19-Nor-corticosteroids in health, in hypertensive states in humans including 17 alpha-hydroxylase deficiency and in the spontaneously hypertensive rat (SHR).
Since Gomez-Sanchez isolated 19-nor-DOC from the urine of rats with adrenal regeneration hypertension, we have demonstrated that 19-nor-DOC is a naturally occurring substance in other hypertensive animal models as well as in man. Certain 19-nor-corticosteroids are potent mineralocorticoids and may have a role in the regulation of systemic arterial blood pressure and could be involved in the pathogenesis of hypertension. We have previously demonstrated that 19-nor-DOC is greatly influenced by ACTH and dexamethasone but less so by high and low sodium diets in normotensive human subjects and, that 19-nor-DOC is greatly increased in some but not all hypertensive patients. Studies by Gomez-Sanchez and by our own group have shown that 19-nor-DOC is not secreted by the adrenal gland directly but rather the adrenal secretes a 19-oic-DOC precursor which is converted peripherally by extra-adrenal tissues. Biosynthesis of 19-oic-DOC has been demonstrated to occur by prior hydroxylation of DOC and progressive oxydation to the acidic form. More recently it has been shown that 19-nor-DOC is excreted in the urine of mammals as a free unconjugated compound but to a greater extent as a 21-monoglucuronide. In the studies described we will report the quantification of urinary excretion of 19-nor-DOC as a free and unconjugated compound and also as a 21-monoglucuronide in patients with hypertension as well as in patients with specific forms secondary hypertension such as that found in 17 alpha hydroxylase deficiency which is a syndrome associated with hypogonadism, hypertension and hypokalemia. In this disorder of cortisol biosynthesis adlosterone production, is not elevated and therefore other known and unknown mineralocorticoid account for the excess in mineralocorticoid activity observed. Our study demonstrated that 19-nor-DOC, the potent hypertensinogenic mineralocorticoid was elevated in both plasma and urine from a young woman with 17-alpha hydroxylase deficiency. This patient was examined for various corticosteroids in basal and ACTH-stimulated, dexamethasone-suppressed and cortisol-treated states. In the basal state, urinary and plasma 17 alpha-hydroxy corticosteroids were decreased but the 17-deoxycorticosteroids were extremely elevated including corticosterone, 18-hydroxy corticosterone, tetrahydro corticosterone, tetrahydro-deoxycorticosterone and 18 hydroxy-tetrahydro-DOC. Both basal urinary free 19-nor-DOC was markedly elevated both by HPLC and radioimmunoassay measurements.(ABSTRACT TRUNCATED AT 400 WORDS)
D000311:Adrenal Glands / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital; D000328:Adult; D000818:Animals; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism / Q000652:urine; D005260:Female; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013250:Steroid Hydroxylases / Q000172:deficiency*
D003900:Desoxycorticosterone; C019026:19-nordeoxycorticosterone; D013250:Steroid Hydroxylases