What Genes are Related to Cushing’s Disease?

Posted on July 29, 2015 by MaryO

genetic

 

The genetic cause of Cushing disease is often unknown. In only a few instances, mutations in certain genes have been found to lead to Cushing disease. These genetic changes are called somatic mutations. They are acquired during a person’s lifetime and are present only in certain cells. The genes involved often play a role in regulating the activity of hormones.

Cushing disease is caused by an increase in the hormone cortisol, which helps maintain blood sugar levels, protects the body from stress, and stops (suppresses) inflammation. Cortisol is produced by the adrenal glands, which are small glands located at the top of each kidney. The production of cortisol is triggered by the release of a hormone called adrenocorticotropic hormone (ACTH) from the pituitary gland, located at the base of the brain. The adrenal and pituitary glands are part of the hormone-producing (endocrine) system in the body that regulates development, metabolism, mood, and many other processes.

Cushing disease occurs when a noncancerous (benign) tumor called an adenoma forms in the pituitary gland, causing excessive release of ACTH and, subsequently, elevated production of cortisol. Prolonged exposure to increased cortisol levels results in the signs and symptoms of Cushing disease: changes to the amount and distribution of body fat, decreased muscle mass leading to weakness and reduced stamina, thinning skin causing stretch marks and easy bruising, thinning of the bones resulting in osteoporosis, increased blood pressure, impaired regulation of blood sugar leading to diabetes, a weakened immune system, neurological problems, irregular menstruation in women, and slow growth in children. The overactive adrenal glands that produce cortisol may also produce increased amounts of male sex hormones (androgens), leading to hirsutism in females. The effect of the excess androgens on males is unclear.

Most often, Cushing disease occurs alone, but rarely, it appears as a symptom of genetic syndromes that have pituitary adenomas as a feature, such as multiple endocrine neoplasia type 1 (MEN1) or familial isolated pituitary adenoma (FIPA).

Cushing disease is a subset of a larger condition called Cushing syndrome, which results when cortisol levels are increased by one of a number of possible causes. Sometimes adenomas that occur in organs or tissues other than the pituitary gland, such as adrenal gland adenomas, can also increase cortisol production, causing Cushing syndrome. Certain prescription drugs can result in an increase in cortisol production and lead to Cushing syndrome. Sometimes prolonged periods of stress or depression can cause an increase in cortisol levels; when this occurs, the condition is known as pseudo-Cushing syndrome. Not accounting for increases in cortisol due to prescription drugs, pituitary adenomas cause the vast majority of Cushing syndrome in adults and children.

Read more about familial isolated pituitary adenoma.

 

How do people inherit Cushing disease?

Most cases of Cushing disease are sporadic, which means they occur in people with no history of the disorder in their family. Rarely, the condition has been reported to run in families; however, it does not have a clear pattern of inheritance.

The various syndromes that have Cushing disease as a feature can have different inheritance patterns. Most of these disorders are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

From http://ghr.nlm.nih.gov/condition/cushing-disease

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Hair Analysis Provides a Historical Record of Cortisol Levels in Cushing’s Syndrome

Posted on July 25, 2015 by MaryO
Exp Clin Endocrinol Diabetes. Author manuscript; available in PMC 2010 Sep 24.
Published in final edited form as:
PMCID: PMC2945912
NIHMSID: NIHMS235640
Hair Analysis Provides a Historical Record of Cortisol Levels in Cushing’s Syndrome
S. Thomson,1 G. Koren,1,6 L.-A. Fraser,2 M. Rieder,3 T. C. Friedman,4 and S. H. M. Van Uum5
Author information ► Copyright and License information ►
The publisher’s final edited version of this article is available at Exp Clin Endocrinol Diabetes
See other articles in PMC that cite the published article.

Abstract

The severity of Cushing’s Syndrome (CS) depends on the duration and extent of the exposure to excess glucocorticoids. Current measurements of cortisol in serum, saliva and urine reflect systemic cortisol levels at the time of sample collection, but cannot assess past cortisol levels. Hair cortisol levels may be increased in patients with CS, and, as hair grows about 1 cm/month, measurement of hair cortisol may provide historical information on the development of hypercortisolism.

We attempted to measure cortisol in hair in relation to clinical course in six female patients with CS and in 32 healthy volunteers in 1 cm hair sections. Hair cortisol content was measured using a commercially available salivary cortisol immune assay with a protocol modified for use with hair.

Hair cortisol levels were higher in patients with CS than in controls, the medians (ranges) were 679 (279–2500) and 116 (26–204) ng/g respectively (P <0.001). Segmental hair analysis provided information for up to 18 months before time of sampling. Hair cortisol concentrations appeared to vary in accordance with the clinical course.

Based on these data, we suggest that hair cortisol measurement is a novel method for assessing dynamic systemic cortisol exposure and provides unique historical information on variation in cortisol, and that more research is required to fully understand the utility and limits of this technique.

Keywords: glucocorticoids, pituitary adenoma, cancer, adrenal gland, hormones, cushing hair
Read the entire article at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945912/

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Lowest cortisol levels found in women with overweight, mild obesity

Posted on July 18, 2015 by MaryO

Women with overweight and class I obesity appear to have the lowest cortisol levels, while more significant obesity appears to be associated with higher cortisol levels, according to recent findings.

In the cross-sectional study, Karen K. Miller, MD, of Massachusetts General Hospital, and colleagues evaluated 60 premenopausal women aged 18 to 45 years: 28 with overweight or obesity, 18 with anorexia nervosa and 21 healthy controls at normal weight. Overweight was defined as BMI 25 to 29.9 kg/m2, and obesity was classified as class I (30-34.9 kg/m2) and class II (35-39 kg/m2).

Anorexia nervosa was classified based on DSM-IV criteria, which includes extreme fear of weight gain, body image dysmorphia, weight that is 85% of ideal body weight and cessation of menstruation for 3 consecutive months. Participants were asked to collect 24-hour urine samples, in addition to 11 p.m. and 7 a.m. salivary samples within 1 week of an inpatient hospital visit. For each sample, researchers assessed creatinine clearance, and urinary free cortisol/creatinine clearance was calculated for each specimen to account for the decreased creatinine and filtered cortisol linked to anorexia nervosa.

During the inpatient visit, participants underwent placement of an IV catheter and fasting blood was sampled every 20 minutes from 8 p.m. to 8 a.m. Fasting cortisol and cortisol binding globulin concentrations were measured at 8 a.m. Participants were asked to take 5 g of oral dexamethasone every 6 hours for 48 hours to decrease endogenous disparities in cortisol levels.

The researchers found that with the exception of dexamethasone-suppression-CRH testing, all cortisol measures exhibited a U-shaped association with BMI, most notably urinary free cortisol/creatinine clearance (P = .0004) and mean overnight serum cortisol (P < .0001).

The lowest cortisol levels were seen in the overweight-class I obesity range, and these were also associated with visceral fat tissue and total fat mass. Participants with anorexia nervosa had higher mean cortisol levels than participants with overweight or obesity. Attenuated inverse relationships were seen between lean mass and some measures of cortisol, and most measures of cortisol were inversely related to posterior-anterior spine and total hip bone mineral density.

According to the researchers, these findings have not determined the precise nature of the relationship between cortisolemia, hypothalamic-pituitary-adrenal activation and adiposity.

“The [hypothalamic-pituitary-adrenal] axis activation associated with obesity and excess adiposity raises the question of whether hypercortisolemia contributes to increased adiposity in the setting of caloric excess, whether increased adiposity drives [hypothalamic-pituitary adrenal] activation, or whether the relationship between hypercortisolemia and adiposity is bidirectional,” the researchers wrote. – by Jennifer Byrne

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/obesity/news/online/%7B73cac1c4-af30-4f24-89e3-86f50d05aaa2%7D/lowest-cortisol-levels-found-in-women-with-overweight-mild-obesity

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The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing’s syndrome

Posted on July 9, 2015 by MaryO

J Clin Endocrinol Metab. 2004 Mar;89(3):1222-6.

Findling JW1, Raff H, Aron DC.

Abstract

Low-dose dexamethasone suppression testing has been recommended for biochemical screening when Cushing’s syndrome is suspected. The criterion for normal suppression of cortisol after dexamethasone is controversial.

To assess diagnostic utility (sensitivity), we report the results of low-dose dexamethasone suppression testing in 103 patients with spontaneous Cushing’s syndrome. There were 80 patients with Cushing’s disease (78%), 13 with the ectopic ACTH syndrome (13%), and 10 with cortisol-producing adrenocortical adenomas (10%). Fourteen (18%) of 80 patients with Cushing’s disease suppressed serum cortisol to less than 5 micro g/dl (<135 nmol/liter) after the overnight 1-mg test, whereas six patients (8%) actually showed suppression of serum cortisol to less than 2 micro g/dl (<54 nmol/liter). In addition, the 2-d, low-dose dexamethasone suppression test yielded false-negative results in 38% of patients when urine cortisol was used and 28% when urinary 17-hydroxycorticosteroids were used. Serum cortisol after the 1-mg test correlated with baseline urinary free cortisol (r = 0.705, P < 0.001), plasma ACTH level (r = 0.322, P = 0.001), and urinary free cortisol after the 2-d test (r = 0.709, P = 0.001).

This study provides evidence that low-dose dexamethasone may suppress either plasma cortisol or urinary steroids to levels previously thought to exclude Cushing’s syndrome and that these tests should not be used as the sole criterion to exclude the diagnosis of endogenous hypercortisolism.

PMID:
15001614
[PubMed – indexed for MEDLINE]

From http://www.ncbi.nlm.nih.gov/pubmed/15001614

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Crooke’s changes common in patients with Cushing’s syndrome, high cortisol production

Posted on July 9, 2015 by MaryO
Oldfield EH, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/JC.2015-2493.
July 8, 2015

 

Evidence of Crooke hyaline changes in the pituitary gland points to a higher likelihood of Cushing’s syndrome in adults, with the changes in basophil cells occurring in 75% to 80% of patients with the hormonal disorder, according to research in The Journal of Clinical Endocrinology & Metabolism.

In a retrospective review of hospital patient records from adults with Cushing’s syndrome who underwent pituitary surgery, researchers also found that a higher degree of cortisol production, as well as exposure to excess glucocorticoids, are often associated with Crooke’s changes in adults.

“The presence of Crooke’s changes is a clear indication of the presence of Cushing’s syndrome, although the absence of Crooke’s changes does not exclude it,” the researchers wrote.

Edward H. Oldfield, MD, FACS, of the department of neurological surgery at University of Virginia Health System, and colleagues analyzed electronic hospital data from 213 consecutive patients with Cushing’s syndrome who received pituitary surgery between 2008 and March 2014. Researchers reviewed analysis of the normal pituitary tissue included with the specimens obtained at surgery, as well as cortisol production measured by 24-hour urine.

Within the cohort, Crooke’s changes occurred in 74% of patients; Crooke’s changes occurred in 81% of patients with an adrenocorticotropic hormone tumor.

Researchers also found that 91% of patients with an adrenocorticotropic hormone-producing tumor and a urinary free cortisol test at least fourfold the upper limit of normal had evidence of Crooke’s changes vs. 74% of patients with a urine cortisol amount that was less than fourfold the upper limit of normal (P = .008).

“Our results clearly demonstrate a correlation between the degree of cortisol production and the presence of Crooke’s changes,” the researchers wrote. “Patients with cortisol production exceeding fourfold upper limit almost all had Crooke’s changes.”

Researchers said study results indicate that the presence of Crooke’s changes may be used to indicate that a patient has Cushing’s syndrome following a pituitary surgery in which no tumor is found.

“However, the absence of Crooke’s changes does not reliably indicate the absence of Cushing’s syndrome, as 19% of patients with a proven [adrenocorticotropic hormone-producing tumor] did not have Crooke’s changes,” the researchers wrote. – by Regina Schaffer

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B838a3557-f284-4fda-b93d-73dbb4823667%7D/crookes-changes-common-in-patients-with-cushings-syndrome-high-cortisol-production

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