Investigation of glucocorticoid receptor polymorphisms in relation to metabolic parameters in Addison's disease

Ross, Ian Louis; Levitt, Naomi; Merwe, Lize van der; Schatz, Desmond; Johannsson, Gudmundur; Dandara, Collet; Pillay, Tahir S; Blom, Dirk

doi:10.1530/eje-12-0808

Cited by 19 publications

(13 citation statements)

References 48 publications

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“…ER22/23EK is a polymorphism located on exon 2 and comprises of two nucleotide substitutions, of which only the second polymorphism results in the substitution of an amino acid which has an impact on the tertiary structure of GR, thereby affecting activation of transcription. The presence of ER22/23EK polymorphism is reported to decrease glucocorticoid sensitivity [103], increase muscle mass [104], BMI, triglyceride levels and hs-CRP [103] and increased the risk of depression.…”

Section: Glucocorticoid Receptor Polymorphismmentioning

confidence: 99%

Glucocorticoid receptor signaling in health and disease

Kadmiel

Cidlowski

2013

Trends in Pharmacological Sciences

701

575

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Glucocorticoids are steroid hormones regulated in a circadian and stres-associated manner to maintain various metabolic and homeostatic functions that are necessary for life. Synthetic glucocorticoids are widely prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD), and inflammatory disorders of the eye. Research in the last few years has begun to unravel the profound complexity of glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies. Glucocorticoids signal through the glucocorticoid receptor, a member of the superfamily of nuclear receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review, we will provide an update on glucocorticoid receptor signaling and highlight the role of GR signaling in physiological and pathophysiological conditions in the major organ systems in the human body.

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Section: Glucocorticoid Receptor Polymorphismmentioning

confidence: 99%

Glucocorticoid receptor signaling in health and disease

Kadmiel

Cidlowski

2013

Trends in Pharmacological Sciences

701

575

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“…Ross et al previously studied the effects of the above polymorphisms in patients with AD and found that the ER22/23EK polymorphism was counter-intuitively associated with an increased BMI, but lower LDL-cholesterol. The mean hydrocortisone dose was higher in patients with either the ER22/23EK or N363S polymorphism [4]. We now report the results of our analysis of the 9β polymorphism in the same cohort.…”

Section: Introductionmentioning

confidence: 59%

“…The ER22/23EK polymorphism was somewhat unexpectedly associated with higher BMI, lower LDLC and higher doses of hydrocortisone. Similarly AD patients with the N363S polymorphism also received higher doses of hydrocortisone [4]. Several other studies of GCR polymorphisms have also either failed to show significant metabolic associations or have shown metabolic alterations that are difficult to reconcile with the reported changes in glucocorticoid sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…Ross et al, previously reported that patients with AD had higher triglycerides (TG), lower high density lipoprotein cholesterol (HDLC), a preponderance of small dense low density lipoprotein (LDL) particles and raised high sensitivity C-reactive protein (hs-CRP) compared with healthy controls. These findings may in part account for the increased rates of cardiovascular disease seen in patients with AD [4].…”

Section: Introductionmentioning

confidence: 93%

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9β Polymorphism of the Glucocorticoid Receptor Gene Appears to Have Limited Impact in Patients with Addison’s Disease

et al. 2014

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BackgroundAddison’s disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9β polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD.Materials and Methods147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction.ResultsGenotype data for the 9β polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9β polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism.ConclusionsThis study did not identify any associations between the 9β polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD.

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“…Importantly, the study did not address effects of extra doses in other types of physical stress, i.e., repeated doses and extensive or prolonged physical activity. Moreover, individual HC requirement is influenced by HC absorption, metabolism and individual sensitivity to glucocorticoids (17,18), and hence proper stress doses would have to be individualized in a clinical setting. Thus, true effects of stress dosing may be concealed by large individual variation and statistical type II error.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure

Šimůnková

Jovanovic²,

Rostrup³

et al. 2016

European Journal of Endocrinology

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Objective: Many patients with primary adrenal insufficiency (Addison's disease) take extra doses of glucocorticoids during stressful events, but a benefit has not been demonstrated in controlled trials. Here, we investigated the effects of a pre-exercise hydrocortisone dose on cardiorespiratory, hormonal and metabolic parameters in response to short-term strenuous physical activity. Design: This was a randomized placebo-controlled, cross-over clinical trial. Participants: Ten women with Addison's disease and 10 age-matched healthy females participated in the study. Measurements: All women in the study underwent maximal incremental exercise testing. A stress dose of 10 mg hydrocortisone or placebo was given 1 h prior to exercise on two occasions. Blood samples were drawn before, and 0, 15 and 30 min post exercise. Oxygen uptake, maximal aerobic capacity, endocrine and metabolic responses to physical activity, as well as health status by questionnaires were evaluated. Results: Maximal aerobic capacity and duration of exercise were significantly lower in patients than in healthy subjects and did not improve with the treatment. After an extra hydrocortisone dose serum cortisol was significantly higher than in the healthy subjects (P!0.001). Post-exercise glucose and adrenaline levels were significantly lower and free fatty acids insignificantly higher in patients irrespective of stress dose. Stress dosing did not alter other metabolic or hormonal parameters or quality of life after the exercise. Conclusions: The patients did not benefit from an extra dose of hydrocortisone in short strenuous exercise. Stress dosing may not be justified in this setting. Whether stress dosing is beneficial in other types of physical activity will have to be examined further.

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Investigation of glucocorticoid receptor polymorphisms in relation to metabolic parameters in Addison's disease

Cited by 19 publications

References 48 publications

Glucocorticoid receptor signaling in health and disease

Glucocorticoid receptor signaling in health and disease

9β Polymorphism of the Glucocorticoid Receptor Gene Appears to Have Limited Impact in Patients with Addison’s Disease

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure

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