Juilee Rege1, Adina F Turcu2, Josephine Z Kasa-Vubu3, Antonio M Lerario2, Gabriela C Auchus1, Richard J Auchus2,4, Joshua M Smith5, Perrin C White6, William E Rainey1,2. 1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. 2. Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. 3. Department of Pediatrics, University of Michigan, Ann Arbor, Michigan. 4. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan. 5. Rocky Mountain Diabetes Center, Idaho Falls, Idaho. 6. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
Abstract
Context: Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of adrenarche include onset of body odor, axillary hair, and pubic hair, which reflect increased androgen action. An early rise in adrenal androgens, or premature adrenarche (PremA), is a risk factor for adverse metabolic profiles in adolescence and adulthood. The bioactive androgens associated with adrenarche and PremA remain poorly understood. The adrenal gland is a potential source of testosterone (T) and the 11-oxygenated derivatives 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT). Objective: The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA. Participants and Methods: With the use of mass spectrometry, 19 steroids including the 11-oxygenated derivatives of T were measured in sera obtained from girls with PremA (n = 37; 4 to 7 years) and age-matched girls (n = 83; 4 to 10 years). Results: In reference population girls, dehydroepiandrosterone, DHEA-S, androstenediol-3-sulfate, T, and 11KT all increased at the onset of adrenarche (6 to 8 years) and beyond (9 to 10 years) (P < 0.05 vs younger subjects 4 to 5 years). T, 11OHT, and 11KT were further elevated in PremA vs age-matched girls (P < 0.001). Circulating concentrations of 11KT during adrenarche and PremA exceeded those of T and 11OHT (11KT > T ≥ 11OHT). Androgen receptor activity and nuclear translocation studies demonstrated that 11KT is a potent androgen similar to T. Conclusions: Our findings suggest that 11KT is the dominant bioactive androgen in children during adrenarche and PremA. Its androgenic capacity suggests that it may be responsible for the phenotypic changes seen in these phenomena.
Context: Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of adrenarche include onset of body odor, axillary hair, and pubic hair, which reflect increased androgen action. An early rise in adrenal androgens, or premature adrenarche (PremA), is a risk factor for adverse metabolic profiles in adolescence and adulthood. The bioactive androgens associated with adrenarche and PremA remain poorly understood. The adrenal gland is a potential source of testosterone (T) and the 11-oxygenated derivatives 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT). Objective: The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA. Participants and Methods: With the use of mass spectrometry, 19 steroids including the 11-oxygenated derivatives of T were measured in sera obtained from girls with PremA (n = 37; 4 to 7 years) and age-matched girls (n = 83; 4 to 10 years). Results: In reference population girls, dehydroepiandrosterone, DHEA-S, androstenediol-3-sulfate, T, and 11KT all increased at the onset of adrenarche (6 to 8 years) and beyond (9 to 10 years) (P < 0.05 vs younger subjects 4 to 5 years). T, 11OHT, and 11KT were further elevated in PremA vs age-matched girls (P < 0.001). Circulating concentrations of 11KT during adrenarche and PremA exceeded those of T and 11OHT (11KT > T ≥ 11OHT). Androgen receptor activity and nuclear translocation studies demonstrated that 11KT is a potent androgen similar to T. Conclusions: Our findings suggest that 11KT is the dominant bioactive androgen in children during adrenarche and PremA. Its androgenic capacity suggests that it may be responsible for the phenotypic changes seen in these phenomena.
Authors: Jan Idkowiak; Gareth G Lavery; Vivek Dhir; Timothy G Barrett; Paul M Stewart; Nils Krone; Wiebke Arlt Journal: Eur J Endocrinol Date: 2011-05-26 Impact factor: 6.664
Authors: Angela Davio; Helen Woolcock; Aya T Nanba; Juilee Rege; Patrick O'Day; Jianwei Ren; Lili Zhao; Hiroki Ebina; Richard Auchus; William E Rainey; Adina F Turcu Journal: J Clin Endocrinol Metab Date: 2020-08-01 Impact factor: 5.958
Authors: Aya T Nanba; Juilee Rege; Jianwei Ren; Richard J Auchus; William E Rainey; Adina F Turcu Journal: J Clin Endocrinol Metab Date: 2019-07-01 Impact factor: 5.958
Authors: Juilee Rege; Scott Garber; Alan J Conley; Ruth M Elsey; Adina F Turcu; Richard J Auchus; William E Rainey Journal: J Steroid Biochem Mol Biol Date: 2019-04-05 Impact factor: 4.292
Authors: Laura C Torchen; Ryan Sisk; Richard S Legro; Adina F Turcu; Richard J Auchus; Andrea Dunaif Journal: J Clin Endocrinol Metab Date: 2020-11-01 Impact factor: 5.958