title: An alternative explanation of hypertension associated with 17α-hydroxylase deficiency syndrome.
abstract: The syndrome of 17α-hydroxylase deficiency is due to the inability to synthesize cortisol and is associated with enhanced secretion of both corticosterone and 11-deoxy-corticosterone (DOC). In humans, corticosterone and its 5α-Ring A-reduced metabolites are excreted via the bile into the intestine and transformed by anaerobic bacteria to 21-dehydroxylated products: 11β-OH-progesterone or 11β-OH-(allo)-5α-preganolones (potent inhibitors of 11β-HSD2 and 11β-HSD1 dehydrogenase). Neomycin blocks the formation of these steroid metabolites and can blunt the hypertension in rats induced by either ACTH or corticosterone. 3α,5α-Tetrahydro-corticosterone, 11β-hydroxy-progesterone, and 3α,5α-tetrahydro-11β-hydroxy-progesterone strongly inhibit 11β-HSD2 and 11β-HSD1 dehydrogenase activity; all these compounds are hypertensinogenic when infused in adrenally intact rats. Urine obtained from a patient with 17α-hydroxylase deficiency demonstrated markedly elevated levels of endogenous glycyrrhetinic acid-like factors (GALFs) that inhibit 11β-HSD2 and 11β-HSD1 dehydrogenase activity (>300 times greater, and >400 times greater, respectively, than those in normotensive controls). Thus, in addition to DOC, corticosterone and its 5α-pathway products as well as the 11-oxygenated progesterone derivatives may play a previously unrecognized role in the increased Na(+) retention and BP associated with patients with 17α-hydroxylase deficiency.
authors.affiliation: Department of Laboratory Medicine and Pathology, The Miriam Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States. Electronic address: dmorris@lifespan.org.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morris
authors.affiliation: Department of Laboratory Medicine and Pathology, The Miriam Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Latif
authors.affiliation: Division of Kidney Diseases and Hypertension, Warren Alpert Medical School of Brown University, Providence, RI, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brem
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000737:chemistry / Q000378:metabolism; D003900:Desoxycorticosterone / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology* / Q000652:urine; D008954:Models, Biological; D015394:Molecular Structure; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*; D013577:Syndrome
chemical_list: D004791:Enzyme Inhibitors; D003900:Desoxycorticosterone; D011374:Progesterone; D012964:Sodium; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D013254:Steroid 17-alpha-Hydroxylase; D003345:Corticosterone; D006854:Hydrocortisone
keywords: 11β-OH-(allo)-5α-preganolone; 17α-Hydroxylase deficiency; 3α,5α-Tetrahydro-corticosterone; Intestinal flora; Kidney 11β-HSD2-GALFs