Androgenic and estrogenic metabolites in serum of mice fed dehydroepiandrosterone: Relationship to antihyperglycemic effects

Abstract The steroid prehormone, dehydroepiandrosterone (DHEA) has potent antihyperglycemic effects when fed in the diet of genetically diabetic C57BLKsJ-dbdb mice. The purpose of this investigation was to analyze changes in sex steroid levels in serum of mice fed DHEA, and to compare the antihyperglycemic potencies of the various metabolites in order to clarify the mechanism of DHEA action. Steroid radioimmunoassays showed that dietary DHEA entered the blood in high concentrations and was actively metabolized to both androgens (testosterone, T; dihydrotestosterone, DHT) and estrogens (estrone, E 1 ; 17β-estradiol, E 2 ). This metabolism did not require intact adrenal glands or gonads. In C57BLKsJ normal (+/+) males, conversion of DHEA to androgens was the prominent feature; in dbdb males, DHEA feeding not only increased serum T and DHT, but also serum E 1 and E 2 levels. The dbdb mice had increased amounts of adipose tissue that sequestered more intravenously injected 3 H-E 2 ; this additional body fat could account for increased aromatization of DHEA-derived estrogen precursors. Comparisons of the relative antihyperglycemic potencies of androgenic and estrogenic steroid metabolites of DHEA in dbdb mice showed that the estrogens and metabolites with estrogenic properties (androstenediol) or those convertible to estrogens (DHEA sulfate) were the most potent. Although 17β-E 2 was effective by injection or per os, DHEA was effective only when administered per os, implicating alimentary tract conversion of DHEA to more biologically active reactants. Based on the pivotal position of DHEA as a prehormone for androgens, estrogens, and etiocholanolones, an explanation of the seemingly paradoxical effects exerted by this compound in blocking autoimmune disease, hyperglycemia, obesity, and neoplasia was proposed.