ACTH and renin in 529 healthy youths: associations to sex, puberty and contraceptives.

Objective: To establish sex- and age-specific reference intervals for plasma concentrations of adrenocorticotropic hormone (ACTH) and direct renin in healthy youth. Design: 529 healthy subjects (5.8-20.4 years) were recruited as part of the third Copenhagen Puberty Study, an ongoing cross-sectional study of healthy Danish participants attending compulsory school and high school. Method: Plasma ACTH and direct plasma renin concentrations were established using GAMLSS statistics, sex- and age-specific reference intervals and standard deviation (SD) scores. Concentrations were evaluated according to pubertal stage and oral contraceptive (OC) use. Results: ACTH concentrations did not differ between sexes. ACTH concentrations were higher in pubertal males than in prepubertal males (P = 0.015); however, this difference was not statistically significant when analyses were restricted to samples collected before 10:00 h. In females, ACTH concentrations did not seem to differ according to pubertal status. In both sexes, renin concentrations were lower in pubertal than in prepubertal subjects (females: P < 0.001; males: P = 0.016). Renin SD scores were lower in OC users than in non-OC users (P = 0.007), while ACTH SD scores did not differ between these groups. Conclusion: Sex- and age-specific reference intervals for plasma concentrations of ACTH and direct renin in young, healthy subjects were provided, reflecting changed levels through puberty and significantly lower renin SD scores in OC users. Application of these biomarkers' SD scores may enhance the management of patients with adrenal disorders. Significance statement: Reliable reference data for plasma ACTH and direct plasma renin in healthy children are limited. This large population-based cohort study of healthy participants attending compulsory school and high school provides comprehensive sex- and age-specific reference intervals for plasma ACTH and renin. Furthermore, absolute concentrations were converted to relative SD scores, thereby providing a more unified and standardized tool for clinical assessment. Reporting ACTH and renin concentrations by pubertal stage represents a novel aspect. These new reference intervals enhance the clinical utility of biomarker-based monitoring and treatment of pediatric endocrine disorders, such as congenital adrenal hyperplasia, addressing a critical gap in current clinical pediatric practice. Clinical trial registration number: NCT04884620.