SUN-461 - Biochemical and Metabolic Improvements with Crinecerfont in Simple Virilizing Congenital Adrenal Hyperplasia

Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency causes impaired cortisol synthesis, leading to increased adrenocorticotropic hormone drive, adrenal hyperplasia, and androgen excess. Many patients require supraphysiologic glucocorticoid doses to suppress androgens, worsening cardiometabolic risk. Crinecerfont, a corticotropin-releasing hormone receptor 1 antagonist, targets upstream pituitary stimulation to improve biochemical control while enabling glucocorticoid reduction.

Case Presentation: A 24-year-old male with simple virilizing CAH (diagnosed age 9) and comorbid attention-deficit/hyperactivity disorder, autism spectrum disorder, and obstructive sleep apnea was maintained on hydrocortisone 40 mg/day (25-10-5 mg dosing) with good medication adherence. Serial monitoring of 17-hydroxyprogesterone (17-OHP; reference 32-307 ng/dL) and androstenedione (reference 50-220 ng/dL) demonstrated persistent elevation despite therapy (March 2025: 17-OHP 3,341 ng/dL, androstenedione 389 ng/dL; July: 17-OHP 3,308 ng/dL, androstenedione 354 ng/dL). Given inadequate biochemical control, crinecerfont 100 mg twice daily was initiated in July 2025 with concurrent increase in hydrocortisone to 45 mg/day (25-10-10 mg). By October, both markers improved substantially: 17-OHP decreased to 2,206 ng/dL (33% reduction from July) and androstenedione normalized to 150 ng/dL (58% reduction). Given this biochemical improvement, hydrocortisone was reduced back to 40 mg/day (20-10-10 mg) in October. Notably, despite the concurrent glucocorticoid dose increase, weight decreased from 161 to 143 lb over the July-to-October interval without structured dietary intervention. Metabolic parameters also improved: total cholesterol 190→169 mg/dL, triglycerides 175→124 mg/dL, high-density lipoprotein cholesterol 39→44 mg/dL, low-density lipoprotein cholesterol 122→102 mg/dL. No crinecerfont-related adverse events occurred.
Learning Points: (1) Crinecerfont can meaningfully improve biochemical control in CAH patients inadequately controlled on high-dose glucocorticoids, addressing the clinical dilemma of balancing androgen suppression against iatrogenic metabolic harm. (2) Upstream corticotropin-releasing hormone receptor antagonism may enable subsequent glucocorticoid dose reduction while maintaining biochemical targets, offering a novel adjunctive strategy. (3) Weight loss and metabolic improvements occurred despite concurrent glucocorticoid dose increase, suggesting crinecerfont's potential to mitigate cardiometabolic complications independent of glucocorticoid reduction, though causality requires longer follow-up.

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