The production of cortisol by the adrenal glands is stimulated by ACTH (Adrenal Cortical Tropic Hormone), which is produced by the pituitary gland in the brain. Thus, overproduction of cortisol can be caused by either a tumor in the pituitary gland (Cushing's disease), or in the adrenal glands (Cushing's syndrome). Less commonly, a tumor producing too much ACTH may be found outside of the pituitary gland. In patients with Cushing's disease, the blood levels of both ACTH and cortisol are elevated. In patients with Cushing's syndrome, the blood level of cortisol is increased in the setting of a low level of ACTH. Rarely, adrenocortical cancers may cause Cushing's syndrome.


There is a great deal of variability throughout the day in the amounts of cortisol produced by the adrenal glands. For this reason, the most sensitive test measures the amount of cortisol excreted in the urine over a 24-hour period. A 24 hour free cortisol level greater than 100 µg is diagnostic of Cushing's syndrome. Patients suspected of having Cushing's syndrome will also undergo a dexamethasone suppression test which helps to determine the cause of the increased cortisol production. A CT or MRI scan is used to determine the location of the tumor.


Patients with Cushing's disease typically have benign tumors of the pituitary gland in the brain. These patients are referred to a neurosurgeon for removal of the tumors. If removal of the pituitary tumor and medications fail to control Cushing's disease, removing both adrenal glands may be indicated. In patients with Cushing's syndrome, an adrenalectomy—surgical removal of the adrenal gland—is curative. This operation is usually performed laparoscopically, through several very small incisions.


Pituitary, 09/25/2013  Review Article

Sundaram NK et al. – A case of possible recurrent Cushing’s disease (CD) is presented and data on current definitions of CD remission, persistence, and recurrence are reviewed.

The number and degree of abnormal test results needed to define recurrence, and the determination of which biochemical test has more significance when there are discrepancies between markers is inconsistent among studies.

Further inquiry is warranted to examine if patients in apparent CD remission who have subtle hypothalamic pituitary adrenal (HPA) axis abnormalities represent distinctive remission subtypes versus mild or early recurrence.

Additional investigation could also explore the degree to which these HPA axis abnormalities, such as alterations in cortisol circadian rhythm or partial resistance to dexamethasone, are associated with persistence of CD morbidities, including neuropsychiatric impairments, alterations in body composition, and cardiovascular risk.

From MDLinx

Damian G. Morris,
Ashley Grossman,
Lynnette K. Nieman







Etiology and Pathophysiology



Pseudo-Cushing's States






Clinical Features






Clinical Spectrum



Diagnosis and Differential Diagnosis



Establishing the Diagnosis of Cushing's Syndrome



Differential Diagnosis of Cushing's Syndrome












Medical Treatment



Special Clinical Scenarios



Cyclic Cushing's Syndrome



Iatrogenic and Factitious Cushing's Syndrome



Chronic Renal Failure



Pediatric Cushing's Syndrome



Cushing's Syndrome in Pregnancy




Harvey Cushing[1,2] was the first to codify the symptom complex of obesity, diabetes, hirsutism, and adrenal hyperplasia, and to postulate that the basophilic adenomas found at autopsy in six of eight patients caused the disease that now bears his name. Shortly thereafter, Walters and colleagues[3]identified the etiologic contribution of adrenal tumors and the therapeutic role of adrenalectomy.

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  • Pituitary Incidentaloma
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  • Endocrine & Nutritional Management of the Post-Bariatric Surgery Patient
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  • Endocrine Treatment of Transsexual Persons
  • Evaluation & Management of Adult Hypoglycemic Disorders
  • Prevention and Treatment of Pediatric Obesity
  • Primary Prevention of Cardiovascular Disease & Type 2 Diabetes in Patients at Metabolic Risk
  • Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism
  • The Diagnosis of Cushing's Syndrome
  • Evaluation & Treatment of Hirsutism in Premenopausal Women
  • Executive Summary: Management of Thyroid Dysfunction during Pregnancy & Postpartum
  • Management of Thyroid Dysfunction during Pregnancy & Postpartum
  • Androgen Therapy in Women

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cushings-ladyNeary NM. J Clin Endocrinol Metab. 2013;doi:10.1210/jc.2012-3754.

In a recent study supported by the NIH, researchers determined that patients with Cushing’s syndrome have a greater risk for developing coronary arterial atherosclerosis, increasing their rate of cardiovascular morbidity. These findings were published in the Journal of Clinical Endocrinology & Metabolism.

The researchers conducted a prospective case-control study of 15 consecutive patients with adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome who were matched with 15 controls (aged 32 to 66 years) with at least one risk factor for cardiac disease (ie, diabetes, hypertension, hyperlipidemia, family history of early-onset coronary artery disease and previous or current smoking).

Researchers used a multidetector CT (MDCT) coronary angiogram scan to measure calcified and noncalcified coronary plaque volume and Agatston scores. Additional variables included fasting lipids, BP, history of hypertension or diabetes and 24-hour urine free cortisol excretion.

According to data, patients with Cushing’s syndrome had significantly greater noncalcified plaque volume and Agatston scores compared with controls (noncalcified plaque volume median [interquartile ranges]: 49.5 vs. 17.9,P<.001; Agatston score: 70.6 vs. 0, P<.05).

Patients with Cushing’s syndrome also demonstrated higher systolic (143 mm Hg) and diastolic (86 mm Hg) BP compared with controls (systolic: 134 mm Hg, diastolic: 76 mm Hg).

The limitations of the study include the small cohort of patients and potential selection bias due to ectopic ACTH secretion. However, the researchers wrote that these findings demonstrate a significant difference between the two groups included in the study.

“Overall, the findings point to the possible causes of cardiovascular morbidity in patients treated with exogenous steroids and indicate the need for further studies of that population,” they wrote.

Disclosure: The researchers report no relevant financial disclosures.



Alice C. Levine, MD Alice C. Levine

  • It has long been recognized that endogenous hypercortisolism (Cushing's syndrome) and administration of supraphysiologic doses of glucocorticoids are associated with increased mortality, primarily due to cardiovascular disease. Excess glucocorticoids induce all of the features of the metabolic syndrome including obesity with central weight gain, hypertension, impaired glucose tolerance/diabetes mellitus and dyslipidemia, all of which increase cardiovascular risk. In this small but well-designed study, the authors attempt to determine whether excess glucocorticoids have a direct adverse effect on the coronary vasculature. Utilizing multidetector computerized tomographic (MDCT) coronary angiography, a validated noninvasive method of assessing calcified and noncalcified coronary plaques, they compared measurements of coronary plaques (Agatston score) in 15 patients with ACTH-dependent Cushing's syndrome (CS) vs. 15 age-, sex- and body weight-matched controls with at least one risk factor for cardiac disease. They found significantly greater coronary calcifications and noncalcified coronary plaque volumes in patients with active or previous hypercortisolism.There are obvious limitations to the study; most notably the small sample size, the predominance of patients with CS due to ectopic ACTH (14/15) and significantly more hypertension in the CS vs. the control group. However, other than the HTN, the groups were well-matched and there was no statistical difference in the Framingham risk scores between groups. This is the first study to demonstrate direct effects of CS on coronary plaque burden.

    The findings, while unsurprising, underscore several important features of CS which endocrinologists need to consider. Firstly, as there were no statistical differences in plaque burden in patients with CS who were eucortisolemic (4/15) vs. those who were hypercortisolemic (11/15) at the time of study, the effects of CS on the coronary vasculature may persist even after biochemical cure. Many previous studies in larger cohorts have similarly demonstrated that the adverse effects of high glucocorticoids on cardiovascular, metabolic, psychiatric and neurocognitive function may be only partially reversible with disease remission. Secondly, even adjusting for all the confounding variables, hypercortisolism seems to be an independent risk factor for the development of coronary artery disease. The possible mechanisms underlying this observation are discussed and include increases in prothrombotic factors, circulating levels of vascular endothelial growth factor (VEGF) and angiogenesis. It is also plausible that cortisol increases atherosclerosis through the mineralocorticoid rather than the glucocorticoid receptor, suggesting the possibility of treating this particular deleterious effect of hypercortisolism with a mineralocorticoid-receptor blocker such as spironolactone.

    Within the CS group, no significant correlations were observed between the coronary plaque volumes and the duration of CS or urinary free cortisol (UFC) either at presentation or at the time of MDCT. Although this lack of correlation may also be attributable to the small sample size, it is well known that the onset of Cushing's syndrome is often insidious and it is impossible to pinpoint the exact duration of the abnormality in most patients. This study's finding of direct, adverse and possibly irreversible effects of hypercortisolism on the coronary vasculature should make endocrinologists even more vigilant in diagnosing and treating the disease as early as possible in its course.

    • Alice C. Levine, MD
    • Professor of medicine, division of endocrinology, diabetes and bone diseases
      Co-Director of The Adrenal Center
      Icahn School of Medicine
      Mount Sinai, New York, NY
  • Disclosures: Levine reports no relevant financial disclosures.


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