Biosynthesis and metabolism of steroid hormones by human adrenal carcinomas.

J.W Brown,L.M Fishman

doi:10.1590/s0100-879x2000001000014

Abstract

Over a 15-year period, our university-based laboratory obtained 125 adrenal tumors, of which 15 (12%) were adrenal cortical carcinomas. Of these, 6 (40% of the carcinomas) occurred in patients with clear clinical manifestations of steroid hormone excess. Adrenal cortical carcinoma cells derived from the surgically resected tumors in 4 of these patients were isolated and established in primary culture. Radiotracer steroid interconversion studies were carried out with these cultures and also on mitochondria isolated from homogenized tissues. Large tumors had the lowest steroidogenic activities per weight, whereas small tumors had more moderately depressed enzyme activities relative to cells from normal glands. In incubations with pregnenolone as substrate, 1 mM metyrapone blocked the synthesis of corticosterone and cortisol and also the formation of aldosterone. Metyrapone inhibition was associated with a concomitant increase in the formation of androgens (androstenedione and testosterone) from pregnenolone. Administration of metyrapone in vivo before surgery in one patient resulted in a similar increase in plasma androstenedione, though plasma testosterone levels were not significantly affected. In cultures of two of four tumors examined, dibutyryl cAMP stimulated 11ss-hydroxylase activity modestly; ACTH also had a significant stimulatory effect in one of these tumors. Unlike results obtained with normal or adenomatous adrenal cortical tissues, mitochondria from carcinomatous cells showed a lack of support of either cholesterol side-chain cleavage enzyme complex or steroid 11ss-hydroxylase activity by Krebs cycle intermediates (10 mM isocitrate, succinate or malate). This finding is consistent with the concept that these carcinomas may tend to function predominantly in an anaerobic manner, rather than through the oxidation of Krebs cycle intermediates.

Highlights

Adrenal cortical carcinoma is a rare disease whose course is often fatal within a short time of recognized onset
Unlike results obtained with normal or adenomatous adrenal cortical tissues, mitochondria from carcinomatous cells showed a lack of support of either cholesterol side-chain cleavage enzyme complex or steroid 11ß-hydroxylase activity by Krebs cycle intermediates (10 mM isocitrate, succinate or malate)
There is no definitive biochemical information to localize the site of the defect in ACTH responsiveness; potential mechanisms might include defective ACTH receptors [24], altered ACTH receptor enzyme coupling or adenylate cyclase activity [25,26], or defects in the cAMP cascade [27]. Various combinations of these factors could, be involved and might vary in different tumors. We present in this communication the results of studies of the biosynthesis of steroid hormones in cell cultures from human adrenal carcinomas and of the in vitro modulation of steroidogenesis in these tumor cells by physiologic and pharmacologic agents

Summary

Introduction

Adrenal cortical carcinoma is a rare disease whose course is often fatal within a short time of recognized onset. Like adenomas, usually produce glucocorticoid hormones independently of pituitary-adrenal axis ACTH control This phenomenon results in an absent or blunted ACTH response, ACTH-responsive tumors have been reported in some animal models [23]. There is no definitive biochemical information to localize the site of the defect in ACTH responsiveness; potential mechanisms might include defective ACTH receptors [24], altered ACTH receptor enzyme coupling or adenylate cyclase activity [25,26], or defects in the cAMP cascade [27] Various combinations of these factors could, be involved and might vary in different tumors. We present in this communication the results of studies of the biosynthesis of steroid hormones in cell cultures from human adrenal carcinomas and of the in vitro modulation of steroidogenesis in these tumor cells by physiologic and pharmacologic agents

Material and Methods

Results and Discussion

17 OH-Prog

Conclusions