{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:39:18Z","timestamp":1792179558536,"version":"4.4.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"5","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,11]]},"abstract":"\nObjective<\/jats:title>\nWe aimed to compare a combined oral contraceptive (COC) plus the antiandrogen spironolactone with the insulin sensitizer metformin in women with polycystic ovary syndrome (PCOS).<\/jats:p>\n<\/jats:sec>\n\nDesign<\/jats:title>\nWe conducted a randomized, parallel, open-label, clinical trial comparing COC (30\u2009\u03bcg of ethinylestradiol and 150\u2009\u03bcg of desogestrel) plus spironolactone (100\u2009mg\/day) with metformin (850\u2009mg b.i.d.) for one year in women with PCOS (EudraCT2008\u2013004531\u201338).<\/jats:p>\n<\/jats:sec>\n\nMethods<\/jats:title>\nThe composite primary outcome included efficacy (amelioration of hirsutism, androgen excess and menstrual dysfunction) and cardiometabolic safety (changes in the frequencies of disorders of glucose tolerance, dyslipidemia and hypertension). A complete anthropometric, biochemical, hormonal and metabolic evaluation was conducted every three months and data were submitted to intention-to-treat analyses.<\/jats:p>\n<\/jats:sec>\n\nResults<\/jats:title>\nTwenty-four patients were assigned to COC plus spironolactone and 22 patients to metformin. Compared with metformin, COC plus spironolactone caused larger decreases in hirsutism score (mean difference 4.6 points, 95% CI: 2.6\u20136.7), total testosterone (1.1\u2009nmol\/L, 0.4\u20131.7), free testosterone (25\u2009pmol\/L, 12\u201339), androstenedione (5.5\u2009nmol\/L, 1.8\u20139.2) and dehydroepiandrosterone sulfate (2.7\u2009\u03bcmol\/L, 1.4\u20134.0). Menstrual dysfunction was less frequent with COC plus spironolactone (OR: 0.06, 95% CI: 0.02\u20130.23). No differences were found in frequencies of abnormal glucose tolerance (OR: 1.7, 95% CI: 0.7\u20134.4), dyslipidemia (OR: 0.6, 95% CI: 0.2\u20131.8) or hypertension (OR: 0.3, 95% CI: 0.5\u20132.0). No major adverse events occurred and biochemical markers were similarly safe with both treatments.<\/jats:p><\/jats:sec>\n\nConclusions<\/jats:title>\nCOC plus spironolactone was more effective than metformin for symptoms of PCOS showing similar safety and overall neutral effects on cardiometabolic risk factors.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-17-0516","type":"journal-article","created":{"date-parts":[[2017,9,15]],"date-time":"2017-09-15T00:50:19Z","timestamp":1505436619000},"page":"399-408","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":30,"title":["Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial"],"prefix":"10.1093","volume":"177","author":[{"given":"Macarena","family":"Alpa\u00f1\u00e9s","sequence":"first","affiliation":[{"name":"Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology & Nutrition, Hospital Universitario Ram\u00f3n y Cajal & Universidad de Alcal\u00e1 & Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria IRYCIS & Centro de Investigaci\u00f3n Biom\u00e9dica en Red Diabetes y Enfermedades Metab\u00f3licas Asociadas CIBERDEM, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"\u00c1lvarez-Blasco","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology & Nutrition, Hospital Universitario Ram\u00f3n y Cajal & Universidad de Alcal\u00e1 & Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria IRYCIS & Centro de Investigaci\u00f3n Biom\u00e9dica en Red Diabetes y Enfermedades Metab\u00f3licas Asociadas CIBERDEM, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Fern\u00e1ndez-Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology & Nutrition, Hospital Universitario Ram\u00f3n y Cajal & Universidad de Alcal\u00e1 & Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria IRYCIS & Centro de Investigaci\u00f3n Biom\u00e9dica en Red Diabetes y Enfermedades Metab\u00f3licas Asociadas CIBERDEM, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Luque-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology & Nutrition, Hospital Universitario Ram\u00f3n y Cajal & Universidad de Alcal\u00e1 & Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria IRYCIS & Centro de Investigaci\u00f3n Biom\u00e9dica en Red Diabetes y Enfermedades Metab\u00f3licas Asociadas CIBERDEM, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor F","family":"Escobar-Morreale","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology & Nutrition, Hospital Universitario Ram\u00f3n y Cajal & Universidad de Alcal\u00e1 & Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria IRYCIS & Centro de Investigaci\u00f3n Biom\u00e9dica en Red Diabetes y Enfermedades Metab\u00f3licas Asociadas CIBERDEM, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"key":"ref21","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.4158\/EP15748.DSC","article-title":"American Association of clinical endocrinologists, American College of endocrinology, and androgen excess and Pcos Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary s\u00edndrome \u2013 part 1","volume":"21","year":"2015","journal-title":"Endocine Practice"},{"key":"ref221","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1080\/13697130500148875","article-title":"Pharmacology of estrogens and progestogens: influence of different routes of administration","volume":"8","year":"2005","journal-title":"Climacteric"},{"key":"ref331","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2337\/dc06-0618","article-title":"Effects of medical therapy on insulin resistance and the cardiovascular system in polycystic ovary syndrome","volume":"30","year":"2007","journal-title":"Diabetes Care"},{"key":"ref281","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1056\/NEJMra041536","article-title":"Polycystic ovary syndrome","volume":"352","year":"2005","journal-title":"New England Journal of Medicine"},{"key":"ref311","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1056\/NEJM199806253382603","article-title":"Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome","volume":"338","year":"1998","journal-title":"New England Journal of Medicine"},{"key":"ref81","first-page":"CD005552","article-title":"Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome","year":"2007","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"ref401","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1093\/humupd\/dmv025","article-title":"Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis","volume":"21","year":"2015","journal-title":"Human Reproduction Update"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.2337\/dc07-0642","article-title":"The increased body iron stores of obese women with polycystic ovary syndrome are a consequence of insulin resistance and hyperinsulinism, and do not result from reduced menstrual losses","volume":"30","year":"2007","journal-title":"Diabetes Care"},{"key":"ref131","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1055\/s-0030-1262855","article-title":"Treatment of polycystic ovary syndrome (PCOS) with metformin ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 concentrations","volume":"42","year":"2010","journal-title":"Hormone and Metabolic Research"},{"key":"ref341","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1210\/jc.2014-1135","article-title":"Body composition is improved during 12 months\u2019 treatment with metformin alone or combined with oral contraceptives compared with treatment with oral contraceptives in polycystic ovary syndrome","volume":"99","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref371","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1093\/humrep\/des225","article-title":"Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study","volume":"27","year":"2012","journal-title":"Human Reproduction"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/0002-9378(81)90746-8","article-title":"Hirsutism: implications, etiology, and management","volume":"140","year":"1981","journal-title":"American Journal of Obstetrics and Gynecology"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1210\/jc.2009-2724","article-title":"Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref291","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1056\/NEJMct0707092","article-title":"Metformin for the treatment of the polycystic ovary syndrome","volume":"358","year":"2008","journal-title":"New England Journal of Medicine"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1210\/jc.2007-0282","article-title":"Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with the polycystic ovary syndrome","volume":"92","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref211","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1210\/jc.2007-2053","article-title":"A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs","volume":"93","year":"2008","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref381","first-page":"CD010334","article-title":"Interventions for hirsutism (excluding laser and photoepilation therapy alone)","year":"2015","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"ref41","first-page":"e25","article-title":"Consensus on women\u2019s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE\/ASRM-Sponsored 3rd PCOS Consensus Workshop Group","volume":"97","year":"2012","journal-title":"Fertility and Sterility"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.tem.2007.07.003","article-title":"Abdominal adiposity and the polycystic ovary syndrome","volume":"18","year":"2007","journal-title":"Trends in Endocrinology and Metabolism"},{"key":"ref111","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/oby.2008.491","article-title":"Antiandrogenic contraceptives increase serum adiponectin in obese polycystic ovary syndrome patients","volume":"17","year":"2009","journal-title":"Obesity"},{"key":"ref361","doi-asserted-by":"crossref","first-page":"3970","DOI":"10.1210\/jc.2005-2250","article-title":"Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref301","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJM199608293350902","article-title":"Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome","volume":"335","year":"1996","journal-title":"New England Journal of Medicine"},{"key":"ref141","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1016\/j.fertnstert.2008.03.082","article-title":"Effects of metformin versus ethinyl-estradiol plus cyproterone acetate on ambulatory blood pressure monitoring and carotid intima media thickness in women with the polycystic ovary syndrome","volume":"91","year":"2009","journal-title":"Fertility and Sterility"},{"key":"ref31","first-page":"1","article-title":"ConwayGDewaillyDDiamanti KandarakisEEscobar polycystic ovary syndrome : a position statement from the European of of","journal-title":"Society Endocrinology European Journal Endocrinology"},{"key":"ref391","first-page":"139","article-title":"Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation","volume":"85","year":"2000","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref251","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.2337\/diacare.22.9.1462","article-title":"Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp","volume":"22","year":"1999","journal-title":"Diabetes Care"},{"key":"ref321","first-page":"1626","article-title":"Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial","volume":"86","year":"2001","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref261","first-page":"1","article-title":"Association Diagnosis and classification of diabetes mellitus Supplement","journal-title":"American Diabetes Diabetes Care"},{"key":"ref181","first-page":"377","article-title":"Diagnostic criteria for polycystic ovary syndrome: towards a rational approach","year":"1992","journal-title":"Polycystic Ovary Syndrome"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1530\/EJE-14-0252","article-title":"European survey of diagnosis and management of the polycystic ovary syndrome: results of the ESE PCOS Special Interest Group's Questionnaire","volume":"171","year":"2014","journal-title":"European Journal of Endocrinology"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1210\/jc.2002-021528","article-title":"A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills","volume":"88","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref151","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1210\/endo-97-1-52","article-title":"Antiandrogenic effect of spirolactones: mechanism of action","volume":"97","year":"1975","journal-title":"Endocrinology"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3109\/09513590.2012.743007","article-title":"Polycystic ovary syndrome and combined oral contraceptive use: a comparison of clinical practice in the United States to treatment guidelines","volume":"29","year":"2013","journal-title":"Gynecological Endocrinology"},{"key":"ref231","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/S0015-0282(00)00718-4","article-title":"Treatment of hirsutism with ethinyl estradiol-desogestrel contraceptive pills has beneficial effects on the lipid profile and improves insulin sensitivity","volume":"74","year":"2000","journal-title":"Fertility and Sterility"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1093\/humupd\/dmr042","article-title":"Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society","volume":"18","year":"2012","journal-title":"Human Reproduction Update"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1093\/humrep\/den095","article-title":"Serum uric acid concentration as non-classic cardiovascular risk factor in women with polycystic ovary syndrome: effect of treatment with ethinyl-estradiol plus cyproterone acetate versus metformin","volume":"23","year":"2008","journal-title":"Human Reproduction"},{"key":"ref01","doi-asserted-by":"crossref","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","year":"2009","journal-title":"Fertility and Sterility"},{"key":"ref241","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.2337\/diacare.21.12.2191","article-title":"Correct homeostasis model assessment (HOMA) evaluation uses the computer program","volume":"21","year":"1998","journal-title":"Diabetes Care"},{"key":"ref161","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1001\/archinte.1961.03620090061007","article-title":"Spironolactone in hypertensive patients. Oligemic and antihypertensive effects","volume":"108","year":"1961","journal-title":"Archives of Internal Medicine"},{"key":"ref351","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1530\/EC-17-0034","article-title":"Effect of oral contraceptives and\/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome","volume":"6","year":"2017","journal-title":"Endocrine Connections"}],"container-title":["European Journal of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/eje.bioscientifica.com\/view\/journals\/eje\/177\/5\/EJE-17-0516.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1530\/EJE-17-0516","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T16:10:59Z","timestamp":1676391059000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ejendo\/article\/177\/5\/399\/6655227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11]]},"references-count":40,"journal-issue":{"issue":"5"},"URL":"https:\/\/doi.org\/10.1530\/eje-17-0516","relation":{},"ISSN":["0804-4643","1479-683X"],"issn-type":[{"value":"0804-4643","type":"print"},{"value":"1479-683X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11]]}}}