{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:08:11Z","timestamp":1790316491825,"version":"4.1.0"},"reference-count":14,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Follistatin is a glycoprotein that represses members of the transforming growth factor-\u03b2 superfamily including activin. Higher follistatin levels have been associated with an increased risk for type 2 diabetes and with polycystic ovary syndrome (PCOS). In non-obese adolescent girls with PCOS, insulin sensitization results in a healthier endocrine-metabolic outcome than oral contraception (OC); we assessed whether those differences are underscored by changes in serum follistatin concentrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Circulating follistatin, endocrine-metabolic markers and hepato-visceral fat were measured longitudinally in 72 girls with PCOS [age, 16 years; body mass index (BMI), 23 Kg\/m<jats:sup>2<\/jats:sup>] randomized to receive PioFluMet [pioglitazone (7.5 mg\/d), metformin (850 mg\/d) and flutamide (62.5 mg\/d), n=17]; EE-CA [an OC containing 35 \u00b5g ethinylestradiol (EE) and 2 mg cyproterone acetate (CA), n=17]; SPIOMET [Spironolactone (50 mg\/d), pioglitazone (7.5 mg\/d) and metformin (850 mg\/d), n=18], or EE-LNG [an OC containing 20 \u00b5g EE and 100 mg levonorgestrel (LNG), n=20]. Twenty-eight age- and BMI-matched healthy girls served as controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pre-treatment follistatin levels were similar in PCOS and controls. OCs raised serum follistatin after 6 months (6.8-fold vs 2.5-fold for EE-CA and EE-LNG, respectively). Neither SPIOMET nor PioFluMet changed follistatin levels. Follistatin correlated negatively with high-molecular weight adiponectin and positively with mean serum insulin concentrations during an oral glucose tolerance test at baseline, and with liver fat after 6 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In girls with PCOS, follistatin levels rise significantly after 6 months on OCs and this increase associates to a worsening of markers of insulin resistance and to changes in liver fat.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1125569","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T09:03:39Z","timestamp":1675933419000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Circulating follistatin concentrations in adolescent PCOS: Divergent effects of randomized treatments"],"prefix":"10.3389","volume":"14","author":[{"given":"Marta","family":"D\u00edaz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"de Zegher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourdes","family":"Ib\u00e1\u00f1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2018.09.005","article-title":"Central obesity, faster maturation, and 'PCOS' in girls","volume":"29","author":"de Zegher","year":"2018","journal-title":"Trends Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1671","article-title":"Treatment of androgen excess in adolescent girls: ethinylestradiol-cyproteroneacetate versus low-dose pioglitazone-flutamide-metformin","volume":"96","author":"Ib\u00e1\u00f1ez","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-1754","article-title":"Ethinyl estradiol-cyproterone acetate versus low-dose pioglitazone-flutamide-metformin for adolescent girls with androgen excess: divergent effects on CD163, TWEAK receptor, ANGPTL4, and LEPTIN expression in subcutaneous adipose tissue","volume":"97","author":"D\u00edaz","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jadohealth.2017.04.010","article-title":"Normalizing ovulation rate by preferential reduction of hepato-visceral fat in adolescent girls with polycystic ovary syndrome","volume":"61","author":"Ib\u00e1\u00f1ez","year":"2017","journal-title":"J Adolesc Health"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvaa032","article-title":"Toward a treatment normalizing ovulation rate in adolescent girls with polycystic ovary syndrome","volume":"4","author":"Ib\u00e1\u00f1ez","year":"2020","journal-title":"J Endocr Soc"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291x(87)90430-x","article-title":"The isolation of polypeptides with FSH suppressing activity from bovine follicular fluid which are structurally different to inhibin","volume":"149","author":"Robertson","year":"1987","journal-title":"Biochem Biophys Res Commun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1998","DOI":"10.1210\/me.2010-0127","article-title":"Regulation of muscle mass by follistatin and activins","volume":"24","author":"Lee","year":"2010","journal-title":"Mol Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"6486","DOI":"10.1038\/s41467-021-26536-w","article-title":"Elevated circulating follistatin associates with an increased risk of type 2 diabetes","volume":"12","author":"Wu","year":"2021","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2013.05.003","article-title":"Follistatin and activins in polycystic ovary syndrome: relationship to metabolic and hormonal markers","volume":"62","author":"Teede","year":"2013","journal-title":"Metabolism"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0246200","article-title":"Circulating resistin and follistatin levels in obese and non-obese women with polycystic ovary syndrome: A systematic review and meta-analysis","volume":"16","author":"Raeisi","year":"2021","journal-title":"PloS One"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2016.07.009","article-title":"Activin a and follistatin in patients with nonalcoholic fatty liver disease","volume":"65","author":"Polyzos","year":"2016","journal-title":"Metabolism"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dep459","article-title":"Increased follistatin levels after oral contraceptive treatment in obese and non-obese women with polycystic ovary syndrome","volume":"25","author":"Chen","year":"2010","journal-title":"Hum Reprod"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa682","article-title":"Effects of oral contraception and lifestyle modification on incretins and TGF-\u00df superfamily hormones in PCOS","volume":"106","author":"Shah","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3390\/metabo4020394","article-title":"Adiponectin isoforms differentially affect gene expression and the lipidome of primary human hepatocytes","volume":"4","author":"Wanninger","year":"2014","journal-title":"Metabolites"}],"container-title":["Frontiers in 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