{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T16:42:10Z","timestamp":1776098530095,"version":"3.50.1"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Polycystic ovary syndrome (PCOS) is a variable disorder that is characterized in adolescents and young women by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity and low-grade inflammation. At present, there is no approved therapy for PCOS. Recent studies indicate that a low-dose combination of flutamide (Flu; a generic androgen-receptor blocker) and metformin (Met; a generic insulin-sensitizer) normalizes the adolescent PCOS spectrum more than an oral contraceptive (OC); in young women, the PCOS spectrum was found to be more normalized by OC plus Flu-Met than by OC alone. Within the pathophysiological cascade of PCOS, Flu-Met seems to counter upstream anomalies like hyperinsulinemia or hyperandrogenism, thereby preventing or reversing downstream effects. In contrast, an OC essentially masks downstream symptoms like hirsutism, acne or irregular menses, whereas the upstream aberrations remain unaltered or may even be worsened. The available experience with Flu-Met is limited but promising. We emphasize that Flu-Met may (as part of its efficacy) induce ovulation but is contra-indicated post-conception because of potential embryotoxicity; therefore, it seems wise to combine Flu-Met with an oral or a transdermal oestro-progestagen or with a non-endocrine method of contraception. May this update prompt further research into Flu-Met\u2019s therapeutic potential in patients with PCOS. Until the abovementioned effects have been broadly confirmed, Flu-Met should not be regarded as a standard therapy for widespread clinical practice.<\/jats:p>","DOI":"10.1093\/humupd\/dmi054","type":"journal-article","created":{"date-parts":[[2006,1,11]],"date-time":"2006-01-11T20:53:49Z","timestamp":1137012829000},"page":"243-252","source":"Crossref","is-referenced-by-count":80,"title":["Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women"],"prefix":"10.1093","volume":"12","author":[{"given":"Lourdes","family":"Ib\u00e1\u00f1ez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis","family":"de Zegher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2006,1,11]]},"reference":[{"key":"2026041311411955000_ABBOTT-ET-AL-2005","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1093\/humupd\/dmi013","volume":"11","author":"Abbott","year":"2005","journal-title":"Hum Reprod Update"},{"key":"2026041311411955000_ANDRADE-ET-AL-1999","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/S0140-6736(99)00564-4","volume":"353","author":"Andrade","year":"1999","journal-title":"Lancet"},{"key":"2026041311411955000_ASUNCION-ET-AL-2000","first-page":"2434","volume":"85","author":"Asunci\u00f3n","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_AZZIZ-ET-AL-2004A","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1210\/jc.2003-032046","volume":"89","author":"Azziz","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_AZZIZ-ET-AL-2004B","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1210\/jc.2003-031122","volume":"89","author":"Azziz","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_AZZIZ-ET-AL-2005","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1210\/jc.2005-0628","volume":"90","author":"Azziz","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_BAUMANN-AND-ROSENFIELD-2002","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1097\/00019616-200207000-00011","volume":"12","author":"Baumann","year":"2002","journal-title":"Endocrinologist"},{"key":"2026041311411955000_BOULMAN-ET-AL-2004","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1210\/jc.2003-031096","volume":"89","author":"Boulman","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_BUGGS-AND-ROSENFIELD-2005","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.ecl.2005.04.005","volume":"34","author":"Buggs","year":"2005","journal-title":"Endocrinol Metab Clin North Am"},{"key":"2026041311411955000_CHEANG-AND-NESTLER-2004","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/S1472-6483(10)60928-5","volume":"8","author":"Cheang","year":"2004","journal-title":"Reprod Biomed Online"},{"key":"2026041311411955000_CHECA-ET-AL-2005","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1093\/humupd\/dmi015","volume":"11","author":"Checa","year":"2005","journal-title":"Hum Reprod Update"},{"key":"2026041311411955000_CIBULA-ET-AL-2005","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1093\/humrep\/deh588","volume":"20","author":"Cibula","year":"2005","journal-title":"Hum Reprod"},{"key":"2026041311411955000_CUSAN-ET-AL-1994","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0015-0282(16)56518-2","volume":"61","author":"Cusan","year":"1994","journal-title":"Fertil Steril"},{"key":"2026041311411955000_DIAMANTI-KANDARAKIS-ET-AL-1995","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/0026-0495(95)90062-4","volume":"44","author":"Diamanti-Kandarakis","year":"1995","journal-title":"Metabolism"},{"key":"2026041311411955000_DIAMANTI-KANDARAKIS-ET-AL-1998","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1210\/jcem.83.8.5041","volume":"83","author":"Diamanti-Kandarakis","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_DIAMANTI-KANDARAKIS-ET-AL-2003","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1210\/jc.2002-021528","volume":"88","author":"Diamanti-Kandarakis","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_DUNAIF-AND-THOMAS-2000","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev.med.52.1.401","volume":"52","author":"Dunaif","year":"2000","journal-title":"Annu Rev Med"},{"key":"2026041311411955000_DUNAIF-ET-AL-1985","first-page":"545","volume":"66","author":"Dunaif","year":"1985","journal-title":"Obstet Gynecol"},{"key":"2026041311411955000_ELTER-ET-AL-2002","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1093\/humrep\/17.7.1729","volume":"17","author":"Elter","year":"2002","journal-title":"Hum Reprod"},{"key":"2026041311411955000_FERNANDEZ-REAL-ET-AL-1998","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.2337\/diabetes.47.11.1757","volume":"47","author":"Fern\u00e1ndez-Real","year":"1998","journal-title":"Diabetes"},{"key":"2026041311411955000_GAMBINERI-ET-AL-2004","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1365-2265.2004.01973.x","volume":"60","author":"Gambineri","year":"2004","journal-title":"Clin Endocrinol"},{"key":"2026041311411955000_GOLDSTEIN-AND-SCALIA-2004","first-page":"2870","volume":"87","author":"Goldstein","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_GOMEZ-ET-AL-1992","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/0002-9343(92)90741-S","volume":"92","author":"Gomez","year":"1992","journal-title":"Am J Med"},{"key":"2026041311411955000_GONZALEZ-ET-AL-2005","doi-asserted-by":"crossref","first-page":"5336","DOI":"10.1210\/jc.2005-0694","volume":"90","author":"Gonzalez","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-AND-DE-2003A","doi-asserted-by":"crossref","first-page":"4720","DOI":"10.1210\/jc.2003-030117","volume":"88","author":"Ib\u00e1\u00f1ez","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-AND-DE-2003B","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/humrep\/deg056","volume":"18","author":"Ib\u00e1\u00f1ez","year":"2003","journal-title":"Hum Reprod"},{"key":"2026041311411955000_IBANEZ-AND-DE-2004A","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1210\/jc.2003-031281","volume":"89","author":"Ib\u00e1\u00f1ez","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-AND-DE-2004B","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1093\/humrep\/deh329","volume":"19","author":"Ib\u00e1\u00f1ez","year":"2004","journal-title":"Hum Reprod"},{"key":"2026041311411955000_IBANEZ-AND-DE-2005","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1210\/jc.2004-1405","volume":"90","author":"Ib\u00e1\u00f1ez","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-1998","doi-asserted-by":"crossref","first-page":"3558","DOI":"10.1210\/jcem.83.10.5205","volume":"83","author":"Ib\u00e1\u00f1ez","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-2000A","first-page":"3251","volume":"85","author":"Ib\u00e1\u00f1ez","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-2000B","first-page":"3526","volume":"85","author":"Ib\u00e1\u00f1ez","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-2001","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1046\/j.1365-2265.2001.01399.x","volume":"55","author":"Ib\u00e1\u00f1ez","year":"2001","journal-title":"Clin Endocrinol"},{"key":"2026041311411955000_IBANEZ-ET-AL-2002","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1210\/jcem.87.6.8568","volume":"87","author":"Ib\u00e1\u00f1ez","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-2003","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1210\/jc.2002-022002","volume":"88","author":"Ib\u00e1\u00f1ez","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-2004A","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.1210\/jc.2004-0047","volume":"89","author":"Ib\u00e1\u00f1ez","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-2004B","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jpeds.2003.08.015","volume":"144","author":"Ib\u00e1\u00f1ez","year":"2004","journal-title":"J Pediatr"},{"key":"2026041311411955000_IBANEZ-ET-AL-2004C","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1210\/jc.2004-0463","volume":"89","author":"Ib\u00e1\u00f1ez","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_IBANEZ-ET-AL-2005A","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1093\/humrep\/dei004","volume":"20","author":"Ib\u00e1\u00f1ez","year":"2005","journal-title":"Hum Reprod"},{"key":"2026041311411955000_IBANEZ-ET-AL-2005B","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1093\/humrep\/dei072","volume":"20","author":"Ib\u00e1\u00f1ez","year":"2005","journal-title":"Hum Reprod"},{"key":"2026041311411955000_IBANEZ-ET-AL-2005C","author":"Ib\u00e1\u00f1ez","year":"2005","journal-title":"Hum Reprod"},{"key":"2026041311411955000_KASHYAP-ET-AL-2004","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1093\/humrep\/deh440","volume":"11","author":"Kashyap","year":"2004","journal-title":"Hum Reprod"},{"key":"2026041311411955000_KELLY-ET-AL-2001","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1210\/jcem.86.6.7580","volume":"86","author":"Kelly","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_KIRCHENGAST-AND-HUBER-2001","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/humrep\/16.6.1255","volume":"16","author":"Kirchengast","year":"2001","journal-title":"Hum Reprod"},{"key":"2026041311411955000_LA-ET-AL-2005","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ejogrb.2004.09.015","volume":"121","author":"La Marca","year":"2005","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2026041311411955000_LABRIE-ET-AL-1988","first-page":"41","volume":"260","author":"Labrie","year":"1988","journal-title":"Prog Clin Biol Res"},{"key":"2026041311411955000_LORD-ET-AL-2003","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1136\/bmj.327.7421.951","volume":"327","author":"Lord","year":"2003","journal-title":"BMJ"},{"key":"2026041311411955000_LUTHY-ET-AL-1988","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/0022-4731(88)90295-6","volume":"31","author":"Luthy","year":"1988","journal-title":"J Steroid Biochem"},{"key":"2026041311411955000_MASTORAKOS-ET-AL-2002","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0015-0282(02)02993-X","volume":"77","author":"Mastorakos","year":"2002","journal-title":"Fertil Steril"},{"key":"2026041311411955000_MITKOV-ET-AL-2005","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ejogrb.2004.06.035","volume":"118","author":"Mitkov","year":"2005","journal-title":"Eur J Obstet Gynecol"},{"key":"2026041311411955000_MORIN-PAPUNEN-ET-AL-2003A","doi-asserted-by":"crossref","first-page":"4649","DOI":"10.1210\/jc.2002-021688","volume":"88","author":"Morin-Papunen","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_MORIN-PAPUNEN-ET-AL-2003B","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1210\/jc.2002-020997","volume":"88","author":"Morin-Papunen","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_MUDERRIS-ET-AL-2000","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3109\/09513590009167658","volume":"14","author":"Muderris","year":"2000","journal-title":"Gynecol Endocrinol"},{"key":"2026041311411955000_NESTLER-2001","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1210\/jcem.86.3.7352-9","volume":"86","author":"Nestler","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_ORIO-ET-AL-2004","doi-asserted-by":"crossref","first-page":"4588","DOI":"10.1210\/jc.2003-031867","volume":"89","author":"Orio","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_ORIO-ET-AL-2005","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1210\/jc.2004-0628","volume":"90","author":"Orio","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_POYET-AND-LABRIE-1985","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/0303-7207(85)90059-0","volume":"42","author":"Poyet","year":"1985","journal-title":"Mol Cell Endocrinol"},{"key":"2026041311411955000_RAUTIO-ET-AL-2005","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1530\/eje.1.01840","volume":"152","author":"Rautio","year":"2005","journal-title":"Eur J Endocrinol"},{"key":"2026041311411955000_REXRODE-ET-AL-2003","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/S1047-2797(03)00053-X","volume":"13","author":"Rexrode","year":"2003","journal-title":"Ann Epidemiol"},{"key":"2026041311411955000_SAHIN-ET-AL-2004","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/09513590400004736","volume":"19","author":"Sahin","year":"2004","journal-title":"Gynecol Endocrinol"},{"key":"2026041311411955000_SETO-YOUNG-ET-AL-2005","doi-asserted-by":"crossref","first-page":"6099","DOI":"10.1210\/jc.2005-0469","volume":"90","author":"Seto-Young","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_SINGH-ET-AL-2000","doi-asserted-by":"crossref","first-page":"211","DOI":"10.2174\/0929867003375371","volume":"7","author":"Singh","year":"2000","journal-title":"Curr Med Chem"},{"key":"2026041311411955000_SJOHOLM-AND-NYSTROM-2005","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/S0140-6736(05)70804-7","volume":"365","author":"Sj\u00f6holm","year":"2005","journal-title":"Lancet"},{"key":"2026041311411955000_STEIN-AND-LEVENTHAL-1935","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0002-9378(15)30642-6","volume":"29","author":"Stein","year":"1935","journal-title":"Am J Obstet Gynecol"},{"key":"2026041311411955000_STOUT-AND-FUGATE-2005","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1592\/phco.25.2.244.56943","volume":"25","author":"Stout","year":"2005","journal-title":"Pharmacotherapy"},{"key":"2026041311411955000_TARKUN-ET-AL-2004","doi-asserted-by":"crossref","first-page":"5592","DOI":"10.1210\/jc.2004-0751","volume":"89","author":"Tarkun","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026041311411955000_TARKUN-ET-AL-2005","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1530\/eje.1.01948","volume":"153","author":"Tarkun","year":"2005","journal-title":"Eur J Endocrinol"},{"key":"2026041311411955000_THE-2004","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/humrep\/deh098","volume":"19","year":"2004","journal-title":"Hum Reprod"},{"key":"2026041311411955000_THOLE-ET-AL-2004","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1159\/000081585","volume":"73","author":"Thole","year":"2004","journal-title":"Urol Int"},{"key":"2026041311411955000_VELAZQUEZ-ET-AL-1994","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/0026-0495(94)90209-7","volume":"43","author":"Velazquez","year":"1994","journal-title":"Metabolism"},{"key":"2026041311411955000_VENTUROLI-ET-AL-2001","first-page":"25","volume":"56","author":"Venturoli","year":"2001","journal-title":"Horm Res"},{"key":"2026041311411955000_VRBIKOVA-AND-CIBULA-2005","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/humupd\/dmi005","volume":"11","author":"Vrbikova","year":"2005","journal-title":"Hum Reprod Update"},{"key":"2026041311411955000_VURAL-ET-AL-2005","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1093\/humrep\/dei100","volume":"20","author":"Vural","year":"2005","journal-title":"Hum Reprod"},{"key":"2026041311411955000_WALLACE-ET-AL-1993","volume":"119","author":"Wallace","year":"1993","journal-title":"Ann Intern Med"},{"key":"2026041311411955000_WYSOWSKI-AND-FOURCROY-1996","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0022-5347(01)66596-0","volume":"155","author":"Wysowski","year":"1996","journal-title":"J Urol"},{"key":"2026041311411955000_WYSOWSKI-ET-AL-1993","doi-asserted-by":"crossref","first-page":"860","DOI":"10.7326\/0003-4819-118-11-199306010-00006","volume":"118","author":"Wysowski","year":"1993","journal-title":"Ann Intern Med"}],"container-title":["Human Reproduction Update"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humupd\/article-pdf\/12\/3\/243\/68064718\/humupd_12_3_243.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humupd\/article-pdf\/12\/3\/243\/68064718\/humupd_12_3_243.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T15:41:42Z","timestamp":1776094902000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humupd\/article\/12\/3\/243\/553949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,1,11]]},"references-count":76,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2006,1,11]]},"published-print":{"date-parts":[[2006,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/humupd\/dmi054","relation":{},"ISSN":["1460-2369","1355-4786"],"issn-type":[{"value":"1460-2369","type":"electronic"},{"value":"1355-4786","type":"print"}],"subject":[],"published-other":{"date-parts":[[2006,5]]},"published":{"date-parts":[[2006,1,11]]}}}