{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T03:36:52Z","timestamp":1790134612362,"version":"4.0.1"},"reference-count":48,"publisher":"Portland Press Ltd.","issue":"7","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,4,16]]},"abstract":"<jats:p>Polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, is a complex endocrinopathy that affects the fertility of 9\u201318% of reproductive-aged women. However, the exact mechanism of PCOS, especially hyperandrogen-induced anovulation, is largely unknown to date. Physiologically, the natriuretic peptide type C\/natriuretic peptide receptor 2 (CNP\/NPR2) system is essential for sustaining oocyte meiotic arrest until the preovulatory luteinizing hormone (LH) surge. We therefore hypothesized that the CNP\/NPR2 system is also involved in PCOS and contributes to arresting oocyte meiosis and ovulation. Here, based on a dehydroepiandrosterone (DHEA)-induced PCOS-like mouse model, persistent high levels of CNP\/NPR2 were detected in anovulation ovaries. Meanwhile, oocytes arrested at the\u00a0germinal vesicle stage correlated with persistent high levels of androgen and estrogen. We further showed that ovulation failure in these mice could be a result of elevated Nppc\/Npr2 gene transcription that was directly increased by androgen (AR) and estrogen (ER) receptor signaling. Consistent with this, anovulation was alleviated by administration of either exogenous human chorionic gonadotropin (hCG) or inhibitors of AR or ER to reduce the level of CNP\/NPR2. Additionally, the CNP\/NPR2 expression pattern in the anovulated follicles was, to some extent, consistent with the clinical expression in PCOS patients. Therefore, our study highlights the important role an overactive CNP\/NPR2 system caused by hyperandrogenism in preventing oocytes from maturation and ovulation in PCOS mice. Our findings provide insight into potential mechanisms responsible for infertility in women with PCOS.<\/jats:p>","DOI":"10.1042\/cs20171394","type":"journal-article","created":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T00:35:19Z","timestamp":1520987719000},"page":"759-776","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["High level of C-type natriuretic peptide induced by hyperandrogen-mediated anovulation in polycystic ovary syndrome mice"],"prefix":"10.1042","volume":"132","author":[{"given":"Xiao","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huarong","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhao","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoliang","family":"Xia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2018,4,6]]},"reference":[{"key":"2021113011001115100_B1","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1093\/humrep\/dep399","article-title":"The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria","volume":"25","author":"March","year":"2010","journal-title":"Hum. Reprod."},{"key":"2021113011001115100_B2","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1210\/jc.2003-032046","article-title":"The prevalence and features of the polycystic ovary syndrome in an unselected population","volume":"89","author":"Azziz","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113011001115100_B3","doi-asserted-by":"publisher","first-page":"E3334","DOI":"10.1073\/pnas.1616467114","article-title":"Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome","volume":"114","author":"Caldwell","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113011001115100_B4","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1210\/er.16.3.322","article-title":"Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion","volume":"16","author":"Ehrmann","year":"1995","journal-title":"Endocr. Rev."},{"key":"2021113011001115100_B5","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1016\/S0015-0282(02)02985-0","article-title":"Androgen production in women","volume":"77","author":"Burger","year":"2002","journal-title":"Fertil. Steril."},{"key":"2021113011001115100_B6","doi-asserted-by":"publisher","first-page":"4237","DOI":"10.1210\/jc.2006-0178","article-title":"Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline","volume":"91","author":"Azziz","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113011001115100_B7","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.fertnstert.2008.06.035","article-title":"The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report","volume":"91","author":"Azziz","year":"2009","journal-title":"Fertil. Steril."},{"key":"2021113011001115100_B8","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1210\/jc.2004-2301","article-title":"Degree of facial and body terminal hair growth in unselected black and white women: toward a populational definition of hirsutism","volume":"91","author":"DeUgarte","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113011001115100_B9","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.1210\/jc.2004-2279","article-title":"Phenotypic variation in hyperandrogenic women influences the findings of abnormal metabolic and cardiovascular risk parameters","volume":"90","author":"Carmina","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113011001115100_B10","doi-asserted-by":"publisher","first-page":"2107","DOI":"10.1093\/oxfordjournals.humrep.a136243","article-title":"Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients","volume":"10","author":"Balen","year":"1995","journal-title":"Hum. Reprod."},{"key":"2021113011001115100_B11","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/0026-0495(94)90209-7","article-title":"Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy","volume":"43","author":"Velazquez","year":"1994","journal-title":"Metabolism"},{"key":"2021113011001115100_B12","first-page":"CD003053","article-title":"Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility","volume":"5","author":"Tang","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"2021113011001115100_B13","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1093\/humupd\/dmi005","article-title":"Combined oral contraceptives in the treatment of polycystic ovary syndrome","volume":"11","author":"Vrbikova","year":"2005","journal-title":"Hum. Reprod. Update"},{"key":"2021113011001115100_B14","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1016\/j.fertnstert.2008.09.018","article-title":"Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society","volume":"92","author":"Moran","year":"2009","journal-title":"Fertil. Steril."},{"key":"2021113011001115100_B15","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1126\/science.1193573","article-title":"Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes","volume":"330","author":"Zhang","year":"2010","journal-title":"Science"},{"key":"2021113011001115100_B16","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1095\/biolreprod56.1.59","article-title":"C-type natriuretic peptide and the guanylyl cyclase receptors in the rat ovary are modulated by the estrous cycle","volume":"56","author":"Jankowski","year":"1997","journal-title":"Biol. Reprod."},{"key":"2021113011001115100_B17","doi-asserted-by":"publisher","first-page":"4377","DOI":"10.1210\/en.2011-1118","article-title":"Estradiol promotes and maintains cumulus cell expression of natriuretic peptide receptor 2 (NPR2) and meiotic arrest in mouse oocytes in vitro","volume":"152","author":"Zhang","year":"2011","journal-title":"Endocrinology"},{"key":"2021113011001115100_B18","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1002\/jcp.24682","article-title":"Brain natriuretic peptide and C-type natriuretic peptide maintain porcine oocyte meiotic arrest","volume":"230","author":"Zhang","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"2021113011001115100_B19","doi-asserted-by":"publisher","first-page":"3094","DOI":"10.1093\/humrep\/der282","article-title":"Pre-ovulatory LH\/hCG surge decreases C-type natriuretic peptide secretion by ovarian granulosa cells to promote meiotic resumption of pre-ovulatory oocytes","volume":"26","author":"Kawamura","year":"2011","journal-title":"Hum. Reprod."},{"key":"2021113011001115100_B20","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1146\/annurev-physiol-022516-034102","article-title":"Regulation of mammalian oocyte meiosis by intercellular communication within the ovarian follicle","volume":"79","author":"Jaffe","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"2021113011001115100_B21","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0303-7207(02)00052-7","article-title":"Ovarian steroid receptors and their role in ovarian function","volume":"191","author":"Drummond","year":"2002","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021113011001115100_B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/10409230290771438","article-title":"Biological role of estrogen and estrogen receptors","volume":"37","author":"Nilsson","year":"2002","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"2021113011001115100_B23","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1477-7827-4-16","article-title":"The role of steroids in follicular growth","volume":"4","author":"Drummond","year":"2006","journal-title":"Reprod. Biol. Endocrinol."},{"key":"2021113011001115100_B24","doi-asserted-by":"publisher","first-page":"e2662","DOI":"10.1038\/cddis.2017.82","article-title":"Estrogen receptors in granulosa cells govern meiotic resumption of pre-ovulatory oocytes in mammals","volume":"8","author":"Liu","year":"2017","journal-title":"Cell. Death Dis."},{"key":"2021113011001115100_B25","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1210\/endo.141.2.7305","article-title":"B-type natriuretic peptide receptor expression and activity are hormonally regulated in rat ovarian cells","volume":"141","author":"Noubani","year":"2000","journal-title":"Endocrinology"},{"key":"2021113011001115100_B26","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/0303-7207(94)90278-X","article-title":"Follicular oestrogen synthesis: the \u2018two-cell, two-gonadotrophin\u2019 model revisited","volume":"100","author":"Hillier","year":"1994","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021113011001115100_B27","doi-asserted-by":"publisher","first-page":"S6","DOI":"10.1016\/S0015-0282(02)02984-9","article-title":"Aromatization of androgens in women: current concepts and findings","volume":"77","author":"Simpson","year":"2002","journal-title":"Fertil. Steril."},{"key":"2021113011001115100_B28","doi-asserted-by":"publisher","first-page":"442","DOI":"10.4103\/1008-682X.161600","article-title":"Androgen receptor splice variants and polycystic ovary syndrome: cause or effect?","volume":"18","author":"Walters","year":"2016","journal-title":"Asian J. Androl."},{"key":"2021113011001115100_B29","doi-asserted-by":"publisher","first-page":"4743","DOI":"10.1073\/pnas.1418216112","article-title":"Alternative splicing of the androgen receptor in polycystic ovary syndrome","volume":"112","author":"Wang","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113011001115100_B30","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1530\/jrf.0.0320221","article-title":"Plasma LH and FSH during different oestrous cycle conditions in mice","volume":"32","author":"Murr","year":"1973","journal-title":"J. Reprod. Fertil."},{"key":"2021113011001115100_B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1095\/biolreprod.112.104810","article-title":"Hormonal coordination of natriuretic peptide type C and natriuretic peptide receptor 3 expression in mouse granulosa cells","volume":"88","author":"Lee","year":"2013","journal-title":"Biol. Reprod."},{"key":"2021113011001115100_B32","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1099\/0022-1317-36-1-59","article-title":"Characteristics of a human cell line transformed by DNA from human adenovirus type 5","volume":"36","author":"Graham","year":"1977","journal-title":"J. Gen. Virol."},{"key":"2021113011001115100_B33","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1093\/molehr\/6.2.146","article-title":"Characterization of an immortalized human granulosa cell line (COV434)","volume":"6","author":"Zhang","year":"2000","journal-title":"Mol. Hum. Reprod."},{"key":"2021113011001115100_B34","doi-asserted-by":"publisher","first-page":"3594","DOI":"10.1242\/dev.112219","article-title":"Dephosphorylation and inactivation of NPR2 guanylyl cyclase in granulosa cells contributes to the LH-induced decrease in cGMP that causes resumption of meiosis in rat oocytes","volume":"141","author":"Egbert","year":"2014","journal-title":"Development"},{"key":"2021113011001115100_B35","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.steroids.2013.05.005","article-title":"Ovulation induction in women with polycystic ovary syndrome","volume":"78","author":"Perales-Puchalt","year":"2013","journal-title":"Steroids"},{"key":"2021113011001115100_B36","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1385\/ENDO:30:1:27","article-title":"Infertility in polycystic ovary syndrome: focus on low-dose gonadotropin treatment","volume":"30","author":"Gorry","year":"2006","journal-title":"Endocrine"},{"key":"2021113011001115100_B37","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.yfrne.2012.02.002","article-title":"A comparison of the neuroendocrine mechanisms underlying the initiation of the preovulatory LH surge in the human, Old World monkey and rodent","volume":"33","author":"Plant","year":"2012","journal-title":"Front. Neuroendocrinol."},{"key":"2021113011001115100_B38","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1097\/MED.0b013e32832afd4d","article-title":"Androgens and polycystic ovary syndrome","volume":"16","author":"Nisenblat","year":"2009","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"2021113011001115100_B39","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1002\/ar.1092310206","article-title":"Changes in ovarian morphology and serum hormones in the rat after treatment with dehydroepiandrosterone","volume":"231","author":"Lee","year":"1991","journal-title":"Anat. Rec."},{"key":"2021113011001115100_B40","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1002\/ar.1092340307","article-title":"Cystogenesis of the ovarian antral follicle of the rat: ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone","volume":"234","author":"Anderson","year":"1992","journal-title":"Anat. Rec."},{"key":"2021113011001115100_B41","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1093\/molehr\/gap089","article-title":"Demethylation of LHR in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome","volume":"16","author":"Zhu","year":"2010","journal-title":"Mol. Hum. Reprod."},{"key":"2021113011001115100_B42","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nrendo.2010.217","article-title":"Polycystic ovary syndrome: etiology, pathogenesis and diagnosis","volume":"7","author":"Goodarzi","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"2021113011001115100_B43","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMcp1514916","article-title":"Polycystic ovary syndrome","volume":"375","author":"McCartney","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"2021113011001115100_B44","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/S0889-8529(05)70077-3","article-title":"Antiandrogen treatment of polycystic ovary syndrome","volume":"28","author":"Rittmaster","year":"1999","journal-title":"Endocrinol. Metab. Clin. North. Am."},{"key":"2021113011001115100_B45","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1056\/NEJMoa063971","article-title":"Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome","volume":"356","author":"Legro","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"2021113011001115100_B46","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.steroids.2011.12.007","article-title":"Neuroendocrine dysfunction in polycystic ovary syndrome","volume":"77","author":"Burt","year":"2012","journal-title":"Steroids"},{"key":"2021113011001115100_B47","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1055\/s-2007-984741","article-title":"Neuroendocrine effects of androgens in adult polycystic ovary syndrome and female puberty","volume":"25","author":"Blank","year":"2007","journal-title":"Semin. Reprod. Med."},{"key":"2021113011001115100_B48","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1073\/pnas.1415038112","article-title":"Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome","volume":"112","author":"Moore","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/132\/7\/759\/446819\/cs-2017-1394.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/132\/7\/759\/446819\/cs-2017-1394.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T11:52:42Z","timestamp":1638273162000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/132\/7\/759\/72037\/High-level-of-C-type-natriuretic-peptide-induced"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,6]]},"references-count":48,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2018,4,16]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20171394","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,6]]}}}