigenetic regulators are in clinical trials. Here, Pfister and Ashworth discuss the biological complexity of epigenetic regulation in cancer and provide an overview of inhibitors that target gain-of-function mutations, as well as synthetic lethal approaches to target loss-of-function mutations in epigenetic regulators.

Marked for death: targeting epigenetic changes in cancer.

Background Initially identified for their capability to induce heterotopic bone formation, bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor β superfamily Using cellular and molecular genetic approaches, recent studies have implicated intra-ovarian BMPs as potent regulators of ovarian follicular function The bi-directional communication of oocytes and the surrounding somatic cells is mandatory for normal follicle development and oocyte maturation This review summarizes the current knowledge on the physiological role and molecular determinants of these ovarian regulatory factors within the human germline-somatic regulatory loop Objective and rationale The regulation of ovarian function remains poorly characterized in humans because, while the fundamental process of follicular development and oocyte maturation is highly similar across species, most information on the regulation of ovarian function is obtained from studies using rodent models Thus, this review focuses on the studies that used human biological materials to gain knowledge about human ovarian biology and disorders and to develop strategies for preventing, diagnosing and treating these abnormalities Search methods Relevant English-language publications describing the roles of BMPs or growth differentiation factors (GDFs) in human ovarian biology and phenotypes were comprehensively searched using PubMed and the Google Scholar database The publications included those published since the initial identification of BMPs in the mammalian ovary in 1999 through July 2016 Outcomes Studies using human biological materials have revealed the expression of BMPs, GDFs and their putative receptors as well as their molecular signaling in the fundamental cells (oocyte, cumulus/granulosa cells (GCs) and theca/stroma cells) of the ovarian follicles throughout follicle development With the availability of recombinant human BMPs/GDFs and the development of immortalized human cell lines, functional studies have demonstrated the physiological role of intra-ovarian BMPs/GDFs in all aspects of ovarian functions, from follicle development to steroidogenesis, cell-cell communication, oocyte maturation, ovulation and luteal function Furthermore, there is crosstalk between these potent ovarian regulators and the endocrine signaling system Dysregulation or naturally occurring mutations within the BMP system may lead to several female reproductive diseases The latest development of recombinant BMPs, synthetic BMP inhibitors, gene therapy and tools for BMP-ligand sequestration has made the BMP pathway a potential therapeutic target in certain human fertility disorders; however, further clinical trials are needed Recent studies have indicated that GDF8 is an intra-ovarian factor that may play a novel role in regulating ovarian functions in the human ovary Wider implications Intra-ovarian BMPs/GDFs are critical regulators of folliculogenesis and human ovarian functions Any dysregulation or variations in these ligands or their receptors may affect the related intracellular signaling and influence ovarian functions, which accounts for several reproductive pathologies and infertility Understanding the normal and pathological roles of intra-ovarian BMPs/GDFs, especially as related to GC functions and follicular fluid levels, will inform innovative approaches to fertility regulation and improve the diagnosis and treatment of ovarian disorders

Oocyte-somatic cell interactions in the human ovary-novel role of bone morphogenetic proteins and growth differentiation factors.

Stroke is the third most common cause of death in the world, and a major source of a disability. This invaluable reference will provide clinicians caring for stroke patients with ready access to the optimal evidence for best practice in acute stroke treatment and secondary prevention. The author, who is a Member of the Editorial Board of the Cochrane Stroke Review Group, describes all available treatments for acute stroke and secondary prevention, the rationale for using them, and, where available, the highest-level evidence (level 1) for their safety and effectiveness. Where level 1 evidence is not available, he offers advice on reasonable practice and information about current research. The evidence for each treatment is followed by the author’s interpretations, and the implications of the evidence in the care of stroke patients. This is therefore an essential resource for clinicians, translating into practice advances that have been made in the treatment and prevention of stroke, and suggesting the most appropriate interventions.

An evidence-based approach.

Angiogenesis depends on proangiogenic and anti-angiogenic molecules that regulate endothelial cell proliferation and migration. Well-regulated angiogenesis plays a pivotal role in many physiological conditions such as reproduction and embryonic development, while abnormal angiogenesis is also the basis of a variety of pathological processes including tumor metastasis and atherosclerotic plaque formation. Melatonin has a variety of biological effects, including inhibition of tumor metastasis, stabilizing atherosclerotic plaques, and the regulation of seasonal reproductive rhythms, etc. During certain pathophysiological processes, melatonin exerts different functions depending on its ability to regulate angiogenesis. This review reveals that melatonin has different effects on neovascularization under different physiological and pathological conditions. In tumors, in age-related ocular diseases, and in a hypoxic environment, melatonin inhibits neovascularization in tissues, while in gastric ulcers, skin lesions, and some physiologic processes, it promotes angiogenesis. We also speculate that melatonin may inhibit the neovascularization in atherosclerotic plaques, thus preventing the initiation and development of atherosclerosis. Most studies suggest that these effects are related to the role of melatonin in regulating of vascular endothelial growth factor and its receptors, but the specific regulatory mechanisms remain disparate, which may lead to the differential effects of melatonin on angiogenesis under different conditions. In this review, we thus summarize some seemingly contradictory mechanisms by which melatonin controls angiogenesis under different pathological and physiological conditions, and urge that the regulatory mechanisms be further studied.

Role of melatonin in controlling angiogenesis under physiological and pathological conditions

Blastocoele expansion degree predicts live birth after single blastocyst transfer for fresh and vitrified/warmed single blastocyst transfer cycles.

Background
The effect of progesterone elevation (PE) on the day of human chorionic gonadotropin (hCG) administration on the pregnancy outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles is a matter of ongoing debate. The replacement of cleavage-stage embryos with blastocyst-stage embryos for transfer was proposed to avoid the possible impairment of PE in fresh cycles. This study aimed to assess the association between PE on the day of human chorionic gonadotropin (hCG) administration and clinical pregnancy rates (CPRs) in IVF/ICSI cycles with embryos transferred at different developmental stages (cleavage and blastocyst). Moreover, a secondary aim was to determine the thresholds at which PE has a detrimental effect on CPRs.

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Progesterone elevation on the day of human chorionic gonadotropin administration adversely affects the outcome of IVF with transferred embryos at different developmental stages

Progesterone plays critical roles in maintaining a successful pregnancy at the early embryonic stage. Human chorionic gonadotropin (hCG) rapidly induces amphiregulin (AREG) expression. However, it remains unknown whether AREG mediates hCG-induced progesterone production. Thus, the objective of this study was to investigate the role of AREG in hCG-induced progesterone production and the underlying molecular mechanism in human granulosa cells; primary cells were used as the experimental model. We demonstrated that the inhibition of EGFR and the knockdown of AREG abolished hCG-induced steroidogenic acute regulatory protein (StAR) expression and progesterone production. Importantly, follicular fluid AREG levels were positively correlated with progesterone levels in the follicular fluid and serum. Treatment with AREG increased StAR expression and progesterone production, and these stimulatory effects were abolished by EGFR inhibition. Moreover, activation of ERK1/2, but not PI3K/Akt, signaling was required for the AREG-induced up-regulation of StAR expression and progesterone production. Our results demonstrate that AREG mediates hCG-induced StAR expression and progesterone production in human granulosa cells, providing novel evidence for the role of AREG in the regulation of steroidogenesis.

Amphiregulin mediates hCG-induced StAR expression and progesterone production in human granulosa cells

Steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step in ovarian steroidogenesis and progesterone (P4) synthesis. Melatonin and its receptors are expressed in human granulosa cells, and have been shown to influence basal P4 production. However, previous studies addressing the regulation of StAR expression by melatonin and its impact on P4 secretion yielded contradictory results. Here, we demonstrate that melatonin upregulates StAR expression in primary cultures of human granulosa-lutein (hGL) cells obtained from women undergoing in vitro fertilization (IVF). Using pharmacological inhibitors, we show that the stimulatory effect of melatonin on StAR expression is mediated via both MT1 and MT2 melatonin receptors. Melatonin exposure activates the PI3K/AKT signaling pathway and its inhibition attenuates the stimulatory effect of melatonin on StAR expression. Moreover, siRNA-mediated knockdown of StAR abolishes melatonin-induced P4 production. Importantly, clinical analyses demonstrate that melatonin levels in human follicular fluid are positively correlated with P4 levels in serum. By illustrating the potential physiological role of melatonin in the regulation of StAR expression and P4 production in hGL cells, our results may serve to improve current strategies used to treat clinical infertility.

/pdf/melatonin-induces-progesterone-production-in-human-granulosa-o8hpep3bpt.pdf

Melatonin induces progesterone production in human granulosa-lutein cells through upregulation of StAR expression.

Study question Does amphiregulin (AREG), the most abundant and important epidermal growth factor receptor (EGFR) ligand in the follicular fluid, regulate aromatase expression in human granulosa-lutein (hGL) cells? Summary answer AREG mediates the hCG-induced up-regulation of aromatase expression and estradiol (E2) production in hGL cells. What is known already AREG expression and secretion are rapidly induced by hCG in hGL cells and mediate physiological functions of LH/hCG in the ovary. EGFR protein is expressed in follicles not only in the pre-ovulatory phase but also throughout the luteal phase of the menstrual cycle. After the LH surge, the human corpus luteum secretes high levels of E2, which regulates various luteal cell functions. Aromatase is an enzyme responsible for a key step in the biosynthesis of E2. However, whether AREG regulates aromatase expression and E2 production in hGL cells remains unexplored. Study design, size, duration This study is an experimental study performed over a 1-year period. In vitro investigations examined the role of AREG in the regulation of aromatase expression and E2 production in primary hGL cells. Participants/materials, setting, methods Primary hGL cells were obtained from women undergoing IVF treatment in an academic research center. Aromatase mRNA and protein levels were examined after exposure of hGL cells to recombinant human AREG, hCG or LH. The EGFR tyrosine kinase inhibitor AG1478, PI3K inhibitor LY294002 and siRNAs targeting EGFR, LH receptor, StAR and AREG were used to verify the specificity of the effects and to investigate the underlying molecular mechanisms. Reverse transcription quantitative real-time PCR (RT-qPCR) and western blot were used to measure the specific mRNA and protein levels, respectively. Follicular fluid and serum were collected from 65 infertile women during IVF treatment. Pearson's correlation analysis was performed to examine the correlation coefficient between two values. Main results and the role of chance Treatment of hGL cells with AREG-stimulated aromatase expression and E2 production. Using pharmacological inhibitors and specific siRNAs, we revealed that AREG-stimulated aromatase expression and E2 production via EGFR-mediated activation of the protein kinase B (AKT) signaling pathway. In addition, inhibition of EGFR activity and AREG knockdown attenuated hCG-induced up-regulation of aromatase expression and E2 production. Importantly, the protein levels of AREG in the follicular fluid were positively correlated with the E2 levels in serum after 2 days of oocyte pick-up and in the follicular fluid of IVF patients. Large-scale data N/A. Limitations, reasons for caution The in vitro setting of this study is a limitation that may not reflect the real intra-ovarian microenvironment. Clinical data were obtained from a small sample size. Wider implications of the findings Our results provide the first evidence that hCG-induced AREG contributes to aromatase expression and E2 production in the luteal phase of the menstrual cycle. A better understanding of the hormonal regulation of female reproductive function may help to develop new strategies for the treatment of clinical infertility. Study funding/competing interest(s) This work was supported by the National Natural Science Foundation of China for Young Scientists (81601253), the specific fund of clinical medical research of Chinese Medical Association (16020160632) and the Foundation from the First Affiliated Hospital of Zhengzhou University for Young Scientists to Lanlan Fang. This work was also supported by an operating grant from the National Natural Science Foundation of China (81820108016) to Ying-Pu Sun. All authors declare no conflict of interest.

Human chorionic gonadotropin-induced amphiregulin stimulates aromatase expression in human granulosa-lutein cells: a mechanism for estradiol production in the luteal phase.

Yiping Yu

Papers

Blastocoele expansion degree predicts live birth after single blastocyst transfer for fresh and vitrified/warmed single blastocyst transfer cycles.

Progesterone elevation on the day of human chorionic gonadotropin administration adversely affects the outcome of IVF with transferred embryos at different developmental stages

Amphiregulin mediates hCG-induced StAR expression and progesterone production in human granulosa cells

Melatonin induces progesterone production in human granulosa-lutein cells through upregulation of StAR expression.

Human chorionic gonadotropin-induced amphiregulin stimulates aromatase expression in human granulosa-lutein cells: a mechanism for estradiol production in the luteal phase.