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

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Hormonal Circadian Rhythms in Patients with Congenital Adrenal Hyperplasia: Identifying Optimal Monitoring Times and Novel Disease Biomarkers M Debono and others Circadian Rhythms in CAH 173:6 727–737 Clinical Study Hormonal circadian rhythms in patients with congenital adrenal hyperplasia: identifying optimal monitoring times and novel disease biomarkers Miguel Debono1,4, Ashwini Mallappa1, Verena Gounden1, Aikaterini A Nella2, Robert F Harrison3, Christopher A Crutchfield2, Peter S Backlund2, Steven J Soldin1, Richard J Ross4 and Deborah P Merke1,2 Correspondence 1National Institutes of Health Clinical Center, Building 10, Room 1-2742, 10 Center Drive, Bethesda, Maryland 20892, should be addressed USA, 2The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, to M Debono USA, 3Department of Automatic Control and Systems Engineering, University of Sheffield, Sheffield, UK and Email 4Academic Unit of Endocrinology, University of Sheffield, Sheffield, UK m.debono@sheffield.ac.uk 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 5b-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and European Journal of Endocrinology maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. Results: A significant rhythm was confirmed for ACTH (r2, 0.95; P!0.001), 17OHP (r2, 0.70; PZ0.003), androstenedione (r2, 0.47; PZ0.043), androsterone (r2, 0.80; P!0.001), testosterone (r2, 0.47; PZ0.042) and progesterone (r2, 0.64; PZ0.006). 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. 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. European Journal of Endocrinology (2015) 173, 727–737 Introduction Congenital adrenal hyperplasia is an autosomal recessive which by impaired negative feedback on the hypothalamic– condition which in 95% of patients is caused by pituitary–adrenal axis, stimulates corticotropin (ACTH) 21-hydroxylase deficiency, an enzyme of the cytochrome synthesis. ACTH secretion is regulated by circadian input P450 family essential for cortisol and aldosterone biosyn- from the central clock in the suprachiasmatic nucleus and thesis (1). This enzyme defect results in cortisol deficiency, follows a circadian pattern with an early morning rise, www.eje-online.org Ñ 2015 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-15-0064 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 10:25:08AM via free access Clinical Study M Debono and others Circadian Rhythms in CAH 173:6 728 reaching a peak in the morning on waking, and slowly deficiency (five simple virilizing; 11 salt wasting) partici- declining towards an evening nadir (2).Inuntreatedor pated. This 24-h serial sampling study was performed as most treated CAH patients, this rhythm is maintained and part of the baseline visit of two clinical trials investigating adrenal androgens, which are also under the influence of the use of circadian hydrocortisone replacement (www. ACTH, are released in a circadian pattern resulting in clinicaltrials.gov identifier no. NCT01735617 and hyperandrogenism and its clinical consequences (3, 4, 5). NCT01859312) and patients were receiving their usual at Patients with CAH suffer from multiple morbidities home medication regimen. The diagnosis of CAH was related to excess androgens or glucocorticoid over-replace- ascertained using medical records and hormonal tests and ment. Thus, the challenge for the endocrinologist is to confirmed by genotype (12). Five patients were on a daily achieve a balance between these two undesirable states. dexamethasone dose (dose range: 0.25–0.5 mg, in hydro- Endocrine Society guidelines have recommended the use of cortisone equivalent (!80)7 9.6–21.3 mg/m2 per day). hydrocortisone in children whereas up to two-thirds of Four of these patients were taking dexamethasone in the adults are commonly receiving intermediate and long-acting evening whereas one patient was taking dexamethasone glucocorticoids (1, 6). A number of strategies have been in the morning. Eleven patients were on twice daily suggested to help guide dose titration, such as measuring prednisone (dose range: 2–7.5 mg (am), 2–5 mg (pm) in 17-hydroxyprogesterone (17OHP) and androstenedione hydrocortisone equivalent (!5)7: 12.0–33.7 mg/m2 per before the early morning hydrocortisone dose in an attempt day. All patients were on a stable glucocorticoid regimen to measure peak hormone levels (7, 8). No definite criteria for a 3 month minimum. Other inclusion criteria included exist as to what time in relation to dose administration this age 18 years and over, plasma renin activity !1.5 times the should be performed in patients on intermediate- and long- upper normal range and a negative pregnancy test. Patients acting glucocorticoids. Synthetic glucocorticoids have who were taking medications that induce hepatic enzymes diverse pharmacokinetic characteristics with wide inter- or interfere with glucocorticoid metabolism, spirono- individual variability and unpredictable effects on rhythm lactone, inhaled, oral or nasal glucocorticoids apart from parameters and hormone concentrations (9, 10),making treatment for CAH, or had taken estrogen-containing oral it problematic for physicians to decide on dose changes contraceptive pill within 6 weeks of recruitment were when measuring random hormone levels. excluded. Patients with clinical or biochemical evidence of We measured hormonal circadian rhythms of CAH hepatic, renal or psychiatric disease, were also excluded. patients on intermediate- and long-acting glucocorticoids. The study was approved by the Eunice Kennedy Shriver In addition to routinely measured hormones, we analyzed National Institutes of Child Health and Development European Journal of Endocrinology profiles of progesterone, DHEA, the precursor to pregna- (NICHD) Institutional Review Board and all patients gave netriol, 5b-pregnane-3a,17a-diol-20-one (5b-pdiol), and their written informed consent. the backdoor pathway metabolites androsterone (also a classic pathway product) and 5a-pregnane-3a,17a-diol- Study design 20-one (pdiol) (11) (Figure 1). The use of multiple hormone levels at different time points provided us with a robust All participants were admitted overnight and blood was measurement of 24-h hormone exposure as opposed to sampled from an i.v. cannula every 2 h (2300 h until a single random hormone concentration as usually 2300 h). Patients continued to take their usual medi- performed in clinical care. Our goal was to evaluate hormo- cations during sampling. The following hormones were nal diurnal rhythms in patients with CAH, which then measured: ACTH, androstenedione, 17OHP, androster- allowed us to determine optimal monitoring time ranges one, DHEA, testosterone and progesterone. Glucocorti- for identifying hormonal suppression and escape from coid levels (dexamethasone, prednisolone) were also hormonal control, and explore novel disease biomarkers. measured. In addition, a 24 h urine sample, timed from 2300 h on Day 1 to 2300 h on Day 2, was collected to measure the backdoor metabolite pdiol and the precursor Patients and methods to pregnanetriol, 5b-pdiol (Fig. 1). Study patients Assays An observational, cross sectional study was carried out at the National Institutes of Health Clinical Center, Bethesda, Hormones were analysed at the NIH Clinical Center MD. Sixteen patients with classic 21-hydroxylase (Bethesda, MD, USA) unless otherwise noted. www.eje-online.org Downloaded from Bioscientifica.com at 09/28/2021 10:25:08AM via free access Clinical Study M Debono and others Circadian Rhythms in CAH 173:6 729 α Pregnenolone β 3 HSD Pregnanetriol 3 HSD 5β reductase 5β-pdiol 17α-hydroxylase Progesterone 17OHP Pdione 17α-hydroxylase α 5α reductase 3 HSD 17OH 17,20-lyase Pregnenolone Pdiol Classic pathway Backdoor 17,20- 17,20-lyase pathway lyase Androstenedione Androsterone DHEA 3βHSD 17βHSD3 Androsterone 17βHSD3 α Etiocholanolone 3 HSD Testosterone DHT Androstanediol 5α reductase 3αHSD 17βHSD6 Figure 1 Pathway of adrenal steroidogenesis. Normally, the principal be converted to pdione via an alternative route termed the route for adrenocortical androgen production is via the classic backdoor pathway (dotted arrows). Androsterone is produced pathway (solid line arrows). In 21-hydroxylase deficiency, large
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