Corticosteroids in Human Blood. VIII. Cortisol Metabolites in Plasma of Normotensive Subjects and Patients with Essential Hypertension 1

Abstract

Results of our previous studies revealed a derangement in the peripheral metabolism of adrenal steroids in patients with essential hypertension. To investigate further this finding, all individual free and conjugated metabolites of cortisol were isolated, identified and quantitated in plasma of 14 normotensive subjects and 13 patients with benign, uncomplicated essential hypertension, following iv administration of a tracer dose of [4-¹⁴C]cortisol. In addition, plasma levels of endogenous cortisol were determined at 8 am and 4 pm in all the subjects examined. The results obtained revealed the following statistically significant differences between ormotensives and hypertensives: 1) Mean plasma concentrations of cortisol metabolites reduced in ring-A with nonreduced 20-ketone, tetrahydrocortisol, tetrahydrocortisone, and their 5α-epimers, were 30% lower in the hypertensives; since these steroids constitute the bulk of the major group of cortisol metabolites-the glucuronide conjugates, plasma levels of this group of conjugates measured in toto were also found to be significantly lower in the hypertensives. 2) Concentrations of cortisol metabolites with nonreduced ring-A (Δ⁴-3-keto configuration preserved) but with reduced 20-ketone and/or hydroxylated at C-6, 20α- and 20β-dihydrocortisol, 6α- and 6²-hydroxycortisol, and 6-hydroxy-20-dihydrocortisol (all 4 isomers), were 73%, 48% and 68% respectively, higher in the hypertensives; since these steroids constitute the bulk of the sulfate-conjugated and nucleoside-complexed metabolites of cortisol, plasma levels of these groups of metabolites, measured in toto, were also found to be higher in the hypertensives. No significant difference was found between normotensives and hypertensives in the am and pm plasma levels of cortisol. These findings, in conjunction with the results of our studies on urinary corticosteroid metabolites, which yielded identical findings, provide evidence for a decreased activity of hepatic cortisol-Δ4-hydrogenase enzyme system and increased activities (presumably compensatorily) of cortisol-20-reductase and 6-hydroxylase enzyme systems in patients with essential hypertension. The interrelation of these findings with those of other investigators studying steroid metabolism in hypertension, points to the possibility that the detected aberration of activities of corticosteroid metabolizing enzymes may be an etiological factor in essential hypertension.