{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:43:14Z","timestamp":1791240194206,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Andrology"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration\/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell\u2010produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin\u2010like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To characterize insulin\u2010like peptide 3 as a biomarker to assess gonadal status in aging men.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and materials<\/jats:title><jats:p>A large European multicenter (European Male Aging Study) cohort of community\u2010dwelling men was analyzed to determine how insulin\u2010like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and discussion<\/jats:title><jats:p>Insulin\u2010like peptide 3 declines cross\u2010sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin\u2010like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin\u2010like peptide 3 is negatively dependent on luteinizing hormone and sex hormone\u2010binding globulin and positively dependent on follicle\u2010stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin\u2010like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin\u2010like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European\u2010wide reference range for insulin\u2010like peptide 3 (95% confidence interval) adjusted for increasing age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Insulin\u2010like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin\u2010dependent short\u2010term regulation and within\u2010individual variation in testosterone.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.13220","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T07:08:38Z","timestamp":1656572918000},"page":"1328-1338","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort"],"prefix":"10.1111","volume":"10","author":[{"given":"Ravinder","family":"Anand\u2010Ivell","sequence":"first","affiliation":[{"name":"School of Biosciences University of Nottingham, University Park Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kee","family":"Heng","sequence":"additional","affiliation":[{"name":"School of Biosciences University of Nottingham, University Park Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Severn","sequence":"additional","affiliation":[{"name":"School of Mathematics University of Nottingham, University Park Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1079-2860","authenticated-orcid":false,"given":"Leen","family":"Antonio","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases and Metabolism Laboratory of Clinical and Experimental Endocrinology KU Leuven Belgium"},{"name":"Department of Endocrinology University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyorgy","family":"Bartfai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynaecology and Andrology Albert Szent\u2010Gyorgy Medical University Szeged Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe F.","family":"Casanueva","sequence":"additional","affiliation":[{"name":"Department of Medicine Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatolog\u00eda Obesidad y Nutricion (CB06\/03), Instituto Salud Carlos III Santiago de Compostela Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilpo T.","family":"Huhtaniemi","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Developmental, Department of Metabolism, Digestion and Reproduction Imperial College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5816-0785","authenticated-orcid":false,"given":"Aleksander","family":"Giwercman","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine Lund University Malm\u00f6 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Maggi","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, \u201cMario Serio\u201d Department of Experimental and Clinical Biomedical Sciences University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence W.","family":"O'Neill","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology Versus Arthritis The University of Manchester &amp; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margus","family":"Punab","sequence":"additional","affiliation":[{"name":"Andrology Unit United Laboratories of Tartu University Clinics Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Rastrelli","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, \u201cMario Serio\u201d Department of Experimental and Clinical Biomedical Sciences University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanta","family":"Slowikowska\u2010Hilczer","sequence":"additional","affiliation":[{"name":"Department of Andrology and Reproductive Endocrinology Medical University of \u0141\u00f3d\u017a \u0141\u00f3d\u017a Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos","family":"Tournoy","sequence":"additional","affiliation":[{"name":"Department of Geriatrics University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Vanderschueren","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases and Metabolism Laboratory of Clinical and Experimental Endocrinology KU Leuven Belgium"},{"name":"Department of Endocrinology University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick C. W.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Manchester University NHS Foundation Trust Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6513-2109","authenticated-orcid":false,"given":"Richard","family":"Ivell","sequence":"additional","affiliation":[{"name":"School of Biosciences University of Nottingham, University Park Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00229"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0911101"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-59-4-756"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deaa271"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/0470870796.ch10"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2008.09.005"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmp011"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.113.108969"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.868313"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13689"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.080204"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2021.06.001"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","DOI":"10.1002\/jcla.23898","article-title":"Clinical value of INSL3 in the diagnosis and development of diabetic nephropathy","author":"Zhu J","year":"2021","journal-title":"J Clin Lab Anal"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2006.00714.x"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2008.03463.x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyr234"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2008.00879.x"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2006.02.004"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007\u20101972"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.10.6079"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2018-0171"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13524"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE\u201012\u20100890"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/joa.12261"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgz246"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031786"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0741"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13001"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1530\/eje.0.1450561"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa145"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100043\u2010107835"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13723"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40842\u2010020\u201000106\u20103"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013\u20102288"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2012.09.009"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab129"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1155\/2008\/905025"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa603"}],"container-title":["Andrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/andr.13220","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/andr.13220","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/andr.13220","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T23:11:07Z","timestamp":1700781067000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/andr.13220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,11]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1111\/andr.13220"],"URL":"https:\/\/doi.org\/10.1111\/andr.13220","archive":["Portico"],"relation":{},"ISSN":["2047-2919","2047-2927"],"issn-type":[{"value":"2047-2919","type":"print"},{"value":"2047-2927","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,11]]},"assertion":[{"value":"2022-03-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}