Studies of dehydroepiandrosterone (DHEA) with the human estrogen receptor in yeast

Dehydroepiandrosterone (DHEA) is a C-19 adrenal steroid synthesized in the human adrenal cortex and serving as a biosynthetic precursor to testosterone and 17 beta-estradiol. Despite the fact that it is one of the most abundant steroid hormones in circulation, the physiological role of DHEA in humans remains unclear. The action of DHEA itself, such as its interactions with receptors and nuclear transcription factors, is not well understood, and a specific DHEA receptor has yet to be identified. Although the activity of DHEA can be due to its metabolism into androgens and estrogens, DHEA has been shown to interact with the androgen receptor and the estrogen receptor (ER) in vitro. We demonstrate in this study that DHEA (3 beta-Hydroxy-5 alpha-androstan17-one) inhibits 17 beta-estradiol (E-2) binding to its receptor in vivo in yeast. DHEA stimulates human ER dimerization in yeast, as determined by ER fusion protein interactions, GAL4 reconstitution and subsequent measurement of increased beta-galactosidase activity. DHEA causes an increase in estrogen response element-dependent beta-galactosidase activity, demonstrating that the ER dimer induced by DHEA is transcriptionally active, but at a concentration of DHEA about 1000 times greater than E-2. Inclusion of the nuclear receptor co-activator RIP140 in the yeast enhances ER transactivation by DHEA or E-2 in a ligand-dependent manner; moreover, only in the presence of RIP140 is DHEA able to stimulate P-galactosidase activity to levels similar to those achieved by E-2. Ligand-receptor interaction for other C-19-steroids was also examined. While 5-androstene-3 beta, 17 beta-diol (ADIOL) displayed estrogenic activity in this system, 4-androstene-17-dione (androstenedione) and 4-androstene-17 beta-ol,3-one (testosterone) did not. We have investigated whether DHEA can interact with the human ER in vivo. Our findings demonstrate a mechanism by which DHEA interacts directly with estrogen signaling systems; however, because DHEA is several orders of magnitude less potent than E-2 in this system, we conclude that it essentially is not an estrogen agonist. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.