The cortisol-cortisone shuttle and hypertension

doi:10.1016/0960-0760(91)90269-B

The Journal of Steroid Biochemistry and Molecular Biology

Volume 40, Issues 4–6, 1991, Pages 501-509

https://doi.org/10.1016/0960-0760(91)90269-B Get rights and content

Abstract

11β-OHSD is an enzyme complex consisting of 11β-DH, converting cortisol to cortisone in man and an 11-keto-reductase performing the reverse reaction. Congenital deficiency of 11β-DH should be considered in any child presenting with mineralocorticoid hypertension and suppression of the renin-angiotensin-aldosterone axis. The keystone to diagnosis is the demonstration of a reduced daily production rate of cortisol and an increase in its plasma half-life. In the majority of cases diagnosis can be made from a urinary steroid metabolite profile indicating a high excretion of cortisol relative to cortisone metabolites. Cortisol is the responsible mineralocorticoid, and as such treatment with the pure glucocorticoid dexamethasone will prevent life-threatening hypokalaemia, although additional antihypertensive drugs are usually required to control blood pressure.

Liquorice and carbenoxolone, for years thought to be direct “agonists” of the mineralocorticoid receptor, in fact cause sodium retention through inhibition of 11β-DH.

The demonstration of 11β-DH activity in the vasculature raises the possibility that it locally modules access of glucocorticoids to mineralocorticoid and possibly glucocorticoid receptors in the vessel wall.

It remains possible that subtle alterations of this cortisol-cortisone shuttle are responsible for other forms of hypertension which are currently classified under the umbrella diagnosis of essential hypertension.

References (66)

T.E. Nicholas et al.
The physiological significance of 11β-hydroxysteroid dehydrogenase in the rat lung
J. Steroid Biochem.
(1982)
C. Monder et al.
11β-hydroxysteroid dehydrogenase: fact or fancy?
Steroids
(1984)
B.E.P. Murphy
Specificity of human 11β-hydroxysteroid dehydrogenase
J. Steroid Biochem.
(1981)
B. Zumoff et al.
Influence of thyroid function on the in vivo cortisol—cortisone equilibrium in man
J. Steroid Biochem.
(1983)
A.K. Agarwal et al.
Cloning and expression of rat cDNA encoding corticosteroid 11β-dehydrogenase
J. Biol. Chem.
(1989)
M.C. Batista et al.
Spironolactone reversible rickets associated with 11β-hydroxysteroid dehydrogenase deficiency syndrome
J. Paediat.
(1986)
G. Phillipou et al.
A new defect in the peripheral conversion of cortisone to cortisol
J. Steroid Biochem.
(1985)
D. Marver et al.
Dihydrocortisol: a potential mineralocorticoid
J. Steroid Biochem.
(1978)
I. Nielsen et al.
Life-threatening hypokalaemia caused by liquorice
Lancet
(1984)
J.A. Molhuysen et al.
A liquorice extract with deoxycortone-like action
Lancet
(1950)

J.G.G. Borst et al.

Synergistic action of liquorice and cortisone in Addison's and Simmond's disease

Lancet

(1953)

W.I. Card et al.

Effects of liquorice and its derivatives on salt and water metabolism

Lancet

(1953)

P.M. Stewart et al.

Mineralocorticoid activity of liquorice: 11β-hydroxysteroid dehydrogenase deficiency comes of age

Lancet

(1987)

C.L. Cope

Metabolic Breakdown

P.A. Osinski

Steroid 11β-ol dehydrogenase in human placenta

Nature

(1960)

A.F. Burton

Inhibition of 11β-hydroxysteroid dehydrogenase activity in rat tissues in vitro and in vivo

Endocrinology

(1965)

J.S. Jenkins

The metabolism of cortisol by human extrahepatic tissues

J. Endocr.

(1966)

K. Hierholzer et al.

Corticosteroid metabolism in isolated rat kidney in vitro

Pflugers Arch

(1984)

I.E. Bush et al.

Metabolism of 11-oxygenated steroids

Biochem. J.

(1968)

W. Wortmann et al.

Metabolism of 1,2-³H-cortisol perfused through human liver in vivo

J. Clin. Endocr.

(1971)

B.E.P. Murphy

Cortisol production and inactivation by the human lung during gestation and infancy

J. Clin. Endocr. Metab.

(1978)

B.J. Whitehouse et al.

The effect of blood-borne factors on adrenal steroid synthesis in the golden hamster

J. Endocr.

(1967)

A.F. Burton et al.

Inactivation of corticosteroids in intestinal mucosa by 11β-hydroxysteroid: NADP oxidoreductase (E.C.1.1.1.146)

Am. J. Gastroent.

(1983)

D. Koerner

11β-hydroxysteroid dehydrogenase of lung and testis

Endocrinology

(1966)

M. Abramovitz et al.

Cortisol-cortisone interconversion in human fetal lung: contrasting results using explant and monolayer cultures suggest that 11β-hydroxysteroid dehydrogenase comprises two enzymes

J. Clin. Endocr. Metab.

(1982)

V. Lakshmi et al.

Evidence for independent-oxidase and 11-reductase activities of 11β-hydroxysteroid dehydrogenase: enzyme latency, phase transitions, and lipid requirements

Endocrinology

(1985)

I.E. Bush

11β-hydroxysteroids dehydrogenase: contrast between studies in vivo and studies in vitro

Adv. Biosci.

(1969)

L. Helllman et al.

The influence of thyroid hormone on hydrocortisone production and metabolism

J. Clin. Endocr. Metab.

(1961)

E.R. Lax et al.

The hormonal regulation of hepatic microsomal 11β-hydroxysteroid dehydrogenase activity in the rat

Acta Endocr.

(1978)

V. Lakshmi et al.

Purification and characterisation of the corticosteroid 11β-dehydrogenase component of the rat liver 11β-hydroxysteroid dehydrogenase complex

Endocrinology

(1988)

S. Ulick et al.

A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol

J. Clin. Endocr. Metab.

(1989)

C.H.L. Shackleton et al.

Hypertension in a four year old child: gas chromatographic and mass spectrometric evidence for deficient hepatic metabolism of steroids

J. Clin. Endocr. Metab.

(1980)

E. Werder et al.

Unusual steroid excretion in a child with low-renin hypertension

Res. Steroids

(1974)

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The cortisol-cortisone shuttle and hypertension

Abstract

J. Steroid Biochem.

Steroids

J. Steroid Biochem.

J. Steroid Biochem.

J. Biol. Chem.

J. Paediat.

J. Steroid Biochem.

J. Steroid Biochem.

Lancet

Lancet

Lancet

Lancet

Lancet

Metabolic Breakdown

Steroid 11β-ol dehydrogenase in human placenta

Nature

Inhibition of 11β-hydroxysteroid dehydrogenase activity in rat tissues in vitro and in vivo

Endocrinology

The metabolism of cortisol by human extrahepatic tissues

J. Endocr.

Corticosteroid metabolism in isolated rat kidney in vitro

Pflugers Arch

Metabolism of 11-oxygenated steroids

Biochem. J.

Metabolism of 1,2-3H-cortisol perfused through human liver in vivo

J. Clin. Endocr.

Cortisol production and inactivation by the human lung during gestation and infancy

J. Clin. Endocr. Metab.

The effect of blood-borne factors on adrenal steroid synthesis in the golden hamster

J. Endocr.

Inactivation of corticosteroids in intestinal mucosa by 11β-hydroxysteroid: NADP oxidoreductase (E.C.1.1.1.146)

Am. J. Gastroent.

11β-hydroxysteroid dehydrogenase of lung and testis

Endocrinology

Cortisol-cortisone interconversion in human fetal lung: contrasting results using explant and monolayer cultures suggest that 11β-hydroxysteroid dehydrogenase comprises two enzymes

J. Clin. Endocr. Metab.

Evidence for independent-oxidase and 11-reductase activities of 11β-hydroxysteroid dehydrogenase: enzyme latency, phase transitions, and lipid requirements

Endocrinology

11β-hydroxysteroids dehydrogenase: contrast between studies in vivo and studies in vitro

Adv. Biosci.

The influence of thyroid hormone on hydrocortisone production and metabolism

J. Clin. Endocr. Metab.

The hormonal regulation of hepatic microsomal 11β-hydroxysteroid dehydrogenase activity in the rat

Acta Endocr.

Purification and characterisation of the corticosteroid 11β-dehydrogenase component of the rat liver 11β-hydroxysteroid dehydrogenase complex

Endocrinology

A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol

J. Clin. Endocr. Metab.

Hypertension in a four year old child: gas chromatographic and mass spectrometric evidence for deficient hepatic metabolism of steroids

J. Clin. Endocr. Metab.

Unusual steroid excretion in a child with low-renin hypertension

Res. Steroids

Metabolism of 1,2-³H-cortisol perfused through human liver in vivo