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. 2025 Jun:116:105749.
doi: 10.1016/j.ebiom.2025.105749. Epub 2025 May 20.

Modelling adrenal steroid profiles to inform monitoring guidance in congenital adrenal hyperplasia

Neil R Lawrence  1 , Jeremy Dawson  1 , Zi-Qiang Lang  2 , Alessandro Prete  3 , Elizabeth S Baranowski  4 , Lina Schiffer  5 , Angela E Taylor  4 , Aude Brac de la Perrière  6 , Angelica Lindén Hirschberg  7 , Anders Juul  8 , Deborah P Merke  9 , John Newell-Price  1 , D Aled Rees  10 , Nicole Reisch  11 , Nike Stikkelbroeck  12 , Philippe A Touraine  13 , Nils Krone  1 , Brian Keevil  14 , Gary S Collins  15 , Wiebke Arlt  16 , Richard J M Ross  17
Affiliations

Modelling adrenal steroid profiles to inform monitoring guidance in congenital adrenal hyperplasia

Neil R Lawrence et al. EBioMedicine. 2025 Jun.

Abstract

Background: There is no consensus on how to monitor adrenal androgens in Congenital Adrenal Hyperplasia (CAH).

Methods: Modelling of serum and salivary steroid profiles in healthy participants and patients with CAH randomised to either standard treatment or modified-release hydrocortisone hard capsules (MRHC).

Findings: Changes in serum 17-hydroxyprogesterone (17OHP) and androstenedione (A4) paralleled each other in healthy participants (n = 19) and patients with CAH (n = 122). However, healthy participants had similar absolute levels of 17OHP and A4 whereas patients with CAH had proportionally higher levels of 17OHP. Cross-correlation showed no lag between serum 17OHP and A4. In CAH, Bayesian multiple change point analysis converged on a 17OHP of 4.5 nmol/l below which in proportion to 17OHP the A4 is lower. Patients on standard treatment had a morning peak in 17OHP and A4 whereas patients on MRHC had relatively flat profiles. Salivary androgens including 11-ketotestosterone correlated with serum 17OHP and A4 in female patients (r = 0.7 to 0.9).

Interpretation: In CAH, elevated 17OHP drives the production of A4. High A4 reflects poor control, but low A4 does not indicate overtreatment. Accepting 17OHP is higher than A4, both measurements give similar reflection of control, and a 17OHP <38 nmol/l (1250 ng/dl) was associated with an A4 in the normal range <5 nmol/l (143 ng/dl) in 95% of patients and in clinical trials was used to define good control. On MRHC, which controls androgen levels over 24 h, a single sample of 17OHP and/or A4 can be used to monitor control. Salivary measurements reflect similar results to serum.

Funding: Diurnal; MRC; NIH; NIHR.

Keywords: 21-Hydroxylase deficiency; Adrenal insufficiency; Congenital adrenal hyperplasia; Glucocorticoid; Hydrocortisone; Modified release hydrocortisone; Monitoring.

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Conflict of interest statement

Declaration of interests A.P., E.B., D.P.M., J.N-P., A.R., N.K. and R.R. report additional COIs: R.R. is a Director of Diurnal Group Plc. A.P. receives unrelated research funds from Diurnal Limited and HRA Pharma. D.A.R. has received honoraria from Neurocrine biosciences. N.R. has received honoraria from Lundbeck, Crinetics, Spruce Biosciences and Neurocrine Biosciences. J.N-P. has received unrelated research funds from Diurnal Group Plc and Crinetics. D.M. received unrelated research funds from Diurnal Limited, Neurocrine Biosciences and Adrenas Therapeutics, all through the National Institutes of Health Cooperative Research and Development Agreements. N.K. has received research funds from Neurocrine Biosciences. G.C. is a NIHR Senior Investigator. A.P. delivered results for this study through the NIHR Birmingham Biomedical Research Centre. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care.

Figures

Fig. 1
Fig. 1
24-h profiles of serum biomarkers. Profiles of 17-OH progesterone (17OHP) and androstenedione (A4) in healthy participants and patients with congenital adrenal hyperplasia (CAH) plotted to show the relationship between 17OHP and A4 within individuals. For patients with CAH 17OHP in nmol/l is overlaid on A4 10× nmol/l to allow comparison as in CAH absolute levels of A4 are ∼10× lower than 17OHP whereas in healthy participants they have similar absolute levels of 17OHP and A4.
Fig. 2
Fig. 2
Cross-correlation of serum 17-OH progesterone and androstenedione by group. Cross-correlation plot of 17-OH progesterone (17OHP) and Androstenedione (A4) in healthy participants and patients with congenital adrenal hyperplasia (CAH) showing there is no lag between markers, with peak at zero demonstrating that the markers change in parallel over time. Points show mean of the estimate within groups, error bars show standard error of the mean, grey lines in background show individual patient cross-correlation plots.
Fig. 3
Fig. 3
Changepoint analysis of 17-OH progesterone on androstenedione. Regression of ln transformed area under curve 17-OH progesterone (17OHP) on androstenedione (A4) in healthy participants and patients with congenital adrenal hyperplasia (CAH). In healthy participants there are higher level of A4 for same levels of 17OHP. Bayesian changepoint analysis of 17OHP on A4 converged on changepoint in patients with CAH at 4.5 nmol/l 17OHP (149 ng/dl) (R^ < 1.008), compared to changepoint in healthy participants at 2.4 nmol/l (80.0 ng/dl) (R^ < 1.020). Grey lines show 25 randomly selected Bayesian posterior model fits close together, thus showing stable convergence of the model.
Fig. 4
Fig. 4
Matrix correlation of serum and salivary steroids. Matrix of Correlations between serum 17-OH progesterone (17OHP), androstenedione (A4) and salivary 17OHP, A4, 11-OH androstenedione, Testosterone and 11-ketotestosterone. Point measurements ln transformed measured at the same time of day. Saliva measured within 9 patients across 3 visits at one study centre.
See this image and copyright information in PMC

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