scholarly journals Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing's syndrome

2012 ◽  
Vol 166 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Laura Trementino ◽  
Gloria Appolloni ◽  
Carolina Concettoni ◽  
Marina Cardinaletti ◽  
Marco Boscaro ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Cushing’S Syndrome ◽  
Low Frequency ◽  
Serum Cortisol ◽  
Protective Role ◽  
Cushing's Syndrome ◽  
Wild Type ◽  
Morning Serum Cortisol ◽  
Midnight Cortisol

ObjectiveGlucocorticoid receptor (GR) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. We evaluate the prevalence of the fourGR(NR3C1) polymorphisms BclI, N363S, ER22/23EK, and A3669G in patients with Cushing's syndrome (CS) compared with healthy controls (HC) and we investigate their role in the development of metabolic abnormalities in patients with CS according to their hormonal profile.Patients and methodsSixty-one patients with CS and 71 sex- and age-matched HC were genotyped.ResultsBclI variant was markedly higher in patients with CS compared with HC (62 vs 41%,P<0.05) while no significant differences were found among other polymorphisms. A very low frequency of N363S and the ER22/23EK was observed.In CS patients, despite the significantly increased levels of morning serum cortisol in BclI carriers compared with wild type no clinical or metabolic differences were found.In contrast, A3669GGRcarriers showed a significantly reduced prevalence of type 2 diabetes mellitus compared with wild type (19 vs 68%,P=0.001) despite the higher levels of both serum morning (21.7±6 vs 27.3±8.6 μg/dl,P=0.009) and midnight cortisol (18.8±5.8 vs 24.0±8.0 μg/dl,P=0.01). The negative association between diabetes and A3669GGRpolymorphism remained significant when data were adjusted for potential confounding factors.ConclusionsThe A3669G polymorphism of theGRgene plays a protective role in patients with CS, attenuating the effects of GC excess on glucose metabolism as shown by their reduced risk of diabetes.

scholarly journals Low-Dose and Standard Overnight and Low Dose-Two Day Dexamethasone Suppression Tests in Patients with Mild and/or Episodic Hypercortisolism

2018 ◽  
Vol 50 (06) ◽  
pp. 453-461 ◽  
Author(s):  
Mona Mojtahedzadeh ◽  
Nesyah Shaesteh ◽  
Mastaneh Haykani ◽  
Jennifer Tran ◽  
Michael Mangubat ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Low Dose ◽  
Serum Cortisol ◽  
Cushing's Syndrome ◽  
Dexamethasone Suppression Test ◽  
Morning Cortisol ◽  
Morning Serum Cortisol ◽  
Suppression Test ◽  
Biochemical Testing ◽  
Dexamethasone Suppression

AbstractWe previously reported on the lack of utility of the 1 mg overnight dexamethasone (DEX) test in mild and/or periodic Cushing’s syndrome, as most patients with the condition suppressed to 1 mg DEX. It is possible that a lower dose of DEX as part of an overnight DEX test might be able to distinguish between mild and/or periodic Cushing’s syndrome and those without the condition. The objective of the current study is to determine the sensitivity and specificity of a 0.25 mg overnight DEX suppression test, the standard 1 mg overnight DEX suppression test, and the two-day low-dose (Liddle test) DEX suppression test with and without correction for DEX levels in patients evaluated for mild and/or periodic Cushing’s syndrome. Thirty patients determined to have Cushing’s syndrome by biochemical testing and 14 patients determined not to have the condition had the 0.25 mg and standard 1 mg overnight DEX suppression test and the two-day low-dose DEX suppression tests. Our results show that morning serum cortisol and cortisol/DEX ratios following an overnight dexamethasone suppression test were similar in patients with Cushing’s syndrome and those not having Cushing’s syndrome. However, a morning cortisol value above 7.6 μg/dl following a dose of DEX of 0.25 mg was found in 12 patients with Cushing’s syndrome and none in those not having Cushing’s syndrome, suggesting that a high cortisol value after this low dose of dexamethasone can indicate that further testing for Cushing’s syndrome is warranted. Our data suggest that the traditional 1 mg overnight or the 2 mg/2 day DEX suppression testing should no longer be used as a screening test in patients who could have mild and/or periodic Cushing’s syndrome, while the 0.25 mg dose of DEX may pick up some patients with mild Cushing’s syndrome.

scholarly journals Primary Macronodular Adrenal Hyperplasia Associated With Autosomal Dominant ARMC5 Mutation

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A154-A154
Author(s):  
Sarah Elizabeth Kerut ◽  
Angela Subauste
Keyword(s):  
Cushing’S Syndrome ◽  
Salivary Cortisol ◽  
Adrenal Glands ◽  
Autosomal Dominant ◽  
Serum Cortisol ◽  
Cushing's Syndrome ◽  
Adrenal Hyperplasia ◽  
Urinary Cortisol ◽  
Adrenocortical Hyperplasia

Abstract Background: Primary macronodular adrenal hyperplasia (PMAH) is an uncommon cause of Cushing’s syndrome. In some cases, this is an inherited disorder due to a mutation in the armadillo repeat-containing 5 (ARMC5) gene. Clinical Case: A 43-year-old African American woman presented to clinic with weight gain, worsening type 2 diabetes mellitus, and symptomatic hypertensive cardiomyopathy. Physical exam was significant for central obesity, bilateral supraclavicular fat pads, acanthosis nigricans and wide striae over the abdomen. Her serum cortisol was 13.8 mcg/dL after 1 mg of dexamethasone (n&lt;1.8 mcg/dL), urinary cortisol was 180 mcg in 24 hours (n=3.5–45 mcg/24h) and two midnight salivary cortisol tests were 227 and 118 ng/dL (n&lt;100 ng/dL). Her ACTH was 2.4 pg/mL (n=7.2–63.3 pg/mL). Computed tomography (CT) of the abdomen showed nodularity, diffuse thickening and low-density (&lt;10 Hounsfield units) of the bilateral adrenal glands. She underwent bilateral adrenalectomy for a diagnosis of PMAH. Pathology showed nodular adrenocortical hyperplasia; the right and left adrenal glands measured 75 grams and 68 grams, respectively. She was started on hydrocortisone and fludrocortisone postoperatively. Over the following two years, she had a 68-pound weight loss, an 86% reduction in her daily insulin requirement and a 10% improvement in her left ventricular ejection fraction. Approximately two years later, the patient’s brother was referred for bilateral macronodular hyperplasia incidentally discovered on a CT of the abdomen. He had a history of hypertension and type 2 diabetes mellitus with cushingoid features on exam. His serum cortisol was 20.7 mcg/dL after 1 mg of dexamethasone, urinary cortisol was 65.1 mcg in 24 hours, two midnight salivary cortisol tests were 232 and 404 ng/dL and ACTH was 2.0 pg/mL. Upon obtaining further family history, the patients reported clinical features of Cushing’s syndrome in their paternal grandmother but denied features in either parent. The second patient had genetic testing which showed a mutation in the ARMC5 gene, c.1777C&gt;T, p.R593W, a mutation previously described. Due to clinical signs of Cushing’s syndrome, he underwent bilateral adrenalectomy in which pathology showed right and left nodular adrenocortical hyperplasia measuring 110 and 73 grams, respectively. He is doing well postoperatively. The patients recently reported their aunt was diagnosed with PMAH and mild Cushing’s syndrome. She had a unilateral adrenalectomy of the larger adrenal gland and is doing well postoperatively. Conclusion: In some cases, Cushing’s syndrome is an inherited disorder. Autosomal dominant mutations in the ARMC5 gene are occasionally seen in PMAH, which causes less than 2% of endogenous Cushing’s syndrome. For all patients diagnosed with PMAH, clinicians should consider screening their family members with a dexamethasone suppression test.

scholarly journals Increased diagnostic probability of subclinical cushing’s syndrome in a population sample of overweight adult patients with type 2 diabetes mellitus

2007 ◽  
Vol 51 (7) ◽  
pp. 1118-1127 ◽  
Author(s):  
Maria Silvia S. Caetano ◽  
Regina do Carmo Silva ◽  
Claudio E. Kater
Keyword(s):  
Type 2 Diabetes ◽  
Cushing’S Syndrome ◽  
Population Sample ◽  
Serum Cortisol ◽  
Final Diagnosis ◽  
Cushing's Syndrome ◽  
False Positive Test ◽  
Populations At Risk ◽  
Overweight Adult

Endogenous Cushing’s Syndrome (CS) is unusual. Patients with subclinical CS (SCS) present altered cortisol dynamics without obvious manifestations. CS occurs in 2-3% of obese poorly controlled diabetics. We studied 103 overweight adult outpatients with type 2 diabetes to examine for cortisol abnormalities and SCS. All collected salivary cortisol at 23:00 h and salivary and serum cortisol after a 1 mg dexamethasone suppression test (DST). Patients whose results were in the upper quintile for each test (253 ng/dL, 47 ng/dL, and 1.8 mg/dL, respectively for the 23:00 h and post-DST saliva and serum cortisol) were re-investigated. Average values from the upper quintile group were 2.5-fold higher than in the remaining patients. After a confirmatory 2 mg x 2 day DST the investigation for CS was ended for 61 patients with all normal tests and 33 with only one (false) positive test. All 8 patients who had two abnormal tests had subsequent normal 24h-urinary cortisol, and 3 of them were likely to have SCS (abnormal cortisol tests and positive imaging). However, a final diagnosis could not to be confirmed by surgery or pathology. Although not confirmatory, the results of this study suggest that the prevalence of SCS is considerably higher in populations at risk than in the general population.

scholarly journals Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing's syndrome?

2015 ◽  
Vol 4 (4) ◽  
pp. 242-248 ◽  
Author(s):  
Sweta Budyal ◽  
Swati Sachin Jadhav ◽  
Rajeev Kasaliwal ◽  
Hiren Patt ◽  
Shruti Khare ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cushing’S Syndrome ◽  
Serum Cortisol ◽  
Cushing's Syndrome ◽  
Single Center ◽  
Subclinical Cushing’S Syndrome ◽  
Single Center Study ◽  
Center Study

Variable prevalence of subclinical Cushing's syndrome (SCS) has been reported in patients with type 2 diabetes mellitus (T2DM), making the need for screening in this population uncertain. It is unknown if this variability is solely due to study-related methodological differences or a reflection of true differences in ethnic predisposition. The objective of this study is to explore the prevalence of SCS in Asian Indian patients with T2DM. In this prospective single center study conducted in a tertiary care referral center, 993 T2DM outpatients without any discriminatory clinical features (easy bruising, facial plethora, proximal muscle weakness, and/or striae) of hypercortisolism underwent an overnight 1 mg dexamethasone suppression test (ODST). ODST serum cortisol ≥1.8 μg/dl was considered positive, and those with positive results were subjected to 48 h, 2 mg/day low dose DST (LDDST). A stepwise evaluation for endogenous hypercortisolism was planned for patients with LDDST serum cortisol ≥1.8 μg/dl. Patients with positive ODST and negative LDDST were followed up clinically and re-evaluated a year later for the development of clinically evident Cushing's syndrome (CS). In this largest single center study reported to date, we found 37 out of 993 (3.72%) patients had ODST serum cortisol ≥1.8 μg/dl. None of them had LDDST cortisol ≥1.8 μg/dl, nor did they develop clinically evident CS over a follow-up period of 1 year. Specificity of ODST for screening of CS was 96.3% in our cohort. None of the T2DM outpatients in our cohort had SCS, hence cautioning against routine biochemical screening for SCS in this cohort. We suggest screening be based on clinical suspicion only.

Effect of Glucocorticoid receptor antagonist administration in a Cushing's syndrome model rat

2019 ◽  
Author(s):  
Toshiro Seki ◽  
Atsushi Yasuda ◽  
Natsumi Kitajima ◽  
Masami Seki ◽  
Masayuki Oki ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Receptor Antagonist ◽  
Cushing’S Syndrome ◽  
Cushing's Syndrome

scholarly journals Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

2000 ◽  
pp. 472-476 ◽  
Author(s):  
NA Huizenga ◽  
WW De Herder ◽  
JW Koper ◽  
P de Lange ◽  
D AJ v Lely ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
The Body ◽  
The Other ◽  
Down Regulation ◽  
Ligand Affinity ◽  
Other Hand ◽  
Receptor Number ◽  
Cortisol Levels

OBJECTIVE: Glucocorticoids (GCs) serve a variety of important functions throughout the body. The synthesis and secretion of GCs are under the strict influence of the hypothalamo-pituitary-adrenal axis. The mechanisms of action of GCs are mediated by the intracellular glucocorticoid receptor (GR). Over the years, many studies have been performed concerning the regulation of GR expression by GC concentrations. METHODS: In the present study, we determined the characteristics of the GR in peripheral mononuclear blood leukocytes (PBML) from thirteen patients with endogenous Cushing's syndrome and fifteen control subjects, using a whole cell dexamethasone binding assay. Furthermore, cortisol concentrations were determined in order to investigate a possible relationship between serum cortisol levels and receptor characteristics. RESULTS: There were no differences in mean receptor number between patients and controls. On the other hand, a significantly lower ligand affinity was identified in cells from patients with Cushing's syndrome compared with controls. A complete normalisation of the ligand affinity was observed after treatment in the only patient tested in this respect, whereas the receptor number was not affected. In patients, there was a statistically significant negative correlation between cortisol concentrations and ligand affinity, which was not found in controls. CONCLUSION: Receptor down-regulation does not occur in PBML from patients with endogenous Cushing's syndrome. On the other hand, there seems to be a diminished ligand affinity which possibly reflects receptor modification in response to exposure to the continuously high cortisol levels in patients with Cushing's syndrome. This assumption is substantiated by the fact that in one patient a normalisation of the ligand affinity after complete remission of the disease was seen.

scholarly journals Glucocorticoid receptor polymorphisms modulate cardiometabolic risk factors in patients in long-term remission of Cushing’s syndrome

Endocrine ◽  
2016 ◽  
Vol 53 (1) ◽  
pp. 63-70 ◽  
Author(s):  
Sean H. P. P. Roerink ◽  
M. A. E. M. Wagenmakers ◽  
J. W. A. Smit ◽  
E. F. C. van Rossum ◽  
R. T. Netea-Maier ◽  
...  
Keyword(s):  
Risk Factors ◽  
Glucocorticoid Receptor ◽  
Cushing’S Syndrome ◽  
Cardiometabolic Risk ◽  
Cushing's Syndrome ◽  
Cardiometabolic Risk Factors ◽  
Glucocorticoid Receptor Polymorphisms

A New Therapeutic Approach in the Medical Treatment of Cushing's Syndrome: Glucocorticoid Receptor Blockade with Mifepristone

2013 ◽  
Vol 19 (2) ◽  
pp. 313-326 ◽  
Author(s):  
Maria Fleseriu ◽  
Mark Molitch ◽  
Coleman Gross ◽  
David Schteingart ◽  
T. Vaughan ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Medical Treatment ◽  
Cushing’S Syndrome ◽  
Therapeutic Approach ◽  
Cushing's Syndrome ◽  
Receptor Blockade

scholarly journals Efficacy of pasireotide in controlling severe hypercortisolism until cardiac transplantation

2017 ◽  
Vol 2017 ◽  
Author(s):  
Roberto Attanasio ◽  
Liana Cortesi ◽  
Daniela Gianola ◽  
Claudia Vettori ◽  
Fulvio Sileo ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Cushing’S Syndrome ◽  
Cardiac Transplantation ◽  
Serum Cortisol ◽  
Primary Treatment ◽  
Cushing's Syndrome ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment ◽  
Undergo Heart Transplantation

Summary Cushing’s syndrome is associated with increased morbidity and mortality. Although surgery is the first-line treatment, drugs can still play a role as an ancillary treatment to be employed while waiting for surgery, after unsuccessful operation or in patients unsuitable for surgery. We were asked to evaluate a 32-year-old male waiting for cardiac transplantation. Idiopathic hypokinetic cardiomyopathy had been diagnosed since 6 years. He was on treatment with multiple drugs, had a pacemaker, an implantable cardioverter and an external device for the support of systolic function. Physical examination showed severely impaired general status, signs of hypercortisolism and multiple vertebral compression fractures. We administered teriparatide, and the few evaluable parameters supported the diagnosis of ACTH-dependent hypercortisolism: serum cortisol was 24.2 µg/dL in the morning and 20.3 µg/dL after overnight 1 mg dexamethasone, urinary free cortisol (UFC) was 258 µg/24 h and ACTH 125 pg/mL. Pituitary CT was negative. Pasireotide 300 µg bid was administered and uptitrated to 600 µg bid. Treatment was well tolerated, achieving dramatic improvement of clinical picture with progressive normalization of serum cortisol and ACTH levels as well as UFC. After 4 months, the patient underwent successful heart transplantation. Many complications ensued and were overcome. Pituitary MRI was negative. On pasireotide 300 µg bid and prednisone 2.5 mg/day (as part of immunosuppressive therapy), morning serum cortisol and ACTH were 15.6 µg/dL and 54 pg/mL respectively, UFC was 37 µg/24 h, fasting glucose: 107 mg/dL and HbA1c: 6.5%. In conclusion, primary treatment with pasireotide achieved remission of hypercortisolism, thus allowing the patient to undergo heart transplantation. Learning points: Untreated Cushing’s syndrome is associated with ominous prognosis. First-line treatment is surgery (at pituitary or adrenal, according to disease localization). A few drugs are available to treat hypercortisolism. Pasireotide is a multi-ligand somatostatin analog approved for treatment of hypercortisolism. Primary treatment with pasireotide was effective in a patient with severe Cushing’s syndrome, allowing him to undergo heart transplantation.

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