{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:20:04Z","timestamp":1784557204902,"version":"3.55.0"},"reference-count":33,"publisher":"Bioscientifica","issue":"3","license":[{"start":{"date-parts":[[2012,6,20]],"date-time":"2012-06-20T00:00:00Z","timestamp":1340150400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.endocrinology.org\/journals\/reuselicence\/"}],"content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:p>Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11\u03b2-hydroxysteroid dehydrogenase type 1 (11\u03b2-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11\u03b2-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11\u03b2-HSD1 is implicated in the development of obesity, and selective 11\u03b2-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11\u03b2-HSD1. We assessed biomarkers for allele combinations of 11\u03b2-HSD1 and H6PDH derived from double heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11\u03b2-HSD1 KO and double KO (DKO) adrenals were \u223c30% larger than WT \u2013 indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2.2-fold higher in H6PDH KO animals and \u223c1.5-fold higher in 11\u03b2-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KO of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11\u03b2-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11\u03b2-HSD1\/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography\/mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11\u03b2-HSD1\/H6PDH deficiency.<\/jats:p>","DOI":"10.1530\/joe-12-0178","type":"journal-article","created":{"date-parts":[[2012,6,21]],"date-time":"2012-06-21T09:53:14Z","timestamp":1340272394000},"page":"367-372","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":11,"title":["Biomarkers of hypothalamic\u2013pituitary\u2013adrenal axis activity in mice lacking 11\u03b2-HSD1 and H6PDH"],"prefix":"10.1530","volume":"214","author":[{"given":"Lianne","family":"Abrahams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina M","family":"Semjonous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil","family":"Guest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Zielinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth G","family":"Lavery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"issue":"32","key":"1_5429222","doi-asserted-by":"crossref","first-page":"18939","DOI":"10.1016\/S0021-9258(19)47248-7","volume":"264","author":"Agarwal","year":"1989","journal-title":"Journal of Biological Chemistry","ISSN":"https:\/\/id.crossref.org\/issn\/0021-9258","issn-type":"print"},{"issue":"11","key":"2_17874137","doi-asserted-by":"publisher","first-page":"4755","DOI":"10.1210\/en.2003-0344","volume":"144","year":"2003","journal-title":"Endocrinology","ISSN":"https:\/\/id.crossref.org\/issn\/0013-7227","issn-type":"print"},{"key":"3_43479622","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1016\/j.bbamcr.2008.03.001","volume":"1783","year":"2008","journal-title":"BIOCHIMICA ET BIOPHYSICA ACTA BBA MOLECULAR CELL RESEARCH"},{"key":"4_43479623","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1517\/13543770902967658","volume":"19","year":"2009","journal-title":"EXPERT OPINION ON THERAPEUTIC PATENTS"},{"key":"5_43479624","first-page":"219","volume":"7","year":"2005","journal-title":"ENDOCRINE ABSTRACTS"},{"issue":"11","key":"6_35288286","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1111\/j.1365-2826.2009.01899.x","volume":"21","author":"Carter","year":"2009","journal-title":"Journal of neuroendocrinology","ISSN":"https:\/\/id.crossref.org\/issn\/0953-8194","issn-type":"print"},{"key":"7_43479625","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1038\/nprot.2011.375","volume":"6","year":"2011","journal-title":"NATURE PROTOCOLS"},{"issue":"2","key":"8_16745088","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S0303-7207(97)04000-8","volume":"127","author":"Condon","year":"1997","journal-title":"Molecular and cellular endocrinology","ISSN":"https:\/\/id.crossref.org\/issn\/0303-7207","issn-type":"print"},{"issue":"12","key":"9_35759964","doi-asserted-by":"publisher","first-page":"4645","DOI":"10.1210\/jc.2009-1412","volume":"94","year":"2009","journal-title":"Journal of Clinical Endocrinology &amp; 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