{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T01:58:39Z","timestamp":1792979919497,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["SNF-162608, SNF-177578, SNF- 199391"],"award-info":[{"award-number":["SNF-162608, SNF-177578, SNF- 199391"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT209492\/Z\/17\/Z"],"award-info":[{"award-number":["WT209492\/Z\/17\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels \u2265 1.7 nmol\/L, and C-reactive protein (CRP) \u2265 1.0 mg\/L. Patients received 100 mg\/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography\u2013tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Median [interquartile range (IQR)] androstenedione increased by 0.5 [\u22120.1, 1.6] nmol\/L (<jats:italic>p<\/jats:italic> = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol\/L [<jats:italic>p<\/jats:italic> = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (<jats:italic>p<\/jats:italic> &amp;lt; 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and\/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings suggest that anakinra suppresses IL-1-mediated chronic low-grade inflammation in PCOS and might attenuate biochemical hyperandrogenemia.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1435698","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T15:17:54Z","timestamp":1726067874000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Effects of interleukin-1 receptor antagonism in women with polycystic ovary syndrome\u2014the FertIL trial"],"prefix":"10.3389","volume":"15","author":[{"given":"Milica","family":"W\u00e4lchli-Popovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Monnerat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela E.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorna C.","family":"Gilligan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Schiffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Arlt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah R.","family":"Vogt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"De Geyter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Hutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc Y.","family":"Donath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Sartorius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Christ-Crain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2018.24","article-title":"Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment","volume":"14","author":"Escobar-Morreale","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMcp1514916","article-title":"CLINICAL PRACTICE. Polycystic ovary syndrome","volume":"375","author":"McCartney","year":"2016","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1210\/er.2011-1034","article-title":"Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications","volume":"33","author":"Diamanti-Kandarakis","year":"2012","journal-title":"Endocr Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(02)03111-4","article-title":"Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus","volume":"77","author":"Ovalle","year":"2002","journal-title":"Fertil Steril"},{"key":"B5","doi-asserted-by":"publisher","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","author":"Wild","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1089\/jwh.2018.7162","article-title":"Is there really increased cardiovascular morbidity in women with polycystic ovary syndrome","volume":"27","author":"Carmina","year":"2018","journal-title":"J Womens Health (Larchmt)"},{"key":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0628","article-title":"Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span","volume":"90","author":"Azziz","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s12958-016-0173-x","article-title":"Genetic, hormonal and metabolic aspects of PCOS: an update","volume":"14","author":"De Leo","year":"2016","journal-title":"Reprod Biol Endocrinol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1016\/j.fertnstert.2010.11.036","article-title":"Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis","volume":"95","author":"Escobar-Morreale","year":"2011","journal-title":"Fertil Steril"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2018.05.004","article-title":"Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"110","author":"Teede","year":"2018","journal-title":"Fertil Steril"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00163-2","article-title":"Polycystic ovary syndrome","volume":"10","author":"Joham","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.fertnstert.2011.11.023","article-title":"Is PCOS an inflammatory process","volume":"97","author":"Duleba","year":"2012","journal-title":"Fertil Steril"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-1002","article-title":"Central fat excess in polycystic ovary syndrome: relation to low-grade inflammation and insulin resistance","volume":"90","author":"Puder","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1042\/bj3100143","article-title":"The effect of interleukin-1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level","volume":"310","author":"Zhang","year":"1995","journal-title":"Biochem J"},{"key":"B16","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nri3452","article-title":"Activation and regulation of the inflammasomes","volume":"13","author":"Latz","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041570126","article-title":"Role of glucose in interleukin-1 beta production by lipopolysaccharide-activated human monocytes","volume":"157","author":"Orlinska","year":"1993","journal-title":"J Cell Physiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1055\/s-00000072","article-title":"Nutrient-induced inflammation in polycystic ovary syndrome: role in the development of metabolic aberration and ovarian dysfunction","volume":"33","author":"Gonz\u00e1lez","year":"2015","journal-title":"Semin Reprod Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4275","article-title":"Targeting inflammation in the treatment of type 2 diabetes: time to start","volume":"13","author":"Donath","year":"2014","journal-title":"Nat Rev Drug Discovery"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.09.028","article-title":"Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond","volume":"70","author":"Libby","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1210\/en.2019-00588","article-title":"Inflammatory stimuli trigger increased androgen production and shifts in gene expression in theca-interstitial cells","volume":"160","author":"Fox","year":"2019","journal-title":"Endocrinology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-019-00737-4","article-title":"Chronic low-grade inflammation in polycystic ovary syndrome: is there a (patho)-physiological role for interleukin-1","volume":"41","author":"Popovic","year":"2019","journal-title":"Semin Immunopathol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioy096","article-title":"Polycystic ovary syndrome: possible involvement of androgen-induced, chemerin-mediated ovarian recruitment of monocytes\/macrophages","volume":"99","author":"Lima","year":"2018","journal-title":"Biol Reprod"},{"key":"B24","doi-asserted-by":"publisher","first-page":"E744","DOI":"10.1152\/ajpendo.00228.2020","article-title":"Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome","volume":"319","author":"Gonz\u00e1lez","year":"2020","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B25","unstructured":"Kineret : EPAR - product information2009"},{"key":"B26","unstructured":"Kineret (Anakinra) - prescribing information"},{"key":"B27","article-title":"Classification of acne","volume":"17","author":"Kligman","year":"1976","journal-title":"Cutis"},{"key":"B28","doi-asserted-by":"publisher","first-page":"123413","DOI":"10.1016\/j.jchromb.2022.123413","article-title":"Multi-steroid profiling by UHPLC-MS\/MS with post-column infusion of ammonium fluoride","volume":"1209","author":"Schiffer","year":"2022","journal-title":"J Chromatogr B Analyt Technol BioMed Life Sci"},{"key":"B29","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1093\/ejendo\/lvac017","article-title":"Classic and 11-oxygenated androgens in serum and saliva across adulthood: a cross-sectional study analyzing the impact of age, body mass index, and diurnal and menstrual cycle variation","volume":"188","author":"Schiffer","year":"2023","journal-title":"Eur J Endocrinol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/BF03401383","article-title":"A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome","volume":"14","author":"Jensterle","year":"2015","journal-title":"Hormones (Athens)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1210\/er.2015-1104","article-title":"The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited","volume":"37","author":"Rosenfield","year":"2016","journal-title":"Endocr Rev"},{"key":"B32","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1007\/s11154-007-9052-2","article-title":"Basic concepts and recent developments in human steroid hormone biosynthesis","volume":"8","author":"Ghayee","year":"2007","journal-title":"Rev Endocr Metab Disord"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.05762","article-title":"Androgen generation in adipose tissue in women with simple obesity\u2013a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5","volume":"183","author":"Quinkler","year":"2004","journal-title":"J Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-3399","article-title":"Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione","volume":"99","author":"O'Reilly","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-4009","article-title":"Defining hyperandrogenism in women with polycystic ovary syndrome: A challenging perspective","volume":"101","author":"Pasquali","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B36","doi-asserted-by":"publisher","first-page":"P1","DOI":"10.1530\/EJE-14-0253","article-title":"The polycystic ovary syndrome: a position statement from the European Society of Endocrinology","volume":"171","author":"Conway","year":"2014","journal-title":"Eur J Endocrinol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0108263","article-title":"Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype","volume":"9","author":"Lerchbaum","year":"2014","journal-title":"PLoS One"},{"key":"B38","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1111\/j.1365-2265.1974.tb03298.x","article-title":"Sex-hormone-binding globulin","volume":"3","author":"Anderson","year":"1974","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad463","article-title":"Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"108","author":"Teede","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.685724","article-title":"The release of peripheral immune inflammatory cytokines promote an inflammatory cascade in PCOS patients via altering the follicular microenvironment","volume":"12","author":"Liu","year":"2021","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s12905-023-02187-5","article-title":"Oral contraceptive pill (OCP) treatment alters the gene expression of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-\u03b1 (TNF-\u03b1), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) in polycystic ovary syndrome (PCOS) women compared to drug-naive PCOS women","volume":"23","author":"Yousuf","year":"2023","journal-title":"BMC Womens Health"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.18632\/aging.v15i10","article-title":"Metformin inhibits ovarian granular cell pyroptosis through the miR-670-3p\/NOX2\/ROS pathway","volume":"15","author":"Zhou","year":"2023","journal-title":"Aging (Albany NY)"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_202205_28845","article-title":"Effect of aerobic exercise on inflammatory markers in polycystic ovary syndrome: a randomized controlled trial","volume":"26","author":"Elbandrawy","year":"2022","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"B44","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/1472-6874-14-93","article-title":"Effect of metformin on serum interleukin-6 levels in polycystic ovary syndrome: a systematic review","volume":"14","author":"Xu","year":"2014","journal-title":"BMC Women's Health"},{"key":"B45","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1186\/s12967-023-04116-4","article-title":"The interplay between androgens and the immune response in polycystic ovary syndrome","volume":"21","author":"Shabbir","year":"2023","journal-title":"J Transl Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1517\/13543784.2015.974804","article-title":"Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease","volume":"24","author":"Esser","year":"2015","journal-title":"Expert Opin Investig Drugs"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa065213","article-title":"Interleukin-1-receptor antagonist in type 2 diabetes mellitus","volume":"356","author":"Larsen","year":"2007","journal-title":"N Engl J Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914","article-title":"Antiinflammatory therapy with canakinumab for atherosclerotic disease","volume":"377","author":"Ridker","year":"2017","journal-title":"N Engl J Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-3285","article-title":"11-oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome","volume":"102","author":"O'Reilly","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B50","unstructured":"Anakinra (Kineret) use during pregnancy"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex305","article-title":"International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors","volume":"56","author":"Youngstein","year":"2017","journal-title":"Rheumatol (Oxford)"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1323955111","article-title":"Interleukin-1 deficiency prolongs ovarian lifespan in mice","volume":"111","author":"Uri-Belapolsky","year":"2014","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-011-2096-3","article-title":"Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations","volume":"32","author":"Kaiser","year":"2012","journal-title":"Rheumatol Int"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.090074","article-title":"Anakinra for rheumatoid arthritis: a systematic review","volume":"36","author":"Mertens","year":"2009","journal-title":"J Rheumatol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00739","article-title":"IL-1 antagonism in men with metabolic syndrome and low testosterone: A randomized clinical trial","volume":"103","author":"Ebrahimi","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0231","article-title":"Low-grade inflammation and estimates of insulin resistance during the menstrual cycle in lean and overweight women","volume":"90","author":"Blum","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-018-4041-1","article-title":"Efficacy and safety of interleukin-1 antagonists in rheumatoid arthritis: a systematic review and meta-analysis","volume":"38","author":"Nikfar","year":"2018","journal-title":"Rheumatol Int"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1435698\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T15:18:01Z","timestamp":1726067881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1435698\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,11]]},"references-count":57,"alternative-id":["10.3389\/fendo.2024.1435698"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2024.1435698","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,11]]},"article-number":"1435698"}}