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Expression Profiles for Steroidogenic Enzymes in Adrenocortical Disease

Divisions of Reproductive and Pediatric Endocrinology (M.H.B., B.M., K.R., P.C.W.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032; Division of Endocrinology (F.M., G.A.), University of Padua, Padua 35100, Italy; Division of Medical Sciences (P.M.S., I.B.), University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom; and Department of Physiology (W.E.R.), Medical College of Georgia, Augusta, Georgia 30912

Address all correspondence and requests for reprints to: Dr. William E. Rainey, Department of Physiology, Medical College of Georgia, 1120 15th Street CA3094, Augusta, Georgia 30912. E-mail: wrainey{at}mcg.edu.

Context: Excess production of aldosterone or cortisol has profound effects on cardiovascular function and impacts other major organ systems. The mechanisms leading to the autonomous hypersecretion of aldosterone or cortisol in aldosterone-producing adenoma (APA) or cortisol-producing adenoma (CPA) are unknown.

Objective: The objective of this study was to compare the expression profiles of several steroid-metabolizing enzymes and transcription factors from normal adrenal (NA), APAs, and CPAs.

Design: RNA from NAs, APAs, and CPAs were analyzed by microarray and real-time RT-PCR.

Setting: This study was performed at academic research laboratories.

Patients: At least nine normal controls and 12 patients with APA or CPA were studied.

Intervention: There was no intervention procedure.

Main Outcome Measure: The main outcome measure was the expression of steroidogenic enzymes in adrenocortical disease.

Results: A microarray indicated a greater than 3-fold increase in the expression of CYP11B2 (aldosterone synthase) in APA, whereas 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2) and HSD17B1 had greater than 3-fold increases in expression in CPA compared with NA. Real-time RT-PCR showed that APAs produced higher levels of HSD3B2, CYP21 (21-hydroxylase), and CYP11B2 mRNA, whereas CPAs produced higher levels of CYP11A (cholesterol side-chain cleavage), CYP17 (17-hydroxylase/17–20 lyase), HSD3B2, and CYP11B1 (11ß-hydroxylase) mRNA compared with normal adrenal. Steroidogenic factor-1, DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome gene 1), and GATA-6 were expressed at higher levels in APAs and CPAs, whereas NURR1 was expressed at higher levels in APAs than in CPAs or NAs.

Conclusion: Elevated production of aldosterone in APAs and of cortisol in CPAs is associated with increased expression of enzymes needed for corticosteroid production along with alterations in transcription factors that enhance the expression of steroid-metabolizing enzymes.

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