{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T07:57:33Z","timestamp":1774166253342,"version":"3.50.1"},"reference-count":41,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":3425,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Ovarian cysts affect women of all ages and decrease fertility. In particular, polycystic ovarian syndrome (PCOS), with multiple follicular cysts, affects 5-10% of women of reproductive age and can result in infertility. Current non-invasive treatments for PCOS can resolve cysts and restore fertility, but unresponsive patients must undergo severe ovarian wedge resection and resort to in vitro fertilization. PCOS is related to the deregulation of leutinizing hormone (LH) signaling at various levels of the hypothalamic-pituitary-ovarian axis and resultant hyper-production of androgens. As insulin resistance and compensatory hyperinsulemia are observed in 50-70% of PCOS patients, deregulated insulin signaling in the ovary is considered an important factor in the disease. Here we report that aged mice, specifically lacking the PKB\u03b2\/AKT2 isoform that is crucial for insulin signaling, develop increased testosterone levels and ovarian cysts also observed in insulin resistant PCOS patients. Young PKB\u03b2\/AKT2 knockout mice subjected to a mouse model of PCOS, by treatment with LH, exhibited a cyst area threefold greater than controls, but without hyperinsulemia. Thus, loss of PKB\u03b2\/AKT2 may predispose mice to ovarian cysts independent of hyperactive insulin signaling. Targeted therapeutic augmentation of specific PKB\u03b2\/AKT2 signaling may therefore provide a new avenue for the treatment and management of ovarian cysts.<\/jats:p>","DOI":"10.1242\/dmm.008136","type":"journal-article","created":{"date-parts":[[2012,1,25]],"date-time":"2012-01-25T05:00:13Z","timestamp":1327467613000},"source":"Crossref","is-referenced-by-count":16,"title":["Loss of PKB\u03b2\/Akt2 predisposes mice to ovarian cyst formation and increases the severity of polycystic ovary formation in vivo"],"prefix":"10.1242","author":[{"given":"David F.","family":"Restuccia","sequence":"first","affiliation":[{"name":"Friedrich Miescher Institute, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debby","family":"Hynx","sequence":"additional","affiliation":[{"name":"Friedrich Miescher Institute, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian A.","family":"Hemmings","sequence":"additional","affiliation":[{"name":"Friedrich Miescher Institute, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2012,1,1]]},"reference":[{"key":"2021042500561035300_b1-0050403","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/978-1-4684-5395-9_38","article-title":"Induction of follicular cysts in rat ovaries by prolonged administration of human chorionic gonadotropin","volume":"219","author":"Bogovich","year":"1987","journal-title":"Adv. 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Invest."},{"key":"2021042500561035300_b13-0050403","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/BF00216340","article-title":"Morphological studies of polycystic mouse ovaries induced by dehydroepiandrosterone","volume":"240","author":"Familiari","year":"1985","journal-title":"Cell Tissue Res."},{"key":"2021042500561035300_b14-0050403","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1172\/JCI16885","article-title":"Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2\/PKB beta","volume":"112","author":"Garofalo","year":"2003","journal-title":"J. Clin. 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Endocrinol."},{"key":"2021042500561035300_b24-0050403","doi-asserted-by":"crossref","first-page":"3781","DOI":"10.1210\/en.2007-0168","article-title":"A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome","volume":"148","author":"Manneras","year":"2007","journal-title":"Endocrinology"},{"key":"2021042500561035300_b25-0050403","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1677\/joe.0.1000133","article-title":"Modulation of rat pituitary gonadotrophin secretion by porcine granulosa cell \u2018inhibin\u2019, LH releasing hormone and sex steroids in rat anterior pituitary cells in culture","volume":"100","author":"Massicotte","year":"1984","journal-title":"J. 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