{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T21:55:53Z","timestamp":1776894953891,"version":"3.51.2"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T00:00:00Z","timestamp":1652227200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD0087314"],"award-info":[{"award-number":["HD0087314"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Obesity is characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism, reducing fertility and increasing risk of pregnancy complications and birth defects. We termed this phenotype \u2018Reprometabolic Syndrome\u2019 and showed that it can be recapitulated by acute infusions of lipid\/insulin into healthy, normal weight, eumenorrheic women. Herein, we examined the broader impact of hyperlipidemia and euglycemic hyperinsulinemia on anterior pituitary trophic hormones and their targets.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Serum FSH, LH, TSH, growth hormone (GH), prolactin (PRL), thyroid hormones (free T4, total T3), cortisol, IGF-1, adiponectin, leptin and creatinine were measured in a secondary analysis of an interventional crossover study of 12 normal weight cycling women who underwent saline and heparin (control) infusion, or a euglycemic insulin infusion with heparin and Intralipid<jats:sup>\u00ae<\/jats:sup> (lipid\/insulin), between days 2\u20135 in sequential menstrual cycles.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>In contrast to the decrease in gonadotropins, FSH and LH, infusion of lipid\/insulin had no significant effects on other trophic hormones; TSH, PRL or GH. Thyroid hormones (fT4 and total T3), cortisol, IGF-1, adiponectin and creatinine also did not differ between saline or lipid\/insulin infusion conditions. Leptin increased in response to lipid\/insulin (p&lt;0.02).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Acute hyperlipidemia and hyperinsulinemia exerted differential, cell type specific effects on the hypothalamic-pituitary-gonadal, adrenal and thyroid axes. Elucidation of mechanisms underlying the selective modulation of pituitary trophic hormones, in response to changes in diet and metabolism, may facilitate therapeutic intervention in obesity-related neuroendocrine and reproductive dysfunction.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0268323","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T18:16:43Z","timestamp":1652293003000},"page":"e0268323","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["A randomized clinical trial demonstrating cell type specific effects of hyperlipidemia and hyperinsulinemia on pituitary function"],"prefix":"10.1371","volume":"17","author":[{"given":"Rosemary","family":"McDonald","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9096-7490","authenticated-orcid":true,"given":"Katherine","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thy B.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Tannous","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Schauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanette","family":"Santoro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8728-571X","authenticated-orcid":true,"given":"Andrew P.","family":"Bradford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,5,11]]},"reference":[{"issue":"2","key":"pone.0268323.ref001","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1093\/humrep\/del400","article-title":"Obesity and time to pregnancy","volume":"22","author":"DC Gesink Law","year":"2007","journal-title":"Hum Reprod"},{"issue":"3","key":"pone.0268323.ref002","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1467-789X.2004.00147.x","article-title":"Effects of obesity on women\u2019s reproduction and complications during pregnancy","volume":"5","author":"Y. Linne","year":"2004","journal-title":"Obes Rev"},{"issue":"7","key":"pone.0268323.ref003","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1210\/jc.2006-2274","article-title":"Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women","volume":"92","author":"A Jain","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"pone.0268323.ref004","doi-asserted-by":"crossref","first-page":"4372","DOI":"10.1210\/jc.2015-1946","article-title":"Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women","volume":"100","author":"ZA Al-Safi","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"pone.0268323.ref005","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.psyneuen.2015.08.014","article-title":"Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review.","volume":"62","author":"AC Incollingo 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Hematol"},{"issue":"5","key":"pone.0268323.ref012","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1210\/er.2012-1076","article-title":"Thyrotropin secretion patterns in health and disease","volume":"34","author":"F Roelfsema","year":"2013","journal-title":"Endocr Rev"},{"key":"pone.0268323.ref013","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.psyneuen.2017.05.018","article-title":"Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis.","volume":"83","author":"EK Adam","year":"2017","journal-title":"Psychoneuroendocrinology."},{"issue":"3","key":"pone.0268323.ref014","doi-asserted-by":"crossref","first-page":"e0247638","DOI":"10.1371\/journal.pone.0247638","article-title":"A randomised trial examining inflammatory signaling in acutely induced hyperinsulinemia and hyperlipidemia in normal weight women-the reprometabolic syndrome.","volume":"16","author":"A Tannous","year":"2021","journal-title":"PLoS One"},{"issue":"1","key":"pone.0268323.ref015","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0022-5223(19)40091-3","article-title":"The effect of hemodilution on plasma levels of cortisol and free cortisol.","volume":"72","author":"KM Taylor","year":"1976","journal-title":"J Thorac Cardiovasc Surg"},{"issue":"9","key":"pone.0268323.ref016","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1210\/jc.2006-0841","article-title":"Thyroid function is intrinsically linked to insulin sensitivity and endothelium-dependent vasodilation in healthy euthyroid subjects","volume":"91","author":"J Fernandez-Real","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"pone.0268323.ref017","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1089\/thy.2010.0180","article-title":"Relationships between thyroid function and lipid status or insulin resistance in a pediatric population","volume":"20","author":"NS Nader","year":"2010","journal-title":"Thyroid"},{"issue":"9","key":"pone.0268323.ref018","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1007\/BF03343627","article-title":"Glucocorticoids inhibit gonadotropin-releasing hormone by acting directly at the hypothalamic level","volume":"22","author":"AE Calogero","year":"1999","journal-title":"J Endocrinol Invest"},{"issue":"4","key":"pone.0268323.ref019","first-page":"1388","article-title":"Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study","volume":"85","author":"MH Samuels","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"pone.0268323.ref020","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1089\/jir.2011.0049","article-title":"Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity","volume":"31","author":"BB Ganesh","year":"2011","journal-title":"J Interferon 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Metab"},{"issue":"3","key":"pone.0268323.ref024","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/sj.ijo.0800807","article-title":"Growth hormone in obesity","volume":"23","author":"M Scacchi","year":"1999","journal-title":"Int J Obes Relat Metab Disord"},{"issue":"3","key":"pone.0268323.ref025","first-page":"914","article-title":"Impaired growth hormone secretion in obese subjects is partially reversed by acipimox-mediated plasma free fatty acid depression","volume":"81","author":"F Cordido","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"pone.0268323.ref026","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1210\/jcem-60-2-290","article-title":"The effect of free fatty acids on growth hormone (GH)-releasing hormone-mediated GH secretion in man.","volume":"60","author":"T Imaki","year":"1985","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"pone.0268323.ref027","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.tem.2020.04.005","article-title":"Insulin and Growth Hormone Balance: Implications for Obesity","volume":"31","author":"Z Huang","year":"2020","journal-title":"Trends Endocrinol Metab"},{"issue":"3","key":"pone.0268323.ref028","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1210\/en.2004-0607","article-title":"Insulin alone increases hypothalamo-pituitary-adrenal activity, and diabetes lowers peak stress responses","volume":"146","author":"O Chan","year":"2005","journal-title":"Endocrinology"},{"issue":"9","key":"pone.0268323.ref029","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1210\/jcem.84.9.5953","article-title":"Supraphysiological hyperinsulinemia acutely increases hypothalamic-pituitary-adrenal secretory activity in humans","volume":"84","author":"B Fruehwald-Schultes","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"issue":"7","key":"pone.0268323.ref030","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1172\/JCI9725","article-title":"Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring","volume":"105","author":"JS Flier","year":"2000","journal-title":"J Clin Invest"},{"issue":"6588","key":"pone.0268323.ref031","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/382250a0","article-title":"Role of leptin in the neuroendocrine response to fasting","volume":"382","author":"RS Ahima","year":"1996","journal-title":"Nature"},{"key":"pone.0268323.ref032","doi-asserted-by":"crossref","first-page":"646271","DOI":"10.1155\/2013\/646271","article-title":"Adipocytokines in thyroid dysfunction","volume":"2013","author":"BI Aydogan","year":"2013","journal-title":"ISRN Inflamm"},{"issue":"1","key":"pone.0268323.ref033","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1677\/joe.0.1740121","article-title":"The role of leptin in the regulation of TSH 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