The adrenal gland is a significant contributor to the circulating androgen pool in women and pre- pubertal children. Unlike the zona glomerulosa (ZG) and zona fasciculata (ZF), the zona reticularis (ZR) is relatively inactive until around 6 years of age when the zone expands and significantly increases the production of DHEA-S. This event is termed adrenarche, and is associated with the initiation of pubic and axillary hair growth as well as development of pubertal body odor and acne. Premature adrenarche (PA) describes an early rise in adrenal androgen production associated with concomitant development of pubic hair. Numerous studies now indicate that children with PA are more likely to have adult onset diseases that include insulin resistance and polycystic ovary syndrome (PCOS). Because of the large number of adults affected by these diseases, a better understanding of PA as a potential cause or early indicator of future disease has a high degree of clinical significance. My laboratory has approached the study of adrenarche by focusing on the adrenal itself and the changes it undergoes during the process of adrenarche. During our past funding period, we demonstrated distinct intra-adrenal changes during adrenarche that would allow the adrenal to produce a novel set of bioactive androgens. Preliminary steroid metabolomic analysis of human adrenal vein samples identified a series of novel androgens, including 112-hydroxytestosterone (11OHT) and 11- ketotestosterone (11KT). 11OHT and 11KT represent novel adrenal-specific steroids because their synthesis requires CYP11B1 (112-hydroxylase), an enzyme expressed almost solely in the human adrenal cortex. Our proposed research will test the overall hypothesis that adrenarche is marked by the production of bioactive androgens that play key roles in the physiologic effects of normal and premature adrenarche. We will address this goal through three specific aims:
Aim 1 will define the human adrenal bioactive androgen metabolome and the levels of these steroids during adrenarche.
Aim 2 will define the adrenocortical biosynthetic pathway for 11OHT and 11KT.
Aim 3 will determine the bioactive androgens that increase during premature adrenarche. Completion of the study goals will significantly increase our understanding of the adrenal products that cause the biochemical and phenotypic manifestations of adrenarche during the pre-pubertal years. Definition of this novel series of adrenal androgens will also provide new biomarkers of adrenal dysregulation that may have implications not only in PA but also in women with adrenal-related hyperandrogenism.

Public Health Relevance

Adrenarche denotes the progressive increase in adrenal androgen production that normally is detected around six years of age. Premature or exaggerated adrenarche appears to be a harbinger of adult diseases, thus increasing its clinical relevance. While DHEA and its sulfate are used to monitor adrenarche, these steroids have no androgenic bioactivity. In this proposal, we will define the bioactive androgens produced by the adrenal and define their role as markers of premature and normal adrenarche.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Margolis, Ronald N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Hui, Xiao-gang et al. (2015) 3?HSD and CYB5A double positive adrenocortical cells during adrenal development/aging. Endocr Res 40:13-Aug
Nakamura, Yasuhiro; Hattangady, Namita G; Ye, Ping et al. (2014) Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA). Mol Cell Endocrinol 384:102-8
Rege, Juilee; Nakamura, Yasuhiro; Wang, Tao et al. (2014) Transcriptome profiling reveals differentially expressed transcripts between the human adrenal zona fasciculata and zona reticularis. J Clin Endocrinol Metab 99:E518-27
Felizola, Saulo J A; Nakamura, Yasuhiro; Ono, Yoshikiyo et al. (2014) PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues. J Mol Endocrinol 52:159-67
Felizola, Saulo J A; Nakamura, Yasuhiro; Hui, Xiao-Gang et al. (2013) Estrogen-related receptor * in normal adrenal cortex and adrenocortical tumors: involvement in development and oncogenesis. Mol Cell Endocrinol 365:207-11
Rege, Juilee; Nakamura, Yasuhiro; Satoh, Fumitoshi et al. (2013) Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab 98:1182-8
Wang, T; Rowland, J G; Parmar, J et al. (2012) Comparison of aldosterone production among human adrenocortical cell lines. Horm Metab Res 44:245-50
Hattangady, Namita G; Olala, Lawrence O; Bollag, Wendy B et al. (2012) Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 350:151-62
Nakamura, Yasuhiro; Rege, Juilee; Satoh, Fumitoshi et al. (2012) Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein corticosteroids before and after adrenocorticotropic hormone stimulation. Clin Endocrinol (Oxf) 76:778-84
Xing, Yewei; Rainey, William E; Apolzan, John W et al. (2012) Adrenal cell aldosterone production is stimulated by very-low-density lipoprotein (VLDL). Endocrinology 153:721-31

Showing the most recent 10 out of 27 publications