Cushing Syndrome

Author: Gail K Adler, MD, PhD; Chief Editor: George T Griffing, MD more...

Updated: Feb 22, 2012

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Background
Pathophysiology
Epidemiology
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Background

Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids.

Individuals with Cushing syndrome can develop moon facies, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae, as shown in the image below.

Physical findings in Cushing syndrome.

Individuals often complain of proximal muscle weakness, easy bruising, weight gain, hirsutism, and, in children, growth retardation. Hypertension, osteopenia, diabetes mellitus, and impaired immune function may occur.

In an emergency situation, remembering that the most common cause of Cushing syndrome is the use of exogenous glucocorticoids is important. Exogenous steroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis that can last for as long as a year after exogenous steroid administration has ended.

An individual with HPA-axis suppression cannot increase steroid production appropriately during a medical illness or other stress and would need to receive stress doses of steroids to avoid adrenal crisis. Thus, in an emergency, the potential for relative adrenal insufficiency should be considered in any patient with Cushing syndrome.

Pathophysiology

Excess levels of either exogenously administered glucocorticoids or endogenous overproduction of cortisol causes Cushing syndrome. Endogenous glucocorticoid overproduction or hypercortisolism that is independent of ACTH is usually due to a primary adrenocortical neoplasm (usually an adenoma but rarely a carcinoma). Bilateral micronodular hyperplasia and macronodular hyperplasia are rare causes of Cushing syndrome.

ACTH-secreting neoplasms cause ACTH-dependent Cushing syndrome. They usually are due to an anterior pituitary tumor, that is, classic Cushing disease (80%). Nonpituitary ectopic sources of ACTH, such as an oat cell carcinoma, small-cell lung carcinoma, or carcinoid tumor, cause the balance of ACTH-dependent disease. Ectopic corticotropin-releasing hormone (CRH) secretion leading to increased ACTH secretion comprise a very rare group of cases of Cushing syndrome.^[1]

Frequency

United States

Most cases of Cushing syndrome are due to exogenous glucocorticoids. The annual incidence of endogenous Cushing syndrome has been estimated at 13 cases per million individuals. Of these cases, approximately 70% are due to Cushing disease, that is, a pituitary ACTH-producing tumor; 15% to ectopic ACTH; and 15% to a primary adrenal tumor.

Mortality/Morbidity

Morbidity and mortality associated with Cushing syndrome are related primarily to the effects of excess glucocorticoids. However, a large primary pituitary tumor may cause panhypopituitarism and visual loss.

In addition, the rare adrenocortical carcinomas are associated with a 5-year survival rate of 30% or less.
Two catastrophic medical crises that occur in glucocorticoid excess states are perforated viscera and opportunistic fungal infections.
Exposure to excess glucocorticoids results in multiple medical problems, including hypertension, obesity, osteoporosis, fractures, impaired immune function, impaired wound healing, glucose intolerance, and psychosis.
Exogenous steroids suppress the HPA axis, with full recovery taking as long as a year after cessation of glucocorticoid administration. Thus, patients who are on or who have taken steroids are at risk for developing an adrenal crisis if steroids are stopped or not increased during an acute illness.
Similarly, lack of cortisol leading to an adrenal crisis may occur in patients with endogenous Cushing syndrome who have undergone resection of an ACTH-producing or cortisol-producing tumor or who are taking adrenal steroid inhibitors.

Sex

The female-to-male incidence ratio is approximately 5:1 for Cushing syndrome due to an adrenal or pituitary tumor.
Ectopic ACTH production is more frequent in men than in women because of the increased incidence of lung tumors in this population.

Age

The peak incidence of Cushing syndrome due to either an adrenal or pituitary adenoma is in persons aged 25-40 years.
Ectopic ACTH production due to lung cancer occurs later in life.

Proceed to Clinical Presentation

Contributor Information and Disclosures

Author

Gail K Adler, MD, PhD Associate Professor of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School

Gail K Adler, MD, PhD is a member of the following medical societies: American Heart Association and Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Frederick H Ziel, MD Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society

Disclosure: Nothing to disclose.

Mark Cooper, MBBS, PhD, FRACP Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

We wish to thank Susanna L Dipp, MD, Fellow, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, for her previous contributions to this entry.

References

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Physical findings in Cushing syndrome.

Diagnosis of Cushing syndrome.

Etiology of Cushing syndrome.

Table. States of Increased and Decreased HPA Activity

Table. States of Increased and Decreased HPA Activity

States of Increased HPA Activity	States of Decreased HPA Activity
Chronic stress^[9] Melancholic depression Anorexia nervosa Obsessive-compulsive disorder Panic disorder Excessive exercise Chronic active alcoholism Alcohol and nicotine withdrawal Diabetes mellitus Central obesity Sexual abuse Hyperthyroidism Premenstrual tension syndrome Cushing syndrome Pregnancy	Adrenal insufficiency Atypical/seasonal depression Chronic fatigue syndrome Fibromyalgia Hypothyroidism Nicotine withdrawal Post glucocorticoid therapy Post-Cushing syndrome Postpartum period Post-chronic stress^[9] Rheumatoid arthritis

View Table List

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