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Adrenarche Results from Development of a 3ß-Hydroxysteroid Dehydrogenase-Deficient Adrenal Reticularis¹

Division of Reproductive Endocrinology (J.S.G., B.R.C., B.A., W.E.R.), Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology (H.S.), Tohoku University School of Medicine, Sendai, Japan; Department of Pathology (L.M.), Children’s Medical Center, Dallas, Texas; Department of Clinical Biochemistry (J.I.M.), University of Edinburgh, Edinburgh, United Kingdom

Address all correspondence and requests for reprints to: William E. Rainey, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9032.

Adrenarche is the increased adrenal production of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) that occurs during the prepubertal period. To date, the exact mechanism initiating adrenarche is unknown, although many factors have been postulated. In the present study, we examined the hypothesis that alterations in intra-adrenal expression of 3ß-hydroxysteroid dehydrogenase (3ßHSD) or 21-hydroxylase (CYP21) within the inner reticularis zone leads to the increased production of 19-carbon (C₁₉) steroids. After conversion of cholesterol to pregnenolone, 17-hydroxylase/17,20-lyase (CYP17) can metabolize pregnenolone through to DHEA. The enzyme 3ßHSD competes for substrate with CYP17 and effectively removes steroid precursor from the pathway leading to DHEA. On the other hand, deficiency in CYP21 expression is known to cause excessive production of adrenal C₁₉ steroids, suggesting that CYP21 could play a role in adrenarche. Thus, a decrease in 3ßHSD or CYP21 expression would allow substrate to flow toward the synthesis of DHEA. To determine whether adrenarche results from a decreased expression of 3ßHSD or CYP21 in the reticularis, immunohistochemical localization of 3ßHSD and CYP21 was performed, and staining intensities compared using adrenal glands from children ages 4 months to 4 yr (n = 12), ages 5–7 yr (n = 9), ages 8–13 yr (n = 9), and adults ages 25–56 yr (n = 8). There were no differences in the zonal expression of CYP21. No difference in 3ßHSD staining was observed between the glomerulosa and fasciculata from any age group. However, children age 8 yr and older show a significant decrease in 3ßHSD expression in reticularis as compared with the fasciculata. No significant difference was noted for 3ßHSD levels between the fasciculata and reticularis for children age 7 yr or younger. The level of 3ßHSD expression in the reticularis continued to decrease in the adult adrenals examined. These findings suggest that as children mature there is a decreased level of 3ßHSD in the adrenal reticularis that may contribute to the increased production of DHEA and DHEAS seen during adrenarche.

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