Hormonal circadian rhythms in patients with congenital adrenal hyperplasia: identifying optimal monitoring times and novel disease biomarkers.
OBJECTIVE
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.


METHODS
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 (r(2), 0.95; P<0.001), 17OHP (r(2), 0.70; P=0.003), androstenedione (r(2), 0.47; P=0.043), androsterone (r(2), 0.80; P<0.001), testosterone (r(2), 0.47; P=0.042) and progesterone (r(2), 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). AUC0-24 h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP.


CONCLUSIONS
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.
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK m.debono@sheffield.ac.uk.
Miguel
M
Debono
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Ashwini
A
Mallappa
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Verena
V
Gounden
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Aikaterini A
AA
Nella
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Robert F
RF
Harrison
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Christopher A
CA
Crutchfield
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Peter S
PS
Backlund
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Steven J
SJ
Soldin
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Richard J
RJ
Ross
National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK National Institutes of Health Clinical CenterBuilding 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, USAThe Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesda, Maryland, USADepartment of Automatic Control and Systems EngineeringUniversity of Sheffield, Sheffield, UKAcademic Unit of EndocrinologyUniversity of Sheffield, Sheffield, UK.
Deborah P
DP
Merke
D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D043582:5-alpha-Dihydroprogesterone / Q000652:urine; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000735:Androstenedione / Q000097:blood; D000738:Androsterone / Q000097:blood; D015415:Biomarkers / Q000378:metabolism; D002940:Circadian Rhythm; D003430:Cross-Sectional Studies; D003687:Dehydroepiandrosterone / Q000097:blood; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D008297:Male; D011241:Prednisone / Q000627:therapeutic use; D011277:Pregnanediones / Q000652:urine; D011374:Progesterone / Q000097:blood; D013739:Testosterone / Q000097:blood; D055815:Young Adult
D015415:Biomarkers; D005938:Glucocorticoids; D006728:Hormones; D011277:Pregnanediones; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D011374:Progesterone; C009026:pregnane-3,17-diol-11,20-dione; D019326:17-alpha-Hydroxyprogesterone; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D043582:5-alpha-Dihydroprogesterone; D000738:Androsterone; D011241:Prednisone