A Single Midnight Serum Cortisol Measurement Distinguishes Cushing’s Syndrome from Pseudo-Cushing States

Posted on August 1, 2015 by MaryO
Dimitris A. Papanicolaou, Jack A. Yanovski, Gordon B. Cutler, Jr. 2 , George P. Chrousos, and Lynnette K. Nieman
Address all correspondence and requests for reprints to: Dimitris A. Papanicolaou, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: papanicd@cc1.nichd.nih.gov.
DOI: http://dx.doi.org/10.1210/jcem.83.4.4733
Received: October 22, 1997
Accepted: January 05, 1998
First Published Online: July 01, 2013
Abstract

Cushing’s syndrome (CS) may be difficult to distinguish from pseudo-Cushing states (PCS) based on physical findings or urinary glucocorticoid excretion. As the lack of diurnal variation in serum cortisol is characteristic of CS, we studied whether diurnal cortisol determinations could discriminate CS from PCS. Two hundred and sixty-three patients were evaluated: 240 had CS, and 23 had PCS. Urine was collected for 24 h for measurement of cortisol and 17-hydroxycorticosteroids (17OHCS). Blood was drawn at 2300, 2330, 0000, 0030, and 0100 h and at 0600, 0630, 0700, 0730, and 0800 h the next morning for serum cortisol determination. The main outcome measure was the sensitivity of these parameters for the diagnosis of CS at 100% specificity. A midnight cortisol value greater than 7.5 μg/dL correctly identified 225 of 234 patients with CS and all PCS patients. This sensitivity (96%) was superior to that obtained for any other measure, including urinary cortisol (45%), 17OHCS (22%), any other individual cortisol time point (10–92%), the morning (23%) or the evening (93%) cortisol mean, and the ratio (11%) of morning to evening values. We conclude that at 100% specificity, a single serum cortisol value above 7.5 μg/dL at midnight discriminates CS from PCS with higher sensitivity than 24-h urinary cortisol or 17OHCS, or other individual or combined measures of serum cortisol.

OVERPRODUCTION of cortisol is the biochemical hallmark of Cushing’s syndrome (CS) regardless of its etiology and is evidenced by increased urinary cortisol excretion, and a decrease in the circadian variation of serum cortisol (1).

Pseudo-Cushing states (PCS), as the name implies, share many of the features of Cushing’s syndrome, including cortisol overproduction. The hypercortisolism of PCS is hypothesized to be caused by increased activity of the CRH neuron, which, in turn, stimulates ACTH production and release (2). PCS are a heterogeneous group of disorders, including chronic alcoholism and alcohol withdrawal syndrome (3, 4), major depression (5), poorly controlled diabetes mellitus (6, 7), and obesity (8). Additionally, transient hypercortisolism may be associated with less obvious psychiatric conditions (e.g. anxiety) in patients with clinical features reminiscent of CS, such as obesity and hypertension, which are common in the general population. The substantial overlap in urinary free cortisol (UFC) excretion and clinical features between some patients with CS and those with PCS can make it difficult to distinguish between the two conditions (9). Thus, although persistent elevation of 24-h UFC in the presence of unequivocal signs of CS (particularly classic moon facies, prominent centripetal obesity, severe proximal muscle weakness, and violaceous striae) suggest the diagnosis of CS, patients with less obvious signs pose a diagnostic dilemma.

Several tests have been proposed to diagnose CS, including 24-h UFC measurements, the 1-mg overnight dexamethasone suppression test (DST) (10), the 2-day DST (1), and the dexamethasone-CRH (Dex-CRH) stimulation test (8). Each has drawbacks. Twenty-four-hour urinary collections are inconvenient and often incomplete. The 1-mg overnight DST is commonly used as a screening test to exclude the diagnosis of CS. This test has two caveats. First, a criterion for the level of serum cortisol suppression to exclude CS has not been developed using modern RIAs. Second, although the test has a false negative rate of only 2%, it has a significant false positive rate, especially in chronically ill (23%) or obese patients (13%) (11) and in patients with major depression (43%) or other psychiatric disorders (8–41%) (12). Even in normal individuals, the test may be consistent with CS in up to 30% (9).

Similarly, the 2-mg 2-day DST, often used as a confirmatory diagnostic test, has a diagnostic accuracy of only 71% (8). An additional problem is the variable metabolic clearance of dexamethasone (13), which is especially problematic in patients receiving medications that induce the cytochrome P450-related enzymes (e.g.phenytoin, rifampin, and phenobarbital) (14) or in patients with renal or hepatic failure. In such cases, neither DST gives reliable results. Finally, the drawbacks of 24-h urine collections apply to the DST as well.

We previously determined that the dexamethasone-CRH test has a diagnostic accuracy of 98% in the distinction of CS from PCS (8, 15). However, although accurate, this test has the drawbacks related to dexamethasone clearance, as discussed above.

Physiological cortisol secretion is characterized by circadian rhythmicity. Serum cortisol concentration reaches its zenith in the morning (0600–0800 h) and its nadir in the night during the first half of normal sleep. Krieger et al. defined the normal circadian rhythm of plasma corticosteroid levels as the pattern where all plasma glucocorticoid levels from 1600–2400 h were 75% or less of the 0800 h value (16). As previous studies have found that obese individuals retain a normal circadian cortisol rhythm (17), we hypothesized that differences in circadian plasma cortisol values would distinguish CS from PCS. To test this hypothesis, we prospectively measured serum cortisol values during the normal nadir and zenith periods in patients being evaluated for CS.

Read the entire study at http://press.endocrine.org/doi/10.1210/jcem.83.4.4733?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

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Experts recommend tumor removal as first-line treatment for Cushing’s syndrome

Posted on July 30, 2015 by MaryO

The Endocrine Society today issued a Clinical Practice Guideline (CPG) on strategies for treating Cushing’s syndrome, a condition caused by overexposure to the hormone cortisol.

The CPG, entitled “Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline,” was published online and will appear in the August 2015 print issue of the Journal of Clinical Endocrinology and Metabolism (JCEM), a publication of the Endocrine Society.

Cushing’s syndrome occurs when a person has excess cortisol in the blood for an extended period, according to the Hormone Health Network. When it is present in normal amounts, cortisol is involved in the body’s response to stress, maintains blood pressure and cardiovascular function, keeps the immune system in check, and converts fat, carbohydrates and proteins into energy. Chronic overexposure to the hormone can contribute to the development of cardiovascular disease, infections and blood clots in veins.

People who take cortisol-like medications such as prednisone to treat inflammatory conditions, including asthma and rheumatoid arthritis, can develop Cushing’s syndrome. The high cortisol levels return to normal when they stop taking the medication. This is called exogenous Cushing’s syndrome.

In other cases, tumors found on the adrenal or pituitary glands or elsewhere in the body cause the overproduction of cortisol and lead to the development of Cushing’s syndrome. The Clinical Practice Guidelines focus on this form of the condition, known as endogenous Cushing’s syndrome.

“People who have active Cushing’s syndrome face a greater risk of death – anywhere from nearly twice as high to nearly five times higher – than the general population,” said Lynnette K. Nieman, MD, of the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, MD, and chair of the task force that authored the guideline. “To reduce the risk of fatal cardiovascular disease, infections or blood clots, it is critical to identify the cause of the Cushing’s syndrome and restore cortisol levels to the normal range.”

In the CPG, the Endocrine Society recommends that the first-line treatment for endogenous Cushing’s syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol. Surgical removal of the tumor is optimal because it leaves intact the hypothalamic-pituitary-adrenal axis, which is integral to the body’s central stress response.

Other recommendations from the CPG include:

  • Tumors should be removed by experienced surgeons in the following situations:— A tumor has formed on one or both of the two adrenal glands.— A tumor that secretes adrenocorticotropic hormone (ACTH) – the hormone that signals the adrenal glands to produce cortisol – has formed somewhere in the body other than the adrenal or pituitary gland.

    — A tumor has formed on the pituitary gland itself.

  • Patients who continue to have high levels of cortisol in the blood after surgery should undergo additional treatment.
  • People who had an ACTH-producing tumor should be screened regularly for the rest of their lives for high cortisol levels to spot recurrences.
  • If patients’ cortisol levels are too low following surgery, they should receive glucocorticoid replacement medications and be educated about adrenal insufficiency, a condition where the adrenal glands produce too little cortisol. This condition often resolves in 1-2 years.
  • Morning cortisol and/or ACTH stimulation tests, or insulin-induced hypoglycemia, can be used to test for the recovery of the hypothalamic-pituitary-adrenal axis in people who have low cortisol levels after surgery. Once the tests results return to normal, glucocorticoid replacement can be stopped.
  • People who have undergone pituitary surgery should be re-evaluated for other pituitary hormone deficiencies during the post-operative period.
  • Patients who have a pituitary tumor and have undergone surgery to remove both adrenal glands should be regularly evaluated for tumor progression using pituitary MRIs and tests for ACTH levels.
  • Radiation therapy may be used to treat a pituitary tumor, especially if it is growing. While awaiting the effect of radiation, which may take months to years, treatment with medication is advised.
  • To assess the effect of radiation therapy, the patient’s cortisol levels should be measured at 6- to 12-month intervals.
  • Medications may be used to control cortisol levels as a second-line treatment after surgery for a pituitary gland tumor, as a primary treatment for ACTH-secreting tumors that have spread to other parts of the body or suspected ACTH-secreting tumors that cannot be detected on scans. Medications also can be used as adjunctive treatment to reduce cortisol levels in people with adrenal cortical carcinoma, a rare condition where a cancerous growth develops in the adrenal gland.
  • People with Cushing’s syndrome should be treated for conditions associated with the disease, such as cardiovascular disease risk factors, osteoporosis and psychiatric symptoms.
  • Patients should be tested for recurrence throughout their lives except in cases where the person had a benign adrenal tumor removed.
  • Patients should undergo urgent treatment within 24 to 72 hours of detecting excess cortisol if life-threatening complications such as serious infection, pulmonary thromboembolism, cardiovascular complications and acute psychosis are present.

More information: The Hormone Health Network offers resources on Cushing’s syndrome at www.hormone.org/questions-and-answers/2012/cushing-syndrome

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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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