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Endocrine Reviews 18 (1): 135-156
Copyright © 1997 by The Endocrine Society

11ß-Hydroxysteroid Dehydrogenase and the Syndrome of Apparent Mineralocorticoid Excess1

Perrin C. White, Tomoatsu Mune2 and Anil K. Agarwal

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas Texas 75235-9063

I. Introduction
II. Biochemistry of Cortisol Metabolism
III. Mineralocorticoid Receptor Function
A. Actions of aldosterone
B. Structure and function of the mineralocorticoid receptor
C. Hypothesis: 11-HSD protects the mineralocorticoid receptor
IV. Loss of Function of 11-HSD
A. Syndrome of apparent mineralocorticoid excess (AME)
B. Licorice intoxication
C. Ectopic ACTH syndrome
D. Essential hypertension
E. Related conditions
V. Functional Roles of 11-HSD
A. Liver
B. Kidney and other mineralocorticoid target tissues
C. Brain
D. Circulatory system
E. Skin
F. Ovary
G. Placenta
H. Other fetal tissues
VI. The Type I (Liver) Isozyme of 11-HSD
A. Terminology
B. Biochemistry
C. Molecular biology
D. Expression
E. Lack of involvement in the syndromes of AME or 11-reductase deficiency
VII. The Type 2 (Kidney) Isozyme of 11-HSD
A. Biochemistry
B. Molecular biology
C. Expression
D. Mutations in HSD11B2 are detected in all patients with AME
VIII. Summary\.




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A. K. Agarwal, G. Giacchetti, G. Lavery, H. Nikkila, M. Palermo, M. Ricketts, C. McTernan, G. Bianchi, P. Manunta, P. Strazzullo, et al.
CA-Repeat Polymorphism in Intron 1 of HSD11B2 : Effects on Gene Expression and Salt Sensitivity
Hypertension, August 1, 2000; 36(2): 187 - 194.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
P. C. White and P. W. Speiser
Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
Endocr. Rev., June 1, 2000; 21(3): 245 - 291.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
J.T. Ross, I.C. McMillen, M.B. Adams, and C.L. Coulter
A Premature Increase in Circulating Cortisol Suppresses Expression of 11{beta} Hydroxysteroid Dehydrogenase Type 2 Messenger Ribonucleic Acid in the Adrenal of the Fetal Sheep
Biol Reprod, May 1, 2000; 62(5): 1297 - 1302.
[Abstract] [Full Text]

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 HypertensionHome page
R. Alzamora, L. Michea, and E. T. Marusic
Role of 11{beta}-Hydroxysteroid Dehydrogenase in Nongenomic Aldosterone Effects in Human Arteries
Hypertension, May 1, 2000; 35(5): 1099 - 1104.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
F. M. Rogerson, N. Dimopoulos, P. Sluka, S. Chu, A. J. Curtis, and P. J. Fuller
Structural Determinants of Aldosterone Binding Selectivity in the Mineralocorticoid Receptor
J. Biol. Chem., December 17, 1999; 274(51): 36305 - 36311.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
B. M. FREY, B. F. X. REBER, B. S. VISHWANATH, G. ESCHER, and F. J. FREY
Annexin I modulates cell functions by controlling intracellular calcium release
FASEB J, December 1, 1999; 13(15): 2235 - 2245.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
J. S. Moore, J. P. Monson, G. Kaltsas, P. Putignano, P. J. Wood, M. C. Sheppard, G. M. Besser, N. F. Taylor, and P. M. Stewart
Modulation of 11{beta}-Hydroxysteroid Dehydrogenase Isozymes by Growth Hormone and Insulin-Like Growth Factor: In Vivo and In Vitro Studies
J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4172 - 4177.
[Abstract] [Full Text]

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S. A. Lloyd-MacGilp, S. M. Nelson, M. Florin, M. Lo, J. McKinnell, J. Sassard, and C. J. Kenyon
11{beta}-Hydroxysteroid Dehydrogenase and Corticosteroid Action in Lyon Hypertensive Rats
Hypertension, November 1, 1999; 34(5): 1123 - 1128.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. Odermatt, P. Arnold, A. Stauffer, B. M. Frey, and F. J. Frey
The N-terminal Anchor Sequences of 11beta -Hydroxysteroid Dehydrogenases Determine Their Orientation in the Endoplasmic Reticulum Membrane
J. Biol. Chem., October 1, 1999; 274(40): 28762 - 28770.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
H. Horigome, A. Horigome, M. Homma, T. Hirano, and K. Oka
Glycyrrhetinic acid-induced apoptosis in thymocytes: impact of 11beta -hydroxysteroid dehydrogenase inhibition
Am J Physiol Endocrinol Metab, October 1, 1999; 277(4): E624 - E630.
[Abstract] [Full Text] [PDF]

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B. S. Nunez, F. M. Rogerson, T. Mune, Y. Igarashi, Y. Nakagawa, G. Phillipov, A. Moudgil, L. B. Travis, M. Palermo, C. Shackleton, et al.
Mutants of 11{beta}-Hydroxysteroid Dehydrogenase (11-HSD2) With Partial Activity : Improved Correlations Between Genotype and Biochemical Phenotype in Apparent Mineralocorticoid Excess
Hypertension, October 1, 1999; 34(4): 638 - 642.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
I. J. Bujalska, S. Kumar, M. Hewison, and P. M. Stewart
Differentiation of Adipose Stromal Cells: The Roles of Glucocorticoids and 11{beta}-Hydroxysteroid Dehydrogenase
Endocrinology, July 1, 1999; 140(7): 3188 - 3196.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
D.B. Hardy, L.E. Pereria, and K. Yang
Prostaglandins and Leukotriene B4 Are Potent Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 2 Activity in Human Choriocarcinoma JEG-3 Cells
Biol Reprod, July 1, 1999; 61(1): 40 - 45.
[Abstract] [Full Text]

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 HypertensionHome page
E. P. Gomez-Sanchez and C. E. Gomez-Sanchez
Maternal Hypertension and Progeny Blood Pressure : Role of Aldosterone and 11ß-HSD
Hypertension, June 1, 1999; 33(6): 1369 - 1373.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
R.-S. Ge, D. O. Hardy, J. F. Catterall, and M. P. Hardy
Opposing Changes in 3{alpha}-Hydroxysteroid Dehydrogenase Oxidative and Reductive Activities in Rat Leydig Cells during Pubertal Development
Biol Reprod, April 1, 1999; 60(4): 855 - 860.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
P. M. Stewart, A. Boulton, S. Kumar, P. M. S. Clark, and C. H. L. Shackleton
Cortisol Metabolism in Human Obesity: Impaired Cortisone->Cortisol Conversion in Subjects with Central Adiposity
J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1022 - 1027.
[Abstract] [Full Text]

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 EndocrinologyHome page
F. E. Brennan and P. J. Fuller
Acute Regulation by Corticosteroids of Channel-Inducing Factor Gene Messenger Ribonucleic Acid in the Distal Colon
Endocrinology, March 1, 1999; 140(3): 1213 - 1218.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
J. Tremblay, D.B. Hardy, L.E. Pereira, and K. Yang
Retinoic Acid Stimulates the Expression of 11ß-Hydroxysteroid Dehydrogenase Type 2 in Human Choriocarcinoma JEG-3 Cells
Biol Reprod, March 1, 1999; 60(3): 541 - 545.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
P. J. Burton and B. J. Waddell
Dual Function of 11ß-Hydroxysteroid Dehydrogenase in Placenta: Modulating Placental Glucocorticoid Passage and Local Steroid Action
Biol Reprod, February 1, 1999; 60(2): 234 - 240.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
M. Tetsuka, M. Milne, G.E. Simpson, and S.G. Hillier
Expression of 11ß-Hydroxysteroid Dehydrogenase, Glucocorticoid Receptor, and Mineralocorticoid Receptor Genes in Rat Ovary
Biol Reprod, February 1, 1999; 60(2): 330 - 335.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
D. Rogoff, Z. Smolenicka, I. Bergadá, G. Vallejo, M. Barontini, J. J. Heinrich, and P. Ferrari
The Codon 213 of the 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Gene Is a Hot Spot for Mutations in Apparent Mineralocorticoid Excess
J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4391 - 4393.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
J. Condon, C. Gosden, D. Gardener, P. Nickson, M. Hewison, A. J. Howie, and P. M. Stewart
Expression of Type 2 11{beta}-Hydroxysteroid Dehydrogenase and Corticosteroid Hormone Receptors in Early Human Fetal Life
J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4490 - 4497.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
R. Sampath-Kumar, S.G. Matthews, and K. Yang
11ß-Hydroxysteroid Dehydrogenase Type 2 Is the Predominant Isozyme in the Guinea Pig Placenta: Decreases in Messenger Ribonucleic Acid and Activity at Term
Biol Reprod, December 1, 1998; 59(6): 1378 - 1384.
[Abstract] [Full Text]

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 FASEB J.Home page
G. Mazzocchi, G. P. Rossi, G. Neri, L. K. Malendowicz, G. Albertin, and G. G. Nussdorfer
11ß-Hydroxysteroid dehydrogenase expression and activity in the human adrenal cortex
FASEB J, November 1, 1998; 12(14): 1533 - 1539.
[Abstract] [Full Text]

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 EndocrinologyHome page
D. Fuster, G. Escher, B. Vogt, D. Ackermann, B. Dick, B. M. Frey, and F. J. Frey
Furosemide Inhibits 11{beta}-Hydroxysteroid Dehydrogenase Type 2
Endocrinology, September 1, 1998; 139(9): 3849 - 3854.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
R. Diaz, R. W. Brown, and J. R. Seckl
Distinct Ontogeny of Glucocorticoid and Mineralocorticoid Receptor and 11beta -Hydroxysteroid Dehydrogenase Types I and II mRNAs in the Fetal Rat Brain Suggest a Complex Control of Glucocorticoid Actions
J. Neurosci., April 1, 1998; 18(7): 2570 - 2580.
[Abstract] [Full Text] [PDF]

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E. P. Gomez-Sanchez
Editorial: First There Was One, Then Two . . . Why More 11{beta}-Hydroxysteroid Dehydrogenases?
Endocrinology, December 1, 1997; 138(12): 5087 - 5088.
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R.-S. Ge, D. O. Hardy, J. F. Catterall, and M. P. Hardy
Developmental Changes in Glucocorticoid Receptor and 11{beta}-Hydroxysteroid Dehydrogenase Oxidative and Reductive Activities in Rat Leydig Cells
Endocrinology, December 1, 1997; 138(12): 5089 - 5095.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. Odermatt, P. Arnold, and F. J. Frey
The Intracellular Localization of the Mineralocorticoid Receptor Is Regulated by 11beta -Hydroxysteroid Dehydrogenase Type 2
J. Biol. Chem., July 20, 2001; 276(30): 28484 - 28492.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
J. L. W. Yau, J. Noble, C. J. Kenyon, C. Hibberd, Y. Kotelevtsev, J. J. Mullins, and J. R. Seckl
Lack of tissue glucocorticoid reactivation in 11beta -hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments
PNAS, April 10, 2001; 98(8): 4716 - 4721.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
J. Hanafusa, T. Mune, T. Tanahashi, Y. Isomura, T. Suwa, M. Isaji, H. Daido, H. Morita, M. Murayama, and K. Yasuda
Altered corticosteroid metabolism differentially affects pituitary corticotropin response
Am J Physiol Endocrinol Metab, February 1, 2002; 282(2): E466 - E473.
[Abstract] [Full Text] [PDF]


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