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Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency.

ABSTRACT: To comprehensively characterize androgens and androgen precursors in classic 21-hydroxylase deficiency (21OHD) and to gain insights into the mechanisms of their formation.Serum samples were obtained from 38 patients (19 men) with classic 21OHD, aged 3-59, and 38 sex- and age-matched controls; 3 patients with 11?-hydroxylase deficiency; 4 patients with adrenal insufficiency; and 16 patients (8 men) undergoing adrenal vein sampling. Paraffin-embedded normal (n = 5) and 21OHD adrenal tissues (n = 3) were used for immunohistochemical studies.We measured 11 steroids in all sera by liquid chromatography-tandem mass spectrometry. Immunofluroescence localized 3?-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) within the normal and 21OHD adrenals.Four 11-oxygenated 19-carbon (11oxC19) steroids were significantly higher in male and female 21OHD patients than in controls: 11?-hydroxyandrostenedione, 11-ketoandrostenedione 11?-hydroxytestosterone, and 11-ketotestosterone (3-4-fold, P < 0.0001). For 21OHD patients, testosterone and 11-ketotestosterone were positively correlated in females, but inversely correlated in males. All 11oxC19 steroids were higher in the adrenal vein than in the inferior vena cava samples from men and women and rose with cosyntropin stimulation. Only trace amounts of 11oxC19 steroids were found in the sera of patients with 11?-hydroxylase deficiency and adrenal insufficiency, confirming their adrenal origin. HSD3B2 and CYB5A immunoreactivities were sharply segregated in the normal adrenal glands, whereas areas of overlapping expression were identified in the 21OHD adrenals.All four 11oxC19 steroids are elevated in both men and women with classic 21OHD. Our data suggest that 11oxC19 steroids are specific biomarkers of adrenal-derived androgen excess.

SUBMITTER: Turcu AF

PROVIDER: S-EPMC4874183 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency.

Turcu Adina F AF Nanba Aya T AT Chomic Robert R Upadhyay Sunil K SK Giordano Thomas J TJ Shields James J JJ Merke Deborah P DP Rainey William E WE Auchus Richard J RJ

European journal of endocrinology 20160210 5

<h4>Objective</h4>To comprehensively characterize androgens and androgen precursors in classic 21-hydroxylase deficiency (21OHD) and to gain insights into the mechanisms of their formation.<h4>Design</h4>Serum samples were obtained from 38 patients (19 men) with classic 21OHD, aged 3-59, and 38 sex- and age-matched controls; 3 patients with 11β-hydroxylase deficiency; 4 patients with adrenal insufficiency; and 16 patients (8 men) undergoing adrenal vein sampling. Paraffin-embedded normal (n = 5) ...[more]

PMID: 26865584

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Project description:ContextChronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer.ObjectiveThe objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9α-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia.DesignThis was a phase 1 dose-escalation study.SettingThe study was conducted at university clinical research centers.ParticipantsWe screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L).InterventionAA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9α-fludrocortisone acetate.Main outcome measureThe primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (< 230 ng/dL [<8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides.ResultsWith 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7-8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2-4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed.ConclusionAA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.

Project description:ContextSyndromes of severe insulin resistance (SIR) include insulin receptoropathy, in which all signaling downstream of the insulin receptor is lost, and lipodystrophy, in which some signaling pathways are impaired and others preserved. Women with SIR commonly have ovarian hyperandrogenemia; adrenal-derived 11-oxygenated androgens, produced by CYP11B1, have not been studied.ObjectiveWe aimed to evaluate classic pathway androgens (androstenedione, testosterone) and 11-oxygenated androgens in women with SIR and hyperandrogenemia, and to elucidate the role of insulin receptor signaling for 11-oxygenated androgen production by comparing lipodystrophy and receptoropathy.MethodsSteroid hormones were quantified using LC-MS/MS in a cross-sectional study of 18 women with hyperandrogenemia and SIR (11 lipodystrophy, 7 receptoropathy) and 23 controls. To assess ovarian vs adrenal origin, steroids were compared in receptoropathy patients with (Ovary+) vs without (Ovary-) ovarian function.ResultsCompared with controls, classic androgens were elevated in both lipodystrophy and receptoropathy, and 11-oxygenated androgens were increased in lipodystrophy (2.9-fold higher 11β-hydroxyandrostenedione (11OHA4), 2.4-fold higher 11-ketoandrostenedione (11KA4), 3.6-fold higher 11-ketotestosterone (11KT); P < 0.01), but not receptoropathy. Product-to-precursor ratios for CYP11B1 conversion of androstenedione to 11OHA4 were similar in lipodystrophy and controls but decreased in receptoropathy (6.5-fold lower than control; P = 0.001). Classic androgens were elevated in Ovary + but not Ovary- patients.Conclusions11-Oxygenated androgens are elevated in lipodystrophy but not receptoropathy. In SIR, insulin receptor signaling is necessary for adrenal hyperandrogenemia but not ovarian hyperandrogenemia; excess classic androgens are derived from the ovaries. Insulin receptor signaling increases adrenal 19-carbon steroid production, which may have implications for more common disorders of mild IR.

Dataset Information

Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency.

Publications

Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency.

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