Age- and sex-specific reference intervals for 11-oxygenated androgens from infancy throughout childhood and adulthood

The adrenal glands are the main source of 11-oxygenated androgens (11-OAs), including the potent 11-ketotestosterone (11-KT) and the weaker metabolites 11β-hydroxyandrostenedione (11-OHA4), 11β-hydroxytestosterone (11-OHT) and 11-ketoandrostenedione (11-KA4). Due to their adrenal origin, 11-OAs allow the differentiation of adrenal and extra-adrenal-produced androgens. However, their clinical use is limited due to the lack of robust age- and sex-specific reference intervals (RIs).

To establish RIs from infancy throughout childhood and adulthood, we performed simultaneous quantification of 11-OHA4, 11-OHT, 11-KA4, 11-KT, and clinically relevant steroid hormones via LC-MS/MS. We analyzed 3,796 serum samples from 2,505 healthy individuals, aged 0.25-80 years, encompassing minipuberty and pubertal stages.

11-OA serum levels increase from infancy throughout childhood and adulthood, with the most pronounced increase during puberty. Significant sex differences were observed, and age-, sex-, and puberty-dependent RIs were established. In contrast to testosterone, 11-OAs exhibited a comparable pattern during the first year of life in both sexes. At 3 and 6 months of age - when testosterone levels were 100- and 10-fold higher, respectively, in males than in females - no correlation was observed between testosterone and the adrenal-derived androgens (11-OAs, A4, and DHEAS) in males.

Established age-, sex-, and puberty-dependent RIs support the clinical interpretation of 11-OA measurements in disorders characterized by androgen excess. The differences in the regulation of classical androgens and 11-OAs during minipuberty suggest that the transient increase in androgens during the first months of life is most likely due to activation of the hypothalamic-pituitary-gonadal axis.