Impact of Modified-Release Hydrocortisone on circadian cortisol rhythms and disease control in Congenital Adrenal Hyperplasia

Background.Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by defects in adrenal steroidogenesis enzymes, most commonly 21-hydroxylase. This deficiency leads to varying phenotypes, from adrenal insufficiency (due to impaired cortisol and, in severe cases, aldosterone synthesis) to hyperandrogenism from adrenal androgen excess. Glucocorticoid therapy remains the standard treatment to replace cortisol and suppress androgens. However, treatment challenges persist, including the need for supraphysiologic doses and difficulty in mimicking the natural cortisol circadian rhythm.Efmody®, a modified-release hydrocortisone (MR-HC), was developed to better replicate this rhythm, particularly in the early morning, aiming to enhance disease control and reduce cardiovascular and metabolic risk. Despite this, real-world data remain limited. Aim of the study.This study investigates the impact of therapy with Efmody® in patients with CAH due to 21OHD, by assessing a series of anthropometric, metabolic, and hormonal parameters and CV risk scores. In a subset of patients, corticotropic axis replacement was also assessed by serial salivary cortisol evaluation throughout the day, to determine whether it could be used as a surrogate marker for disease control. Materials and methods.The cohort analysed consists of 36 adult patients with CAH, in whom clinical, metabolic and hormonal parameters were assessed at baseline, 6, 12 and 18 months following the initiation of therapy with MR-HC. Results.MR-HC treatment improved biochemical control: reductions were observed in ACTH [median of 150.15 ng/L (IQR:71.9-369.2) vs. 25.7 ng/L(8.6-77.5) at 6 months, p=0.0078; vs.35 ng/L(13.1-82.5) at 12 months, p=0.0001], androstenedione [19.25 nmol/L(9.3-29.9) vs. 7.7 nmol/L(2.35-19) at 6 months, p=0.0277; vs.10 nmol/L(4.9-20.2) at 12 months, p=0.0008], and 17OHP [470 nmol/L (83.7-597) vs. 52.5 nmol/L(15.7-368.5) at 6 months, p=0.0002; vs. 64.3 nmol/L(27-87.6) at 12 months, p=0.0016]. In males, the A/T ratio decreased at 12 months [1.55 (0.5-4.5) vs.0.5 (0.2-1.9), p=0.0078]. In females, androstenedione [17.6 nmol/L(11.8-28.8) vs.8.1 nmol/L(3.7-13.8) at 6 months, p=0.0181; vs. 10 nmol/L(6.5-16.6) at 12 months, p=0.0195], testosterone [2.83 nmol/L(1.1-4.4) vs. 0.89 nmol/L(0.19-2.5) at 6 months, p=0.0052; vs.1.1 nmol/L(0.6-2.8) at 12 months, p=0.0017], and progesterone [17 nmol/L(9.7-29) vs.4.5 nmol/L(1.1-11) at 6 months, p=0.0067; vs. 2.5(1.8-12.8) at 12 months, p=0.0322] declined. The proportion achieving disease control rose: in males from 31% to 43%(6 months) and 60%(12 months) (p=0.500 at both 6 and 12 months vs. baseline); in females from 20% to 59% (6 months) (p=0.031 vs. baseline), 38%(12 months) (p=0.125 vs.baseline), and 40%(18 months). After MR-HC initiation, menstrual cycle regularity improved from 30% at baseline to 45% at 6 months, 46% at 12 months and 29% at 18 months. At 12 months morning salivary cortisol increased(p=0.0313) and insulinemia(p=0.0167), triglycerides(p=0.0180) and VAI(p=0.0167) decreased.Total cholesterol(p=0.0379 at 6 months;p=0.0179 at 12 months) and LDL(p=0.0041 at 12 months;p=0.0391 at 18 months) increased.Circadian salivary cortisol showed single morning peaks in most cases.The composite median curve peaked at 07:00 with an AUC of 38.05 nmol/L·h. Controlled patients had a higher AUC (52.35 vs 32.25 nmol/L·h) despite similar curve shapes peaking at 7:00. Conclusions. MR-HC improves hormonal control in CAH patients, without increasing hydrocortisone dosage. Salivary cortisol profiles and AUC analyses closely mimick physiological rhythms and highlight the value of salivary monitoring for individualized care. While TG, insulin and VAI improved, the rise in TC and LDL cholesterol warrants CV monitoring and personalised treatment.