Biochemical markers for cardiovascular risk following treatment in endogenous Cushing’s syndrome

Kristo, Cybéle; Ueland, Thor; Godang, Kristin; Aukrust, Pål; Bollerslev, Jens

doi:10.1007/bf03346383

Cited by 22 publications

(17 citation statements)

References 29 publications

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“…These parameters all improved or normalized after successful therapy (180,181,182,183). specifically with the length of exposure to GCs, and functional modifications have been also reported.…”

Section: European Journal Of Endocrinologymentioning

confidence: 75%

Metabolic comorbidities in Cushing's syndrome

Ferraú

Korbonits

2015

European Journal of Endocrinology

145

121

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Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

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Section: European Journal Of Endocrinologymentioning

confidence: 75%

Metabolic comorbidities in Cushing's syndrome

Ferraú

Korbonits

2015

European Journal of Endocrinology

145

121

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“…According to our results, Kristo et al in a longer follow-up period (range 5-69 months) observed the persistence of high OPG values after CS remission. The authors correlated the absence of OPG normalization with an increased inflammation pattern persistence, which might represent a pro-atherogenic profile (32).…”

Section: Discussionmentioning

confidence: 95%

“…In addition, during a 3-month period of high-dose GC treatment (60 mg prednisolone per day), it was observed that OPG decreased after 2 weeks and returned to baseline after 3 months, while soluble RANKL serum levels increased (30). In contrast, considering CS, in three studies, OPG serum levels were found to be higher in patients compared to healthy controls (14,31,32). The increased OPG levels in CS might be a compensation to protect bone from the damage that occurs in long and uncontrolled endogenous cortisol excess, while the decrease in OPG in GC-treated patients could reflect the direct effect of GC on osteoblastic cells.…”

Section: Discussionmentioning

confidence: 97%

Persistent increase of osteoprotegerin levels after cortisol normalization in patients with Cushing's syndrome

Camozzi¹,

Sanguin²,

Albigier³

et al. 2010

European Journal of Endocrinology

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Objective: Osteoprotegerin (OPG) has been identified as a decoy receptor that inhibits osteoclast differentiation and, more recently, as a paracrine regulator of vascular calcification. OPG is suppressed by glucocorticoids (GC); however, results from experimental and clinical studies are not univocal. The aim of this study was to evaluate OPG and bone metabolism in patients with Cushing's syndrome (CS) before and after cure. Design and methods: Twenty-six patients with CS (all women, mean age: 39.1G11.9 years) and 24 ageand gonadal status-matched healthy women were studied for bone mineral density, bone metabolism, OPG, and receptor activator of nuclear factor-kB ligand at baseline. Twelve patients were also studied 6-18 months after surgery, with persistent normalization of cortisol levels. Results: OPG was significantly higher and osteocalcin (OC) was significantly lower in CS patients than in controls (OPG: 4.17G1.23 vs 2.95G0.79 pmol/l, PZ0.00001; OC: 15.0G6.1 vs 18.8 G6.8 ng/ml, PZ0.04 in CS and controls respectively). After cure, we found no difference in OPG levels, despite a significant increase in OC levels (from 16.4G11 to 37.2G15 ng/ml, PZ0.03). Conclusion: Patients with CS showed increased OPG serum levels that remained unchanged after recovery, despite a restoration of bone formation. We speculate that high levels of OPG could reflect the persistent damage of the GCs on cardiovascular system. European Journal of Endocrinology 162 85-90

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“…Plausibly, steroids, especially corticosteroids, are associated with attenuated degrees of VEGF-induced angiogenic responses in humans (13) and in experimental animal models (16,25). Serum VEGF levels are elevated in patients with Cushing's syndrome when compared with those suffer from essential hypertension (18), suggesting some functional linkages of VEGF and steroid pathways in humans. We propose that regulation of caveolin-1 abundance by nuclear steroid receptor pathways may uncover a novel mechanism at which exposure to excess steroids, including agonists for GR and MR, leads to perturbed sensitivities of vascular endothelium to angiogenic growth factors such as VEGF.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone induces caveolin-1 in vascular endothelial cells: implications for attenuated responses to VEGF

Igarashi

Hashimoto

Shoji

et al. 2013

American Journal of Physiology-Cell Physiology

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roids exert direct actions on cardiovascular cells, although underlying molecular mechanisms remain incompletely understood. We examined if steroids modulate abundance of caveolin-1, a regulatory protein of cell-surface receptor pathways that regulates the magnitudes of endothelial response to vascular endothelial growth factor (VEGF). Dexamethasone, a synthetic glucocorticoid, induces caveolin-1 at both levels of protein and mRNA in a time-and dosedependent manner in pharmacologically relevant concentrations in cultured bovine aortic endothelial cells. Aldosterone, a mineralocorticoid, but not the sex steroids 17␤-estradiol, testosterone, or progesterone, elicits similar caveolin-1 induction. Caveolin-1 induction by dexamethasone and that by aldosterone were abrogated by RU-486, an inhibitor of glucocorticoid receptor, and by spironolactone, a mineralocorticoid receptor inhibitor, respectively. Dexamethasone attenuates VEGF-induced responses at the levels of protein kinases Akt and ERK1/2, small-G protein Rac1, nitric oxide production, and migration. When induction of caveolin-1 by dexamethasone is attenuated either by genetically by transient transfection with small interfering RNA or pharmacologically by RU-486, kinase responses to VEGF are rescued. Dexamethasone also increases expression of caveolin-1 protein in cultured human umbilical vein endothelial cells, associated with attenuated tube formation responses of these cells when cocultured with normal fibroblasts. Immunohistochemical analyses revealed that intraperitoneal injection of dexamethasone induces endothelial caveolin-1 protein in thoracic aorta and in lung artery in healthy male rats. Thus steroids functionally attenuate endothelial responses to VEGF via caveolin-1 induction at the levels of signal transduction, migration, and tube formation, identifying a novel point of cross talk between nuclear and cell-surface receptor signaling pathways.receptors; signal transduction; growth factors; endothelial function; angiogenesis STEROID HORMONES THAT ACT through nuclear glucocorticoid, mineralocorticoid, and sex steroid receptors play essential roles in the maintenance of animal body homeostasis. In pathophysiological contexts, agonists for these steroid receptors are capable of exerting direct actions on cardiovascular cells, besides modulating water balance and blood pressure. For example, glucocorticoid receptor (GR) agonists downregulate endothelial nitric oxide synthase (eNOS) expression in rodent blood vessels (38) and in cultured endothelial cells (39). Clinically, hypercortisolemia in Cushing's syndrome is correlated with higher overall cardiovascular risk (26, 35) and with attenuated endothelium-dependent flow-mediated vasodilation responses in forearm arteries (1, 4). Mineralocorticoid receptor (MR) agonists also exert direct cardiovascular actions, for example, by decreasing glucose-6-phosphate dehydrogenase activity of endothelial cells (20) or by inducing eNOS "uncoupling" (28). It has clinically been known that patients suffering from pri...

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Biochemical markers for cardiovascular risk following treatment in endogenous Cushing’s syndrome

Cited by 22 publications

References 29 publications

Metabolic comorbidities in Cushing's syndrome

Metabolic comorbidities in Cushing's syndrome

Persistent increase of osteoprotegerin levels after cortisol normalization in patients with Cushing's syndrome

Dexamethasone induces caveolin-1 in vascular endothelial cells: implications for attenuated responses to VEGF

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