{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T17:21:30Z","timestamp":1758043290452,"version":"3.44.0"},"reference-count":31,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["P20AA017830\u201001","R21AA026875","U01AA027487"],"award-info":[{"award-number":["P20AA017830\u201001","R21AA026875","U01AA027487"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Sex\u2010related hormones and proteins may underlie sex differences in alcohol use disorder characteristics and consequences. Previous reports suggest steroid sex hormones may influence alcohol consumption behaviors while proteins that regulate their circulation levels are rarely investigated. Following up on our earlier study of individual sex\u2010related hormones' associations with alcohol dependence (AD), this study measured the associations between the combinations of sex\u2010related hormones and proteins and AD in a larger sample.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Sex\u2010stratified case\u2010control comparison and clustering of plasma sex\u2010related hormone and protein levels, plus a genome\u2010wide association study on the AD\u2010associated hormone and protein combinations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Addiction treatment programs in the United States.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>Four hundred treatment\u2010seeking recently abstained AD patients (median\u2009=\u200924.5\u00a0days) and 388 age\u2010and\u2010sex\u2010matched controls from a community biobank (male:female \u2248 2:1).<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements<\/jats:title><jats:p>Plasma levels of total testosterone, estrone (E1), estradiol (E2), follicle\u2010stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG) and albumin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>In males, we found higher E2 [<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.13, <jats:italic>P<\/jats:italic><jats:sub>unadjusted<\/jats:sub>\u2009&lt;\u20090.001, false discovery rate (FDR)\u2009=\u20090.005], progesterone (<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.01, <jats:italic>P<\/jats:italic><jats:sub>unadjusted<\/jats:sub>\u2009=\u20090.025, FDR\u2009=\u20090.054), LH (<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.12, <jats:italic>P<\/jats:italic><jats:sub>unadjusted<\/jats:sub>\u2009=\u20090.017, FDR\u2009=\u20090.044) and albumin (<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.09, <jats:italic>P<\/jats:italic><jats:sub>unadjusted<\/jats:sub>\u2009&lt;\u20090.001, FDR\u2009=\u20090.005) in AD patients than controls; in females, we observed lower E1 (<jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.24, <jats:italic>P<\/jats:italic><jats:sub>unadjusted<\/jats:sub>\u2009=\u20090.024, FDR\u2009=\u20090.113) and progesterone (<jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22121.86, <jats:italic>P<\/jats:italic><jats:sub>unadjusted<\/jats:sub>\u2009=\u20090.026, FDR\u2009=\u20090.113) and higher albumin (<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.18, <jats:italic>P<\/jats:italic><jats:sub>unadjusted<\/jats:sub>\u2009&lt;\u20090.001, FDR\u2009=\u20090.001) in AD patients than controls. Three principal components (PCs), reflecting hormone signatures, were statistically significantly associated with AD in each sex: PC1 (TT, E2 and SHBG; <jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.15, <jats:italic>P<\/jats:italic>\u2009=\u20090.016), PC3 (E1, progesterone and albumin; <jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.28, <jats:italic>P<\/jats:italic>\u2009=\u20090.007) and PC4 (SHBG and albumin; <jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.34, <jats:italic>P<\/jats:italic>\u2009=\u20090.001) in males; PC3 (progesterone and albumin; <jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.38, <jats:italic>P<\/jats:italic>\u2009=\u20090.009), PC4 (TT and albumin; <jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.49, <jats:italic>P<\/jats:italic>\u2009=\u20090.001) and PC5 (TT and progesterone; <jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.54, <jats:italic>P<\/jats:italic>\u2009=\u20090.004) in females. Statistically significant <jats:italic>SNP<\/jats:italic> \u00d7 <jats:italic>group<\/jats:italic> associations were found in females between PC4 and polymorphisms in <jats:italic>RP51004I9.1<\/jats:italic> (top SNP: rs6082693; <jats:italic>P<\/jats:italic>\u2009=\u20095.41E\u201012) and in males between PC3 and a genomic locus that contained <jats:italic>SLC35E4<\/jats:italic>, <jats:italic>DUSP18<\/jats:italic> and <jats:italic>OSBP2<\/jats:italic> (top SNP: rs13053277; <jats:italic>P<\/jats:italic>\u2009=\u20091.77E\u201007).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Three sex\u2010related hormone and protein signatures appear to be associated with alcohol dependence in each sex. Peripheral levels of sex\u2010related hormones and proteins, as well as their combinations, could be altered in people with alcohol dependence who have abstained for a few weeks compared with controls, and such differences may be sex\u2010specific.<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.70104","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T04:44:17Z","timestamp":1750049057000},"page":"2107-2117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Associations of plasma sex\u2010related hormone and protein levels and alcohol dependence"],"prefix":"10.1111","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4989-8782","authenticated-orcid":false,"given":"Ada Man\u2010Choi","family":"Ho","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychology Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer R.","family":"Geske","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa K.","family":"Pazdernik","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T. Cameron","family":"Waller","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Batzler","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacey J.","family":"Winham","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-6130","authenticated-orcid":false,"given":"Victor M.","family":"Karpyak","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychology Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2015.08.023"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2001.tb02242.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.35946\/arcr.v40.2.04"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2018.12.010"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12589"},{"issue":"2","key":"e_1_2_10_7_1","first-page":"255","article-title":"Pathophysiology of the effects of alcohol abuse on the endocrine system","volume":"38","author":"Rachdaoui N","year":"2017","journal-title":"Alcohol Res"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2023.109781"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.alcalc.a008300"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2019.01.029"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/Bf03349782"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1781(94)02580-c"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/34.6.903"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.13386"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.153.9.1195"},{"key":"e_1_2_10_16_1","first-page":"42","volume-title":"Measuring alcohol consumption: psychosocial and biological methods","author":"Sobell LC","year":"1992"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2013.06.006"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.158.16.1789"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2236"},{"volume-title":"Using multivariate statistics","year":"2013","author":"Thabachnick BG","key":"e_1_2_10_20_1"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-021-01097-0"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219"},{"issue":"1","key":"e_1_2_10_25_1","first-page":"7","article-title":"Androgen\u2010oestrogen imbalance in men with chronic alcoholism and fatty liver","volume":"22","author":"Myking O","year":"1987","journal-title":"Alcohol Alcohol"},{"issue":"2","key":"e_1_2_10_26_1","first-page":"326","article-title":"Alcohol\u2010induced testicular atrophy. An experimental model for hypogonadism occurring in chronic alcoholic men","volume":"69","author":"Van Thiel DH","year":"1975","journal-title":"Gastroenterology"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1590\/s0041-87811999000300006"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/54.1.138"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/acer.14874"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0187698"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.20230027"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13679-014-0129-4"}],"container-title":["Addiction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/add.70104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T05:17:34Z","timestamp":1757654254000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/add.70104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,16]]},"references-count":31,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1111\/add.70104"],"URL":"https:\/\/doi.org\/10.1111\/add.70104","archive":["Portico"],"relation":{},"ISSN":["0965-2140","1360-0443"],"issn-type":[{"type":"print","value":"0965-2140"},{"type":"electronic","value":"1360-0443"}],"subject":[],"published":{"date-parts":[[2025,6,16]]},"assertion":[{"value":"2024-10-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}