Hormonal circadian rhythms in patients with congenital adrenal hyperplasia

Identifying optimal monitoring times and novel disease biomarkers

Miguel Debono, Ashwini Mallappa, Verena Gounden, Aikaterini A. Nella, Robert F. Harrison, Christopher A. Crutchfield, Peter S. Backlund, Steven J. Soldin, Richard J. Ross, Deborah P. Merke

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objectives: The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. Design: This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. Methods: Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. Results: A significant rhythm was confirmed for ACTH (r2, 0.95; P2, 0.70; P=0.003), androstenedione (r2, 0.47; P=0.043), androsterone (r2, 0.80; P2, 0.47; P=0.042) and progesterone (r2, 0.64; P=0.006). The mean (S.D.) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0-24h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP. Conclusion: In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.

Original languageEnglish (US)
Pages (from-to)727-737
Number of pages11
JournalEuropean Journal of Endocrinology
Volume173
Issue number6
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

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Congenital Adrenal Hyperplasia
Androsterone
Circadian Rhythm
Glucocorticoids
Progesterone
Biomarkers
Androstenedione
Prednisone
Adrenocorticotropic Hormone
Androgens
Hormones
17-alpha-Hydroxyprogesterone
Bayes Theorem
Dehydroepiandrosterone
Cushing Syndrome
National Institutes of Health (U.S.)
Periodicity
Dexamethasone
Testosterone
Cross-Sectional Studies

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Hormonal circadian rhythms in patients with congenital adrenal hyperplasia : Identifying optimal monitoring times and novel disease biomarkers. / Debono, Miguel; Mallappa, Ashwini; Gounden, Verena; Nella, Aikaterini A.; Harrison, Robert F.; Crutchfield, Christopher A.; Backlund, Peter S.; Soldin, Steven J.; Ross, Richard J.; Merke, Deborah P.

In: European Journal of Endocrinology, Vol. 173, No. 6, 01.12.2015, p. 727-737.

Research output: Contribution to journalArticle

Debono, M, Mallappa, A, Gounden, V, Nella, AA, Harrison, RF, Crutchfield, CA, Backlund, PS, Soldin, SJ, Ross, RJ & Merke, DP 2015, 'Hormonal circadian rhythms in patients with congenital adrenal hyperplasia: Identifying optimal monitoring times and novel disease biomarkers', European Journal of Endocrinology, vol. 173, no. 6, pp. 727-737. https://doi.org/10.1530/EJE-15-0064
Debono, Miguel ; Mallappa, Ashwini ; Gounden, Verena ; Nella, Aikaterini A. ; Harrison, Robert F. ; Crutchfield, Christopher A. ; Backlund, Peter S. ; Soldin, Steven J. ; Ross, Richard J. ; Merke, Deborah P. / Hormonal circadian rhythms in patients with congenital adrenal hyperplasia : Identifying optimal monitoring times and novel disease biomarkers. In: European Journal of Endocrinology. 2015 ; Vol. 173, No. 6. pp. 727-737.
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abstract = "Objectives: The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. Design: This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. Methods: Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. Results: A significant rhythm was confirmed for ACTH (r2, 0.95; P2, 0.70; P=0.003), androstenedione (r2, 0.47; P=0.043), androsterone (r2, 0.80; P2, 0.47; P=0.042) and progesterone (r2, 0.64; P=0.006). The mean (S.D.) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0-24h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP. Conclusion: In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.",
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AU - Mallappa, Ashwini

AU - Gounden, Verena

AU - Nella, Aikaterini A.

AU - Harrison, Robert F.

AU - Crutchfield, Christopher A.

AU - Backlund, Peter S.

AU - Soldin, Steven J.

AU - Ross, Richard J.

AU - Merke, Deborah P.

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N2 - Objectives: The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. Design: This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. Methods: Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. Results: A significant rhythm was confirmed for ACTH (r2, 0.95; P2, 0.70; P=0.003), androstenedione (r2, 0.47; P=0.043), androsterone (r2, 0.80; P2, 0.47; P=0.042) and progesterone (r2, 0.64; P=0.006). The mean (S.D.) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0-24h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP. Conclusion: In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.

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