Hormonal Circadian Rhythms in Patients with Congenital Adrenal Hyperplasia: Identifying Optimal Monitoring Times and Novel Disease Biomarkers

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 corticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione (A ₄), androsterone, dehydroepiandrosterone (DHEA), testosterone, progesterone and 24-hour 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 (T _minAC) and maximal (T _maxAC) adrenocortical hormone levels after dose administration were 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 (SD) T _minAC and T _maxAC for 17OHP and A ₄ were: morning prednisone [4.3(2.3) and 9.7(3.5) hours], evening prednisone [4.5(2.0) and 10.3(2.4) hours], and daily dexamethasone [9.2(3.5) and 16.4(7.2) hours]. AUC _0-24hr progesterone, androsterone and 24-hour 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.