Daily Cortisol Production Rate in Man Determined by Stable Isotope Dilution/Mass Spectrometry

Esteban, Nora V.; Loughlin, T.; Yergey, Alfred L.; Zawadzki, Joanna K.; Booth, John D.; Winterer, Jorg; Loriaux, D. Lynn

doi:10.1210/jcem-72-1-39

Cited by 438 publications

(215 citation statements)

References 18 publications

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“…Thus, the K187N mutation in one subunit possibly could negatively affect the activity of an adjacent WT subunit. This type of effect has been reported for the enzyme biotin carboxylase, where an inactivating mutation in the active site of one monomer of the protein was found to have a dominant negative effect on the other monomer, resulting in a 285-fold decrease in activity (21). The experimental evidence from the hybrid WT/K187N dimer constructed in the present study suggests that this is indeed the case for 11β-HSD1.…”

Section: Discussionsupporting

confidence: 85%

“…The mothers had urine biochemistry identical to that found in their offspring, with lower THF+5α-THF/THE and cortol/cortolone ratios, whereas both fathers demonstrated normal values for these parameters (Table 1). To examine secondary activation of the hypothalamic-pituitaryadrenal axis, we summed the values of all cortisol and cortisone metabolites to provide an index of total secretion rate (reported as μg/24 h) (21). An increased cortisol secretion rate was clearly suggested in both patients and their mothers, but levels for the fathers were within the reference range (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Cortisone-reductase deficiency associated with heterozygous mutations in 11β-hydroxysteroid dehydrogenase type 1

Lawson¹,

Walker

Lavery

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum. Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess. To date, only mutations in H6PD, which encodes an enzyme supplying cofactor for the reaction, have been identified as the cause of disease. Here we examined the HSD11B1 gene in two cases presenting with biochemical features indicative of a milder form of CRD in whom the H6PD gene was normal. Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1. The R137C mutation disrupts salt bridges at the subunit interface of the 11β-HSD1 dimer, whereas K187N affects a key active site residue. On expression of the mutants in bacterial and mammalian cells, activity was either abolished (K187N) or greatly reduced (R137C). Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly. Simultaneous expression of mutant and WT 11β-HSD1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutants on both the yield and activity of 11β-HSD1 dimers. Thus, these heterozygous mutations in the HSD11B1 gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Cortisone-reductase deficiency associated with heterozygous mutations in 11β-hydroxysteroid dehydrogenase type 1

Lawson¹,

Walker

Lavery

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Such treatment results in periods of very high and very low cortisol levels. Furthermore, new estimates show endogenous cortisol production rates of 5.4-6.1 mg/m 2 per day (7,8), which are lower than was previously thought. The possible roles of the normal pulsatile and circadian cortisol rhythms and their relevance to the glucocorticoid replacement therapy were recently reviewed (9).…”

Section: Introductionmentioning

confidence: 58%

“…Based on the recent estimates of endogenous cortisol production (7,8) and repeated salivary cortisol sampling, an HC dose of 10 mg/m 2 body surface area/ 24 h was chosen as the start dose for further studies.…”

Section: Patients and Designmentioning

confidence: 99%

Continuous subcutaneous hydrocortisone infusion in Addison’s disease

Løvås

Husebye²

2007

eur j endocrinol

140

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Objective: The conventional replacement therapy in Addison's disease (AD) does not restore the normal diurnal cortisol rhythm. We explored the feasibility and safety of continuous s.c. hydrocortisone infusion (CSHI) as a novel mode of glucocorticoid replacement therapy. Design and methods: Seven patients with AD were treated with CSHI in an open-labelled clinical study for up to three months. Adequacy of glucocorticoid replacement was assessed by 24 h blood and saliva sampling in one patient and by salivary cortisol day curves in six outpatients. Subjective health status was monitored by the Short Form-36 questionnaire. Results: CSHI re-established the circadian variation and normal levels of cortisol in the patients, with minor day-to-day variation. Most of the patients could reduce their glucocorticoid dose considerably without adverse reactions. The treatment was well tolerated and positively evaluated by the patients. Conclusions: CSHI is technically feasible and safe in patients with AD. A daily dose of w10 mg/m 2 body surface area/day restores the circadian variation and normal levels of salivary cortisol in most patients, which is close to the estimated daily requirement. We hypothesise that selected patients will benefit from restoration of the circadian cortisol rhythm.

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“…O cortisol tem meia-vida de 90 minutos no plasma e é metabolizado pelo fígado e excretado pelas vias renal e hepática. 1 Sua produção é regulada pelo eixo hipotalâmico-hipofisário-supra-renal e é também influenciada pelo ritmo circadiano, situações de estresse e por seu feedback negativo sobre os receptores de glicocorticóides do hipotálamo e da hipófise.…”

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Corticosteróides sistêmicos na prática dermatológica. Parte I: Principais efeitos adversos

Freitas

Souza

2007

An. Bras. Dermatol.

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Reumo: Há quase 60 anos os corticosteróides sistêmicos têm sido amplamente utilizados na área de dermatologia, trazendo benefícios para muitas doenças em decorrência de suas ações antiinflamatórias e imunossupressoras. O desafio de seu uso consiste em contrabalançar os efeitos benéficos e as atividades farmacológicas indesejáveis. Infelizmente, os avanços no conhecimento sobre os mecanismos de ação dos corticosteróides não resultaram no desenvolvimento de regimes com mínima toxicidade. Dessa maneira, este artigo de revisão discorre sobre os aspectos farmacológicos dos corticosteróides sistêmicos, bem como suas principais indicações de uso e efeitos colaterais da administração em altas doses e/ou por longos períodos de tempo. Artigo de Revisão INTRODUÇÃOA indicação do corticosteróide na terapêutica da artrite reumatóide, por Phillip Hench, em 1949, foi um marco na Medicina. Desde então, os corticosteróides mostraram-se eficazes no tratamento de diversas afecções cutâneas, devido a suas propriedades imunossupressoras e antiinflamatórias.A utilização prolongada dos corticosteróides, assim como a retirada rápida da medicação, pode causar diversas complicações.O objetivo deste artigo é alertar os dermatologistas sobre os principais efeitos adversos decorrentes da terapêutica com corticosteróides sistêmicos e como evitá-los ou minimizá-los. FARMACOLOGIA E FARMACOCINÉTICAO principal exemplo de glicocorticóide produzido pelo organismo é o cortisol (hidrocortisona), sintetizado no córtex adrenal a partir do colesterol. Em condições normais, somente 5% do cortisol circula livremente, sendo o restante inativo (95% ligado à globulina ligadora de cortisol, e 5% à albumina). 1 A secreção diária de cortisol varia de 10 a

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Daily Cortisol Production Rate in Man Determined by Stable Isotope Dilution/Mass Spectrometry

Cited by 438 publications

References 18 publications

Cortisone-reductase deficiency associated with heterozygous mutations in 11β-hydroxysteroid dehydrogenase type 1

Cortisone-reductase deficiency associated with heterozygous mutations in 11β-hydroxysteroid dehydrogenase type 1

Continuous subcutaneous hydrocortisone infusion in Addison’s disease

Corticosteróides sistêmicos na prática dermatológica. Parte I: Principais efeitos adversos

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