Classic congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder caused by a defect in the enzyme cascade regulating adrenal steroidogenesis; in approximately 95% of cases the defect is located in CYP21A2, the gene encoding 21-hydroxylase, and is characterized by defective adrenal steroidogenesis and cortisol deficiency. Due to the loss of physiological cortisol feedback on the hypothalamus and pituitary corticotropic cells, ACTH secretion is increased. This results in the accumulation of 17-hydroxyprogesterone (17OHP) proximal to the enzymatic defect in steroidogenesis, which in turn stimulates overproduction of the adrenal androgen precursor androstenedione and adrenal hyperplasia.
Treatment of CAH is tailored to the patient and disease severity, aiming to replace cortisol and aldosterone deficiencies while controlling androgen excess and avoiding glucocorticoid overtreatment. Immediate-release hydrocortisone administered multiple times daily remains the recommended first-line treatment in growing children, whereas adult patients are frequently treated with hydrocortisone, prednisone, prednisolone or dexamethasone.
However, conventional glucocorticoid regimens cannot adequately reproduce the physiological circadian rhythm of cortisol secretion. In physiological conditions, ACTH-driven cortisol secretion follows a clear circadian rhythm characterized by low evening levels, nocturnal increase between 2:00 and 4:00 a.m., a morning peak upon awakening, and progressive decline during daytime.
Dual daytime dosing of immediate-release hydrocortisone in CAH can control ACTH-driven adrenal androgen secretion during the day; however, because of its rapid absorption into the bloodstream and short half-life, the evening dose of hydrocortisone cannot adequately suppress the nocturnal ACTH surge and ACTH-driven adrenal androgen overproduction.
Consequently, patients are often exposed to supraphysiological glucocorticoid doses during nighttime hours in an attempt to control morning hyperandrogenism. The disruption of physiological cortisol homeostasis contributes to poor cardiometabolic profile, obesity, insulin resistance, impaired fertility, reduced quality of life, and increased cardiovascular morbidity and mortality observed in patients with CAH.
Bone health may also be impaired in patients with CAH because of chronic glucocorticoid exposure and androgen imbalance. Previous studies demonstrated reduced lumbar and femoral bone mineral density and increased fracture risk in both male and female patients.
Modified-release hydrocortisone (MR-HC; Efmody®) is a multiparticulate formulation developed to better reproduce physiological cortisol circadian rhythm through chronotherapy. Previous phase II and phase III studies demonstrated improved biochemical control, reduction in androgen excess, lower glucocorticoid exposure, improved fertility outcomes, and sustained long-term efficacy compared with conventional glucocorticoid regimens.
However, real-world longitudinal data regarding long-term biochemical, metabolic, cardiovascular, reproductive and skeletal outcomes remain limited, particularly in adult patients transitioning from pediatric to adult endocrine care.
The present study is a single-center, retrospective and prospective, longitudinal, open-label observational cohort study aimed at evaluating the long-term real-world outcomes of chronotherapy with modified-release hydrocortisone in adult patients with genetically confirmed 21-hydroxylase deficiency CAH.
Retrospective clinical, biochemical and radiological data already available from routine clinical care will be collected from medical records, while prospective observational follow-up will continue according to routine endocrine clinical practice.
Age ≥18 years;
Genetically confirmed diagnosis of 21-hydroxylase deficiency congenital adrenal hyperplasia;
Transition from conventional glucocorticoid therapy to modified-release hydrocortisone according to routine clinical practice;
Stable glucocorticoid and mineralocorticoid therapy before transition;
Age <18 years;
Pregnancy or breastfeeding;
Severe uncontrolled medical or psychiatric illness;
Use of glucocorticoids for indications other than CAH;
Approximately 32 patients are currently available for retrospective and prospective analysis. Additional eligible patients may be enrolled prospectively during the observational phase. All patients who come for an appointment at the endocrinology clinics of IRCCS San Raffaele for routine clinical evaluations
Other
Cross-sectional
Not listed
Change From Baseline in Morning Serum 17- Hydroxyprogesterone and Androstenedione Concentrations
Morning serum 17-OH progesterone (17OHP) and D4-androstenedione levels under conventional therapy and during MR-HC treatment
Change From Baseline in Morning Serum 17-Hydroxyprogesterone (17OHP) and Androstenedione Concentrations During Modified-Release Hydrocortisone Treatment
Morning serum 17OHP and androstenedione concentrations measured during conventional glucocorticoid therapy and after transition to MR-HC.
Change From Baseline in Morning Plasma ACTH and Cortisol Concentrations and Midnight Salivary Cortisol Levels
Morning plasma ACTH and cortisol concentrations and midnight salivary cortisol levels.
Change From Baseline in Plasma Renin Activity and Serum Sodium and Potassium Concentrations
Plasma renin activity and serum sodium and potassium concentrations as indicators of mineralocorticoid control.
Number of Adrenal Crises and Episodes Requiring Glucocorticoid Stress Dosing
Occurrence of adrenal crises and episodes requiring stress-dose glucocorticoid administration.
Change From Baseline in Bone Turnover Markers and DXA-Derived Bone Mineral Density During Long-Term Follow-Up
Longitudinal assessment of skeletal outcomes including biochemical bone turnover markers and DXA-derived bone mineral density.
Longitudinal Changes in Integrated Biochemical and Clinical Outcomes Beyond 12 Months of Follow-Up
Long-term biochemical, endocrine, metabolic, anthropometric, reproductive, and clinical outcomes during continued MR-HC treatment.
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