Leiter E H, Beamer W G, Coleman D L, Longcope C
Metabolism. 1987 Sep;36(9):863-9. doi: 10.1016/0026-0495(87)90095-3.
The steroid prehormone, dehydroepiandrosterone (DHEA) has potent antihyperglycemic effects when fed in the diet of genetically diabetic C57BL/KsJ-db/db 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, E1; 17 beta-estradiol, E2). This metabolism did not require intact adrenal glands or gonads. In C57BL/KsJ normal (+/+) males, conversion of DHEA to androgens was the prominent feature; in db/db males, DHEA feeding not only increased serum T and DHT, but also serum E1 and E2 levels. The db/db mice had increased amounts of adipose tissue that sequestered more intravenously injected 3H-E2; 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 db/db mice showed that the estrogens and metabolites with estrogenic properties (androstenediol) or those convertible to estrogens (DHEA sulfate) were the most potent. Although 17 beta-E2 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.
类固醇前体激素脱氢表雄酮（DHEA）添加到遗传性糖尿病C57BL/KsJ-db/db小鼠的饮食中时，具有显著的降血糖作用。本研究旨在分析喂食DHEA的小鼠血清中性类固醇水平的变化，并比较各种代谢产物的降血糖效力，以阐明DHEA的作用机制。类固醇放射免疫分析表明，饮食中的DHEA以高浓度进入血液，并被积极代谢为雄激素（睾酮，T；双氢睾酮，DHT）和雌激素（雌酮，E1；17β-雌二醇，E2）。这种代谢不需要完整的肾上腺或性腺。在C57BL/KsJ正常（+/+）雄性小鼠中，DHEA向雄激素的转化是主要特征；在db/db雄性小鼠中，喂食DHEA不仅增加了血清T和DHT水平，还增加了血清E1和E2水平。db/db小鼠的脂肪组织量增加，能隔离更多静脉注射的3H-E2；这种额外的体脂可能解释了DHEA衍生的雌激素前体芳构化增加的原因。比较DHEA的雄激素和雌激素类固醇代谢产物在db/db小鼠中的相对降血糖效力表明，雌激素以及具有雌激素特性的代谢产物（雄烯二醇）或可转化为雌激素的代谢产物（硫酸脱氢表雄酮）效力最强。虽然17β-E2通过注射或口服有效，但DHEA仅在口服时有效，这表明DHEA在胃肠道转化为更具生物活性的反应物。基于DHEA作为雄激素、雌激素和本胆烷醇酮前体激素的关键地位，提出了对该化合物在阻断自身免疫性疾病、高血糖、肥胖和肿瘤形成中看似矛盾的作用的解释。
