Adrenarche denotes the marked increase in DHEA and DHEA-S production from the adrenal zona reticularis that normally occurs at around 6 years of age. The phenotypic result of adrenarche is pubarche or the development of axillary and pubic hair that occurs in both girls and boys at about age 8. Premature or exaggerated adrenarche may be a harbinger of diseases that manifest in adulthood, thus increasing its clinical relevance. While the exact trigger that induces adrenarche remains poorly understood, the biochemical alterations in adrenal androgen production clearly reflect changes in the expression of key enzymes and cofactors in the adrenal zona reticularis. In this proposal, we focus on the mechanisms that regulate the expression of these key enzymes and cofactors during adrenarche.
In Specific Aim 1, we will use microarray analyses to compare the transcription profiles of the zona reticularis at the site where DHEA-S is produced and the zona fasciculata, where cortisol is made. The increase in DHEA-S production seen at adrenarche at least partly reflects an increase in the C17-20 lyase activity of steroid 17a-hydroxylase (CYP17), presumably secondary to increased expression of the electron donor cytochrome b5, and an increase in DHEA-sulfotransferase (SULT2A1). Preliminary data already have identified differences in certain key transcription factors that may modify the expression pattern of the DHEA-S producing enzymes. Studies proposed in Specific Aim 2 will focus on the roles of these transcription factors to up-regulate cytochrome b5 and SULT2A1, as well as other genes identified in our microarray studies as key components of zona reticularis function. The noncytochrome P450 enzyme 3b-hydroxysteroid dehydrogenase (HSD3B2) has the unique ability to remove precursors from the pathway leading to DHEA-S thereby inhibiting adrenal androgen biosynthesis. HSD3B2 is expressed at high levels in cortisol-producing cells of the zona fasciculata but is absent in the reticularis once adrenarche is initiated.
In Specific Aim 3, we will define the molecular mechanisms that block HSD3B2 expression in the zona reticularis. Collectively, the proposed studies will provide a detailed picture of the molecular alterations that occur in the adrenal cortex during adrenarche and should also elucidate the intra-adrenal mechanisms regulating adrenal androgen production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069950-05
Application #
7675435
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Margolis, Ronald N
Project Start
2005-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$272,211
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Rege, Juilee; Turcu, Adina F; Kasa-Vubu, Josephine Z et al. (2018) 11-Ketotestosterone Is the Dominant Circulating Bioactive Androgen During Normal and Premature Adrenarche. J Clin Endocrinol Metab 103:4589-4598
Gomez-Sanchez, Celso E; Lewis, Mark; Nanba, Kazutaka et al. (2017) Development of monoclonal antibodies against the human 3?-hydroxysteroid dehydrogenase/isomerase isozymes. Steroids 127:56-61
Rege, Juilee; Karashima, Shigehiro; Lerario, Antonio M et al. (2016) Age-dependent Increases in Adrenal Cytochrome b5 and Serum 5-Androstenediol-3-sulfate. J Clin Endocrinol Metab 101:4585-4593
Turcu, Adina F; Nanba, Aya T; Chomic, Robert et al. (2016) Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol 174:601-9
Taylor, Matthew J; Sanjanwala, Aalok R; Morin, Emily E et al. (2016) Synthetic High-Density Lipoprotein (sHDL) Inhibits Steroid Production in HAC15 Adrenal Cells. Endocrinology 157:3122-9
Campana, Carmela; Rege, Juilee; Turcu, Adina F et al. (2016) Development of a novel cell based androgen screening model. J Steroid Biochem Mol Biol 156:17-22
Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Hui, Xiao-gang et al. (2015) 3?HSD and CYB5A double positive adrenocortical cells during adrenal development/aging. Endocr Res 40:8-13
Rege, Juilee; Nishimoto, Hiromi Koso; Nishimoto, Koshiro et al. (2015) Bone Morphogenetic Protein-4 (BMP4): A Paracrine Regulator of Human Adrenal C19 Steroid Synthesis. Endocrinology 156:2530-40
Campana, Carmela; Pezzi, Vincenzo; Rainey, William E (2015) Cell-based assays for screening androgen receptor ligands. Semin Reprod Med 33:225-34
Satoh, Fumitoshi; Morimoto, Ryo; Ono, Yoshikiyo et al. (2015) Measurement of peripheral plasma 18-oxocortisol can discriminate unilateral adenoma from bilateral diseases in patients with primary aldosteronism. Hypertension 65:1096-102

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