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      Evaluation of Follicular Synchronization Caused by Estrogen Administration and Its Reproductive Outcome

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          Abstract

          To evaluate multiple follicular development synchronization after estrogen stimulation in prepubertal mice, follicular responsiveness to gonadotropin superovulation, the prospective reproductive potential and ovarian polycystic ovary syndrome (PCOS)-like symptoms at adulthood, prepubertal mice were intraperitoneally injected with estrogen to establish an animal model with solvent as control. When synchronized tertiary follicles in ovaries, in vitro oocyte maturation and fertilization rates, blastocyst formation rate, developmental potential into offspring by embryo transfer, adult fertility and PCOS-like symptoms, and involved molecular mechanisms were focused, it was found that estrogen stimulation (10μg/gBW) leads to follicular development synchronization at the early tertiary stage in prepubertal mice; reproduction from oocytes to offspring could be realized by means of the artificial reproductive technology though the model mice lost their natural fertility when they were reared to adulthood; and typical symptoms of PCOS, except changes in inflammatory pathways, were not remained up to adulthood. So in conclusion, estrogen can lead to synchronization in follicular development in prepubertal mice, but does not affect reproductive outcome of oocytes, and no typical symptoms of PCOS remained at adulthood despite changes related to inflammation.

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          Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles.

          To explore the feasibility of luteal-phase ovarian stimulation using hMG and letrozole in terms of ovarian response and pregnancy outcome using frozen-thawed embryo transfer.
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            Rodent models for human polycystic ovary syndrome.

            Polycystic ovary syndrome (PCOS) is the most frequent female endocrine disorder, affecting 5%-10% of women, causing infertility due to dysfunctional follicular maturation and ovulation, distinctive multicystic ovaries and hyperandrogenism, together with metabolic abnormalities including obesity, hyperinsulinism, an increased risk of type 2 diabetes, and cardiovascular disease. The etiology of PCOS is unclear, and decisive clinical studies are limited by ethical and logistic constraints. Consequently treatment is palliative rather than curative and focuses on symptomatic approaches. Hence, a suitable animal model could provide a valuable means with which to study the pathogenesis of the characteristic reproductive and metabolic abnormalities and thereby identify novel and more effective treatments. So far there is no consensus on the best experimental animal model, which should ideally reproduce the key features associated with human PCOS. The prenatally androgenized rhesus monkey displays many characteristics of the human condition, including hyperandrogenism, anovulation, polycystic ovaries, increased adiposity, and insulin insensitivity. However, the high cost of nonhuman primate studies limits the practical utility of these large-animal models. Rodent models, on the other hand, are inexpensive, provide well-characterized and stable genetic backgrounds readily accessible for targeted genetic manipulation, and shorter reproductive life spans and generation times. Recent rodent models display both reproductive and metabolic disturbances associated with human PCOS. This review aimed to evaluate the rodent models reported to identify the advantages and disadvantages of the distinct rodent models used to investigate this complex endocrine disorder.
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              Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells.

              The existence of a putative membrane estrogen receptor (ER) has been supported by studies accomplished over the past 20 yr. However, the origin and functions of this receptor are not well defined. To study the membrane receptor, we transiently transfected cDNAs for ERalpha or ERbeta into Chinese hamster ovary (CHO) cells. Transfection of ERalpha resulted in a single transcript by Northern blot, specific binding of labeled 17beta-estradiol (E2), and expression of ER in both nuclear and membrane cell fractions. Competitive binding studies in both compartments revealed near identical dissociation constants (K(d)S) of 0.283 and 0.287 nM, respectively, but the membrane receptor number was only 3% as great as the nuclear receptor density. Transfection of ERbeta3 also yielded a single transcript and nuclear and membrane receptors with respective Kd values of 1.23 and 1.14 nM; the membrane receptor number was only 2% compared with expressed nuclear receptors. Estradiol binding to CHO-ERalpha or CHO-ERbeta activated Galphaq and G(alpha)s proteins in the membrane and rapidly stimulated corresponding inositol phosphate production and adenylate cyclase activity. Binding by 17-beta-E2 to either expressed receptor comparably enhanced the nuclear incorporation of thymidine, critically dependent upon the activation of the mitogen-activated protein kinase, ERK (extracellular regulated kinase). In contrast, c-Jun N-terminal kinase activity was stimulated by 17-beta-E2 in ERbeta-expressing CHO, but was inhibited in CHO-ERalpha cells. In summary, membrane and nuclear ER can be derived from a single transcript and have near-identical affinities for 17-beta-E2, but there are considerably more nuclear than membrane receptors. This is also the first report that cells can express a membrane ERbeta. Both membrane ERs activate G proteins, ERK, and cell proliferation, but there is novel differential regulation of c-Jun kinase activity by ERbeta and ERalpha.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 May 2015
                2015
                : 10
                : 5
                : e0127595
                Affiliations
                [1 ]Shanghai Medical College, Institute of Reproduction and Development, Fudan University, Shanghai, P. R. China
                [2 ]Key Laboratory of Contraceptive Drugs and Devices of National Population and Family Planning Commission of China, Shanghai Institute of Planned Parenthood Research, Shanghai, P. R. China
                [3 ]Department of Food Science, Shanghai Business School, Shanghai, P. R. China
                [4 ]Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China
                Institute of Zoology, Chinese Academy of Sciences, CHINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ZGS QJC. Performed the experiments: BW YS LY XG. Analyzed the data: XG JW ZGS. Contributed reagents/materials/analysis tools: LY YS. Wrote the paper: BW ZGS.

                Article
                PONE-D-15-02931
                10.1371/journal.pone.0127595
                4444187
                26010950
                11ea9e47-c6a2-4d3f-82bb-8190c00438b4
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 29 January 2015
                : 16 April 2015
                Page count
                Figures: 3, Tables: 3, Pages: 16
                Funding
                The authors were funded by the National Natural Science Foundation of China (81170569, 81370682, both to ZGS); http://isisn.nsfc.gov.cn/egrantweb/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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