{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:24:17Z","timestamp":1765545857863},"reference-count":52,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,8,1]]},"abstract":"<jats:p>To evaluate the role of TNF-\u03b1 in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-\u03b1 levels, as well as several polymorphisms in the promoter region of the TNF-\u03b1 gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index.<\/jats:p>\n               <jats:p>Hyperandrogenic patients presented with mildly increased serum TNF-\u03b1 levels as compared with controls (mean[median] \u00b1 sd: 7.2[7.0] \u00b1 3.3 pg\/ml vs. 5.6[4.4] \u00b1 4.0 pg\/ml, P &amp;lt; 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-\u03b1 was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls.<\/jats:p>\n               <jats:p>The TNF-\u03b1 gene polymorphisms studied here (\u22121196C\/T, \u22121125G\/C,\u2212 1031T\/C, \u2212863C\/A, \u2212857C\/T, \u2212316G\/A, \u2212308G\/A, \u2212238G\/A, and\u2212 163G\/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the \u2212308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-\u03b1 levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants.<\/jats:p>\n               <jats:p>In conclusion, our present results suggest that the TNF-\u03b1 system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-\u03b1 system and androgen excess is needed before considering TNF-\u03b1 as a significant contributing factor to the development of hyperandrogenism.<\/jats:p>","DOI":"10.1210\/jcem.86.8.7770","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:07:29Z","timestamp":1389200849000},"page":"3761-3767","source":"Crossref","is-referenced-by-count":8,"title":["TNF-\u03b1 and Hyperandrogenism: A Clinical, Biochemical, and Molecular Genetic Study"],"prefix":"10.1210","volume":"86","author":[{"given":"He\u0301ctor F.","family":"Escobar-Morreale","sequence":"first","affiliation":[{"name":"Departments of Endocrinology (H.F.E.-M., R.M.C., J.S.), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa M.","family":"Calvo","sequence":"additional","affiliation":[{"name":"Departments of Endocrinology (H.F.E.-M., R.M.C., J.S.), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose\u0301","family":"Sancho","sequence":"additional","affiliation":[{"name":"Departments of Endocrinology (H.F.E.-M., R.M.C., J.S.), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose\u0301 L.","family":"San Milla\u0301n","sequence":"additional","affiliation":[{"name":"Molecular Genetics (J.L.S.M.), Hospital Ramo\u0301n y Cajal, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071618152796000_R1","first-page":"2434","article-title":"A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain.","volume":"85","author":"Asuncio\u0301n","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071618152796000_R2","first-page":"377","article-title":"Diagnostic criteria for polycystic ovary syndrome: towards a rational approach","author":"Zawadzki","year":"1992","journal-title":"In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Boston: Blackwell Scientific Publications;"},{"key":"2020071618152796000_R3","doi-asserted-by":"crossref","first-page":"14956","DOI":"10.1073\/pnas.95.25.14956","article-title":"Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome.","volume":"95","author":"Legro","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071618152796000_R4","first-page":"217","article-title":"Phenotype and genotype in polycystic ovary syndrome.","volume":"53","author":"Legro","year":"1998","journal-title":"Recent Prog Horm Res"},{"key":"2020071618152796000_R5","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1210\/endo-126-5-2711","article-title":"Effects of tumor necrosis factor-\u03b1 in vitro on steroidogenesis of healthy and atretic follicles of the rat: theca as a target.","volume":"126","author":"Roby","year":"1990","journal-title":"Endocrinology"},{"key":"2020071618152796000_R6","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1095\/biolreprod61.4.993","article-title":"Tumor necrosis factor-\u03b1 stimulates proliferation of rat ovarian theca-interstitial cells.","volume":"61","author":"Spaczynski","year":"1999","journal-title":"Biol Reprod"},{"key":"2020071618152796000_R7","doi-asserted-by":"crossref","first-page":"4864","DOI":"10.1210\/endo.137.11.8895358","article-title":"Tumor necrosis factor-\u03b1 and its second messenger, ceramide, stimulate apoptosis in cultured ovarian follicles.","volume":"137","author":"Kaipia","year":"1996","journal-title":"Endocrinology"},{"key":"2020071618152796000_R8","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0026-0495(99)90100-2","article-title":"Elevated serum levels of tumor necrosis factor\u03b1 in normal-weight women with polycystic ovary syndrome.","volume":"48","author":"Gonzalez","year":"1999","journal-title":"Metabolism"},{"key":"2020071618152796000_R9","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1093\/HUMREP\/10.6.1352","article-title":"Immunoactive interleukin-1 beta and tumour necrosis factor-\u03b1 in thecal, stromal and granulosa cell cultures from normal and polycystic ovaries.","volume":"10","author":"Jasper","year":"1995","journal-title":"Hum Reprod"},{"key":"2020071618152796000_R10","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1172\/JCI117936","article-title":"Increased adipose tissue expression of tumor necrosis factor-\u03b1 in human obesity and insulin resistance.","volume":"95","author":"Hotamisligil","year":"1995","journal-title":"J Clin Invest"},{"key":"2020071618152796000_R11","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1172\/JCI118504","article-title":"The expression of TNF \u03b1 by human muscle. 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