Long-term treatment of mineralocorticoid excess syndromes

Mantero, Franco; Opocher, Giuseppe; Rocco, Stefano; Carpenè, G.; Armanini, Decio

doi:10.1016/0039-128x(94)00018-8

Cited by 46 publications

(21 citation statements)

References 17 publications

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“…As a compromise, partial or incomplete replacement will substantially reduce but not normalize DOC yet mitigate long-term consequences of glucocorticoid therapy. Adjunctive treatments are likely to be necessary in this case, using mineralocorticoid antagonists as described in the next section, as glucocorticoid therapy alone might not achieve good blood pressure control [71]. …”

Section: Treatmentmentioning

confidence: 99%

Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic

Auchus

2017

The Journal of Steroid Biochemistry and Molecular Biology

175

150

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Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major reactions: steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most severe mutations in the cognate CYP17A1 gene abrogate all activities and cause combined 17-hydroxylase/17,20-lyase deficiency (17OHD), a biochemical phenotype that is replicated by treatment with the potent CYP17A1 inhibitor abiraterone acetate. The adrenals of patients with 17OHD synthesize 11-deoxycorticosterone (DOC) and corticosterone but no 19-carbon steroids, similar to the rodent adrenal, and DOC causes hypertension and hypokalemia. Loss of 17,20-lyase activity precludes sex steroid synthesis and leads to sexual infantilism. Rare missense CYP17A1 mutations minimally disrupt 17-hydroxylase activity but cause isolated 17,20-lyase deficiency (ILD), Mutations in the POR gene encoding the required cofactor protein cytochrome P450-oxidoreductase causes a spectrum of disease from ILD to 17OHD combined with 21-hydroxylase and aromatase deficiencies, sometimes including skeletal malformations. Mutations in the CYB5A gene encoding a second cofactor protein cytochrome b5 also selectively disrupt 17,20-lyase activity and cause the purest form of ILD. The clinical manifestations of these conditions are best understood in the context of the biochemistry of CYP17A1.

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Section: Treatmentmentioning

confidence: 99%

Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic

Auchus

2017

The Journal of Steroid Biochemistry and Molecular Biology

175

150

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“…Signs and symptoms of the syndrome can be partially or fully reversed by treatment with the MR-antagonist spironolactone [4,[57][58][59] or kidney transplantation [48], evidence for the crucial role of the renal 11ßHSD2 in MR protection [26,27]. Normally plasma cortisol levels are in the sub-micromolar range, while aldosterone levels are sub-nanomolar; even in 11ßHSD protected cells intracellular levels of glucocorticoid are ∼10x those of aldosterone [60].…”

Section: Apparent Mineralocorticoid Excess (Ame)mentioning

confidence: 99%

The role of the 11β-hydroxysteroid dehydrogenase type 2 in human hypertension

Ferrari

Lovati

Frey

2000

Journal of Hypertension

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Please cite this article as: Paolo Ferrari, The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension, BBA -Molecular Basis of Disease (2009Disease ( ), doi:10.1016Disease ( /j.bbadis.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTSchoner: BBADIS-09-126, Revision 1 BBA-Series Molecular Basis of Disease, special issue on Hypertension: Chapter 4, Ferrari SUMMARYCortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor (MR), although in vivo only aldosterone acts as a physiologic agonist of the MR, despite circulating levels of cortisol in humans and corticosterone in rodents being three orders of magnitude higher than aldosterone levels. In mineralocorticoid target organs the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) inactivates 11-hydroxy steroids, to their inactive keto-forms, thus protecting the nonselective MR from activation by glucocorticoids. The gene is highly expressed in all sodium-transporting epithelia, particularly in the kidney and colon, but also in human placenta and vascular wall. Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, compromised 11ßHSD2enzyme activity results in activation of the MR by cortisol, causing sodium retention, hypokalaemia, and salt-dependent hypertension. Whereas mutations or inhibition of 11ßHSD2 by licorice have been clearly shown to produce a congenital or acquired syndrome of mineralocorticoid excess, the questions remaining are the extent to which subtle abnormalities in MR/11ßHSD2 mechanisms may contribute to essential hypertension. Studies in patients with essential hypertension showed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites, suggesting a deficient 11ßHSD2 activity. These abnormalities may be genetically determined, as suggested by the association of a microsatellite flanking the HSD11B2 gene with hypertension in black patients with end-stage kidney disease and with salt sensitivity of blood pressure in healthy subjects. These findings indicate that variants of the HSD11B2 gene may contribute to the enhanced blood pressure response to salt and possibly to hypertension in humans.

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“…In patients with PA, the antihypertensive efficacy of epithelial sodium channel blockers, such as amiloride and triamterene, is suboptimal. Spironolactone is effective as monotherapy in approximately 50% of patients with PA, whereas 75% of patients on amiloride need additional antihypertensive drugs to achieve BP control [63,64]. Calcium channel blockers (CCBs) may reduce aldosterone secretion and BP by blocking the influx of calcium into the adrenal glomerulosa cells.…”

Section: Management Of Bilateral Forms Of Pamentioning

confidence: 99%

Treatment of primary aldosteronism: Where are we now?

Karagiannis

2011

Rev Endocr Metab Disord

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Primary aldosteronism (PA) is an important cause of secondary hypertension, is being increasingly diagnosed and may account for more than 10% of hypertensive patients, both in primary care and in referral centers. Aldosterone excess is associated with adverse cardiovascular, renal and metabolic effects that are in part hypertension-independent. Laparoscopic adrenalectomy remains the mainstay of treatment for unilateral forms of PA, whereas medical treatment is recommended for bilateral forms of PA. However, a favourable surgical outcome depends on several factors and many patients are not suitable for this treatment. On the other hand, surgery in patients considered to have bilateral PA may contribute to better blood pressure control. In this review, established and novel strategies for the management of different types of PA are discussed.

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Long-term treatment of mineralocorticoid excess syndromes

Cited by 46 publications

References 17 publications

Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic

Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic

The role of the 11β-hydroxysteroid dehydrogenase type 2 in human hypertension

Treatment of primary aldosteronism: Where are we now?

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